asymmetric catalysis as a method for the synthesis of chiral organophosphorus compounds

Tetrahedron: Asymmetry 25 (2014) 865–922

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Tetrahedron: Asymmetry

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Tetrahedron: Asymmetry Report Number 151

Asymmetric catalysis as a method for the synthesis of chiralorganophosphorus compounds

http://dx.doi.org/10.1016/j.tetasy.2014.05.0100957-4166/� 2014 Elsevier Ltd. All rights reserved.

Abbreviations: Ac, acetyl; An, anisyl; Ar, aryl; BINOL, 1,10-bi-2-naphthol; Bn,benzyl; Boc, tert-butoxycarbonyl; Bu, butyl; Bz, benzoyl; cat, catalyst; Cbz,benzyloxycarbonyl; COD, cyclooctadiene; conv, conversion; Cy, cyclohexyl; DABCO,1,4-diazabicyclo[2.2.2]octane; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; de, diaste-reomeric excess; DKR, dynamic kinetic resolution; DMF, N,N-dimethylformamide;dmpe, 1,2-bis(dimethylphosphino)ethane; DMSO, dimethylsulfoxide; ee, enantio-meric excess; Et, ethyl; Fmoc, 9-fluorenylmethoxycarbonyl; Fu, furanyl; Hex, hexyl;L, Lig, ligand; MBD, 4-methoxybenzoic acid; Me, methyl; Mes, mesyl; Mnt,(1R,2S,5R)-menthyl; MTBE, methyl tert-butyl ether; nphth, naphthyl; Oct, octyl;Pent, pentyl; Ph, phenyl; Piv, pivaloyl; PMHS, polymethylhydrosiloxane; PMP, p-methoxyphenyl; PNBA, p-nitrobenzoic acid; Pr, propyl; py, pyridyl; SP, sparteine; Q,quinine; QN, quinidine; HQN, hydroquinidine; TADDOL, a,a,a0 ,a0-tetraaryl-1,3-dioxolane-4,5-dimethanol; TBAB, tetra-n-butylammonium bromide; TBDPS, tert-butyldiphenylsilyl; TBS, tert-butyldimethylsilyl; THF, tetrahydrofuran; Tf, trifluo-romethanesulfonyl; TFA, trifluoroacetic acid; TMS, trimethylsilyl; Tl, tolyl; TPP,tetraphenylporphyrin; Ts, 4-toluenesulfonyl (tosyl).⇑ Corresponding author. Tel.: +380 44 573 2555; fax: +380 44 5732552.

E-mail address: [email protected] (O.I. Kolodiazhnyi).

Oleg I. Kolodiazhnyi ⇑, Valery P. Kukhar, Anastasy O. KolodiazhnaInstitute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Str., 1, Kiev, Ukraine

a r t i c l e i n f o

Article history:Received 4 February 2014Revised 9 April 2014Accepted 15 May 2014Available online 4 July 2014

a b s t r a c t

This review discusses methods for the metallo-, organo- and biocatalytic asymmetric synthesis of chiralorganophosphorus compounds with many applications in stereoselective synthesis with references toupdated literature reports as well as the author’s original research. Asymmetric catalytic hydrogenationand reduction with chiral organometallic complexes, together with actively used asymmetric organocat-alytic versions of various reactions enable us to synthesize chiral organophosphonates and phosphinateswith high enantioselectivity and purity. Asymmetric catalysis is also an effective tool to realize someclassic reactions of phosphorus chemistry in a stereospecific manner.

� 2014 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8662. Asymmetric hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866

2.1. Asymmetric hydrogenation of alkene phosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8662.2. Asymmetric hydrogenation of ketophosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872

3. Asymmetric reduction and oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
3.1. Reduction with complex metal hydrides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
3.1.1. Reduction of C@O bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8743.1.2. Reduction of C@N and C@C bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877

3.2. Biocatalytic reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8783.3. Asymmetric oxidation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880

4. Asymmetric electrophilic catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881
4.1. Catalytic electrophilic substitution at the phosphorus atom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 882
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4.2. Catalytic electrophilic substitution in a side chain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
5. Asymmetric catalysis with chiral diamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8876. Asymmetric addition of phosphorus nucleophiles to multiple bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890
6.1. Phospha-aldol reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8906.2. Phospha-Mannich reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8956.3. Phospha-Michael reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9006.4. Addition to ketophosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9106.5. Catalytic asymmetric modification of P-ylides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 912

7. Asymmetric cycloaddition reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9148. Miscellaneous methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9169. Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 918

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919

P(O)(OR")2 P(O)(OR")2

H H

1 2

H2

Cat*

Cat*=chiral catalyst

Scheme 1. Asymmetric catalytic hydrogenation of unsaturated phosphonates.

1. Introduction

Chiral phosphorus compounds play an important role in manyareas of science including biologically active pharmaceuticals,agrochemicals, and ligands for transition metal complexes. Recentyears have seen a steady growth in the use of chiral organophos-phorus catalysts in asymmetric synthesis. Complexes with transi-tion metals containing PAMP, DIPAMP, DIOP, CHIRAPHOS ligandsare widely used for the asymmetric formation of C–H and C–Cbonds. Many methods can be used to prepare enantiomericallypure organophosphorus compounds including classical resolutionvia diastereoisomers, chemical kinetic resolution, enzymatic reso-lution, chromatographic resolution, and asymmetric catalysis.Asymmetric synthesis and asymmetric catalysis have been, andremain, a primary research field of chemistry. Therefore, methodsfor the asymmetric synthesis of organophosphorus compoundshave been studied extensively in many academic and industrialresearch laboratories.2–4 Over the last few years, great successhas been achieved in the asymmetric synthesis of organophospho-rus compounds, primarily with phosphine ligands for catalyzedasymmetric hydrogenation reactions, and many articles devotedto the synthesis of chiral organophosphorus compounds have beenpublished.1–4

Various asymmetric metallocomplexes, organo- and biocataly-sis, have been devoted to the synthesis of separate classes of orga-nophosphorus bonds. The present review discusses all types ofasymmetric catalysis of organophosphorus compounds and com-pares their advantages.1–7 The review describes the asymmetriccatalytic hydrogenation, reduction of unsaturated compounds, oxi-dation, electrophilic and nucleophilic substitution at the phospho-rus atom, the addition of phosphorous nucleophiles, cycloadditionreactions, and others. Currently, asymmetric catalysis is one of themost convenient methods for the synthesis of chiral organophos-phorus compounds. Therefore, it is interesting to analyze the datadedicated to the asymmetric synthesis of chiral organophosphoruscompounds published over the last 15 years.5

2. Asymmetric hydrogenation

Homogeneous asymmetric hydrogenation with chiral com-plexes of transition metals is one of the most important industrialmethods for the preparation of enantiomerically pure organic mol-ecules. Asymmetric hydrogenation of prochiral aminophospho-nates, ketophosphonates, and ketoiminophosphonates is one ofthe most effective, practical, and economic synthetic methods forthe preparation of chiral organophosphorus compounds.2 Variouschiral complexes of transition metals, bearing chiral phosphineligands, have been used as catalysts for the asymmetric hydrogena-tion of unsaturated phosphorus compounds. The asymmetric cata-lytic hydrogenation of phosphonates containing C@C, C@O, or C@Nbonds, has used rhodium, ruthenium, and iridium complexes with

chiral bis-phosphine ligands.8,9 Nojori first published the applica-tion of BINAP-Ru catalysts for the asymmetric hydrogenation ofketophosphonates.9–11

2.1. Asymmetric hydrogenation of alkene phosphonates

Asymmetric catalytic hydrogenation of unsaturated phospho-nates is widely used in the synthesis of aminophosphonates andaminophosphonic acids of biological interest (Scheme 1).12–33

Some examples of the most often used ligands for hydrogenationof unsaturated phosphonates are shown in Scheme 2.

The first work devoted to the asymmetric synthesis of amino-phosphonates by catalytic hydrogenation of unsaturated phospho-nates, was published approximately thirty years ago. Schollkopfet al.12 in 1985 reported asymmetric hydrogenation ofN-[1-(dimethoxyphosphoryl)-ethenyl]formamide, using a rhodiumcatalyst with (+)-DIOP 10 chiral ligand to afford the (1-amino-ethyl)phosphonate L-19 in good yields and 76% ee enantioselectiv-ity. The initially formed formamide L-19 was hydrolyzed withconc. hydrochloric acid to give the aminophosphonic acid L-20.Crystallization from water/methanol increased the enantiomericpurity of L-20 up to 93% ee (Scheme 3).

The hydrogenation of a-enamidophosphonates has attractedthe interest of several groups as a method for the synthesis ofchiral aminophosphonates and a number of articles have beenpublished on this subject. Oehme et al.13 reported that chiralRh(I) complexes with BPPM ligands 6 or PROPRAPHOS 7 are activecatalysts for the asymmetric hydrogenation of (E)-phen-ylenamidophosphonates displaying high reaction rates andrelatively high stereoselectivities. For example, the hydrogenationof amidovinylphosphonates 21a,b catalyzed by the BPPM(6)/Rhcomplex, afforded a-aminophosphonates 22a,b with 96% ee, andsince PROPRAPHOS 7 is available in both configurations, (R)- and(S)-a-aminophosphonic acid esters 22c could be obtained withenantioselectivities of 88–96% ee (Scheme 4).

Burk et al.14 proposed cationic rhodium complexes of C2 symmet-ric DuPHOS 4a,b and BPE 5a,b ligands as effective catalysts for theasymmetric hydrogenation of N-aryl and N-benzyloxycarbonyl-enamido phosphonates 23 (Scheme 4). The catalyst Et-DuPHOS/Rh(COD) provided good enantioselectivity for both types of

NCO2t-Bu

PPh2

Ph2P

6, (S,S)-BPPM 13

8, (S)-BINAP 9-11

P P

5a, (S,S)-Me-BPE,14

5b, (S,S)-Et-BPE 14

OO

PPh2

NPr-i

PPh2

H

7, (S)-PROPRAPHOS 13

O

O

PPh2

PPh2

10, (S,S)-DIOP 12,139, (S,S)-NORPHOS 13

PPh2

PPh2

P P

R

R

R

R

4a, (S,S)-MeDuPhos, R=Me,14,15

4b, (S,S)-EtDuPhos, R=Et, 14

4c, (S,S)-PrDuPhos, R=Pr 14

P PMe

RR

Me

11, (S,S)-MiniPhos 15,22-25

P PMe

t-Bu

t-Bu

Me

3, (S,S)-BisP*15,22-25

PPh2t-Bu2P

12 22-25,27

HN

O

OP

PPh2

13, (R,R)-THNAPhos 26,31

PPh2

PPh2

Fe OO

OP

R'

R'

PR2

PCy2PPh2

Fe

16, (S,R)-JOSIPHOS18,2115, TangPhos24

P

H

PH

PPh2

PPh2

17, (S)-PHANEPHOS 21

14a, R=Ph, R'=H; P-OP 22-24,29

14b, R=i-Pr, R'=H; 14c, R=i-Pr, R'=t-Bu,

Scheme 2. Typical chiral ligands used in asymmetric catalysis with organophsophorus compounds.

H

H P(O)(OMe)2

NHCHO

P(O)(OMe)2

NHCHOH

Rh-(+)-DIOP 10

[α]D = - 12.9

L-19, 76%ee

P(O)(OH)2

NH2

H

L-20, 93% ee[α]D= -15.6 (1M NaOH)

H2

18

* *

Scheme 3. Hydrogenation of N-[1-(dimethoxyphosphoryl)ethenyl]formamide 18in the presence of a chiral rhodium/(+)-DIOP catalyst.

O. I. Kolodiazhnyi et al. / Tetrahedron: Asymmetry 25 (2014) 865–922 867

substrates 23 (95% and 94% ee, respectively). The reaction was com-pleted in 12 h in methanol at room temperature and a pressure of

P(O)(OR")2

NHBz

H

Ph

BzNH

Rh(I)/Lig

R"=Me (a), Et (b), H (c); Lig = 6-10

21a,b

H2

Lig/ee/Conf. = (2S,4S)-6, 96%, (S); (R)-7, 89%, (R); (S(4R,5R)-9, 63%, (S); (2S,3S)-10, 83%,

Scheme 4. Asymmetric hydrogenation of vinylphosphonates 21 in the presence of rhoMeOH; catalyst prepared in situ using Rh(COD)2]BF4.

4 atm to give the aminophosphonates with enantioselectivitiesof up to 95% ee.14 Similar results were earlier obtained byBeletskaya, Gridnev and others with the Rh/(R,R)-t-Bu-BisP⁄ catalyst(Table 1).15–17

Wang et al.18 applied readily available and inexpensive chiralphosphine–aminophosphine ligands 26 for the enantioselectivehydrogenation of various a-enol ester phosphonates and a-enam-ido phosphonates. The phosphine–aminophosphine ligands 26exhibited superior enantioselectivities to those obtained withBoPhos analogues 27. Very good enantioselectivities (93–97% ee)were achieved in the hydrogenation of various substrates catalyzed

Bn

P(O)(OR")2H

22a,b

*Bn

P(O)(OH)2BzNHH

22c

*

)-7, 92%, (S); (R)-Ph-β-GlupOH,13b 91%, (R);(S); (S)-PPCyclopent, 91%, (S)

dium catalysts (25 �C, 0.1 MPa H2, 1 mmol substrate, 0.01 mmol catalyst, 15 MI of

P(O)(OEt)2

R

AcNH

H [Rh(COD))(PP*)]BF4

H2 (40-90 bar)P(O)(OEt)2

R

AcNH

H

HH *

R = i-Pr, Ph Conv 100%, 89-92% ee

PPh2

O

O

O

O PPh2

34, (R)-SYNPHOS

P(t-Bu)2

PPh2Fe

33, (R,S)-DPPF-t-BP

MeMe

PPh2

Ph2P

35, (R)-Me-CATPHOS

Scheme 7. Asymmetric hydrogenation of b-N-N-vinylphosphonates with rhodiumcomplexes containing chiral ligands 33–35.

Table 1Enantioselective hydrogenation of enamidophosphonates 23 catalyzed by Rh com-plexes bearing DuPhos 4a, b, BPE 5a, b and BisP 3 ligands

P(O)(OMe)2

NHRH

H

Me

P(O)(OMe)2RHNH

MeOH, 4 atm H2, 25oC

2423

Lig/Rh(COD)OTf,

R Lig Conv (%) ee (%) Config Refs.

Ac (R,R)-3 100 90 (R)-(�) 15Ac (S,S)-4a 100 93 (R)-(�) 14Ac (S,S)-4b 100 95 (R)-(�) 14Ac (S,S)-4c 90 68 (R)-(�) 14Cbz (S,S)-5a 88 88 (R)-(�) 14Cbz (S,S)-4a 72 90 (R)-(�) 14Cbz (S,S)-4b 100 94 (R)-(�) 14Cbz (S,S)-5c 100 81 (R)-(�) 14Cbz (R,R)-5b 93 57 (S)-(+) 14


by an (S)-26/[Rh(COD)]BF4 complex, thus demonstrating the highpotential of these ligands 26 in the preparation of optically activea-aminophosphonates 25 (Scheme 5).

N

PPh2

R'

PPh2

H2 (10 atm)(S)-26 / [Rh(COD)]BF4 (1 mol%)

P(O)(OMe)2

CH2R

CbzHNH

R

P(O)(OMe)2

NHCbz

H

25a, R=H, Ph, 96% ee

(S)-26a,b

25b, R=Ph, 96% ee,

98-99%

R'=H (a), Me (b)

NR PPh2

Fe

27a R=H, H-BoPhos27b, R=Me, Me-BoPhos

PPh2

24

Scheme 5. Hydrogenation of a-enamidophosphonates 24 catalyzed by Rh/(S)-26complex.

Asymmetric hydrogenation of b-enamidophosphonates cata-lyzed by iridium complex followed by desulfidation afforded2-amino-1-phosphinoalkanes 30 and offers a new approach to chi-ral N,P-ligands that can serve as ligands in asymmetric reactions.Oshima et al. developed a convenient method for the synthesis ofchiral phosphine sulfides 29.19 Chiral iridium complexes contain-ing chiral ferrocene ligand 12 catalyzed the enantioselectivehydrogenation of alkenthiophosphonates 28 with the formationof optically active (E)-2-amino-1-thiophosphinylalkanes 29 in highyields and with high ee, however the absolute configuration of theresultant compounds was not determined. The subsequent desulf-idation of phosphine sulfides 29 led to the formation of 2-amino-1-phosphinoalkanes 30, including the optically active phosphines 31and 32 (Scheme 6).

R'

R2N H

P(S)Ph2 R'

R2N

28

[IrCl(cod)]2/AgBF4/12

Ts(Bn)N

Ph PPh2

31, 93% yield, 97%ee

*

H2

Scheme 6. Enantioselective hydrogenation of vin

Boerner et al. showed that the Rh-catalyzed asymmetric hydro-genation of prochiral b-N-acetylamino-vinylphosphonates led tothe formation of chiral b-N-acetylamino-phosphonates with excel-lent yields (up to 100%) and with high enantioselectivities (89–92%ee) (Scheme 7). The reaction was dependent on the chiral bidentatephosphorus ligand and the solvent employed. In some cases, aninversion of the induced chirality was observed by using the corre-sponding E- or Z-isomeric substrates.20 Catalysts were generatedin situ by mixing [Rh(COD)2]BF4 with equimolecular amounts ofbidentate phosphorous ligand. The phosphines 16, 33–35 werethe most effective among 240 chiral ligands. The highest enanti-oselectivity was achieved in dichloromethane or THF, at room tem-perature and a hydrogen pressure of 4 bar. The enantiomeric purityof the hydrogenation products was determined by HPLC, howeverthe absolute configurations of the products were not reported.20

Doherti et al.21 have reported that rhodium complexes with(R,S)-JOSIPHOS 16 or (R)-Me-CATPHOS 35 ligands are effectivecatalysts for the asymmetric hydrogenation of (E)- and(Z)-b-aryl-b (enamido)phosphonates, but well-known ligands suchas TangPhos 15, PHANEPHOS 17, and DuPhos 4 were ineffective.These complexes, Rh/16 and Rh/35, form a complementary pairof catalysts for the efficient asymmetric hydrogenation of(E)- and (Z)-b-aryl-b-(enamido)phosphonates, respectively. In themajority of cases, hydrogenation with these catalysts affordedphosphonates in good yields (72–97%) and with very good enanti-oselectivity (99% ee). The authors reported the specific rotations ofthe products, however the absolute configurations were notdetermined (Table 2).

Phosphine-phosphinites and phosphine-phosphites are exam-ples of nonsymmetric ligands that differ in the electronic and thesteric properties of their respective binding groups.22a–c The P-OPligands studied in asymmetric hydrogenation encompass diversecarbon backbones and stereogenic elements between the twophosphorus functionalities, many of which provide a highly stereo-differentiating environment around the catalytic rhodium metal

P(S)Ph2

HH*

N

PhO

O

PPh2

32, 99% yield, 89% ee

R2N

R' PPh2

29 30

*

*

(Me3Si)3SiH

ylphosphonates 28 with iridium complexes.

P(O)(OMe)2

OBzR

H

[Rh(Lig)nbd)]BF4

S/C=100, H2, 4 atm, 18h P(O)(OMe)2

OBz

H

37 (S)- or (R)- 38

R *

Scheme 9. Asymmetric hydrogenation of a-benzoyloxyethenphosphonates.15

PO

O

R'

O OMeOMe

Ph

Figure 1. Preferable organization of the intermediate Rh–olefin complex for the

Table 2Enantioselective hydrogenation of (E)-/(Z)-b-aryl-b-(enamido) phosphonates withrhodium complexes containing the ligands (R,S)-JOSIPHOS 16 and (R)-Me-CATPHOS3518

1 mol% [Rh(1,5-COD)2]BF41 mol % Ligand

H2 (5 atm)

*RC6H4

P(O)(OEt)2HNAc

RC6H4

P(O)(OEt)2AcHN

H

Ligand E/Z R Yield (%) ee (%)

(R,S)-16 Z 4-Me 77 99 (+)(R,S)-16 Z H 72 97 (+)(R,S)-16 Z 4-F 66 96 (+)(R,S)-16 Z 4-Cl 81 94 (+)(R,S)-16 Z 4-Br 79 >99 (+)(R,S)-16 Z 4-MeO 82 >99 (+)(R)-35 E 4-Me 94 >99 (+)(R)-35 E H 97 99 (+)(R)-35 E 4-F 78 >99 (+)(R)-35 E 4-Cl 80 99 (+)(R)-35 E 4-Br 87 99 (+)(R)-35 E 4-MeO 79 99 (+)


center. The hydrogenation of various functionalized alkenes cata-lyzed by Rh/P-OP complexes led to the formation of products withhigh enantioselectivities even at low loadings of the catalyst. Forexample, Pizzano et al. studied the hydrogenation of b-(acyla-mino)vinylphosphonates 35 with Rh/P-OP catalysts 14 leading tothe formation of b-acyliminophosphonates 36 with enantioselec-tivities of up to 99% ee.22a

Analysis of these results showed that catalysts containing elec-tron-donating groups such as P(i-Pr)2, were more active and enan-tioselective than the PPh2 substituted catalysts. NMR studies onthe interaction between vinylphosphonates and the catalyst indi-cated the formation of chelates with the olefin cis to the phosphitegroup of the Rh(P-OP)+ fragment. In all cases, the catalyst contain-ing (S)-P-OP ligands afforded (R)-enantiomers while those with(R)-P-OP ligands led to the formation of (S)-hydrogenated products(Scheme 8).

P(O)(OEt)2BzNH

R H35

P(O)(OEt)2BzNH

R HH

36, 94-99% ee

H67-100%

H2[Rh(COD)[(S)-14]BF4

R=Ph, p-Tl, p-An, p-An, 4-BrC6H4, 2-ClC6H4

Scheme 8. Hydrogenation of b-(acylamino)vinylphosphonates 35 with Rh/(S)-P-OPcatalyst.

stereochemical sense of the asymmetric hydrogenation of 37.25

[Rh(COD)(Lig=14a,b)]BF4(R)-3837 + H2

Scheme 10. Hydrogenation of b-arylalkenphosphonates 37 catalyzed by the[Rh(cod)(14)]BF4 complex.25

Significant attention has been paid to the asymmetric hydroge-nation of a- and b-enolphosphonates, as a method for the synthesisof chiral hydroxyphosphonates which, as well as aminophospho-nates, exhibit diverse and interesting biological and biochemicalproperties. Chiral phosphinic ligands 1,2-bis(alkylmethylphosphi-no)ethanes (BisP) 3 and bis(alkylmethylphosphino)methanes(MiniPHOS) 11 display high enantioselectivity in the hydrogena-tion of diethyl benzoyloxyethenphosphonate 37 catalyzed by rho-dium complexes.15,22–25 An important feature of these ligands isthat a bulky and a small alkyl group (methyl group) are bound toeach phosphorus atom. These ligands form five- or four-memberedC2-symmetric chelates, and therefore the imposed asymmetricenvironment ensures high enantioselectivity in catalytic asymmet-ric reactions. The asymmetric catalytic hydrogenation of 37 was

performed in methanol at 4 bar pressure of H2 to give (S)-a-ben-zoyloxyethylphosphonates 38 with 93% ee (Scheme 9).

The hydrogenation of enolphosphonates 37 catalyzed by rho-dium complexes with chiral P-OP ligands 41 also proceeded withgood enantioselectivity.25 Complexes [Rh(COD)(41)]BF4 show flux-ional behavior in solution, consistent with backbone oscillationaround the coordination plane (Fig. 1). Depending upon the stericcharacteristics of the ligands and substrate, the hydrogenationscatalyzed with these complexes provide products with enantiose-lectivity of >90% ee as shown in Scheme 10. Detailed studies ofthe phosphane-phosphite ligands 41 demonstrated the influenceof the steric characteristics on the enantioselectivities, 98% eewas thus obtained with substrates bearing an alkyl substituent atthe b-position, while for their aryl counterparts values of up to92% ee were achieved.

Rh/P-OP complexes are excellent catalysts for enantioselectivehydrogenations of b-(acyloxy)vinylphosphonates (Scheme 11).For example, the hydrogenation of substrates 42 catalyzed by com-plex [Rh(COD)[(S)-14a,b]BF4 led to the formation of chiral phos-

P(O)(OMe)2

R

42a-i

(MeO)2(O)P

R[Rh(COD)(S)-14]BF4

-

PO3H2

OH

H2N

44

H

(R )-43a, 99% ee

H

H2, 4 atm, 25oC, CH2Cl2

R=Me, i-Pr, Bu, 4-Tl, 4-An, 4-BrC6H4, 2-Nphth,CH2NHBoc; R'=Ph, t-Bu

R"C(O)O-

R"C(O)O-

Scheme 11. Enantioselective hydrogenation of b-(acyloxy)vinylphosphonates 42catalyzed by rhodium complexes of chiral P-OP ligands 14.

Table 3Rh-Catalyzed asymmetric hydrogenation of a-enolphosphonates 45

Entry Lig R Solvent Yield (%) ee (%) (config) Refs.

1 4a Ph CH2Cl2 96 92 (nd)* 182 13 Ph CH2Cl2 — 99.4 (nd) 263 13 p-FC6H4 i-PrOH — 99.9 (nd) 264 13 p-ClC6H4 i-PrOH — 99.9 (nd) 265 13 p-An i-PrOH — 99.9 (nd) 266 13 m-An i-PrOH — 99.8 (nd) 267 13 m-ClC6H4 i-PrOH — 99.3 (nd) 268 13 o-ClC6H4 i-PrOH — 99.9 (nd) 269 13 1-Nphth i-PrOH — 99.2 (nd) 2610 13 2-Thienyl CH2Cl2 — 99.3 (nd) 2611 26a p-FC6H4 CH2Cl2 99 96 (+) 1812 26a p-ClC6H4 CH2Cl2 98 94 (+) 1813 26a p-BrC6H4 CH2Cl2 95 97 (+) 1814 26a p-NO2C6H4 CH2Cl2 99 95 (+) 1815 26a p-An CH2Cl2 99 95 (S) 1816 26a m-An CH2Cl2 98 96 (+) 1817 26a 1-Nphth CH2Cl2 98 95 (+) 1818 26a 2-Thienyl CH2Cl2 98 95 (+) 1819 26a H CH2Cl2 94 93 (S) 1820 26a Me CH2Cl2 99 96 (S) 1821 26a Et CH2Cl2 99 96 (S) 1822 26a (CH2)9CH3 CH2Cl2 97 96 (S) 1823 26a OMe CH2Cl2 99 94 (S) 1824 26a OEt CH2Cl2 99 93 (+) 1825 26a Ph CH2Cl2 98 96 (S) 1826 26b Ph CH2Cl2 97 85 (S) 18


phonates 43 with good yields and enantioselectivities of 95–99%ee.22 It was noticed that the b-alkyl substrates were more reactivethan b-aryl, and reacted for a short time with full conversion.Phosphonates 43 were transformed without racemization intothe corresponding alcohols. For example, the deprotection of aphosphonate 43 gives easy access to b-hydroxy-c-aminophos-phonic acid 44 which are precursors of biologically interestingphosphono-GABOB. The NMR data and the magnitude of couplingconstants 1JRh,P of the 31P nuclei of P-OP ligands indicated a cis ole-fin coordination to the phosphite: d = 13.6 (dd, JP,Rh = 140 Hz,JP,P = 63 Hz, PC), 14.9 [s, P(O)(OMe)2], 132.0 (dd, JP,Rh = 262 Hz,JP,P = 62 Hz, PO) (Fig. 2).22

* (nd) = the stereochemistry was not defined.

P

RhO

OPX

R

Ph+

X=O, NH

(RO)2P(O)

Figure 2. Coordination mode of vinylphosphonates for a complex {Rh(42)[(S)-14b]}BF4. P(O)(OMe)2

R OBz

HCH2R

P(O)(OMe)2BzOH

a = Lig/Rh(COD)OTf, S/C 125, MeOH, 4 atm H2, 25oC, 24-48 hLig = BPE 5a, DuPhos 4a-d

a

45

46

*

Scheme 13. Hydrogenation of enolphosphonates 45 in the presence of cationicrhodium catalysts.

Wang et al.26 developed an enantioselective method for thesynthesis of a-benzyloxyphosphonates by hydrogenation of eno-lphosphonates 45, including b-aryl-, b-alkoxy-, and b-alkylsubsti-tuted substrates, in the presence of rhodium complexescontaining unsymmetrical phosphine–phosphoramidite ligandsTHNAPhos 13. After asymmetric hydrogenation, the phosphonates46 were prepared with very high enantioselectivities of up to 99.9%ee (Scheme 12). Rhodium complexes with phosphine–aminophos-phine ligands 26a also displayed a good enantioselectivity of 97%ee in the asymmetric hydrogenation of dimethyla-benzoyloxyetenphosphonates 45, containing a-aryl, a-alkyl,and a-alkoxy substituents. The enantioselectivity of phosphine–aminophosphine ligands 26a was higher than that with the well-known BoPhoz and DuPhos ligands (Table 3).

P(O)(OMe)2

OBzR

H[Rh(COD)2]BF4/13 or 26 (1.1 mol%)

H2, 10 bar, solvent, RT P(O)(OMe)2

CH2R

BzOH

46, ee up to 97-99.9%45

Scheme 12. Asymmetric hydrogenation of b-alkoxy and b-aryl substrates.

Hydrogenation of enolphosphonates 45 in the presence of cat-ionic rhodium catalysts Lig/Rh(COD) OTf containing C2-symmetricligands (Lig) BPE 5a, b or DuPHOS 4a–d occurred with good ee atroom temperature and a low pressure of hydrogen. The higheststereoselectivity for the unsubstituted enolphosphonates 45 was

obtained with the Et-DuPHOS-Rh catalyst. Alkyl-substituted eno-lbenzoate substrates 45 were reduced with optimum enantioselec-tivity using the less bulky Me-DuPHOS-Rh as shown inScheme 13.14

Chiral phosphine–phosphoramidite ligand 47, (S)-HY-Phos,which was prepared by a simple two-step method from1-naphthylamine and BINOL-phosphite, was successfully appliedin the Rh-catalyzed asymmetric hydrogenation of functionalizedolefins, including a-(acetamido) cinnamates, enamides, and eno-lphosphonates, with 98–99% ee (Scheme 14).26,32,33 The asymmet-ric hydrogenation of vinylphosphonates 45 catalyzed by rhodiumcomplexes, containing (R,R)-TADDOL or (S)-BINOL-phosphitederivatives of indole (Indolphos ligands) were also reported andgave enantiomerically enriched (S)-phosphonates 46 with goodyields and 32–87% ee.37,38

Rhodium complexes containing ClickFerrophos II 50 and(R)-MonoPhos 51 ligands were used as catalysts for the hydrogena-tion of various unsaturated phosphonates.28–31 The hydrogenationof a,b-unsaturated phosphonates 48 including b-alkyl, aryl-, and

R H

P(O)(OR')2BzO

R

P(O)(OR')2BzO

50 or 51/Rh(COD)2]BF4

48 49, up to 96% ee

H2 (5 atm), CH2Cl2), RT*

N

O

O

R=

(ClickFerrophos II)50, Ar=3,5-Xyl

N

NN

PAr2

Ph

Me

PPh2

Fe

O

OP

51, (R)-MonoPhos

BnN

NBn

O

OP N

R

R'

O

52 (DpenPhos) R=H, Bn; R'=Me, i-Pr

Scheme 15. Hydrogenation of unsaturated phosphonates catalyzed by rhodium complexes with ligands 50–52.

46, conversion 100%,ee=95-99%

P(O)(OMe)2

R OBz

HCH2R

P(O)(OMe)2BzOH

45

(S)-47/Rh(COD)OTf

S/C 125, MeOH4 atm H2, 25oC, 24-48 h

HN

O

OP

PPh2

47, (S)-HY-Phos

O

OP N

PPh2

Me

IndolPhos

Scheme 14. Asymmetric hydrogenation of R-substituted enolphosphonates 45 catalyzed by (S)-HY-Phos-Rh 47.


b-dialkylphosphonates, (Z)-b-enolphosphonates, anda-phenylethylphosphonates, allowed the preparation of thecorresponding chiral phosphonates in good yields and with highenantioselectivities (up to 96% ee). Zhang et al. reported thatRh(I) complexes of monodentate phosphoramides bearing primaryamines (DpenPhos) 52 effectively catalyze the asymmetrichydrogenation of a- or b-acyloxy a,b-unsaturated phosphonates45, 48 providing the corresponding biologically important chirala- or b-hydroxyphosphonates 46, 49 with high enantioselectivities(93–96% ee) (Scheme 15).39

The asymmetric hydrogenation of alkenephosphonates repre-sents an attractive method for the preparation of chiral

alkylphosphonates and chiral tertiary phosphine oxides that canbe used as new drugs or new chiral ligands. Genet andBeletzskaya reported the enantioselective hydrogenation of vinyl-phosphonates 53 catalyzed by complexes of iridium containingphenyloxazoline ligands 55–57.16,17 The effectiveness of chiraliridium catalysts (70–94% ee) was proved on a number of sub-strates. For example, the optically active 1-arylethylphosphinates54e, which are phosphorous analogues of Naproxen [Ar = 2-(6-MeO-Nphth)], were synthesized with 92–95% ee by the hydroge-nation of vinylphosphonates in methylene chloride, at roomtemperature or gentle heating and an H2 pressure of 5–60 bar(Scheme 16).

R

P(O)(OEt)2

R

P(O)(OEt)2

[Rh(COD)]2]BF4 (1 mol%)

H2 (10 bar), CH2Cl2, rt

(R,S)-FAPhos-Bn 60d (2.2 mol%)61, 90-98% eeR = Alk, Ar

Scheme 18. Hydrogenation of b-unsaturated phosphonates catalyzed by an Rh/(Rc,Sc)-FAPhos-Bn complex.

P(O)(OEt)2Ar [Ir(cod)(L*)]+[BArF](1mol%)

Me

P(O)(OEt)2Ar*

O

N P(o-Tl) 2

t-Bu

O N

O

PCy2

Ph

Ph Ph

O N

O

Ph

Ph Ph

PPh2

L*=

Ar=Ph, 4-PhC6H4, 1-Nphth, 2-Nphth, 2-(6-MeO-Nphth)

54

55 56 57

53

H2 (5 bar), CH2Cl2, 40 oCHH

H

Scheme 16. Enantioselective catalytic hydrogenation of vinylphosphonates 53.


A number of chiral alkylphosphonates 59 bearing a b-stereo-genic center, were synthesized by catalytic hydrogenation of thecorresponding b-substituted a,b-unsaturated phosphonates 58using rhodium complexes with ferrocene based monophosph-oramidite ligands 60 (Scheme 17). Under mild conditions, thehydrogenation proceeded with 100% conversion to give productswith high enantioselectivities; 99.5% ee in case of the (E)-sub-strates, and 98.0% ee in case of the (Z)-substrates. Hydrogenationwith the Rh/(Rc,Sc)-FAPhos catalyst led to the formation of com-pounds 59 with the (R)-configuration,31,32 although in other casesthe absolute configurations of the products were not defined.Asymmetric hydrogenation of b,c-unsaturated phosphonatescatalyzed by an Rh/(Rc,Sc)-FAPhos–Bn complex led to the forma-tion of chiral b-substituted alkanephosphonates 61 with 98% ee(Scheme 18).33

Diphenylvinylphosphine oxides and di- and trisubstitutedvinylphosphonates 62 were employed as substrates for asymmet-ric hydrogenations catalyzed by iridium complex 64. Completeconversion and excellent enantioselectivities (up to and above99% ee) were observed for a range of substrates with both aromaticand aliphatic groups at the prochiral carbon atom. A large numberof compounds 63 with high enantioselectivities were described.The hydrogenation of electron-deficient carboxyethylvinylphosph-onates was also carried out with stereoselectivities of up to 99% ee(Scheme 19).34

Chiral 1-aryl or 1-alkyl substituted ethylphosphonates 66 weresynthesized with enantioselectivities of 92–98% ee and very goodyields by asymmetric hydrogenation of the corresponding 1-arylor 1-alkylethenylphosphonates 65 in the presence of rhodiumcomplexes containing P-chiral aminophosphine–phosphineBoPhoz-type ligands 67. The authors reported that this catalyst isespecially effective for the asymmetric hydrogenation of 1-aryl-ethenylphosphonates. A number of substrates were hydrogenatedwith this catalyst with enantioselectivities of up to 98% ee. Hydro-genation proceeded under mild conditions (room temperature,

Ar

P(O)(OEt)2

Ar

P(O

[Rh(cod)]2]BF4 (1 mol%)

58(R,S)-FAPhos (2.2 mol%)

59, 100% Conv

*H

H2 (40 atm), CH2Cl2, rt

Ar=Ph, 3-Tl, 4-Tl , 4-An, 3-CF3C6H4, 4-CF3C6H4, 4-FC6H4, 4

Scheme 17. Hydrogenation of a,b-unsaturated pho

10 bar H2, and 0.2 mol % of catalyst) to provide chiral 1-aryl or1-alkylsubstituted ethylphosphonates 66 (Scheme 20).35,36

2.2. Asymmetric hydrogenation of ketophosphonates

Chiral complexes of transition metals catalyze the hydrogena-tion and hydroxylation of prochiral ketones. From a practical pointof view, catalytic asymmetric hydrogenation and hydroxylation ofketophosphonates is a convenient method for the synthesis ofchiral hydroxyphosphonates.8–10 Asymmetric catalytic synthesisof a-amino and a-hydroxyphosphonates 69 attracts much interestbecause of the pharmaceutical activity of such compounds. Thesynthetic approaches described are based on asymmetric hydroge-nation using various catalysts, in particular Ru(II)–BINAP com-plexes.40 Noyori et al.9,10 in 1995–96 disclosed that Ru(II)-BINAP(1 mol % [RuCI2(R)-BINAP](dmf)n) complexes catalyze the enantio-selective hydrogenation of b-ketophosphonates 68 in methanolunder a low pressure of hydrogen and at 30 �C with formation ofthe corresponding b-hydroxyphosphonates in very high yieldsand with 97% ee. Hydrogenation with a (S)-BINAP-Ru(II) catalystafforded predominantly the (R)-products, while the (R)-BINAPcomplexes formed the (S)-enriched compounds (Scheme 21).

Racemic a-acetamido-b-ketophosphonates 70 were hydroge-nated in the presence of an (R)-BINAP-Ru catalyst to give(1R,2R)-hydroxyphosphonates 71 with high diastereoselectivity(syn:anti = 97:3) and with enantioselectivity of 98% ee (Scheme 22).The hydrogenation of racemic, configurationally labile, rac-70 ledto the formation of four diastereomers (1R,2R)-, (1R,2S)-, (1S,2R)-,and (1S,2S)-71.10 However, the optimization of the reaction condi-tions and high stereoselectivity of the (R)-BINAP ligand predomi-nantly gave (1R,2R)-a-amido hydroxyphosphonates 71 with highenantio- and diastereoselectivities (98:2 dr and 95% ee for thesyn-isomer). The product (1R,2R)-71 was successfully transformedinto enantiomerically pure (1R,2R)-phosphothreonine 72 in 92%yield (Scheme 22).9 The acid hydrolysis of 71 afforded phospho-threonine 72 in good yield. This method gave phosphaalanine,phosphaethylglycine, and phosphaphenylalanine with high enan-tiomeric purity. It was noticed that E-alkenes were more reactivethan their Z-isomers.11

Noyori also developed a method for the synthesis of theantibiotic fosfomycin 74 using asymmetric hydrogenation cata-lyzed by a BINAP–Ru complex. Fosfomycin 74 was obtained in84% yield, with 98% ee for syn-isomer and with a syn:anti ratio of90:10, by starting from racemic b-keto-a-bromphosphonaterac-72 (Scheme 23).10

)(OEt)2

, 98-99.5%ee

N

O

OP

R

60

Fe

(Rc,Sc)-FAPhosR=H (a), R=Me (b), R=Et (c), R= Bn (d)

-BrC6H4, 4-ClC6H4, 2-nphth

sphonates catalyzed by Rh/(Rc,Sc)-FAPhos 60.

P(O)Ph2

PhP(O)Ph2

Ph

Ir catalyst (0.5 mol%)

H2 (50 bar), CH2Cl2, rt*

S

N

NP

Ir

PhPh

Ph

+

64, 99% conv, >99% ee62 63

BArF-

P(O)(OEt)2Ph

CO2Et

64 (1 mol%)

H2 (100 bar), CH2Cl2, rt

P(O)(OEt)2Ph

CO2Et

>99% ee

*

H

Scheme 19. Asymmetric hydrogenation of carboxyethylvinylphosphonates 62.

PNaphth

Ph

N

PArAr

6567, Ar = 4-CF3C6H4

66

P(O)(OR)2

R'

H

HP(O)(OR)2

R'

[Rh(cod)]2]BF4 (1 mol%)67(1.1 mol%)

H2 (10 bar), CH2Cl2, rtFe

Scheme 20. Asymmetric hydrogenation of substrates 65 with catalyst Rh/(SC,RFc,RP)-67.

O

R1 P(O)(OMe)2

O

(R)-BINAP(8)-Ru(II)

H2/MeOH

OH

R1 P(O)(OMe)2

O

R1 = Me, R2 = H (a); R1 = Me, R2 = Et (b); R1 = R2 = Me (c); R1 = C5H11, R2 = Me (d);R1 = i-Pr, R2 = Me (e); R1 = C5H5, R2 = Me (f); (R1 = Me, R2 = Br (g)

69a-g

*

R2 R2 R2 R2

68

Scheme 21. Catalytic asymmetric hydrogenation of ketophosphonates 68.


In 1996, Genet reported the asymmetric hydrogenation ofketophosphonates catalyzed by chiral (S)-BINAP-Ru 68 and

RP(OMe)2

O O

NHCOMe(R)-BINAP-Ru

R

OH

rac-70a,b (1R,2>98% ee (sR=Me (a), Ph (b)

H2 (4 atm) 25 "C, MeOH

Scheme 22. Enantioselective synth

(R)-MeO-BIPHEP 76 complexes and obtained hydroxyphospho-nates 75 with high yields and enantioselectivities of up to 99% ee(Scheme 24).41,42 The authors hydrogenated a wide variety ofb-ketophosphonates and b-ketothiophosphonates, includingheterocycles, catalyzed by chiral Ru(lI) complexes, with highenantioselectivities. Asymmetric hydrogenation of diethyl2-oxopropylphosphonate at atmospheric pressure and 50 �C with(S)-BINAP/Ru(II) led to the formation of b-hydroxyphosphonates75 with a complete conversion and with 99% ee.

Asymmetric hydrogenation of a-amido-b-ketophosphonates 70catalyzed by atropisomeric ruthenium complexes 78, 79 withSunPhos ligands, via dynamic kinetic resolution (DKR) led to theformation of the corresponding b-hydroxy-a-amidophosphonates77 with high diastereoselectivities (up to 99:1 dr) and enantiose-lectivities (up to 99.8% ee) for the major diastereomer. Catalystswere prepared using atropoisomeric (S)-SunPhos ligands and[RuCl2(benzene)]2. Hydrogenation was carried out under 10 barof hydrogen pressure, at 50 �C in methanol to give chiral phospho-nates 77 with 98.0% ee for the syn-isomer and in 97:3 syn:antiselectivity (Scheme 25).43,44

P(OMe)2

O

NHCOMeMe

P(OMe)2

OH O

NH2

HCl/ 95oCrecryst

R)-71a,byn) >99% yield

(1R,2R)-72a, phosphothreonine92% yield

R=Me

esis of phosphothreonine 72a.

MeP(OMe)2

O O

Br(R)-BINAP-Ru

MeP(OMe)2

OH O

Br

rac-72 (1R,2S)-7398%ee (syn) 84% yield

74, (S)-Fosfomycin

O

Me

P(OMe)2

O

H

H

H2 (4 atm) 25 "C, MeOH

Scheme 23. Enantioselective synthesis of Fosfomycin 74.

R1 P(OMe)2

O O

R2[RuCl(benzene)79]Cl R1

P(OMe)2

OH O

R2

ee up to 99.9%R1=Alk, Ar; R2=H, Me, Br

80 81

H2 (10 bar), 50 °C, MeOH * *

Scheme 26. Hydrogenation of b-ketophosphonates 80 with Ru-(S)-SunPhos cata-lyst 79.

R'P(OR)2

O X

R'P(OR)2

OH X

X = O,S; R = Me, Et, R' = Alk, Ar, c-Alk, 1-thiophenyl

ee = 70-99%

75

PR2R'

R' PR2

(S)-BIPHEP, R = Cy, R' = Me(S)-BIPHEMP, R = Ph, R' = Me(S)-BIPHEP, R = Ph, R ' =OMe

76L=68 or 76

H2 (1-100 atm), 20-50oC, MeOH

[(COD)Ru(L)]BF4-

Scheme 24. BINAP-Ru (II)-catalyzed asymmetric hydrogenation of b-ketophosphonates.

O

NHCOMe

P(O)(OMe)2

O

Ph

OH

NHCOMe

P(O)(OMe)2

O

Ph[RuCl(benzene)L=78,79]Cl

78, Ar=Ph, (S)-SunPhos79, Ar=4-MeC6H4, (R)-Tl-SunPhos

70b 77

Ru

ClPPh2

Ph2P

O

O

O

O

+

Cl-

H2 (10 bar), 50 °C, MeOH

Scheme 25. Dynamic kinetic resolution of a-amido-b-ketophosphonates 70 viaasymmetric hydrogenation catalyzed by ruthenium complexes 78 and 79.


Hydrogenation of b-ketophosphonates 80 catalyzed by Ru-(S)-SunPhos afforded the corresponding b-hydroxyphosphonates 81with enantioselectivity of >99% ee. Hydrogenation of methyl, ethyl,and isopropyl (2-oxo-2-phenylethyl)phosphonates led to theformation of alcohols 77 with 99.7, 95.5, and 90.0% ee, correspond-ingly. It was found that additives increased the diastereo- andenantioselectivities of the reaction. For example, the addition ofcatalytic amounts of CeCl3�7H2O raised the stereoselectivity ofthe reaction to 99:1 dr and 99.8% ee.43 Electron-donating groupsin the para-position of the phenyl group of the ketophosphonates

increased both the yields and ee values of the products, whileelectron-withdrawing groups reduced the chemical yields(Scheme 26).

Goulioukina et al.45 reported the reduction of ketophosphonatescatalyzed by a palladium catalyst with BINAP or (R)-MeOBIPHEPligands leading to the formation of hydroxyphosphonates withhigh yields and moderate enantioselectivities (30–55% ee).

3. Asymmetric reduction and oxidation

Enantioselective reduction of prochiral ketophosphonates is animportant method for the preparation of enantioenriched hydrox-yphosphonates used as biologically active compounds andreagents for the synthesis of many enantiopure products.5a–d,45

Various methods for the enantioselective reduction of keto- andketiminophosphonates have been developed, including reductionwith chirally modified boranes, complex metal hydrides, biocata-lytic reduction, and others. A number of enantioenriched hydrox-yphosphonates and aminophosphonates were prepared by thismethod. Biocatalytic reduction is an especially convenient methodincluding the use of Baker’s yeast and other microorganisms for thereduction of ketophosphonates.

3.1. Reduction with complex metal hydrides

One of the best methods for the asymmetric catalytic reductionof ketophosphonates is reduction with chiral modified borohy-drides, including those immobilized on a polymer. In this regard,asymmetric CBS (Corey, Bakshi, Shibata) catalytic reduction repre-sents an effective method for the preparation of various chiralalcohols.46,47

3.1.1. Reduction of C@O bondsReduction of a-ketophosphonates 82 with catecholborane as a

reducing reagent and the oxazaborolidine 84 as a catalyst gaveenantiomerically enriched hydroxyphosphonates 85 with goodenantioselectivities (Scheme 27).48–51 Enantioselective reductionof a-ketophosphonates led to the formation of a-hydrox-yarylmethylphosphonates 86–88 with enantioselectivities rangingfrom moderate to good (up to 80% ee). Mayer investigated themechanism of the catalytic reduction by ab initio MO calculations(Fig. 3).48 According to Corey’s model, the carbonyl group of thea-ketophosphonates 82 is complexed to the boron atom of the(S)-2-n-butyloxazaborolidine 84c in such a way that the hydride

O

R' P(OR)2

O

OH

R' P(OR)2

O

HOBH

O

82 R=Alk, Ar 85, 21-79% ee60-98% yield

83

84

R = MeO, EtO, i-PrO, t-BuO; R' = Ph, 2-FPh, 2-ClPh2-BrPh,2IPh, 2-NO2Ph, 3-ClPh, 4-ClPh, 2-An, 4-An, 2-Tl, 4-Tl, etc

12 mol%,toluene, -20o C

F

F

P(O)(OEt)2

OH

P(O)(OEt)2

OH

P(O)(OEt)2

OH

86, 96% yield>99%ee

87, 85% yield95% ee

88, 85% yield90% ee

N BO

PhPh

R"

84a-c, R"=Me (a), Et (b), Bu (c)

Scheme 27. Enantioselective reduction of ketophosphonates 84 by catecholborane85.

R'(RO)2P(O)

O(1S)-89

R'(RO)2P(O)

OH

HNaBH4-Pro

(S)-91a-c (R)-91a-c

Me3SiCl/NaIH2O

82

R=Et, Mnt; R'= Ph, Tl, An-2

R'(RO)2P(O) OH

H

+

(1R)-90THF

R'(HO)2P(O)

OH

HR'

P(O)(OH)2HO

H

N CO2H + NH

BH3O

O

H

-

92, NaBH4-Pro

NaBH4-H2

Na+H

Scheme 28. Reduction of acylphophonates with NaBH4-Pro 92.

Table 4Asymmetric reduction of ketophosphonates to hydroxyphosphonates

O

R(R'O)2P(O)(CH2)n

HO

R

H (CH2)nP(O)(OR')2NaBH4/A

THF, -30o +20oC*

Entry R R0 n Yield (%) A Config ee (%)

1 Ph Mnt 0 90 L-Pro (S) 52.6

2 2-F-C6H4 Mnt 0 90 L-Pro (S) 79.2

3 2-An Mnt 0 90 L-Pro (S) 60.6

3 Ph Mnt 0 95 L-TA (R) 92.4

4 Ph Mnt 0 98 D-TA (S) 465 2-F-C6H4 Mnt 0 97 L-TA (S) 80.56 2-An Mnt 0 96 L-TA (S) 747 Pyperonyl Mnt 0 97 L-TA (S) 968 i-Pr Mnt 0 97.6 L-TA (S) 689 Ph Et 0 95 L-TA (S) 6010 Ph Et 0 94 D-TA (R) 6011 CH2Cl Et 1 86 L-TA (S) 8012 CH2Cl Et 1 82 D-TA (R) 8013 CH2Cl Mnt 1 94 L-TA (S) 9614 CH2Cl Mnt 1 80 D-TA (R) 8215 Ph Et 1 95 D-TA (S) 44

NO B

BO

H HH P

RO O

OR

Cl

A

Figure 3. Model of the reaction complex of 82, (S)-84c, and borane.


from the borane complexed to the nitrogen atom attacks the car-bon atom from the Re face. This leads to the differentiation of thetwo residues flanking the carbonyl group; the phosphoryl groupis the ‘large’ substituent whereas the aromatic system is the ‘small’group. The co-ordination of the borohydride with an oxazoboroli-dine nitrogen atom increases the acidity of the intracyclic boronatom to facilitate the reduction of ketone 82.

Enantiopure carboxylic acids of natural origin were applied forchiral modification of borohydrides.52–65In particular, the chiralreductant NaBH4-Pro 92 obtained from NaBH4 and (S)-proline,reduced ketophosphonates 89 with 50–70% ee. This reagent wasapplied in the synthesis of a number of hydroxyphosphonates 91(Scheme 28).52

A noteworthy method is the enantioselective reduction of keto-phosphonates by borohydrides in the presence of tartaric acid.54–57

Natural (R,R)-(+)-tartaric acid and borohydride form a chiral com-plex that is a convenient stereoselective reagent for the reductionof ketophosphonates.57,60 Reduction of ketophosphonates 93 withthis complex was performed upon cooling to �30 �C in THF. Reduc-tion of diethyl a-ketophosphonates 93b with the NaBH4/(R,R)-TAchiral complex yielded diethyl (1S)-a-hydroxyphosphonates 94bwith an enantiomeric purity of 60%, while reduction of dimenthylketophosphonates 93c led to the formation of (1S)-a-hydrox-yphosphonates 94c with 80–93% de. Reduction of ketophospho-nates with the NaBH4/(S,S)-TA chiral complex led to the formationof (R)-hydroxyphosphonates 95. The stereoselectivity of reductionof ketophosphonates 93 containing chiral menthyl phosphates with

NaBH4/(R,R)-TA was higher than in the case methyl or ethylphosphates (Table 4 and Scheme 29).52,58–65

Reduction of chiral di-(1R,2S,5R)-dimenthyl ketophosphonates93c with the chiral complex (R,R)-TA/NaBH4 proceeded with dou-ble asymmetric induction to afford the (S)-b-hydroxyphosphonates94 with higher enantioselectivity than in the case of reduction ofdiethyl 2-ketophosphonates 93b (Table 4). For example, the stereo-isomers of dimenthyl 2-hydroxy-3-chloropropylphosphonate(S)- and (R)-97b were prepared with 96% ee.60 These compoundsrepresent useful chiral synthons for the synthesis of enantiomeri-cally pure b-hydroxyphosphonates,59–66 such as biologicallyimportant chiral b-hydroxyphosphonic acids, phosphono-carnitin98 and c-amino-b-hydroxypropylphosphonic acid (phosphono-GABOB) 99 in multigram quantities (Scheme 30).59 The treatmentof (S)-97a,b with potash in a mixture of acetonitrile with DMF inthe presence of potassium iodide, led to epoxide (R)-100a with99% de. Reaction of epoxide 100 with sodium azide in the presenceof ammonium chloride in methanol led to the formation of(R)-2-hydroxy-3-azidopropylphosphonate 101, that, by reactionwith Ph3P, was converted into the aziridine 102 in high yield(Scheme 30).65,66

Interesting catalysts for asymmetric reduction are oxazophosp-holidine–borohydride complexes, which reduce aromatic and

93a-c(S)-94a-c (R)-95a-c

TA - Tartaric Acid, n=0,1R = Me (a), Et (b), (1S,2R,5R)-Mnt (c); R' = Alk, Ar, CH2Cl, piperonyl

NaBH4/(R,R)-TA NaBH4/(S,S)-TAO

PRO

RO

HR'

OH

O

PRO

RO

OHR'

H

O

PRO

RO

R'

OTHF, -30oC THF, -30oCnnn

Scheme 29. The reduction of ketophosphonates 93 with NaBH4/(R,R)-or (S,S)-TA.

(RO)2P

OH

H

Cl

O

(R)-97a,b

(RO)2P

O

Cl

O

96(R)-98, 99% ee

P

OH

H

O

NMe3

O-

+

(R)-99, 99% ee

P

OH

H

NH3

O +(RO)2P

HN

H

O

(S)-101a

(RO)2P

O

H

O

(S)-100a

HO

HO O-

(RO)2P

OH

H

N3

O

a b

cd

e

fR=Mnt (a), Et (b)

(S)-102

e

Scheme 30. Synthesis of biologically important b-hydroxyphosphonates 98–101 starting from 97b. Reagents and conditions: (a) NaBH4/L-TA, THF, �30 �C ? +20 �C; (b)Me3SiBr/MeOH/Me3N; (c) K2CO3/KI; (d) Bn2NH, H2/Pd-c; (e) NaN3/NH4Cl; (f) Ph3P/–P3PO.

R'

O

P(O)(OR)2Me

HO

P(O)(OEt)2

PhH

H[RuCl(p-cymene)]2 (2 mol%)103 (8 mol%)

HCO2H:NEt3DMSO (0.1 M) rt

R = Me, Et, i-Pr; R' = CH(Me)Ph H2N NHSO2C6H3Ph2-2,6

Ph Ph

anti:syn=20:1, 99.5:0.5 er

103

10482

Scheme 31. Reduction of acylphosphonates 102 with formic acid and triethylamine, catalyzed by a Ru-complex.

R=Bn (a), p-BnOC6H4CH2 (b);Me2CHCH2 (c), Me (d)

R

PhtN

O

P(O)(OEt)2

R

PhtN

OH

P(O)(OEt)2R

PhtN

OH

P(O)(OEt)2+

R

PhtN

OH

P(O)(OEt)2O

BHO

BH3, Me2STHF, rt

105a-d

106 107

108a-d, 66-77%

84a, toluene, -60°C

66%

dr=8:1 -10:1

Scheme 32. Reduction of ketophosphonates 105 with catecholborane and oxazoborolidine 86a.


aliphatic ketophosphonates by heating in toluene to give hydrox-yphosphonates with moderate enantioselectivity.67

Corbett and Johnson52 recently described a method for theselective dynamic kinetic resolution of a-aryl acylphosphonates

82, providing b-stereogenic a-hydroxyphosphonic acid derivatives.The reduction of acylphosphonates 82 with formic acid andtriethylamine, catalyzed by a RuCl[(S,S)-TsDPEN] (p-cymene)complex containing chiral aminosulfonamide ligand 103, led to


the formation of (R)-hydroxyphosphonates 104 with high diaste-reo- and enantioselectivities of up to 99% ee. The absolute config-urations of the products was established as (1R,2R) via X-raycrystallographic analysis, confirming the anti-orientation of theOH and Ar groups (Scheme 31).

Barco et al. described the diastereoselective borohydridereduction of b-phthalimido-a-ketophosphonates 105 catalyzedby chiral oxazoborolidines 84a leading to the formation ofb-amino-a-hydroxyphosphonates 108. The reduction of 105 witha borohydride–dimethylsulfide complex in THF led to the forma-tion of (S,S)- and (S,R)-diastereomeric mixture 106, 107 (dr = 8:1to 10:1), at the same time the reduction of ketophosphonates105 with catecholborane and oxazoborolidine 84a (12 mol %) intoluene at �60 �C provided only the single (S,S)-diastereomer 108in good yield. The stereochemistry of these reductions fits withCorey’s model, which involves a transition state where thephosphonate moiety represents the large group. Hydride attackoccurring preferentially from the Re face produces the (S)-configu-ration at the newly created stereogenic center. The phosphonates108a–d were eventually reacted with hydrazine to furnish diethyl2-amino-1-hydroxyphosphonates in quantitative yields(Scheme 32).68

3.1.2. Reduction of C@N and C@C bondsOnly a few examples of the enantioselective reduction of phos-

phorus compounds bearing C@N or C@C bonds have beendescribed. An interesting example of the enantioselective reductionof iminophosphonates was reported by Mikołajczyk.69 The CBScatalytic reduction of 1-imino-2,2,2-trifluoroethylphosphonates

R = Me, Et

N

P(O)(OEt)2R

Ts

TsCl/Et3N114

115, 20-65% ee

P(O)(OEt)2

NHR'

Ph

H

(S)-117

HCO2NH4/Pd81%

R' = Ts, 34-65% eeR' = H, 50% ee

R = Ph

81-84%

Scheme 35. Asymmetric synthesis of a- an

NH

F3C P(O)(OR)2 F3C

R = Et, Pr

OBH

O

109 110

/ 84a (5 mol%)

65-98%

THF, -15o C

Scheme 33. Asymmetric reductio

N

RRP(O)(OEt)2

NXO

X=H, Ts; base = SP, QN

113, 8-72%

R=Me, Et, Ph;

112

base(0.05–0.25 eq)

69-95%

Scheme 34. Asymmetric synthesis of

led successfully to the formation of aminophosphonates 110 (yield65–98% and 30–72% ee). The reduction of 109 with catecholborane(catBH) catalyzed by methyloxazaborolidine 84a formed amino-phosphonates 110 and aminophosphonic acid 111 in 92–98% yieldsand with 72% ee. Evidently the starting iminophosphonates 109activated with the electron-withdrawing CF3 group are able tocoordinate the reagent/catalyst (Scheme 33).

Palacios et al. described a method for the asymmetric synthesisof 2H-azirine-2-phosphonates 113.70 The key step of the method isa base-mediated Neber reaction of p-toluenesulfonyloximesderived from phosphonates. Alkaloids and solid-phase bound chiralamines were used as catalysts. The best results were obtained withquinidine (69–95% yields, up to 72% ee). In other cases, the stere-oselectivity was either low or moderate. The subsequent reductionof 2H-azirines 113 with sodium borohydride in ethanol gave cis-aziridine-phosphonates 114 with moderate ee (up to 65% ee)(Scheme 34). The ring opening of enantiomerically enrichedN-unsubstituted aziridine 114 by catalytic transfer hydrogenationwith ammonium formate and palladium on carbon led to the for-mation of enantiomerically enriched the b-aminophosphonates116. The absolute configuration of b-aminophosphonates 116 wasestablished by chemical correlation with enantiomerically pureb-aminophosphonates prepared by the Karanewsky methodfrom c-amino alcohols. This correlation also established theabsolute configuration of azirines 114 and aziridines 113(Scheme 35).71

A wide range of 3-aryl-4-phosphonobutenoates 118 werereduced with PMHS in the presence of a Lig/Cu(OAc)2 H2O catalyst,where Lig = (S)-SegPhos 120, (S,R)-t-Bu-JosiPhos 121,

P(O)(OEt)2

R

HNR'HCO2NH4/Pd/MeOH

66-81%

(R)-116

H

R' = Ts, 20-24% eeR' = H, 24% ee

d b-aminophosphonates 116 and 117.

NH2

P(O)(OR)2

,

NH2

F3C P(O)(OH)2

HCl/H2O

111

O

30-72% ee

n of iminophosphonates 109.

P(O)(OEt)2

H

, Q, HQN

ee

EtOH/0oCHN

P(O)(OEt)2R

H

114, ee up to 65%

NaBH4

81-91%

2H-azirine-2-phosphonates 114.

RP(O)(OMe)2

CO2Me

RP(O)(OMe)2

CO2Me120/Cu(OAc)2

.H2O (1 mol%)

PMHS (4eq)/t-BuOH (4 eq)

118 119

H

*

R = Ph , 2-An 3-An, 4-An. 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-NO2C6H4 .3-ClC6H4,2-nphth, 2-thienyl

O

O

O

O PPh2

PPh2

120, (S)-SegPhos77-95%, 72-94% ee

FePPh2

PR2

121, R = t-Bu, Conv 98%, 90% ee122, R = Mes, Conv 100%, 50% ee

H

123, Conv 98%, 92% ee

PTl2

PTl2

Scheme 36. (S)-Segphos/Cu(OAc)2�H2O catalyzed reduction of 3-aryl-4-phospho-nobutenoates 118.

Saccharomycescerevisae

OH

P(O)(SEt)2N3

124 (S)-125, 92% ee

PO3Et2O OH

PO3Et2

77%

126

(R,S)-127:(R,R)-128 = 2:1


70% OH

PO3Et2+

(R,S)-127, 100% ee (R,R)-128

O

P(O)(SEt)2N3

OP(OEt)2

O O

P(OEt)2

OH

78 %

130, 97% ee


129

*

Scheme 37. Biocatalyzed reduction of oxopropylphosphonates.

PO3Et2

O

R PO3Et2

OH

R

Rhodotorula glutinis

R = H, Me, i-Pr, PhCH2CH2

132, 99% ee131

81%

Scheme 38. Asymmetric reduction of a-ketophosphonates with Rhodotorulaglutinis.


(S,R)-XyliPhos 122 and (S)-TolBINAP 123 (1–5 mol %) in tert-butanol with good enantioselectivities of up to 94% ee as shownin Scheme 36.72 Various silanes were screened (PMHS, PhSiH3,1,1,3,3-tetramethyldisiloxane) with similar results, although PMHSwas superior with respect to enantioselectivity. The reduction wasinfluenced by the steric and electronic effects of the substrates. Thesubstrates with an electron-withdrawing group at the para-posi-tion of the phenyl ring were reduced in higher ee value than thosewith an electron-donating group. A similar reduction of enaminephosphonates was also recently reported.73,74

3.2. Biocatalytic reduction

Enzyme catalysis (biocatalysis) has found an increasing numberof applications in organic chemistry including the synthesis ofoptically active compounds.75 Living microorganisms that excreteenzymes directly into the reaction medium can be used to carryout biocatalytic reactions in which racemic or prochiral substratesare transformed into enantiopure compounds.75–98 The biosynthe-sis of phosphorus compounds was carried out using various yeasts,microscopic fungi, and bacteria that are sources of biocatalystswhich can be isolated and used separately.

The reduction of ketones with Saccharomyces cerevisiae, that is,Baker’s yeast, is the most studied and widely used method of bio-conversion, because this biocatalyst is accessible and universal,and the process is easily realizable.76–90

Yeast-catalyzed asymmetric reduction of diethyl 2-oxoalkylphosphonates 124 and 126, respectively, led to 2-hydrox-yalkylphosphonates 125 and 127, 128 obtained in good yields andwith enantiopurity as high as about 97–100%.76,84 The reduction ofphosphonate 126 afforded a mixture of diastereomers 127, 128 in atotal yield of 70% and an (R,S):(R,R) ratio of 2:1 (Scheme 37). A sim-ilar biocatalyzed reduction of diethyl 2-oxopropylphosphonate 129resulted in the formation of 2-hydroxyalkylphosphonate 130 with97% ee [the (R)-configuration was tentatively assigned for 130].76

According to spectroscopic studies, this hydroxyphosphonateexists in a ‘frozen’ conformation due to the formation of an intra-molecular hydrogen bond between the phosphonate oxygen atomand the hydroxyl hydrogen atom (Scheme 37).81

The microorganisms Rhodotorula rubra, Rhodotorula glutinis,Cladosporium sp., Verticillium sp. and Saccharomyces cerevisiae wereused for the enantioselective reduction of diethyl-a-ketophospho-nates which are rapidly hydrolyzed in water with cleavage of theC–P bond. In order to suppress the hydrolysis of a-ketophospho-nates 131, the process was carried out under anhydrous conditions.The reaction catalyzed by freeze-dried cells immobilized on Celite R630 resulted in the production of a-hydroxyphosphonates.79–87 The

best results were obtained in the reduction of compounds 131 cata-lyzed by immobilized Rhodotorula glutinis cells in anhydrous hex-ane, viz., the products 132 were obtained with an enantiopurity ashigh as 99% (Scheme 38).79 Reduction in the presence of Saccharomy-ces cerevisiae gave only (S)-enantiomer 135, while the reaction in thepresence of Rhodotorula rubra afforded (R)-hydroxyphosphonate133. The products were obtained with ee >90%.90 The addition ofethyl chloroacetate or methyl vinyl ketone to Baker’s yeast reducingmedium also led to changes in the absolute configuration of theproduct, that is, the (R)-stereoisomer of 2-hydroxyphosphonatewas formed. With no additives, (S)-2-hydroxyphosphonate formedwith 99% ee. The asymmetric reduction of halogenated diethyl2-ketoalkylphosphonates with dry yeast gave the correspondingdiethyl 2-hydroxyphosphonates in good yields and with satisfactoryenantiopurity. Reduction of ketophosphonates was carried out at30 �C under aerobic conditions. In the case of chemically unreactivecompounds, anaerobic reduction was used. The stereoselectivity ofthe reduction depended on the nature of the 3-substituted-2-oxopropylphosphonates. Electron-withdrawing groups in the sidechain caused the enantioselectivity of the products to decrease.For instance, the enantiomeric purity and chemical yields of the3-bromo-2-hydroxypropylphosphonates were higher than thoseof the corresponding chloroderivatives. Also, biocatalyzed reductionof phosphonates 134 bearing CF3 or C3F7 groups proceeded with lowenantiomeric excesses (20–52% ee).88 Bulky isopropyl groups at thephosphorus atom also hampered the process (Scheme 39).

The 2-substituted-2-hydroxyalkylphosphonates 141 thusobtained were used as chiral reagents for the synthesis of phospho-rus-containing analogues of bioactive molecules, such as carnitineand GABOB.84a,88 An improved enantioselective synthesis ofhydroxyphosphonate (R)-141 involves double biocatalysis toobtain the enantioenriched products. Subsequent reduction ofazide (S)-137 with hydrogen in the presence of palladium afforded3-amino-2-hydroxypropylphosphonate (S)-138, which was treatedwith bromotrimethylsilane and methanol to form phospho-GABOB(S)-139 in high yield and with high ee (Scheme 40).

O P(OR)2

OHO P(OR)2

OO

P(O)(OEt)2

n=1 n=2,3

*

(S)-144143142

R = Me, Et, i-Pr, n=1-3; a = fermented yeast, 38oC, added glucose,b = dry yeast/acetone, 30oC

a b

70-76% ee

Scheme 41. Enantioselective reduction of cyclic dialkyl 3-oxoalk-1-enylphospho-nates 143.

( O)2P(O)O

R"

OH

R"

Geotrichum candidum

H2O/i-PrOH

144, 50-90% eeR' = Et, Me; R" = Me, Bu, Ph, (CH2)3Ph

*R' ( O)2P(O)R'

Scheme 42. Reduction of diethyl 2-oxopropylphosphonates with Geotrichumcandidum.

O

P(O)(OR)2N3

OH

P(O)(OR)2N3

OHP(O)(OR)2H2N

OHP(O)(O-)OHH3N+

Pd/C (10 mol%)

136 137, 77 %, 92 % ee

138 (S)-139


R=Me, Et, i-Pr, Bu

Me3SiBr

MeOH

H2O, 30 oC, 12 h

95%

H2O, 30 oC, 12 h

(EtO)2P(O)

O

Cl

140

(EtO)2P(O) Cl

OH

(HO)2P(O)

OH

NMe3

(R)-98(R)-(+)-141

+

H H

Scheme 40. Examples of 2-ketophosphonates reduction with Saccharomyces cerevisiae.

O

XPO3Et2

OH

XPO3Et2

OH

XPO3Et2

Rhodotorularubra


50%10%

(S)-135(R)-133 134

X = Me, CH2Cl, CH2Br, CF3, C3F7

Scheme 39. Asymmetric reduction of b-ketophosphonates with microorganisms.


Mikolajczyk et al.84b developed a method for the chemoenzy-matic synthesis of phosphocarnitine enantiomers using microbio-logical reduction in the key step of the process. Phosphocarnitine98 was synthesized from diethyl 2-oxo-3-chloropropylphospho-nate 140 in three steps including reduction, additional enzymaticpurification of enantioenriched phosphonates (R)-(+)-141 and(S)-(�)-141, transformation of compound 141 to a phosphonic acidand the final reaction with trimethylamine resulting in trimethy-lammonium salt (R)-98. Bioreduction of ketone 140 resulted inhydroxyphosphonate 141 (90% ee) which was then subjected toadditional enzymatic resolution in the presence of CALB to givean enantiopure product. This technique gave both enantiopurephosphonates (R)-(+)- and (S)-(�)-141, which can then be con-verted into phosphocarnitine enantiomers (Scheme 40).84b

Attolini et al.85,86 carried out the enantioselective reductions ofcyclic dialkyl 3-oxoalk-1-enylphosphonates 143 with various typesof yeast, such as fermented yeast and freeze-dried dry yeast, aswell as acetone extracts from dry powdered yeast. Reduction ofthe six- and seven-membered enones (n = 2, 3) with fermentedyeast led to the corresponding phosphonates 142 in satisfactoryyields and with enantiomeric excesses ranging from moderate togood. At the same time, the reduction of five-membered enon-ephosphonate 143 involved the C@C double bond and gave a cyclicketone 144 with low ee. For the six-membered rings, it was foundthat bulky substituents at the phosphorus atom increased theenantioselectivity of the reduction to 95% ee. The reduction ofsix-membered enonephosphonates 143 with acetone yeast extractincreased the yields of the reduction products, although theirenantiomeric purity remained almost the same. As the volume ofthe alkyl substituents at the phosphorus atom in the six-membered compounds 143 (n = 2) increased from Me to Et andi-Pr, the enantiomeric purity of the compounds increased from45% to 95%. The (S)-absolute configurations of the six-memberedhydroxyphosphonates 144 were determined by chemical correla-tions (Scheme 41).

Microscopic fungi Geotrichum candidum (milk mold) available astwo different strains, IFO 4597 and IFO 5767, usually exhibit highstereoselectivity in the reduction of ketones of different structures.The reduction of diethyl 2-oxoalkylphosphonates with Geotrichum

candidum led to the formation of diethyl (+)-(R)-2-hydrox-yalkylphosphonates 144 with 50–90% ee and in satisfactory yields.However the authors suppose that the absolute configuration ofcompounds 144 demands further confirmation (Scheme 42).94a

Racemic ethyl 1-hydroxybenzyl(phenyl)phosphinate 145 con-sists of four stereoisomers: a laevorotatory pair (Rp,R) and (Sp,S)and a dextrorotary pair (Rp,S) and (Sp,R). In the presence of addi-tives, which raised the efficacy of the bioconversion of the diaste-reoisomers, the separation of the phosphinate 145 intodiastereomers (Rp,R)-148 and (Sp,R)-149 with enantiomeric excess>99% ee and yield of 48%94b was possible (Scheme 43).

Fosfomycin is an antibiotic containing an asymmetric epoxygroup, that acts against Gram-negative and Gram-positive bacteria.The synthesis of Fosfomycin and its trans-(1S,2S)-diastereomer,using as a key step the enzymatic reduction of a ketophosphonateto the chlorohydrins 150, 151 by the action of YDR 368w and YHR

POHO

EtO

PhPh

POHO

EtO PhPhP

OO

EtO Ph

Ph +

145 146 147

columnchromatography

PhP

OHO

EtO

Ph

(Rp,R)-148

POHO

EtO Ph

Ph

(Sp,R)-149

H

+H H

H

Geotrichumcandidum

Scheme 43. Bioconversion of diastereoisomers 145 by fungi Geotrichum candidum.


104w enzymes (NADPH-dependent aldo-keto reductases) wasdeveloped. YDR 368w and YHR 104w provided high ee and devalues in the synthesis of the syn-(1R,2S)-150 and anti-(1S,2S)-151 isomers of the intermediate products, which were thenconverted into fosfomycin 152 and its trans-(1S,2S)-isomer 153(Scheme 44).96

Cl

P(O)(OMe)2

O Cl

P(O)(OMe)2

OH

Cl

P(O)(OMe)2

OH

Cl

P(O)(OH)2

OH

Cl

P(O)(OH)2

OH

YDR368w

97%

YHR104w

89%

92%

P(O)(ONa)2

H

O

H

trans-(1S,2S)-153

P(O)(ONa)2H

OH

syn-(1R,2S)

anti-(1S,2S)

anti-(1S,2S)-151, 99% ee

syn-(1R,2S)-150, 99% ee

10M NaOH

10M NaOH

152

1) Me3SiBr

1) Me3SiBr2) MeOH

2) MeOH

Scheme 44. Asymmetric synthesis of (�)-fosfomycin 152 and its trans-diastereo-mer 153.

Hydrolytic oxirane ring opening in substituted 1,2-epox-yphosphonates was carried out under the action of microbial cellcultures.80,91,97 In contrast to chemical hydrolysis, phosphorus-containing oxiranes were mainly converted into erythro-1,

HPO3Et2

O

PO3Et2

O

+ (1S

(1R154

Beauveria bassiana

dioxane-water, 24oC

Scheme 45. Microbiological hydrolysis

2-dihydroxyphosphonates containing small amounts of the threo-isomers under biocatalysis conditions. For example, chemicalhydrolysis of compound 154 led to a mixture of threo- and ery-thro-stereoisomers 155–156 with an 85:15 ratio. At the same time,microbiological hydrolysis by Beauveria bassiana fungi gave thesestereoisomers in a total yield of 59% and in a 42:58 ratio.80,97 Theerythro-isomer was obtained with 100% ee and the threo-isomerwas obtained with 98% ee as the (2S)-enantiomer (Scheme 45).

3.3. Asymmetric oxidation

There are only a few examples of asymmetric oxidation of orga-nophosphorus compounds.99–108 One of them is the synthesis ofFosphomycin 152 and Fosphadecin 159, which are well-known asantibiotics used against Gram-negative and Gram-positive bacteria.Kobayashi et al.99 used for their preparation the Sharpless asym-metric dihydroxylation of trans-propenylphosphonate 157. Theoxidation of alkene 157a (R0 = Me) with AD-Mix-a led to the forma-tion of diol 158 in 65% yield and with >99% ee after crystallizationfrom a mixture of hexane/ethyl acetate (yield 95% and 78% eebefore crystallization). Subsequent monosulfonylation of theresulting diol 158 and treatment with K2CO3 in acetone affordedthe dibenzyl epoxide 152a (R = Bn) and then the fosfomycin 152b(R = H). Asymmetric dihydroxylation of olefine 157 (R0 = C5H11)was carried out with a modified Sharpless conditions of AD-mix-aand MeSO2NH2 in t-BuOH with the formation of diol 160 in 85%yield and with 96% ee After recrystallization the pure diol wasobtained and converted into epoxide 161 (Scheme 46).

Sisti,103 and then Thomas and Sharpless101 reported on thecatalytic asymmetric synthesis of b-aminophosphonates via amin-ohydroxylation of a,b-unsaturated phosphonates with a potassiumosmium (VI) complexes bearing (DHQ)2PHAL ligands. Thesyn-b-amino-a-bromination of unsaturated phosphonates wasperformed under typical Sharpless reaction conditions with excessN-bromoacetamide.102

Krawczyk et al.104 synthesized the optically active epoxides 162using the asymmetric oxidation of enolphosphates 161 with NaOClin the presence of Mn(III)(salen)complex 163. The hydrolysis of

PO3Et2

OH

OH

H

PO3Et2

OH

OHH

H

+

PO3Et2

OH

OHH

H

PO3Et2

OH

OHH

H+

,2S)-155 (1R,2S)-156

,2R)-155 (1S,2R)-156

of oxiranes by Beauveria bassiana.

P(OR)2R'

O

P(OR)2

OOH

OH

P(OR)2

OOH

OSO2Ar

P(OR)2

O

OH H

AD-mix−α

R'=MeAr=Tl, p-O2NC6H4

PO

O

OHH H

phosphodecin,159phosphamycin, 152a,b

O P

O

OHO O N

NN

N

NH2

HO OH

157

ArSO2Cl B

158R= Bn (a), H (b) 95 %, 78 % ee

t-BuOH-H2O, 0 oC K2CO3, acetone,rt

Et3N, CH2Cl2,5 oC, 49-67 %

P(OR)2R

OP(OR)2C5H11

OOH

OH

P(OR)2

OC5H11

OH H

AD-mix−α

160, 85%, 96% ee 161157, R=C5H11

MeSO2NH2,t-BuOH-H2O, 0 oC

Scheme 46. Asymmetric oxidation of alkenphosphonates 157 with AD-Mix-a.

R'

H Ar

R'

H Ar

OP(O)(OR)2

O(R,R)-Salen 163

R'

H Ar

O

162

NaOCl H3O+OP(O)(OR)2

68-96% ee

R=Et, i-Pr, Ph, p-An; R'=Me, Et, Pr, Ph; Ar= Ph, p-An

t-Bu

t-Bu

O

N

t-Bu

t-Bu

O

NMn

Cl

163

Scheme 47. Asymmetric oxidation of enolphosphates with the NaOCl/Mn(III)(salen).


162 led to the formation of chiral hydroxy a-ketones in good yieldsand with enantioselectivity of 68–96% ee (Scheme 47).

Chen et al.108 have described the kinetic resolution of a-hydrox-yphosphonates 164, catalyzed by chiral vanadyl(V)methoxide com-plex 165 bearing N-salicylidene-a-aminocarboxylates, effectinghighly enantioselective and chemoselective aerobic oxidations atambient temperature. Excellent reaction rates and selectivityfactors (krel >99) were observed in the cases of the most electron-withdrawing 4-nitro and 4-carbomethoxy substrates 164. Thereactions were completed at 50% conversion, leading to recoveryof the (S)-enantiomers (S)-164 with 99% ee. This method works wellwith various a-aryl- and a-heteroaryl-a-hydroxyphosphonates. Itwas found that the more sterically encumbered diastereomericadduct B was faster reacting for the subsequent a-proton elimina-tion process leading to a-ketophosphonate 165 with concomitantreduction of the vanadyl(V) species 166 into the correspondingvanadium(III)OH (Scheme 48).

An asymmetric synthesis of benzenesulfinates bearing a phos-phonate group at the ortho-position, based on the diastereoselectiveoxidation of the corresponding sulfenates was developed by theaction of chiral Davis oxaziridines.106,107 A practical synthesis ofboth enantiomers of diisopropyl (2-methylsulfinyl)phenylphospho-nate in enantiomeric excess of close to 85% was also reported.

Kafarski et al.75 described the kinetic resolution of a-amino-phosphonates by the biocatalytic oxidation of aminophosphonicacids. Several fungal strains, Beauveria bassiana, Cuninghamellaechinulata, Aspergillus fumigatus, Penicillium crustosum, and Clado-sporium herbarum, were used as biocatalysts to resolve racemicmixtures of 1-aminoethanephosphonic acid using L/D-amino acidoxidase activity. The best result [42% ee of the (R)-isomer] wasobtained with a strain of Cuninghamella echinulata. Biotransforma-tions were carried out in a phosphate buffer (pH 6.11) (Scheme 49).

4. Asymmetric electrophilic catalysis

Nucleophilic and electrophilic catalyses have been well-knownfor many years. There are many examples of asymmetric nucleo-philic or electrophilic activations of organophosphorus compoundsthat have attracted the attention of many chemists. Usually theelectrophilic catalysts used are Lewis acids and nucleophilic cata-lysts employ organic bases. Lewis acids catalyze reactions throughelectrophilic activation of organic groups. The addition of a Lewisacid to the substrate containing a free electronic pair, is accompa-nied by an increase of reactivity of the complex generated. Typicalexamples of electrophilic asymmetric activation of organophos-phorus compound by chiral Lewis acids are catalytic alkylation

OH

P(O)(OBn)2R

O

P(O)(OBn)2R

OH

P(O)(OBn)2R+O2/toluene

164 165 (S)-164

166

Br

Br

O

N O

V

O

OMe

O

OH

166

O

N OV

O

O

O

P

H

HO

O

O

O V*

*

*

V(O)*-(R)-substrate pairless stable but H-more accessible

B

Scheme 48. Effect of substituents on the asymmetric aerobic oxidation of racemic a-hydroxyphosphonates.

RP

HR'

RP

HR'

RP

M(L*)R'

RP

M(L*)R'

RP

ER'

RP

ER'

(Rp)-167

(Sp)-167

kinv

kR

kS

M/L*

M/L*

B

Keq

A

E

E

Scheme 50. Mechanism of catalytic electrophilic substitution at trivalentphosphorus.

NH2

PO3H2

NH2

PO3H2H

O

PO3H2

+biocatalyst

Scheme 49. Biocatalytic resolution of racemic 1-aminoethanephosphonic acid.


reactions, arylation, halogenations, catalysis of chemical reactionsby enzymes, and others.

4.1. Catalytic electrophilic substitution at the phosphorus atom

Over the last few years, the catalytic asymmetric synthesis oftertiary phosphines has attracted the attention of many chemists.Interesting results have been published in articles andreviews.109–135 One route leading to a-stereogenic phosphines iselectrophilic substitution at the phosphorus atom of secondaryphosphines, as a result of asymmetric catalysis in which the catalystactivates a phosphorous nucleophile or a carbon electrophile, creat-ing an asymmetric environment, that is, creating a preference forone of the Si or the Re faces at the reactive center.109–113 Upon reac-tion with a chiral metal complex, racemic secondary phosphines areconverted into diastereomeric metal-phosphide complexes A or B,which interconvert rapidly by P-inversion. If the equilibriumA ¡ B is faster than the reaction of A or B with electrophile E, thenP-stereogenic phosphines 167, in which pyramidal inversion is

slow, can be formed enantioselectively. The product ratio in thisdynamic kinetic asymmetric transformation depends both on Keq

and on the rate constants kS and kR (Scheme 50).

For example, Glueck114–120 found that the racemic secondaryphosphines 167 form with a platinum complexPt(Me-Duphos)(Ph)(Br) and NaOSiMe3 in toluene adduct 168,which interconvert rapidly by P-inversion (Sp)-168 ¡ (Rp)-169.Adduct 168 was isolated and studied by low-temperature NMRand X-ray monocrystal analysis. The crystal structure of the adductshowed that the major enantiomer of 168 had an (RP)-absoluteconfiguration.121

The treatment of adduct 169 with benzyl bromide led to the for-mation of tertiary phosphine (Rp)-170 with 77% ee and to initial


catalyst Pt(Me-Duphos)(Ph)(Br), which confirms the proposedmechanism. Substitution at the tricoordinated phosphorus atomof the secondary phosphine 167 proceeded with retention of abso-lute configuration at phosphorus, according to classical representa-tions. On the basis of these results, the authors came to aconclusion that the enantioselectivity was determined mainly bythe thermodynamic preference for one of the interconverting dia-stereomers of (Sp)-168 ¡ (Rp)-169, although their relative ratesof alkylation were also important (Curtin–Hammett kinetics)(Scheme 51).122

IpsP

HMe

IpsP

MeCH2Ph

(Rp)-170, 77% ee

rac-167

P

PPt

P

Ph

IpsMe

(Rp)-169

Pt(Me-Duphos)(Ph)(Br)

-Pt(Me-Duphos)(Ph)(Br)

P

PPt

P

Ph

Ips

Me

(Sp)-168

PhCH2Br

NaOSiMe3

Scheme 51. Asymmetric alkylation of secondary phosphines 167 catalyzed by Pt(II)complexes.

The asymmetric arylation or alkylation of racemic secondaryphosphines catalyzed by chiral Lewis acids led in many cases to theformation of enantiomerically enriched tertiary phosphines.121,128

Chiral complexes of ruthenium, platinum, and palladium were used.For example, the chiral complex Pt(Me-Duphos)(Ph)Br catalyzed theasymmetric alkylation of secondary phosphines with various RCH2X(X = Cl, Br, I) compounds with formation of tertiary phosphines (ortheir boranes 172) in good yields and with 50–93% ee.114,115,121 Theenantioselective alkylation of secondary phosphines with benzylhalides catalyzed by complexes [RuH(i-Pr-PHOX)2]+ led to the forma-tion of tertiary phosphines 172 with 57–95% ee.121,124 Catalyst [(R)-difluorphos)(dmpe)Ru(H)][BPh4] was effective in the asymmetricalkylation of secondary phosphines with benzyl bromides, whereas(R)-MeOBiPHEP/dmpe was more effective in case of benzyl chlorides(Scheme 52).124–126

The arylation of secondary phosphines with aryl halides, cata-lyzed by chiral complexes of platinum,114–118 ruthenium, 124,125

palladium,126–134 in many cases proceeded with good

PHMe

R + R'CH2Cl

171

+ NaOCMe2Et

R' (ee)=Ph (75%), p-An (85%), o-Tl (57%), 1-NPy (48%), Furyl (68%), m-ClCH2C6H4 (95%), m

NO

PPh2

(R)-i-Pr-PHOX

O

O

O

O

F

F

F

F

(R)-DIFLUOROPH

Lig=

Scheme 52. Asymmetric alkylation of sec-phosph

enantioselectivity to give enantiomerically enriched tertiary phos-phines.110 For example, the reaction of aryl iodides with secondaryarylphosphines 171, catalyzed by the chiral complex Pd((R,R)-Me-Duphos) (trans-stilbene), furnished tertiary phosphines 173 withenantioselectivities of up to 88% ee.117–119 The arylation of second-ary phosphines 171 with ortho-aryl iodides, catalyzed by the in situgenerated complex Pd2 (dba)3 � CHCl3, containing chiral ligandEt,Et-FerroTANE 174 and LiBr, led to the formation of the corre-sponding tertiary phosphines with an enantioselectivity of 90%ee.130 The palladium complex 176 also showed high enantioselec-tivity in the arylation of secondary phosphines.129,130 Some exam-ples of the arylation reaction of secondary phosphines with low eehave been described. The asymmetric arylation of phosphineboranes with anisyl iodide, catalyzed by the chiral complex ofoxazoline phosphine 175 led to the formation of enantiomericallyenriched tertiary phosphines 173 with 45% ee.129 A complex of(R,S)-t-Bu-JOSIPHOS catalyzed the arylation of PH(Me)(Ph)(BH3)by o-anisyl iodide with the formation of PAMP-BH3 with 10% ee(Table 5).112

The reaction of secondary phosphine boranes 177 with anisyliodide, catalyzed by a chiral Pd complex with (S,S)-Chiraphos, pro-ceeded with retention of absolute configuration at the phosphorusatom.122,132 The addition of Pd((S,S)-Chiraphos)(o-An) to enantio-enriched secondary phosphine 177 in the presence of NaOSiMe3

led to the formation of stable complex 179. Heating this complexto +50 �C in excess diphenylacetylene converted it into (Rp)-180in 70% yield and with an enantiomeric purity of 98% ee(Scheme 53).

Alkylation of silylated alkylarylphosphines 181 instead of P–Hphosphines for the preparation of chiral tertiary phosphines ledin some cases to an appreciable increase in the enantioselectivity.For example, as reported by Toste and Bergman,129 the reaction ofarylsubstituted iodides 181 with silylphosphines catalyzed byPd(Et-FerroTANE)Cl2, in the presence of N,N0-dimethyl-N,N,N-pro-pylene (DMPU) led to the formation of P-chiral tertiary phosphinesulfides 182 with 98% ee (Scheme 54).

Enantioselective intramolecular cyclization of secondary phos-phines 183 or their boranes, catalyzed by chiral palladium (diphos-phine) complexes, afforded P-stereogenic benzophospholanes 184with moderate stereoselectivity (70% ee). This reaction providedchiral phospholanes which are valuable ligands in asymmetriccatalysis (Scheme 55).134

Examples of electrophilic additions of secondary phosphines toalkenes or alkynes have been described. Gluck135–140 reported theplatinum catalyzed enantioselective alkylated/arylation of primaryphosphines, that proceeded with the formation of chiral phos-phaacenaphthenes. The reaction was catalyzed by chiral platinumor palladium complexes, bearing an (R,R)-MeDUPHOS 4 ligand and

[RuH(Lig](dmpe)]+ (BPh4)-

(10% mol)P R'

MeR

BH3

17270-96%

phth (59%),-ClCH2C6H4 (74%)

*BH3 THF

PPh2

PPh2

OS

X

X

PPh2

PPh2MeO

MeO

X=H, (R)-MeOBIPHEPX=Cl, (R)Cl-MeOBIPHEP

ines 171, catalyzed by chiral Ru complexes.

Table 5Arylation of secondary phosphines 171, catalyzed by chiral palladium complexes

ArI, Me3SiONaR

PH

Me RP

MeAr

[Pd*]171

*

173

R ArI Catalyst Yield (%) ee (%) Refs.

2-PhC6H4 2-t-BuOCOC6H4I 174/CHCl3/Pd2dba3/LiBr/NEt3 76 90 (S) 1292-An 2-t-BuOCOC6H4I 174/CHCl3/Pd2dba3/LiBr/N-Me-piperidine 43 86 (S) 1292-CF3C6H4 2-t-BuOCOC6H4I 174/CHCl3/Pd2dba3/LiBr/NEt3 39 93 (R) 1302-PhC6H4 2-MeOCOC6H4I 174/CHCl3/Pd2dba3/LiBr/NEt3 69 85 (S) 1302-PhC6H4 2-OCHC6H4I 174/CHCl3/Pd2dba3/LiBr/NEt3 71 63 (S) 130t-Bu 3-AnI 175/MeCN/PdL2/K2CO3 — 45 1312-An 3-AnI 175/MeCN/PdL2/K2CO3 — 45 1312,4,6-(i-Pr)3C6H2 PhI 176 84 78 (S) 1272,4,6-(i-Pr)3C6H2 PhI 176 89 75 (S) 1282,4,6-(i-Pr)3C6H2 4-AnI 176 96 82 (S) 1282,4,6-(i-Pr)3C6H2 p-PhOC6H4I 176 89 88 (S) 128

PFe

P

L*=

Et,Et-FerroTANE

NO

P

o-BiPh

Ph

174, Pd2dba3 (SCRP)-175, Pd2dba3

P

P

PdI

Ph

176

[Pd*]=

I

PHPh

BH3

[Pd(Me-DuPhos)(stilbene)]

PPh BH3

184, 70% ee183

NaOSiMe3

89%

Scheme 55. Enantioselective intramolecular cyclization of secondary phosphines183.

+Ph

P

BH3

Me

Pd(II)/(R,R)-4

185 186, 42% ee

*Ph

PH

BH3

Metoluene, 35oC,

conversion 70%

Scheme 56. Electrophilic addition of secondary phosphines to alkynes.

BH3

PH Me

PhNa

P Me

BH3

Ph

[Pd]P

BH3

Me

Ph

(Sp)-177

179

BH3

PMe

Ph

(Rp)-180

[Pd]=Pd((S,S)-Chiraphos)

PhC

retention

retention178

[Pd]NaOSiMe3

Δ

I

An-o

o-An

CPh

o-An

Scheme 53. Reaction of 177 with anisyl iodide catalyzed by a chiral Pd(S,S)-Chiraphos complex.

P

MeSi(i-Pr)3Ph

[Pd(Et-FerroTANE)Cl2]

DMPU, 60oC, BH3 THFP

MePh

RSR

I

+

182181then S8

Scheme 54. Reaction of aryl iodides 181 with silylphosphines catalyzed by a Pdcomplex.


proceeded with the formation of P-chirogenic phosphines 186 butwith low ee (Scheme 56).141,142

Attempts to apply chiral ammonium salts as phase transfer cat-alysts in the asymmetric alkylation of racemic secondary phos-phines were undertaken. However, the alkylation of phenylphosphine borane with methyl iodide in the presence of a chiralquaternary cinchonine ammonium salt proceeded also with lowenantioselectivity (17% ee).143

4.2. Catalytic electrophilic substitution in a side chain

Alkylation: a number of successful syntheses of chiral alkylatedketophosphonates were realized by enantioselective catalysis withchiral bis(oxazoline)-copper complexes. For example, Shibata,144

recently reported on the enantioselective alkylation of b-keto-phosphonates 187 with aromatic alcohols as electrophiles, cata-lyzed by Cu(II)(OSO2CF3)2/189a–c leading to the formation ofproducts 188 in good yields and with relatively high enantioselec-tivity. The asymmetric vinylogous aldol reaction between a-ketophosphonates 82 and 2-(trimethylsilyloxy)furan was also realizedby using bis(oxazoline)-copper catalyst 189d (Scheme 57).145

Enantioselective alkylation of b-ketophosphonates 187 withpropargylic alcohols 191 in the presence of thiolate dirutheniumcomplex 194 and a chiral complex of copper bearing a bis(4,5-diphenyl-4,5-dihydrooxazoline) ligand 189 as cocatalyst, led tothe formation of alkylated propargyl products 193 in good yieldsand with diastereoselectivity of 16:1 to 20:1 and enantioselectivi-ties up to 97% ee146 (Scheme 58).146

HO

o-Ano-An+

O

P

O

OEt

OEtO

P

O

OEt

OEt

o-An

o-An

Cu(OTf)2/189a-c-20oC, CH2Cl2

187188 (80-87% ee)

68%

82O OSiMe3

OO

R'OH

P(O)(OR)2

Cu(OTf)2/189dCH2Cl2,-20oC

up to 86%

<98% ee, < 99:1% dr

(RO)2P(O)C(O)R'+

190

N

O

N

O

R R

R" R"

R'R'

a) R+R = -CH2CH2-, R'+R" = o-phenylene b) R = Me, R'+R" = o-phenylenec) R+R = -CH2CH2-, R' = R" = Ph; d) R = Me, R' = i-Pr, R"=H

189a-d

Scheme 57. Enantioselective catalytic alkylation of b-ketophosphonates witharomatic alcohols.

N

R

O

P(O)(OR)2R'R +

N

R

O

Nu

R

R

catalyst

195

Nu=MeOH/DBU, morpholine

197

N

N

O

ScN

O

TfO OTfOTf

198

catalyst = 198-201

OR

NHR

SNH

F3C

CF3

200, R=H, TIPS

R= or quinine

O

R'

P

*

C

Ar = Ph, 4-Tl, 3,5-X = BF4,OTf, SbF

Scheme 59. Enantioselective Friedel–Crafts alkylatio

OH

Ar +O

P(OEt)2

O 194 (11 mol%)Cu(OTf)2 (10 mol%189 (5 mol%)NH4BF4 (10 mol%

187191 82-97%

0 oC, THF

Ar = 1-Nphth, 2-Npht, p-C6H4X, X = H, Me, Cl, OMe

Scheme 58. Enantioselective alkylation of b-keto


The Friedel–Crafts enantioselective alkylation of indoles witha,b-unsaturated ketophosphonates, catalyzed with various chiralmetallocomplexes and organocatalysts has attracted significantattention.147–152 In 2003 Evans reported that the pybox-scandium(III) triflate complex 198 catalyzes the conjugatedaddition of indole to a,b-unsaturated acylphosphonates 195 to giveacylphosphonates 196 with high yields (51–83%) and enantioselec-tivities of up to >99.147,148 Yamamoto used chiral aluminumcomplexes 199 for asymmetric phosphonylation of indoles andachieved enantioselectivities of 98% ee and yields of 85%.151

Jørgensen et al.149 have performed a variety of stereoselectiveconjugate additions of carbon-based nucleophiles (oxazolones,indoles, and 1,3-dicarbonyl compounds) to a,b-unsaturated acylphosphonates catalyzed by chiral thioureas 200 and obtainedproducts in satisfactory yields and with enantioselectivities of72–90% ee. The stereoselectivity of the 1,3-dicarbonyl addition toacyl phosphonates is believed to originate from bifunctional coor-dination of the nucleophilic and electrophilic reaction partners tothe quinine-derived catalyst. It was proposed that the acyl phos-phonate is hydrogen bonded to the squaramide motif, placing thealkene side chain in the sterically less-demanding area away fromthe C-9 center of the catalyst, while the 1,3-dicarbonyl compoundis deprotonated and directed for nucleophilic attack by the tertiarynitrogen atom of the catalyst. The R-group of the nucleophile is ori-ented away from the reaction site and the subsequent conjugate

196

Nu

N

R

O

P(O)(OR)2

R'R

N Bu-tO

Al

N Bu-tO

X

199, (TBOx)AlX

(R)

P

OPd

OROR

P

indole

P

PPd

OH2

NCMe

Ar

Ar

201

2X

Ar2

Ar2

Me2C6H3, 3,5-Me2C6H3 2,6-(i-Pr)2-4-(9-anthryl)C6H26, PF6

2+

n with a,b-unsaturated ketophosphonates 195.

Ar

O

P(O)(OEt)2

)

)Ru Ru

S

S

Cp

Cl

Cp

Cl

R

R

194 (R=Me, i-Pr)193, 64-97% eeanti/syn 20:1

phosphonates 187 by propargylic alcohols.


addition approaches the Si-face of the C@C bond, accounting forboth the enantio- and diastereoselectivities of the reaction.Subsequent treatment of the reaction mixture with methanol andDBU led to the formation of methyl 3-(indol-3-yl)-propanoates197 in good yields (65–82%) and with high enantioselectivities(up to 99% ee). The high selectivity of the reaction was explainedby coordination of the b,c-unsaturated a-ketophosphonate 195with palladium catalyst 201 by a two-centered co-ordinate bondin a bidentate fashion as the indole attacks the double bond, asshown in formula C.152 Since the Re face of the double bond ofthe phosphonate was blocked preferentially by one of the phenylgroups of the (R)-BINAP, the addition of indole proceeded fromthe Si face in a highly enantioselective manner.

Bachu and Akiyama150 used a BINOL-phosphoric acid 201 as acatalyst for this reaction. A variety of indoles underwent enantiose-lective Friedel–Crafts alkylation with a,b-unsaturated ketophosph-onates 195 in the presence of 10 mol % of chiral BINOL-basedphosphoric acid (Scheme 59).

+

O

P

R2

O

R1

OR3

OR3

O

P

R2

O

R1

OR3

OR3

Cl

203,

N

O

O

Cl

204-Zn(SbF6)2(10mol%)

NOO

N

O

Ph Ph

74-92% ee202a-f

205

O

N

Ph

O

N

Ph

N

204

Ph Ph

CH2Cl2, rt

80-92 %

Scheme 60. Catalytic chlorination of the b-ketophosphonates by NFSI.

PhSO2

N

PhSO2

F

O

P

R'

O

R

OEt

OEtF

206

204-Zn(ClO4)2

(20mol%)+

O

P

R'

O

R

OEt

OEt46-71%

70-91% ee207,202

R=Ph, 2-Np, Me, R'=Me, Allyl, R+R'=(CH2)2

Scheme 61. Enantioselective fluorination of b-ketophosphonates by N-fluoroben-zenesulfonimide 204.

SO2PhN

SO2Ph

F

206

Pd Cat 1-10 mol%+

O

P

R'

O

R

OEt

OEtEtOH, 1M

P(OEt)2

O

( )n

P(O)(OEt)2

209 [n=1, 2]

RR

202

208, 96%ee 210, RPh (995% ee

57-97%

O

F

O

F**

Scheme 62. Enantioselective fluorination of b-ketophosphonate

Wang153 reported the asymmetric catalytic alkylation of N-(diphenylphosphinoyl) imines with moderate enantioselectivities.

Halogenation: Bernardi and Jørgensen154 have developed acatalytic enantioselective chlorination and fluorination ofb-ketophosphonates, using N-chlorosuccinimide (NCS) and N-flu-orobenzenesulfonimide (NFSI). The reaction proceeded smoothlyfor both acyclic and cyclic b-keto phosphonates 202 giving thecorresponding optically active a-chloro and a-fluoro-b-ketophosphonates 203 in high yields and enantioselectivities using an(R,R)-204/Zn(II) catalyst. The acyclic b-keto phosphonates withboth aromatic and alkyl substituents at the b-position were con-verted into the corresponding optically active a-chloro b-ketophosphonates 203 in yields of 80–98% and with enantioselectivi-ties of 78–94% ee (Scheme 60).

The catalytic fluorination of the b-ketophosphonates by NFSIusing a chiral 204/Zn(II) catalyst also proceeds readily. For the fluo-rination reaction, a more easily prepared catalyst formed by a com-bination of Zn(ClO4)2�6H2O and Ph-DBFOX 204 in the presence of4 Å molecular sieves was used with comparable results. The intro-duction of two stereogenic centers in ligand 205 improved theenantioselectivity to 91% ee Enantioselective fluorination ofb-ketophosphonates 202 performed by the action of N-fluoroben-zenesulfonimide (NFSI) 206 catalyzed by zinc complexes withligand 204, resulted in formation of the optically active a-fluo-rine-b-ketophosphonates 207 with yields from moderate to goodand enantioselectivities of up to 91% ee (Scheme 61).154,155

Sodeoka et al.156–158 have developed an efficient catalyticenantioselective fluorination of cyclic and acyclic b-ketophospho-nates by the action of NFSI in the presence of chiral palladium com-plexes 211, 212 (1–10 mol %), containing (R)-BINAP ligands. Thefluorination proceeded under mild conditions (in alcohol, acetoneor THF, at room temp) and led to the formation of chiral fluorinatedketophosphonates 207 in yields of 57–97% and enantioselectivitiesof 94–96% ee. a-Fluorinated phosphonates were then convertedinto phosphonic acids (Scheme 62).

The absolute configuration predominating in the reaction indi-cates that the fluorinating reagent reacts from the less hinderedside of the enolates, because the two ethoxy groups of theb-ketophosphonates 202 are positioned to cause the minimumamount of steric repulsion with the aryl group on the phosphineas shown in Figure 4.

Palladium catalysts 214, bearing BINAP type ligands have beenutilized for the synthesis of various fluorinated cyclic and acyclicketophosphonates 207, 209, and 213.159a,b The researchers testedthis reaction with various fluorinating reagents (NSFI, Selectfluor,N-fluoro-4-methylpyridinium-2-sulfonate). The best results wereobtained with NSFI, which fluorinated b-ketophosphonates toafford the a-fluorinated b-ketophosphonates 207, 209, and 213in yields of 50–93% and with an enantioselectivity of 87–97% ee.The complexes with ligands (R)-DM-BINAP or (R)-DM-SEGPHOS,which form chiral enolate complexes with b-ketophosphonates,

O

P

R'

O

R

OEt

OEtF

)

207

P

'

OOEt

OEt

O

=Me (94% ee).5% ee)

PdOH2P

P OH2

2 TfO-

2 TfO-PdO P

POPd

P

P

211

212

H

H

F

s by NFSI catalyzed by the palladium complexes 211, 212.

+PhC(O) P(O)(OEt)2

Me

N

HC

X

CO2Et

2

202aX=ROCO, Ts; R=Me, Et, Ph, Bn

218

H

N

O

N

O

ZnPhTfO OTf

N

O

N

O

ZnPhPh

TfO OTf

220 221

Scheme 65. Enantioselective addition

P

O

R

PdO

R

P P

Re-face

Si-face

EtO

EtO

Figure 4. Plausible transition state model for catalytic fluorination of 202 with 206.

O

P(OEt)2

R'

O

R

F

213

OP(O)(OR)2

( )n

OP(O)(OEt)2

209 R=Me, Et, i-PrR'=H, 5,7-Me2, 6-OMe

R'

n=0, 1207, R=Ph, Et, CH=CHMe,4-ClC6H4, 4-An R'=Me, Bn

FF*

**

P

Pd

O

P

O

P(OEt)2R

R'

2TfO-

2+

PAr2

PAr2

214

P

P

=

a) Ar=Ph, (R)-BINAPb) Ar= 4-merhylphenyl, (R)-Tl-BINAPc) Ar= 3,5-dimethylphenyl, (R)-Xylyl-BINAP

Scheme 63. Catalytic enantioselective fluorination of b-ketophosphonates.

N

N

CO2Et

EtO2C

PO

P(OEt)2

R'

O

R +

202

R = Et, Ph, 4-An, 4-ClC6H4, Allyl; R' = Me, Bn

TH

+

O

P(OR)2

O

N

N

CO2Et

EtO2C

216, R = Me, Et, i-Pr

Scheme 64. Enantioselective amination of b-ketophosphon


were the most effective for a broad range of palladium catalysts.Other catalysts provided low yields and moderate enantioselectiv-ities. Organocatalytic enantioselective sulfenylations of b-ketophosphonates under similar conditions were also reported(Scheme 63).160

Amination: Kim et al. studied the enantioselective amination ofb-ketophosphonates 202, catalyzed by chiral palladium complexes211 and 212, containing BINAP ligands. The treatment ofb-ketophosphonates with diethyl azodicarboxylate (DEAD) undermild reaction conditions, afforded substituted b-ketophosphonates215 and 217 in satisfactory yields and with very good ee(Scheme 64).159,161

Jørgensen reported on the enantioselective addition ofb-ketophosphonates to imines or azodicarboxylates, catalyzed bychiral complexes of copper or zinc with bis-oxazoline ligands220–222, leading to the formation of chiral amination products.After deprotection, the corresponding optically active a-amino-b-hydroxyphosphonic acid derivatives were obtained in yields of90% and with enantioselectivities of >90% ee. The (R,R)-absoluteconfiguration of the optically active aminophosphonates wasdefined by X-ray crystal analysis (Scheme 65).162,163

The asymmetric alkylation of phosphonates and phosphine oxi-des 223 by Grignard reagents catalyzed by copper complexes withthe chiral ligands TaniaPhos 226 or 227 led to the formation of chi-ral phosphorus synthons 224 and 225 was reported(Scheme 66).164

5. Asymmetric catalysis with chiral diamines

Since Evans et al.165 discovered that prochiral alkyl(dimethyl)phosphine boranes can undergo the enantioselective deprotona-tion of one methyl group using butyllithium and (�)-sparteine,

PhC(O) P(O)(OEt)2

Me

XNH H

CO2Et20-222 (10 mol%)

ee=85-98% ee, (R,R)-219

85-98%

CH2Cl2, rt

Ph

N

O

N

O

ZnPhPh

TfO OTf

PhPh

222

of b-ketophosphonates to imines.

RR'

OP(OEt)2

O

NCO2Et

NHCO2Et

d-cat 211,212(2.5 mol %)

215, 99% ee

50-93%

F, acetone, rt

O

P(OR)2

O

NCO2Et

NHCO2Et

Pd-cat 211(2.5 mol %)

acetone, rt

217, 62-92%, 91-99% ee

ates, catalyzed by the palladium complexes 211, 212.

R

P(O)R'2Br

Alk

P(O)R'2

Me

P(O)Ph2

Alk

AlkMgBrCuX/226 (5 mol%)CH2Cl2, -80oCCH2Cl2, -80oC

R = H, Me; R = MeO, EtO, Pher to 98:2

up to 98% ee

224 223

225

RMgBr\CuX/227 (5 mol%)

R=MeR=H

Fe

NPPh2 PPh2

226, (R,R)-TaniaPhos

O

OP N

Ph

Ph

227

Scheme 66. Asymmetric alkylation of phosphine oxides 223 by Grignard reagents.


these compounds have been widely used for the synthesis of P-chirogenic borane phosphines. Lithium alkyls form chiral com-plexes 228 with sparteine and related chiral diamines, which wereinvestigated by single crystal X-ray analysis (Scheme 67).166–168

Table 6Enantioselective deprotonation of dimethylarylphosphine boranes 113 with a chiral spart

BH3

P

MeMeR

s-BuLi/ligand BH3

PMe

R

OH

PhPh

(R)-232229

Ph2CO

Ligand/R R Yield (%)

(�)-Sparteine Ph 88(�)-Sparteine o-An 81(�)-Sparteine Nphth 86(�)-Sparteine o-Tl 64(�)-Sparteine Cy 67(�)-Sparteine t-Bu 83234, R = Me Cy 77234, R = Me t-Bu 78234, R = i-Pr Ph 85234, R = i-Pr t-Bu 82

NN

Li

R

NN+ t-BuLi

228(-)-sparteine

Scheme 67. Complex of (�)-sparteine with t-butyllitium.

BH3

P

MeMeR

BH3

P

MeR

E

BH3

P

MeCH2LiR

E+

-78oC

229 230 231

228

Scheme 68. Reaction of lithium derivative 230 with various electrophiles.

Prochiral dimethylarylphosphine boranes react with a chiralsparteine–alkyllithium complex 228 to undergo enantioselectivedeprotonation of one of the methyl groups to form lithium deriva-tive 230, which reacts with electrophiles (E+) to give P-chiralcompounds 231 (Scheme 68).169–186

Chiral lithium derivatives 230 are very reactive and can be eas-ily transformed into various chiral tertiary phosphines. Lithiumalkyldimethylphosphine borane derivatives 230 are widely usedin the synthesis of chiral diphosphine ligands. For example, thereaction of intermediate chiral lithium derivative 230 withbenzophenone gives P-chirogenic phosphines 233 with satisfac-tory yields and with enantioselectivities of up to 92% ee.165,177

Enantioselective deprotonation of tertiary dimethylphosphines229 can be achieved by the action of a complex of s-BuLi with suchchiral natural diamines such as sparteine, (�)-cytisine 233177, andderivatives of cytisine 234 (Table 6).

Enantioselective deprotonation of alkydimethylphosphine bor-anes by a sec-BuLi/(�)-sparteine complex, and subsequent treat-ment of the carbanion with CO2, led to the formation ofphosphorylated carboxylic acids 236.179,186 The oxidation of 230with molecular oxygen in the presence of triethyl phosphite gavealkyl(hydroxymethyl)methylphosphine boranes 237a with91–93% ee in examples with bulky alkyl groups, and 75–81% ee

eine (or cytisine derivative)-alkyllithium complex

HN

N

O

NR'

N

H

(-)-cytisine 233 234

ee (%) Config Refs.

79 (S) 165,17783 (S) 16582 (S) 16587 (S) 16570 (S) 17776 (S) 17774 (R) 17792 (R) 17773 (R) 17790 (R) 177

BH3

P

MeR COOH

237a,b

BH3

P

MeR OR

BH3P

MeR SR'

R = Ph, t-Bu, 1-Ad, CyR' = Ph, t-Bu, o-Tl, 2-Nphth, Cy, Bn, p-NO2Ph

236

238 (n=0,1)

/(EtO)3P

BH3

P

MeCH2LiR

230

BH3

P MeR

BH3

P

MeR

R = i-Pr, t-Bu, Et3C, 1-Ad,c-C6H11, c-C5H9

235

CO2

PhSSPh O2

CuCl2

R = H (a), Ts (b)

BH3

NaSR'

Scheme 69. Reactions of lithium derivative of dimethylarylphosphine boranes 230with various electrophiles.

BH BHBH


in the case of cyclohexyl or phenyl groups.178,181 The reduction ofthe carboxyl group of 236 with borane provided the (R)-tosylates(or mesylates) 237b with 90% ee and excellent yields. P-Chiralphosphine-sulfide 238 were prepared by reaction of (R)-tosylates237b with sodium thiolates in DMFA at room temperature or bysuccessive reaction of 230 with phenyl disulfide179,180 The homo-coupling of compounds 230 with copper chloride led to the forma-tion of diphosphines 235.174,181,182,189 Genet reported that anincrease in the amount of chiral diamine augments the enantiose-lectivity of the reaction (Scheme 69).181

Imamoto174 has developed a number of methods for the prepa-ration of C2-symmetric bis-phosphines 239, containing alkylgroups at phosphorus (BisP⁄ ligands). These compounds representelectron-rich ligands, which were used in rhodium catalyzedasymmetric hydrogenation with high enantioselectivity.183 Enan-tioselective deprotonation of dimethylarylphosphine borane 229with subsequent homocoupling with copper(II)pivalate Cu(OPiv)2

led to the formation of C2-symmetric products 239 with 96–99%ee (Scheme 70).165,174

The lithium derivative of alkyldimethylphosphine borane 230was used to prepare diphosphine ligands of various struc-tures,188–204 including, P-chiral ethylenediphosphines 240, bearinga ferrocene group,189 bis-phosphine boranes 3 (BisP⁄),186phosphol-anes (TangPhos 15), and others.184,194 Complexes of rutheniumwith bis-phosphines 3 were used as catalysts for the asymmetric

P

Me

(Sp)-240

FeP

MeR P Me

t-Bu

R=Me, t-Bu, Et3C, Ad, Cp, Cy3 (BisP*), 98 % ee

Scheme 71. P-chiral asymmetric diphosphines, prep

BH3

PMe

MeAr

s-BuLi/LBH3

P

MeAr P

Ar

BH3

Me

(S,S)-239L = (-)-sparteine

+ Meso-

229

Cu(OPiv)2

Et2O, -78- -20oC

Scheme 70. Synthesis of C2-symmetric diphosphine borohydrides 239.

hydrogenation of (acylamino)acryles with enantioselectivities of99.9% ee.174,175 The application of chiral carbanions 230 allowedthe development of synthetic approaches to P-chiral asymmetricdiphosphines 241 (Scheme 71).183

P-Chiral diphosphines with a methylene bridge and bulky alkylgroups on each phosphorus atom 242 (MiniPHOS ligands) were syn-thesized, starting from the chiral lithium derivative 230. The subse-quent reaction with RPCl2, methylmagnesium bromide and boraneafforded the diphosphine boranes (R,R)-242 and their meso-isomer.The purification of the reaction mixture by crystallization and deb-oration resulted in pure MiniPHOS in a yield of 13–28% and with99% ee (Scheme 72).175,176 Improved synthetic routes to methy-lene-bridged P-chiral diphosphine ligands via tertiary phosphine–boranes 242 without the formation of meso-isomers has also beenreported.176 The use of (�)-sparteine or a (+)-sparteine surrogateas chiral catalysts facilitates access to P-stereogenic phosphineswith the opposite configuration.190 This method was exemplifiedby the catalytic asymmetric synthesis of each enantiomer of precur-sors to Mini-PHOS 243,201 trichickenfootphos 244 and t-Bu-Qui-noxP⁄ 245. Ligand 245 exhibited very good asymmetric inductionin the Pd-catalyzed asymmetric allylic substitutions of 1,3-diphe-nyl-2-propenyl acetate (up to 98.7% ee) and in Ru-catalyzed asym-metric hydrogenations of ketones (up to 99.9% ee) (Scheme 72).191

Convenient methods for the synthesis of P-chiral tertiary phos-phines were developed by catalytic deprotonation of tertiary dim-ethylphosphine sulfides. For example, selective deprotonation of246 with the complex n-BuLi/(�)-sparteine and subsequentreaction with CO2 gave acid 247 with 72%.ee. Crystallization fromethanol led to the enantiomerically pure (R,R)-247. The subsequentcondensation of 247 with a chiral amino alcohol and desulfuriza-tion of 248 with Raney Ni afforded the phospholane-oxazoline(S,S)-249 in high yield (Scheme 73).187

Livinghouse et al.203 reported that the phosphide obtained bytreatment of tert-butylphenylphosphine borane 250 with thes-BuLi/(�)-sparteine complex, can be dynamically resolved, andthey observed that the enantioselectivity depends on the timeand temperature. It was found that stirring the suspended (�)-spar-teine-lithium complex of 250 for one hour at room temperatureprior to alkylation resulted in an increase in ee up to 95% in the case

P

Ph

P

Ph

(R,R)-241, 99% ee

PMe

Fe

ared by starting from lithium derivatives 230.

3

P

MeCH2LiR

3

PMe

R

3

P

MeRMeMgBr

BH3 THF

P Me

R

P

MeR

1) CF3SO3H2) KOH

242, 99% ee

243

230

Pt-Bu

t-Bu

Pt-Bu

Me Pt-But-BuP

N

N

Me

Me244245

R = i-Pr, t-Bu, Ph, c-C6H11

RPCl2

Scheme 72. Synthesis of MiniPHOS ligands, starting from chiral lithium derivative230.

PS t-Bu

BuLi/sparteineCO2

t-BuP

S

H

COOH

rac-246 (R,R)-247, 71% ee

t-Bu

N

O

P

S

H

R N

O

P

H

R

H2N

HO

REDC/HOBt

248, 70% 249

R=i-Pr, t-Bu, Ph, Bn, i-Bu

Raney Ni

-78oC

DMF, 70oC;MsCl, CH2Cl2

MeCN

80--95%t-Bu

Scheme 73. Synthesis of Mini-PHOS ligandes.


of monodentate phosphines, and to diastereoisomeric ratios of 22:1in the case of diastereoisomeric bidentate phosphines. The subse-quent reaction with ((CH2)nX)2 led to the formation of enantiome-rically pure diphosphines 252 (Scheme 74).

The N-POP-directed asymmetric deprotonation of benzylicamines using BuLi/(�)-sparteine complex provides an efficientmethod for the synthesis of chiral NC-a- and NC-a,a-derivativeswith total selectivity with respect to competing allylic and ortho-phenyl lithiation. The reaction represents a convenient methodfor the synthesis of chiral N-POP protected nitrogen heterocycles(Scheme 75).204

6. Asymmetric addition of phosphorus nucleophiles to multiplebonds

The rapid development of the chemistry and biology of phos-phonic acid derivatives over the last decade has been determinedby the development of highly effective methods for their prepara-tion. Chiral phosphonic acids can be prepared by various routes.The main method for the synthesis of phosphonates is the phos-phonylation of carbonyl compounds, mainly via the phospha-aldol

O

NPh2P

Ph

Ph

N

O

NPh2P

LBuLi, sparteine

-90oC, toluene

E=MeI, MeOTf, Me3SnCl, PhCHO, EtOCOCH2Br253

O

NPh2P

Ph

O

NPh2P

Ph

BuLi, sparteine

(R)-256, er

CH2=CHCH2Br

255

Scheme 75. Synthesis of chiral N-POP-prot

H3B

PH

t-BuPh

s-BuLi/(-)-sparteine

-78oC +20oC -78oC

BH3

PLi

t-BuPh

251rac-250

Scheme 74. Dynamic resolution with

reaction, phospha-Mannich reaction or phospha-Michael reac-tion.5,205–208

6.1. Phospha-aldol reaction

Two types of phospho-aldol reaction are possible: (a) the reac-tion of dialkylphosphites with carbonyl reagents proceeding in thepresence of a base catalyst, which shifts the P(O)H ¡ P–OH tauto-meric equilibrium toward the H(O)-form; and (b) the additionreaction of phosphoric acid triesters to carbonyl compounds pro-ceeding in the presence of proton donating reagents (phenol, car-boxylic acids, hydrochlorides of aniline, etc.) or Lewis acids. Theaddition reaction of phosphoric acid esters with carbonyl com-pounds (the Abramov reaction) involves two steps: the first stepis the formation of a P–C bond while the second step is the cleav-age of the ester function with the formation of a phosphonylgroup.206,209 In the case of chiral catalysts, the asymmetric versionof the Abramov reaction is possible.207–210

The asymmetric phospho-aldol reaction has been studiedintensively, because a-hydroxyphospohonates are important com-ponents of enzyme inhibitors. The preparation of hydroxyphospho-nates also used catalytic methods including metallocomplexcatalysis, organo- and biocatalysis, leading to the formation of func-tionalized molecules with high enantiomeric purity and, thereforehaving high potential in synthetic chemistry (Scheme 76).206–211

Shibasaki described the first enantioselective hydroxyphosphonyla-tion of aldehydes, catalyzed by the heterobimetallic complexes ALB260 [Al,Li(binaphthoxyd)2] and LLB 261.212–215 Shibuya used Sharp-less catalyst 262216,217 and ALB.218,219 Spilling has tested complexesof chiral diols with Ti(Oi-Pr)4.220 The best results were obtained inthe reaction of dimethylphosphite with cinnamaldehyde, catalyzedby a complex of titanium isopropoxide with (S,S)-cyclohexanediol263. Qian obtained analogous results (35–74% ee) in the Abramov reac-tion catalyzed by lanthanum complexes bearing BINOL ligands.221

These results have already been reviewed (Scheme 76).5,207

Nakajima reported on the asymmetric phospho-aldol reactioncatalyzed by transition metal complexes bearing the chiral BINAPOligand 267. The BINAPO ligand represents a weak Lewis base,

N

Ph

i

Ph

O

NPh2P

PhE

PhE

80-97%

254, de=80-99%

O

NPh2P

Ph

Grubb's catalyst

98%

(R)-257, er=75:25=75:25

ected nitrogene heterocycles 254, 257.

-78oC

X X

P PBH3

t-Bu

H3B

t-Bu Ph

Ph

252n=3-7

n

n

the sec-butyl/sparteine-complex.

PRO

HORO

R"

O-

H PRO

ORO

R"

OHH

R=MeO, EtO; ArO; R'=H, Alk, Me3Si259

+

Cat

Cat = Bronsted base or Lewis acid

(RO)2POHRCH=O

258

*

O

O

O

OAl

Li+

-

260, ALB

O

OTi

i-PrO

i-PrO

O

O

O

OLn

Li+

-

261, LLB

Li+

Cat=

O

OTi

i-PrO

i-PrO

CO2i-Pr

CO2i-Pr

262 263

Scheme 76. Asymmetric catalytic phospho-aldol reaction.


which together with silicon tetrachloride and a tertiary amine,catalyzes the enantioselective phosphonylation of aldehydes withtrialkylphosphites in high yields and with moderate enantioselc-tivities. The catalytic activity of BINAPO has been tested on severalaldehydes, mostly containing aromatic substituents.222,223 Thereaction proceeded easily at low temperature in dichloromethanesolution and gave the enantiomerically enriched hydroxyphospho-nates 259 (Scheme 77).

(RO)2POH +O

OO(RO)2P

(S)- or (R)-260

(R)-265

toluene or THF20oC

Scheme 78. Double and triple asymmetric

(EtO)3P + R'CH=O PO R'

OHH

EtOEtO

CH2Cl2, -78oC

P(O)Ph2

P(O)Ph2

264, (S)-BINAPO

(S)-BINAPO

263

SiCl4, i-Pr2NEt

Scheme 77. BINAPO catalysis of the phospho-aldol reaction.

The strategy for the synergistic activation by two or severalreaction centers represents a convenient approach to raise the ste-reoselectivity from asymmetric catalysis. Double and threefoldasymmetric induction has been applied to increase the stereoselec-tivity of phospha-aldol reactions. Double stereoselectivity wasachieved in the case of reaction of chiral di(1R,2S,5R)-menthylphosphite with chiral 2,3-D-isopropylidene-(R)-glyceraldehyde265. The reaction of glyceraldehyde with dimenthylphosphite inthe presence of chiral (R)-ALB catalyst 260, proceeded under thestereochemical control of three chiral inductors, Compounds 266were obtained with 95% ee after recrystallization (Scheme 78).224

Fen et al. proposed the bifunctional chiral Al(III)–BINOL complexfor the effective enantioselective hydrophosphonylation of alde-hydes. A number of aromatic, heteroaromatic, a,b-unsaturated,and aliphatic aldehydes were phosphonylated in the presence ofthis catalyst with the formation of a-hydroxyphosphonates 259in yields of up to 99% and with enantioselectivities of up to 87%ee under mild reaction conditions shown (0 �C) (Scheme 79).225

The development of bifunctional catalysts of BINOL derivativesand cinchona alkaloids in combination with Ti(Oi-Pr)4 for theasymmetric hydrophosphonylation of aldehydes has beenreported. The chiral Lewis base (cinchona alkaloid) of the bifunc-tional catalyst co-ordinates to the central metal of a chiral Lewisacid (BINOL–Ti complex), with the formation of an organometalliccomplex. In comparison with the usual bifunctional catalysts in

O

O

HO

(1R,2R)-266

OH

OH

HO

(1R,2R)-267

(O) (HO)2P(O)

induction of phospho-aldol reactions.

(EtO)2P(O)H + RCH=OP

O R

OHEtOEtO

10mol% Et2AlCl, 10 mol% 268

10 mg 3 Å MS, THF, 0oC259

* H

OH

OH

N

N

R"

R"

Ph

Ph

R" = H (a), Me (b)268

Scheme 79. Bifunctional chiral Al(III)/268 catalyst for the enantioselective hydro-phosphonylation of aldehydes.

N

H

N

X

O

O

X

TiO

RO P

O

OR

HPrO

O

R

H

Si-faceattacked

Figure 5. Coordination of the asymmetric induction of the chiral ligand, metal-ion,and substrate.

OH

OH

X

X

OH

OH

X = H (a), I (b), 3,5-(CF3)2C6H3 (c),2,4,5-Me3C6H2 (d), 9-phenanthryl (e)

271a-e 272

273 = cinchonidine, 274 = quinine275 = cinchonine, 276 = quinidine

N

N

HO

H

Y

N

N

OH

H

Y

Scheme 80. Catalysts for the phospha-aldol reaction.

Table 7Double asymmetric catalysis of phospha-aldol reactions initiated by BINOL-quinine/Ti(Oi-Pr)4

(MeO)2P(O)H + RCH=O P

O R

OH

H

MeO

MeOm-xylene, -20oC

(R)-271b/273a/Ti(Oi-Pr)4 (2.5 mol%)

270a269

Entry R t (�C) Yields (%) ee (%)

1 Ph 6 92 942 3-Tl 8 90 953 4-Tl 8 92 944 2-An 8 95 965 2-ClC6H4 4 99 906 4-ClC6H4 8 87 907 4-NO2C6H4 4 99 908 1-Nphth 6 97 >999 2-Nphth 6 97 >9910 PhCH2CH2 12 96 9211 Cy 18 93 9212 n-Oct 12 98 9413 i-Pr 24 90 94


which Lewis acid/Lewis base (LA/LB) exists in one moleculethrough covalent bonds, in this case there is a coordination ofasymmetric induction of the chiral ligand, a metal-ion, and sub-strate (Fig. 5), that provides the high efficiency of the catalyst, that

is, the activity and enantioselectivity of the catalyst were raised(Scheme 80 and Table 7).226

Optically active aluminum-salen complexes 278 catalyze theenantioselective hydrophosphonylation of aldehydes to yield thecorresponding a-hydroxyphosphonates.227–235

Kee et al.231–234 have reported that the hydrophosphonylationof aromatic aldehydes with diorgano-H-phosphonates, catalyzedby Al(salen) and Al(salen) complexes, containing cyclohexandi-amine substituents, passed with moderate enantioselectivities upto 61% ee, X-ray analysis of Al(salen) complexes showed that theypossess a di-m-hydroxo structure and that the salen ligand occu-pies the cis-b-conformation. Katsuki et al.228,229 reported that theaddition of potassium carbonate significantly enhanced thereaction rate of the Al(salen)-catalyzed asymmetric hydrophos-phonylation of aldehydes with dimethyl phosphonate. The enanti-oselectivity of hydrophosphonylation increased to 93–98% ee evenif the catalyst loadings were reduced (Scheme 81).

Chemists have studied the mechanism of hydrophosphonyla-tion of dimethyl phosphite with benzaldehyde catalyzed by theAl(salen) complex, using density functional theory (DFT) and ONI-OM methods, and came to a conclusion that the stereochemistry ofthe reaction catalyzed by a chiral Al(salen) complex was controlledby steric repulsion between the ortho t-Bu groups of the ligand anddimethylphosphite, as well as the coordination mode of thedimethylphosphite to the catalyst (Fig. 6). The high enantioselec-tivity was explained by the unique structure of the complex, whichhas a deformed trigonal-bipyramidal configuration allowing thesalen ligand to occupy a cisoid position in which the chiral aminogroup is located close to the aluminum atom.231 The replacementof an achiral cyclohexyl group in complex 278 with a chiral (R)-binaphthyl, increasing the molecular asymmetry of catalyst 279,increased the enantioselectivities of the reaction (Table 8).229,230

Katsuki et al.227–230 studied in detail chiral, trigonal-pyramidalmetal (salen) complexes 279a–i. Complexes 279a,b, containingcobalt were inactive. At the same time, the aluminum complexes279c–i catalyzed the enantioselective hydrophosphonylation ofdimethylphosphite with various aldehydes. The complexes 279possessing tert-butyl group in the C3 and C30 positions catalyzedthe reaction in good yields and with good enantioselectivity.Substituents in the C5 and C50 positions also influenced yieldsand enantioselectivities, though to a lesser degree. Complexes279 containing Br at C3, were the most effective catalysts from

Table 9Asymmetric hydrophosphonylation of aldehydes 277 with catalysts 279c–i230

Entry 279c–i R00 Time (d) Yield (%) ee (%) Config

1 c p-ClC6H4 4 29 11 (R)2 d p-ClC6H4 4 86 76 (R)3 e p-ClC6H4 3 100 65 (R)4 f p-ClC6H4 5 83 68 (R)5 g p-ClC6H4 3 78 84 (R)6 h p-ClC6H4 3 69 78 (R)7 i p-ClC6H4 3 68 83 (R)8 g Ph 5 62 79 (R)9 g p-FC6H4 5 69 82 —10 g p-An 2 55 79 (R)11 g p-Tl 2 82 80 (R)12 g o-FC6H4 2 69 80 —13 g o-Tl 2 79 75 —14 g PhCH2CH2 1 71 83 —15 g c-Hex 1 86 86 —16 g n-Hex 2 79 86 —17 g (E)-PhCH=CH 2 82 64 (R)

(MeO)2P(O)H + R"CH=O (MeO)2(O)P

R"

OHCat (10mol%)

THF, -15oC, 48 h

270a

t-Bu

R

O

N

t-Bu

R

O

NAl

ClCat=

278a,b R = t-Bu (a), Et2MeC (b)

R

R'

O

N

R

R'

O

NM

X

279a-i

269 277*

Scheme 81. Hydrophosphonylation of aldehydes with dimethyl phosphonate catalyzed by chiral Al(salen)-complexes.

O

Al

O

NN

O O

P

H

H

P OOMe

MeO

OMeMeO

t-Bu

t-Bu

t-Bu

t-Bu

Energy -Favored

β1-TS3/4-(S)

Figure 6. Optimized structures of the transition states in the deprotonation ofDMHP in the actual system.

Table 8Asymmetric hydrophosphonylation of aldehydes 277 with catalyst 278a

Entry R R0 Yield (%) ee (%) Config Refs.

1 p-NO2C6H4 t-Bu 95 94 (S) 2272 p-ClC6H4 t-Bu 88 88 (S) 2273 p-An t-Bu 87 81 (S) 2274 o-ClC6H4 t-Bu 96 91 — 2275 (E)-PhCH@CH t-Bu 77 83 (S) 2276 PhCH2CH2 t-Bu 94 91 — 2277 i-Pr t-Bu 89 89 — 2278 Et t-Bu 61 89 (S) 2279 p-NO2C6H4 Et2MeC 98 98 — 228,22910 p-ClC6H4 Et2MeC 95 98 — 228,22911 o-ClCC6H4 Et2MeC 94 97 — 228,22912 (E)-PhCH@CH Et2MeC 97 95 — 228,22913 PhCH2CH2 Et2MeC 93 97 — 228,229


the viewpoint of enantioselectivity (84% ee). Electron donatinggroups in the para-position to the OH group, and bulky ortho-sub-stituents R0 (t-Bu, Ad, Et2MeC) increased the enantioselectivity ofreaction (Scheme 81, Table 9).

Chiral complexes of Al(III) with tridentate Schiff bases 282a–ecatalyzed the asymmetric hydrophosphonylation of aldehydesand trifluoromethylketone without any side reactions. The chiralligand influenced the enantioselectivity and the derivatives of L-valinol catalyzed the reaction of dialkylphosphites with variousalkyl, arylaldehydes, and trifluoromethylketones with higherenantioselectivity, than other ligands.237–240 Ligands with largeortho-substituents on the phenol group, such as adamantyl, alsoraised enantioselectivities (to 85% ee). The reaction with acetophe-none proceeded with low enantioselectivity, but in high yields.238

Counterions of complexes 283/Et2AlX where X = Cl, Et, i-PrO alsoinfluenced the reaction enantioselectivity; the highest enantiose-lectivities were attained with Et2AlCl (Schemes 82 and 83).

Yamamoto et al.236 synthesized a-hydroxy- and a-aminophos-phonates in high yields and with high enantioselectivity usingthe bis(8-chinolinato) (TBOx)Al complex 285 (0.5–1 mol %). Underthe optimized reaction conditions, the electron-rich aldehydeswere more reactive and more selective than electron deficientaromatic aldehydes. Aliphatic aldehydes also reacted as well withsatisfactory selectivity. All reactions proceeded very rapidly, inhigh yields and enantioselectivities. Reducing the catalyst loadingto 0.5 mol % did not influence the enantioselectivity or yield. Thebest results were obtained with phosphites containing trifluoro-ethyl groups (Scheme 84).

Over the last few years, several articles have been devoted tothe organocatalysis of the phosphoaldol reaction, initiated by basesof natural origin.242–248 For example Wynberg et al.244,245 reportedthat quinine catalyzes the enantioselective phosphor-aldolreaction of dialkyl phosphites with ortho-nitrobenzaldehyde withmoderate enantioselectivities. The stereoselectivity of the reactionincreased, when dimenthyl phosphite was reacted with aldehydes,owing to double asymmetric induction (Scheme 85).246,247

In 2009 Ooi et al.242 proposed trisaminoiminophosphorane 287,generated in situ from chiral P-spiro-tetraaminophosphoniumsalts and potassium tert-butoxide, as a very effective catalyst forphosphaaldol reactions. Within the catalysts studied, iminophos-phoranes 287, containing electronodonating substituents on a

(MeO)2(O)P

Ar

OH

CF2X282a / Et2AlCl, 10 mol%+

O

CF2XAr

yield up to 98%, 90% ee

t-Bu

Ad

OH

NH OH

X = F, Cl

Ar = XC6H4, X = H, 4-Me, 4-Br, 4-Cl, 4-F

283

281

R

R'

OH

N OH

282a, R = R' = t-Bu282b, R = R' = H282c, R = H, R' = t-Bu282d, R = H, R' = NO282e, R = Ad, R' = t-Bu

282a-e

280

(MeO)2P(O)HTHF, -15oC *

2

Scheme 82. Asymmetric hydrophosphonylation of aldehydes catalyzed by chiral complexes 282a–e.

(EtO)2P(O)H + RCH=O P

O R

OHEtO

EtO283/Et2AlCl, 10 mol%

CH2Cl2/THF, -15oC, 60h

263

H*

Scheme 83. Abramov reaction catalyzed by complexes 283/Et2AlCl.

(RO)2P(O)H

O

H

OH

PRO

ORO H

OH

PRO

ORO H

X

X

X

+

(R )-286 a-e

(S)-286 a-e

Mnt=

II

I

R = (1R,2S,5R)-Mnt, X = 2-NO2 (a); R = (1R,2S,5R)-Mnt, X = 2-MeO (b); R = Me, X = H (c);R = Me, X = 2-MeO (d); R = Me, X=2-NO2 (e); I = QN, CN, II = QND, CND, Cat=Quinine

Scheme 85. Phosphor-aldol reaction of dialkylphosphites with aldehydes catalyzedby cinchona alkaloids.


benzene ring showed the highest catalytic activity even whenreduced to 1 mol % and at �98 �C. The reaction occurred withaliphatic, heteroaromatic, and aromatic aldehydes to give thecorresponding a-hydroxyphosphonates in high yields and withenantioselectivities of up to 99% ee. The authors came to aconclusion that the reaction proceeds through the formation ofhighly active dimethyl phosphite salt with a chiral

(CF3CH2O)2P(O)H + RCH=O

F3CC

F3CCH

(R)-279 (1 mol%)hexane, r.t.

u

up to 96%

Scheme 84. Synthesis of a-hydroxy- and a-aminophosphon

tetraaminophosphonium cation which is responsible for thestereochemistry of the addition reaction (Scheme 86).242

The reaction between aromatic ketoesters and dimethyl phos-phite, catalyzed by cinchona-derived thiourea organocatalyst 288led to the formation of hydroxyphosphonates 288 and 289 withgood yields and enantioselectivities. These organocatalysts actedas bifunctional promoters, which can activate electrophiles (react-ing as a hydrogen-bond donor) and nucleophiles (reacting as aBrønsted base). The best results were obtained with cinchonidinethiourea organocatalysts. In the transition state D, the ketoester

P

O R

OHH2O

2O H

p to 97% ee284

N t-BuO

Al

N t-BuO

Cl

285

(R)

ates using the bis(8-chinolinato) (TBOx)Al complex 285.

+R H

OR

OH

(MeO)2(O)PCat (5 mol%)/THF/-98oC

90-99%270,91-99% ee

(MeO)2P(O)H

269

Cat=P

NH

HN

N

HN

ArAr

H

HAr

Ar+

Ar =Ph (a), p-CF3C6H4 (b), p-Tl (c), p-An (d)

287a-d

Cl-

Scheme 86. Abramov reaction catalyzed by triaminoiminophosphorane 287.

(PhO)2P(O)HN

O

O

R2

+N

HO

O

R2

P(O)(OR)2

274 (20mol%)

0oC, CH2Cl2

290

R1 R1

*

Scheme 88. The phospho-aldol reaction of diphenyl phosphite with N-alkylatedisatins catalyzed by quinine 274.


is activated by a hydrogen bond with the thiourea fragment. Inaddition, because of presence of a quinuclidine nitrogen atom,the corresponding phosphonate–phosphite equilibrium is shiftedtoward the phosphite form (Scheme 87).240,248

The phospho-aldol reaction of diphenylphosphite withN-alkylated isatins catalyzed with quinine 274 and quinidine 276proceeded with satisfactory enantioselectivity. By using thismethod, a number of N-alkylated isatin derivatives 290 were pre-pared in good yields (up to 99%) and with moderate enantioselec-tivities (average 40–67% ee). However the absolute configurationsof compounds 290 were not defined (Scheme 88).243

The studies of Kee249 and Wiemer250 dedicated to the catalytichydrophosphonylation of aldehydes should be also mentioned. Aseries of Lewis bases were screened for Abramov-type phosphineadditions to aldehydes. A phosphine oxide aziridinyl phosphonatecatalyzed the Abramov reaction in 96% yield and with 42% ee.251

(MeO)2P(O)HO

R

CO2MeP

OMeO

MeO

+

(S)-289, 88-(R)-289, 80

288

269

Scheme 87. Reaction of ketoesters with dimethylp

6.2. Phospha-Mannich reaction

The synthesis of enantioenriched a-aminophosphonates andaminophosphonic acids by means of asymmetric catalytic hydro-phosphonylation of imines or an asymmetric reaction has attractedconstant interest.252–271 A special case of the phospha-Mannich isthe Kabachnik–Fields reaction representing a one-pot, three-component procedure, which includes carbonyl compound, amine,and dialkyl phosphite.252,253 For asymmetric aminophosphonyla-tion, catalysts such as chiral metal complexes, LLB,254 chiral thio-ureas, BINOL phosphoric acid and quinine254 were usedsuccessfully. Cherkasov256 investigated the kinetics and the reactionmechanism. Shibasaki et al.255 reported examples of asymmetricMannich reactions. The asymmetric addition of dimethyl phosphiteto imines catalyzed by LLB, LPB, and LSB bimetallic complexesresulted in the formation of aminophosphonates with 50–96% ee.Martens et al.257 described the asymmetric addition of dimethyl-phosphite to thiazolines catalyzed by heterobimetallic lanthanum-potassium-binol complex (R)-Ln-PB, where Ln = lanthanoid metal,P = potassium, B = (R)-bi-2-naphthol, leading to the formation of(S)-291 with 98% ee and in 98% yield (Scheme 89).

Feng261,263 reported that the N,N0-dioxide (292)/Sc(III) complexcatalyzes three-component Kabachnik–Fields reactions, yielding

OHR

CO2Me N

N

NH

NHPhSH

91%ee-90%ee 288

*

N

O

N

NH

HS

NH

R\

O

O

R\

H O-P(OMe)2

D

hosphite catalyzed by cinchona-thiourea 288.

N

S MeMe

MeMe HN

SMe Me

Me Me

P(O)(OMe)2

(R)-LnPB (5-20mol%)

(S)-291

(MeO)2POH

THF/toluene 1:7, 50o C

Scheme 89. Asymmetric addition of dimethylphosphite to thiazolines catalyzed byLnPB.


the corresponding a-aminophosphonates with good yields andenantioselectivities of up to 87% ee (Scheme 90).

List et al.262 described an attractive example of the asymmetricKabachnik–Fields reaction. The reaction of three-component mix-ture consisting of an aldehyde, P-anisidine, and di-3-pentyl phos-phite, catalyzed by chiral atropoisomeric acid 293 (p-anthracenylreplaced analogue TRIP) led to the formation of aminophospho-nates 294 in high yield, good diastereoselectivity, and enantiose-lectivity. Some derivatives of L-proline also effectively catalyze

++

295

dr=19:1, er=95:5

R

ArCHOH

NH2

P(O)(OH)2HAr

R

H

NH2

OMe

Me3SiBr

(NH4)2Ce(NO3)6

(t-C5H11)2P(O)H

Scheme 91. Catalytic asymmetric three-c

+NH2

OH

HN

HO

P(O)(OPh)2R292/Sc(II)THF, -20oC

N+

NH

O

O

Ar

N+

NH

O

O

Ar

292, Ar = 2,6-i-Pr3C6H3

(PhO)2P(O)H *RCHO +

R = Ph, 4-Tl, 3-An, 4-An, 4-PhC6H4, 2-Nphth,4-F-C6H4,4-ClC6H4, 4-NO2C6H4,

79-96%

81-87% ee

Scheme 90. Asymmetric tricomponent Kabachnik–Fields reactions catalyzed bycomplex (292)/Sc(III).

the asymmetric Kabachnik–Fields reaction.262b The reaction pro-ceeded by dynamic kinetic resolution and was catalyzed by chiralphosphorous acid 293. It was found that bulky alkyl substituentseffect the stereoselectivity of reaction. The highest levels of stere-oselectivity were attained in the case of aldehydes containingbranched alkyl substituents (isopropyl, cyclopentyl, and cyclo-hexyl). On the contrary, aldehydes containing R = methyl and ethyl,reacted with low stereoselectivity (Scheme 91).

Akiyama et al.264 studied the reaction of imines with dialkylphosphites, catalyzed by the chiral Brønsted acid 3,30-bis[3,5-di(trifluoromethyl)phenyl)-1,10-8-binaphthyl-2,20-diyl 298.The reaction led to the formation of a-aminophosphonates 297with moderate yields and good enantioselectivities of up to 90%ee (Scheme 92). The authors proposed a nine-membered transitionstate E to explain the stereoselectivity of reaction. The authorscame to the conclusion that phosphoric acid works as a bifunc-tional chiral Brønsted acid bearing both Brønsted acidic andBrønsted basic sites. The phosphate probably plays 2 roles: (a)the phosphoric acid hydrogen activates the imine as a Brønstedacid; (b) phosphoryl oxygen activates the nucleophile by coordi-nating with the hydrogen of the phosphite as a Brønsted base, thuspromoting Re-facial attack to the imine and increasing the enanti-oselectivity by a proximity effect.266 The substrate structure is theimportant factor influencing the result of reaction, because thereaction of diisopropylphosphite with aldimines, containing elec-tron accepting groups in the ortho-position of the phenyl ring(CF3, NO2, Cl) proceeded with the highest enantioselectivities(Table 10).

Yamanaka and Hirata have performed DFT theoretical studies(BHandHLYP/6-31G⁄, Gaussian 98 package) on the mechanism ofthis reaction. The calculations confirmed that the reaction pro-ceeded via the nine-membered zwitterionic transition state (TS)with the chiral phosphoric acid, where the aldimine and phosphitecould be activated by the Brønsted acidic site and Lewis basic site,

O

OP(O)OH

i-Pr

i-Pr 9-Anth

i-Pr

i-Pr

9-Anth

HN

P(O)(OC5H11-t)2HAr

R

OMe

H

293

293

294

omponent Kabachnik–Fields reaction.


respectively. The Si-facial attacking TS was less favored by the ste-ric repulsion of the 3,30-aryl groups on the chiral phosphoric acidwith the bulky phosphite. When using the aldimine derived frombenzaldehyde, the Re-facial attacking TS is destabilized to decreasethe enantioselectivity in agreement with experiment.265

Nhaduri and Li267 synthesized fluorinated cinnamaldehydimines296 and aminophosphonates 297 possessing antibacterial proper-ties. They confirmed that the reaction of imines 296 with dialkylphosphites in the presence of chiral acids 298 in xylene proceedswith high enantioselectivity to give the a-aminophosphonates 297with >90% ee and yields of 30–65%. The asymmetric catalysis ofphospha-Mannich reaction with the magnesium salt of chiral BINOLphosphonic acid was reported.268 Martens et al.257,258 havedescribed the diastereoselective hydrophosphonylation of cyclicimines, using heterobimetallic lanthanum BINOL complexes as chi-ral inductors with a satisfactory diastereoselectivity (dr � 95:5). TheBF3-activated addition of binaphthol-phosphite to 3-thiazolineyielded almost exclusively 4-thiazolidinylphosphonates the struc-tures of which were proven by X-ray crystal analysis. Theoreticalstudies of the mechanism of the enantioselective reaction by atwo-layer ONIOM (B3LYP/6-31G (d)/AM1) method showed thatthe reaction proceeds in two-steps, involving proton-transfer and

Table 10Asymmetric synthesis of a-aminophosphonates 297

Entry X R

1 Ph MeO2 PhCH@CH MeO3 o-Tl MeO4 o-NO2C6H4 MeO5 PhCH@CH MeO6 p-CH3C6H4CH@CH MeO7 p-ClC6H4CH@CH MeO8 o-CH3C6H4CH@CH MeO9 o-ClC6H4CH@@CH MeO10 o-NO2C6H4CH@CH MeO11 o-CF3C6H4CH@CH MeO12 1-naphthyl-CH@CH MeO13 m-CF3C6H4 PhCH@CH14 p-CF3C6H4 PhCH@CH15 m-CF3C6H4 PhCH@CH16 p-CF3C6H4 PhCH@CH17 m-CF3C6H4 p-FC6H4CH@CH18 m-CF3C6H4 p-FC6H4CH@CH

N

X

R

+ (R'O)2P(O)H m-xy

R '= Et, i-Pr, Ph; X = H, F, OMeR = Me, Ph, 4-FC6H4, 3-FC6H4, 4-CF3C6H4, 3-C

296

70-

O

O

P

O

OH

CF3

CF3

CF3

CF3298

Scheme 92. Reaction of imines with dialkyl phosp

nucleophilic addition, which is the stereo-controlling step. Theenergy differences between Si-facial attack and Re-facial attack aresignificant for the hydrophosphonylation of the aldimine.266

Katsuki described a one pot Kabachnik–Fields reaction catalyzedby salen complex 278 that proceeded with satisfactory enantiose-lectivities (Scheme 93).241 Optically active aluminum (salen) com-plexes 278 effectively catalyze the hydrophosphonylation ofaldimines to afford the corresponding a-aminophosphonates 299and 301 with high enantioselectivity.241 The highest enantioselec-tivities were attained with alkynyl or alkenylaldimines, preparedfrom phenylpropargylaldehyde and diphenylmethylamine withaldimines, containing an R = 4-methoxy-3-methylphenyl group atnitrogen. The high catalytic activity of the complex was attributedto its unique structure: the distorted trigonal bipyramidal configu-ration allowed the salen ligand to take a cis-like structure whereinthe chiral amino group was located close to the metal center(Scheme 94).

Sterically constrained 8-aluminum bis-(TBOx) complex 305 dis-played high enantioselectivity in the reaction of dialkyl phosphiteswith aldimines. The hydrophosphonylation of aldimines,substituted with various groups and catalyzed by complex 305proceeded with high enantioselectivity even when the catalyst

R0 Yield (%) ee (%) Refs.

Et 99 43 264Et 70 73 264i-Pr 76 69 264i-Pr 72 77 264i-Pr 92 84 264i-Pr 88 86 264i-Pr 97 83 264i-Pr 80 82 264i-Pr 82 87 264i-Pr 92 88 264i-Pr 86 90 264i-Pr 76 81 264Et 64 83.6 267n-Pr 65 82.8 267n-Pr 68 88.8 267n-Bu 71 83.7 267n-Bu 73 90.6 267C2H4OEt 70 84.6 267

HN

R

X

P(O)(OR')2

lene, rt298

297, 52-90%ee

F3C6H4

99%

O

OP

O

O

CF3

CF3

CF3

CF3

H

H

OP

OR

OR

N

Ar

H

Ar

E

hites, catalyzed by chiral Brønsted acid 298.

P

O

NHR'MeO

MeO

R

H(R)-278a,10 mol%

299a-h

O

R HR'NH2, MS 4Å

THF, r.t., 3-4 h

(MeO)2P(O)H,

THF, -15oC, 24h

R' = 3-Me(4-MeO)C6H3, CHPh2

Scheme 93. The asymmetric hydrophosphonylation of aldimines.


loading was decreased to 0.5–1 mol %. The enantioselectivity of thereaction depended on the size of the substituent at the nitrogenatom. Electron rich aldimines showed higher activity while thereaction of electron deficient aldimines proceeded with lowenantioselectivity, though with high yields of aminophospho-nates.231 Cyclic (R)-BINOL phosphoric acids, used as chiral Brønstedacids (10 mol %) catalyzed the hydrophosphonylation of aldimineswith diisopropyl phosphite at room temperature to give amino-phosphonates with enantioselectivities ranging between good tohigh (Scheme 95).

Jacobsen and Joly studied the nucleophilic addition ofdi(o-nitrobenzyl)phosphite to N-benzylimines 306 in the presenceof chiral thioureas 307 as the catalyst. This reaction provides ageneral and convenient access to a wide range of highly enantiome-rically enriched a-aminophosphonates. High enantioselectivitieswere obtained across a wide range of both aliphatic and aromaticsubstrates. In general, the best reaction rates were realized with

(CF3CH2O)2P(O)H + RCH=N-R

F3CH2

F3CH2CO305, (1 mol%)

hexane, r.t.

304, up

up to 96%

R'=P(O)Ph2

303

Scheme 95. Hydrophosphonylation of aldimines, cat

O

MeMeO

(R)-278a, 10 mol%

THF, -15oC, 24h

NAr

R+

300a-hAr = 3-Me(4-MeO)C6H3

(MeO)2P(O)H

Scheme 94. One pot Kabachnik–Fields h

aliphatic imines, while electron-poor aromatic substrates requiredlonger reaction times and, in certain cases, elevated temperatures.Products of the hydrophosphonylation were transformed intoa-aminophosphonic acids. The treatment of adducts with H2/Pd-C(20 mol %) afforded enantiomerically enriched a-aminophosphonicacids with high yields and with retention of enantiomeric purityfrom the catalytic reaction (Scheme 96).269

Petersen et al.270 studied the effect of chiral bases on the phos-phora-Mannich reaction of N-protected arylimines 311 with diet-hylphosphite. The reaction was carried out in xylene at ambienttemperature or at �20 �C. At low temperatures, the yields of reac-tion products were reduced and the reaction rate decelerated,while the enantiomeric purity of the aminophosphonates 312decreased. Among the catalysts studied, the biggest efficacy wasdisplayed by quinine. Electron-donating and electron-acceptingsubstituents on a benzene ring had no significant effect on thereactivity and enantioselectivity. The authors have assumed thatthe free hydroxyl group at the C-9 atom of the catalyst enforcedimine activation owing to hydrogen bond formation (Scheme 97).

Nakamura et al.271 used quinine and quinidine as catalysts forthe enantioselective hydrophosphonylation of aldimines 313.N-(6-Methyl-2-pyridylsulfonyl)imines 313 prepared from aro-matic aldehydes, reacted with diphenylphosphite, to give products314 with quantitative yields and high enantioselectivities. Methylhydrocupreine and hydroquinidine were used as organocatalystsand led to the formation of both enantiomers of compounds 313with comparable enantioselectivity. It was supposed that in thetransition state the hydroxyl group of the catalyst activates the

P

O R

NH-R'CO

to 97% ee

N t-Bu

OAl

N t-Bu

OCl

305

(R)

alyzed by 8-aluminum bis-(TBOx) complex 305.

P *NHArO

RH

301a-h

P *

O

NH2HO

HO

Ph

H

anode oxidation

302

MeOH/H2O, 0oC

R=Ph

ydrophosphonylation of aldimines.

N

R'

Ph

H

307toluene

308, 68-90% ee

(RO)2(O)H +

R' = Ph, 3-pentyl

O

PRO

RO

R'

HN Ph

N

HO

t-Bu O t-Bu

O

NH

NH

St-Bu

N

O

R

R'

R = H, R' = Bn; R = R' = Me

307

306

Conv. 90-100%

Scheme 96. Asymmetric addition of di(o-nitrobenzyl)phosphite to N-benzyliminescatalyzed by chiral thioureas 307.

(PhO)2P(O)H +

N

R R'

SO2Mes

NHSO2Mes

R'(PhO)2P

ORCat A or B

(2 mol%)

toluene, -20oC*

Cat A = Hydroquinine, Cat B = Hydroquinidine

312313

311

POPhO

OPh

N MeHSO2Mes

PhNa

N

H

N

O

MeO H

(S)-314

F

Scheme 98. Enantioselective hydrophosphonylation of aldimines 313 catalyzed byhydroquinine or hydroquinidine.

R1R2P(O)H +TsNH R3

P(O)R1R2

316, 56-90%ee

N

R3 H

317 (10 mol%)-60oC

Ts

N

N

N

NNN+

PhPh

H

317, Ar = 3,5-(CF3)2C6H3

315

Ar4B-

H75-98%

314

Ar4B-

Scheme 99. Reaction of H-phosphines with N-tosylimines 315 catalyzed byguanidinium salts 317.

(EtO)2P(O)H +HN

O

O

(S)-310, 88-94% ee

52-69%

quinine

N

Ar H

O

O

(10 mol%)

+20- -20oC

309

(EtO)2(O)P ArH

Scheme 97. Phosphora-Mannich reaction of N,N-protected arylimines withdiethylphosphite.


imine because of hydrogen bond formation, while the quinuclidinenitrogen atom of the catalyst acts as the Brønsted base to activatethe phosphite (Structure F). Deprotection of the hydrophosphony-lation products and subsequent deprotection of phosphonategroup led to the formation of optically active a-aminophosphonicacids (Scheme 98).

Tan et al.272 have reported on the phospha-Mannich reaction ofH-phosphines with N-tosylimines 315 for the synthesis ofa-aminophosphine oxides and phosphinates 316. Guanidiniumsalt 317 showed high catalytic activity. The reaction was

performed with threefold excess of N-phosphinates with an addi-tive of K2CO3, for achievement of a high level of stereoinductionand acceptable reaction rates. Aminophosphinate 316 containingthe stereogenic center at the phosphorus atom were formed as amixture of two diastereoisomers with a predominance of the(S)-isomer (Scheme 99).


The addition of a phosphorous nucleophile to imines inMannich-type reactions represents one of the most useful methodsfor the preparation of enantioenriched a-aminophosphonates.Optically active, aminophosphonates 319 were prepared via theaddition of carbon nucleophiles to iminophosphonates with forma-tion of a C–C bond as was shown by Kobayashi.273 The addition of3 Å molecular sieves (3 Å; MS) and the slow addition of thesubstrates were found to improve the yield, selectivity, andreproducibility (71% yield, 86% ee) (Scheme 100).

N

(EtO)2P(O) H

Troc

Nphth Nphth

HNNH

PhPh

+

R

SiMe3NH

(EtO)2P(O)

TrocR

0oC, CH2Cl2

36-71%, ee=80-89%

320/Cu(OTf)2(10mol%)

318 319

320

3Å MS

R = SEt, SPh, Ph, CH3, R=H

Scheme 100. Mannich addition reaction of alkenes to iminophosphonates.

OTBS

RMe2N

+

O

P(O)(OMe)2

O

Me2N

RP(O)(OMe)2

OH1) 327 (20 mol%)toluene, -80oC

2) 5% HF/MeCN

anti-326325

Zhao and Dodda have developed an enantioselective method forthe synthesis of enantioenriched a-aminopropargylphosphonates321. High yields and good enantioselectivities (60–81% ee) wereachieved using a complex of monovalent copper and pybox ligand322 as the catalyst. A loading of �2 mol % of catalyst was sufficientenough to give a reasonable conversion. Under the optimized reac-tion conditions (2 mol % of loading catalyst, CHCl3 as solvent, roomtemperature), the reaction was successful with various terminalalkynes (Scheme 101).274,275

Ph +N

P(O)(OEt)2

PMP NH

P(O)(OEt)2

PMP

Ph*

CuX/322 (2 mol%)rt

N

OO

NN Ph

Ph

Ph

Ph

322

321, up to 74% ee

55-92%,

Scheme 101. Enantioselective synthesis of enantioenriched a-amin-opropargylphosphonates 321.

Scheme 103. Mukaiyama reactions of a-ketophosphonate with N-acetal-O-ketenes325, catalyzed by Taddol 328.

Palacios has described a simple asymmetric synthesis of 2H-azi-rin-2-phosphine oxides 323 from easily accessible oximes, usingchiral amines immobilized on a polymer. These heterocycles areuseful intermediates for the synthesis of a-ketamides and phos-phorylated oxazoles. The key step is a solid-phase bound achiral

N

R

OTsO

PR2

N

MeON

R323R = EtO, Ph

Scheme 102. Example of diastereosele

or chiral amine-mediated Neber reaction of ketoxime tosylatesderived from phosphine oxides. The reaction of 2H-azirines withcarboxylic acids yielded phosphorylated ketamides. The ring clo-sure of the ketamides with triphenylphosphine and hexachloroeth-ane in the presence of triethylamine led to the formation ofphosphorylated oxazoles 324 (Scheme 102).276

The reaction of silyl enolates with aldehydes, catalyzed by tita-nium tetrachloride was developed by Mukaiyama,277 and was alsoapplied as a convenient method for the preparation of chiralphosphorus compounds. Several reports on the application of theenantioselective Mukaiyama aldol reaction in the asymmetric syn-thesis of hydroxyphosphonates have appeared. For example, Rawalet al.278 have reported a highly stereoselective aldol Mukaiyamareaction of diethyl a-ketophosphonate with N-acetal-O-ketenes325, catalyzed by commercially accessible TADDOL 328(Scheme 103). The stereoselectivity of the reaction was increasedby lowering the temperature. The tert-butyldimethylsilyl (TBDMS)group could be easily removed from the final product by treatmentwith a 5% solution of HF in CH3CN. All tertiary alcohols 326 pos-sessing tertiary and quaternary stereogenic centers were obtainedwith good yields and both high enantio- and diastereoselectivities.The lactam-derived enol ether reacted readily with acetyl phos-phonate to afford the aldol product 327 with near complete diaste-reoselectivity, albeit with a lower with ee value (Scheme 104).278

The enantioselective reaction of silyl enolates with N-a-imi-nophosphonates 329 catalyzed by chiral copper complexes withligand 331, led to chiral a-aminophosphonates 330 in high yieldsand with good enantioselectivity (Scheme 105).279

6.3. Phospha-Michael reaction

The phospha-Michael Reaction is a nucleophilic addition ofphosphoric anion to an activated multiple bond and is one of themost useful methods for the formation of P–C bonds. A particularversion of the phospha-Michael reaction is the Pudovik reaction,that includes the addition of phosphites to an activated C@C bond,catalyzed by Brønsted bases or Lewis acids.280 The asymmetricphospha-Michael reaction can be accomplished by two main

H

P(O)R2O N

R P(O)R2

R'O

R' OH

Ph3P/C2Cl6324

ctive phospha-Mannich additions.

O

O

Ar Ar

Ar Ar

OH

OH

327, Ar = 1-Naphthyl

+

327 (20 mol%)5% HF/MeCN

O

P(O)(OMe)2

N

OTBSMe

N

OMe

P(O)(OMe)2

HOH

H

32899.1 dr, 75% ee

72%

toluene, -80oC

Scheme 104. TADDOL catalyzed Mukayama reaction.

R2PH +CN

[Ni(Pigiphos)(L)](ClO4)2

H

CNR2P

Me

(S)-334

Scheme 107. Enantioselective phospha-Michael addition of secondary phosphines,catalyzed by an organonickel complex.

O

(EtO)2P NTroc

OSiMe3

R+ Cu(OTf)2/331 (10 mol%)

O

(EtO)2P

NH O

R

Troc

α-Nphth α-Nphth

HNNH

PhPh

329 330

331

ee=87-94%

R = Ph, p-Tl, ClC6H4, p-BrC6H4. p-IC6H4, p-An, 3,4-Cl2C6H4Nphth, m-NO2C6H4, Me, t-BuS

70-88%

Scheme 105. The enantioselective reaction of silyl enolates with N,N-a-iminophosphonates 329.


methods; organometallic and organocatalytic. Organometalliccatalysis is the most convenient for primary and secondary phos-phine additions to activated C@C bond with formation of chiral ter-tiary phosphines. The organocatalysis method is most often usedfor the asymmetric addition of trivalent phosphorus acids to aC@C bond. Organocatalysts can be used and include alkaloids, inparticular quinine, or derivatives of amino acids, the most commonis L-proline. The addition of primary or secondary phosphines toelectron-deficient alkenes is a convenient method for the prepara-tion of chiral tertiary phosphines of interest as ligands for com-plexes with transitive metals.281,282 For example Gluck describedthe addition of secondary phosphines to activated olefins, cata-lyzed by platinum complex 333 bearing chiral ligand Pt(R,R)-Me-Duphos) trans-stilbene), which resulted in chiral phosphines 332in good yields and moderate enantioselectivity (Scheme 106).282

Later Togni et al.283,284 reported on an asymmetric hydrophosphin-ation reaction of methacrylonitrile with secondary phosphines,catalyzed by dicationic nickel complex [Ni(Pigiphos)(THF)](ClO4)2

335. The reaction led to the formation of chiral 2-cyanopropyl-phosphines 334 in good yield and ee’s up to 94%. The absolute con-figuration of the obtained tertiary phosphine was defined as (S)(Scheme 107). The authors proposed a mechanism involvingcoordination of methacrylonitrile to the dicationic nickel catalystfollowed by a 1,4-addition of the phosphine and then

R(Ph)PH + CO2t-Bu P

R

Ph333

33

Scheme 106. Asymmetric hydrophosphination of

rate-determining proton transfer: A = methacrylonitrile ligand,B = Ni ketenimine intermediate and C = Ni-coordinated hydropho-sphination product. The mechanism was supported by an experi-mentally determined rate law, a large primary deuterium isotopeeffect kH/kD 4.6(1) for the addition of t-Bu2PH(D), the isolation ofthe species [Ni(k3-Pigiphos)(kN-methacrylonitrile)]2+, and DFTcalculations of model compounds. This mechanism assumesstereospecific transfer of a proton, reversible bonding P–C, and alsothe formation of an unusual Ni ketenimine intermediate(Scheme 108).284

Sabater developed interesting chiral palladacycles withN-heterocyclic carbene ligands starting from commercially avail-able enantiomerically pure benzylamines. These complexes existin the form of two atropisomers 336A ¡ 336B that were isolatedusing column chromatography and characterized by NMR

CO2t-Bu

2

*

P P

Me

Me

Me

MePh

Ph333

Pt

olefines, catalyzed by platinum complex 333.

Fe

Fe

P

P PNi

Cl

BPh-4

335

Ph2 Ph2

+

N[Ni]

CN

HPR2

PR2CN

NPR2

[Ni]N PHR2[Ni]

H

nucleophilicattack

nucleophilicproton transfer

-+

C B

A

Scheme 108. (a) Pigiphos-nickel(II) complex 335 (left); (b) catalytic cycle for the hydrophosphination of methylacrylonitrile by complex [Ni(3-Pigiphos) (NCMeCCH2)]2+

(right).

Pd NN

NI

Me

Antr

Me

Me

Antr

N

N

Me

Pd

I

N

Me

Me

336A 336B

Pd

OAc

PPh2Ph2P

Me Me

(S,S)-337

Scheme 109. Atropoisomerism 333A ¡ 333B of complexes.


spectroscopy (Scheme 109).285 The epimerization of the isolatedcomplexes slowly occurs in solution. The authors used complexes336 as catalysts in the 1,4-additions of diarylphosphines to a,b-unsaturated ketones 338 and resulted in the formation of tertiaryphosphine oxides 339 in good yields, but moderate enantioselec-tivities.285 At the same time chelate complexes of palladium(S,S)-337 catalyzed the asymmetric 1,4-addition of diarylphos-

O

RR+ PhPH2

(S)-341 (15 moEt3N

-80oC rtTHF

, X=H, F, Cl, Brp-XC6H4, m-C6H4R=

Scheme 111. Synthesis of chiral terti

O

R'R + Ph2PHO

R'R

PO

1) 336 or (S,S)-337 (2mol%)CH2Cl2, rt, 2h

2) aq H2O2, rt

339

Ph2

338

Scheme 110. Asymmetric addition of diarylphosphines to enones catalyzed bypalladium complexes (S,S)-336 or (S,S)-337.

phines to a,b-unsaturated ketones 338 with formation of chiralphosphine oxides 339 in good yields and with good enantioselec-tivities (63–93% yields, 90–99% ee) (Scheme 110).286,287

Cyclic palladium complexes 341 catalyzed the diastereo- andenantioselective addition of primary and secondary phosphinesto enones and enamines.288,289 The reaction of bis(enones) withphenyl phosphine allows the intermolecular construction of chiraltertiary phosphoric heterocycles 340 in a one pot method in highyields and with high enantioselectivities as shown inScheme 111.289 This highly active, chemo- and enantioselectivereaction was also used for the synthesis of a number of chiraltertiary enaminophosphites 342 (Scheme 112).288

The Michael addition of dialkyl phosphites to nitroalkenes inthe presence of lithium aluminum bis(binaphthoxide) complex(S)-ALB 260, afforded b-nitrophosphonates 343, precursors ofb-aminophosphonic acids with good enantioselectivities.290 Thereaction was performed in toluene at room temperature, at15 mol % loading of the catalyst (Scheme 113).

The addition of R2P(O)H compounds to the C@C bond proceedsmore easily than the addition of secondary phosphines and usuallyfurnishes products with high yields and enantioselectivities.291–297

For example, Ishihara recently reported on an enantioselective1,4-hydrophosphinylation of a,b-unsaturated esters with diarylphosphine oxides and an enantioselective 1,2-hydrophosphonyla-tion of a,b-unsaturated ketones with dialkyl phosphites by theuse of chiral magnesium(II) binaphtholate aqua complexes as

P

O

R R

Ph

Pd

P

PhPh

NCMe

NCMe-

(S)-341

l%)

ee up to 97%

340

ClO4

ary phosphoric heterocycles 334.


cooperative Brønsted/Lewis acid–base catalysts.291 Wang et al.292–

297 reported on the asymmetric 1,4-addition reaction of diethylphosphite to simple enones, catalyzed by a dinuclear zinc complex344, leading to the formation of ketophosphonates 345 in highyields and with enantioselectivities of up to 99% ee (Scheme 114).This catalytic phospha-Michael reaction was screened with a num-ber of b-aryl or alkyl substituted enones, which afforded adducts346 with good enantioselectivities (Scheme 115).

The asymmetric Michael addition of phosphinic acids to enones,promoted by organocatalysts proceeds even more success-fully.298,299 Chiral alkaloids and amino acids are rather effective

O

NR O

O

+ Ar2P(O)H

Et2Zn/3tolu

Ar = 4-An, 4-FC6H4R = Me, i-Pr, Bu, 2-Furyl, 2-Nphth, 4-XC6H4, where X =

O

Ph Ph + (RO)2P(O)H

Et2Z

R=Et (a), Me (b), Pr (c)

Scheme 115. Asymmetric reactions of 1,4 additions of R2P(O)H

L2

HO

N NOH

OH R

R

R

RO

N NO

OR

R

R

RZn Zn

Et

R=Ph (a), 1-thiophen (b) 344a,b

Et2Zn

Scheme 114. Di-nuclear zinc complexes 344.

ArNO2 + (RO)2P(O)H

P(O)(OEt)2

ArNO2

(S)-ALB, 260

343

toluene, RT, 2d

Scheme 113. The Michael addition of dialkyl phosphites to nitroalkenes catalyzedby (S)-ALB 260.

N

R'R

+ Ph2PH

-80oC rt

Ts (S)-341 (6 mol%)Et3N HN

R'R

PPh2Ts

yield up to 99%ee up to 99%

342

THF

R = Ph, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, Ph,R' = Ph; R' = Ph, Ph, Ph, Ph, CH=CHPh, 2-thienyl

Scheme 112. Addition of diphenylphosphine to a,b-nonsaturated imines, catalyzedby palladium complex (S)-341.

catalysts of these reactions, including quinine, dihidroquinineand their derivatives, especially thioureas of cinchona alkaloids.Lattantzi and Russo300 reported on the enantioselective asymmet-ric additions of diphenylphosphine oxides to chalcones, catalyzedby dihydroquinine. The reaction proceeded in good yields,providing products 345 with 89% ee. The crystallization of enanti-omerically enriched adducts 347 gave enantiomerically pure com-pounds. Other alkaloids such as cupreine, cupreidine, and thioureaderivatives of cinchona alkaloids, were inefficient catalysts. On thecontrary, dihydroquinine efficiently catalyzed the Michael additionreaction.300 Taking into account the absolute configuration ofadducts 347, a transition state G for the dihydroquinine-catalyzedadditions of diphenylphosphine oxide to chalcones was postulated(Scheme 116).

The Michael addition of secondary phosphines and phosphitesto nitroalkenes represents a convenient synthetic route to opticallyactive b-nitrophosphonates which, because of the high syntheticutility of the nitro group, can be easily transformed into chiral func-tionalized phosphonates. For example, the Michael addition of

44b (10 mol%)ene/Py/RT

O

N

R

O

O

Ar2P(O)

34593-99% ee

93-99%

H, Me, MeO, F, Cl, Br

O

(RO)2(O)P

Ph

Ph

n/344b (10mol%)toluene/RT

346a,b, ee=25-99%54-78%

compounds to enones, catalyzed by zinc complexes 344.

O

R'R + Ph2P(O)HO

R'RCat (10 mol%)

toluene, rt

Cat = dihydroquinine

*

Ph2P=O

347

N

P

O HPh

Ph

O

OH

N

MeO

G

Scheme 116. (a) 1,4-addition of diarylphosphines to enones catalyzed by com-plexes 333; (b) postulated transition state for a phospha-Michael-additioncatalyzed by dihydroquinine.

(PhO)2(O)H + RNO2

R

(PhO)2P

O

NO2

348, 40-86% ee

60-85%

(HO)2P

O

NH2

1) H2/Pd(OH)2

2) H2/PtO2

349, yield 48%

quinine

MeOH

C6H4Cl-4

Scheme 117. Reaction of diphenylphosphite with nitroalkenes catalyzed byquinine.


diphenylphosphite to nitroalkenes, catalyzed by quinine representsa convenient method for the synthesis of enantiomerically enrichedb-nitroalkylphosphonates 348 which were converted to chiralb-aminophosphonates 349. Using this method, Wang synthesizeda number of enantiomerically enriched b-nitrophosphates and ami-nophosphonates bearing different aromatic and heterocyclicgroups at the a-carbon atom (Scheme 117).301 Zhao et al.302 foundthat adding molecular sieves (MS 4 Å or 3 Å) to the reaction mixtureimproved the yields and enantioselectivities of the reaction The MSact as a scavengers of water and acid to remove the impurities in thephosphite samples and may facilitate the equilibrium between thephosphonate and phosphite forms of diphenylphosphite. After sucha modification of the reaction procedure, high and reproducibleyields of the desired b-nitrophosphonates were obtained in verygood ee values (up to 84% ee).

+ 3Me

O

R

Ph2P(O)H

R, yield, ee = NO2, 90%, 92%; MeO, 97%, 85%; Br, 9

+

O

351a (10 mol

CH2Cl2/rt, 12Ph2P(O)H

S

NH

NNH

H

R

351a-c

Scheme 118. Phospha-Michael reaction cat

High efficiency in phospha-Michael reactions have been foundwith urea derivatives of cinchora alkaloids.303,304 For example,Wen et al.303 used thiourea-quinines 351 for the enantioselectiveorganocatalytic phospha-Michael reaction of cyclic b-unsaturatedketones with diarylphosphine oxides. Optically active products350 and 352, bearing quaternary chiral carbon stereocenters wereprepared in high yields and with enantioselectivities of up to 98%ee (Scheme 118).

The development of N,N-dialkylthyourea derivatives as effectivebifunctional organocatalysts for the Michael addition of chalconesand malonates to nitroolefines305–307 led Melchiorre to apply thesecatalysts to the asymmetric addition of phosphines to nitroole-fins.305 This organocatalytic approach, providing a direct route topotentially useful enantiopure P,N-ligands, constitutes a bridgebetween the two complementary areas of asymmetric catalysis:organo- and metal-catalyzed transformations. Various chiralN,N-dialkylthiourea catalysts were tested, including (DHQ)2PHAL,thiourea-based derivatives of aminonaphthalene, and others. How-ever only the thiourea-based derivatives of cinchona alkaloidderivatives 354 gave satisfactory results. The reduction of nitrocompounds to amines followed by crystallization of the productsincreased the enantiomeric excess of the aminophosphines 335up to 99% ee (Scheme 119).

Enantioselective phospha-Michael additions of diphenyl phos-phonate to nitroolefins were also achieved by means of conforma-tionally flexible 1,3-diamine-tethered guanidinium/bisthioureaorganocatalyst 356. Nitroolefins bearing various aromatic andaliphatic substituents gave phospha-Michael adducts 355 with90–98% ee. Monomeric or oligomeric catalysts were used, depend-ing on the presence or absence of water. The addition of waterimproved the enantioselectivity up to 98% ee. Among the solventstested, the highest enantioselectivities (89% ee) were observed intoluene. The reaction proceeded at 1 mol % of loading of catalystto give the addition products with 99% yield and 95% ee.308,309

The absolute configuration of the products was determined to be(R) on the basis of comparison of specific rotations of the productssynthesized with known compounds (Scheme 120).

51a (10 mol%)

CH2Cl2/rt, 12h

Me

O

P

OPh

PhR

3524%, 94%

O

P

OPh

Ph

%)

h

350, 90%, 98% ee

NR'2

R = OMe, R' = H (a)R = H. R' = H (b)R = OMe; R' = Me (c)

alyzed by urea derivatives of cinchora.

RNO2

Ph2PH +

R

PPh2

NO2

354

Et2O-i-PrOH 9:1,-40oC

R

Ph2P

NO2

BH3

R

P

NHBoc

BH3

NaBH4, MeOH

355, 50-95% yield, 99% ee

353, 86%, 67% ee

THF, -40oC

R = 4-Tl, 2-FC6H4, 1-thiophen, 2-BnOC6H4

Cat=HN

N

N

HN

S

MeO

CF3

CF3

67-90% yield36-67% ee

354

NiCl2

Boc2O

HCOOH, NaBH4

Ph2

Scheme 119. Asymmetric hydrophosphination of nitroalkenes and the reduction of nitro compounds to amines.

NO2

R'

Ar + R2P(O)HP(O)R2

R'

NO2

Ar

N

N

NH

t-Bu t-Bu

R = 1-Naphthyl

357 (10mol%)

358

PRR

NH2

Cl

359, 70%, >99%ee

Et2O

Scheme 121. Reaction of diarylphosphine oxides with nitroalkenes catalyzed bychiral guanidines 357.

NO2R + (PhO)2P(O)H

P(O)(OPh)2

NO2R

356, HClK2CO3 (50 mol%)

N+

NH

NH

NH

NH

ArNH

NH

Ar

SS

356, Ar=3,5-(CF3)2C6H2

355, 77-98%toluene:H2O=2:1

18h, 0-30oC(R) ee up to 98%

Scheme 120. Phospha-Michael reaction with various nitroolefines catalyzed by356.


Chiral guanidines and guanidinium salts are excellent enantio-selective catalysts for a variety of reactions including Strecker,Diels–Alder, and Michael reactions.310–312 Tan et al.310 reported thatchiral guanidines 357 catalyze the reaction of diarylphosphineoxides with nitroalkenes resulting in the formation of chiralb-aminophosphine and b-aminophosphine oxides 358 with highenantioselectivities. They found that with 10 mol % of chiral bicyclicguanidine, the addition of diphenyl phosphine oxide to b-nitrosty-rene proceeded smoothly in various solvents. The reaction betweendi(1-naphthyl) phosphine oxide and b-nitrostyrene was optimizedto 91% ee by lowering the reaction temperature to 40 �C. The enan-tiomeric purity of compounds 358 was improved to 99% ee after arecrystallization from MeOH or t-BuOMe–CH2Cl2 (Scheme 121).The reaction proceeded easily even at a catalyst loading of1 mol %, and despite such a low loading of catalyst aromatic, hetero-aromatic, and aliphatic nitroalkenes reacted with dialkyl

phosphites, furnishing the adducts 354 in high yields and enanti-oselectivities. The method was used in the synthesis of biologicallyimportant b-aminophosphonates 359. The reduction of b-nitro-alkylphosphine oxide 358 with zinc in muriatic acid and then withtrichlorosilane led to the formation of enantiomerically pureb-aminophosphines 359 with 99% ee.311

Cullen and Rovis have developed an intramolecular asymmetricStetter reaction employing vinylphosphine oxides and vinylphosph-onates as electrophilic acceptors. Both aromatic and aliphaticsubstrates were tolerated providing cyclic keto phosphonates andphosphine oxides 360 and 363. The treatment of aldehydes 360and 363 with N-heterocyclic carbene catalyst 361 led to the additionof an acyl anion equivalent into a vinylphosphine oxide(Scheme 122) or a vinylphosphonate Michael acceptor (Scheme 123)and the formation of compounds 362, 364 in good to excellent yieldsand enantioselectivities.313

PR

X

O

O

RR'

PR

O

RX

O

R'

NNN

O

C6F5

(20 mol%)

20 mol% KHMDStoluene, 23oCX = O, S, CH2

R = EtO, PhO, PhR' = H, 3 -Cl, 3-Br, 2-MeO, 3-MeO

65-99%; up to 95% ee

360

361

BF4-

362

+

Scheme 122. Intramolecular asymmetric Stetter reaction of vinylphosphineoxides 360.

PXO

OOEt

OEt

PO

X

O

OEtEtO

X = O,CH2 94%; 88% ee (X = O)66%, 74% ee (X = CH2)

20 mol% 361

KHMDS, PhMe

364363

Scheme 123. Intramolecular asymmetric Stetter reaction of vinylphosphonates362.


Various proline derivatives, in particular compounds 367, dis-played high organocatalytic activity in phospha-aldol reactions.For example, the asymmetric addition of diphenylphosphine toenals, catalyzed by pyrrolidine derivatives 367 led to the formationof chiral tertiary phosphines 366 containing aryl, heteroaryl, alkyl,and alkenyl groups in 70–90% yields and with enantioselectivitiesof 75–98% ee.314 The reaction proceeded as a 1,4-addition ofdiphenylphosphine to conjugated bonds of unsaturated substates.The highest stereoselectivity of reaction was observed in the caseof iminium complexes, with a trans-configuration. The high stere-oselectivity has its origins in a combination of the orientations ofthe iminium complexes, with E-trans-configuration, and efficientsteric shielding of the Re-face of this iminium complex by the bulkychiral group of the protected diarylprolinol catalyst.298 The highestenantioselectivities were obtained in reaction of enals withdiphenylphosphine, catalyzed by diarylprolinol bearing 3,5-bis(trifluoromethyl)phenyl groups, in toluene or chloroform in thepresence of additives of 2-fluorobenzoic acid (Scheme 124).315

Cordova et al.315 studied the mechanism of asymmetric hydro-phosphination of a,b-unsaturated aldehydes. They performed den-sity functional theory (DFT) calculations on the P–C bond-formingstep. The transition state leading to the (S)-product was calculatedto have the lowest energy. The authors came to a conclusion thatthe bulky substituent shields the Re-face (R = Ar) of the E-iminium

O

H

R'

+

H

PPh Ph

R'

Ph

365,

36770-90%

NH

OTMSAr

Ar

367a-c

Ar = Ph (a), 3,5-Me2C6

R = Me, Et, i-Pr CH3CH=CH, Ph, 4-MeOC6H4, 4-NO2C6H4o-Cl-C6H4, 4-BrC6H4, 3-BrC6H4, 2-Naph, 2-furyl, BnOCH2C

CH2Cl2, rt

Scheme 124. Reaction of enals

ion leading to Si-facial attack. The rate-determining step for thereaction is the conversion of P(III) to P(V), which occurs via a nucle-ophilic SN2-type dealkylation. The mechanistic studies of this reac-tion316 showed that the first step of the catalytic process, after theiminium ion e formation, is the addition of phosphite d to theb-carbon atom of a, leading to the phosphonium ion-enamineintermediate f. The next step is a transformation of P(III) to P(V),which was performed via a nucleophilic substitution on the alkylchain in the a-position to the oxygen atom of f, leading to thephosphonate-enamine intermediate g. The overall result of thesetwo steps is the conversion of trivalent phosphorus into pentava-lent phosphorus. Hydrolysis of g regenerates the catalyst andliberates the optically active phosphonate c (Scheme 125).

Jørgensen reported an enantioselective phosphonylation ofa,b-unsaturated aldehydes with trialkylphosphites, catalyzed bydiarylprolinol 367c in combination with a Brønsted acid and anucleophile. Organocatalytic enantioselective reaction of b-phos-phonylated aliphatic a,b-unsaturated aldehydes proceeded withgood yields and enantioselectivities (up to 88% ee). Optically activeb-aldehydophosphonates 368, formed as by the b-phosphonylationof b-nonsaturated aldehydes, are chiral synthons and can be usedfor the preparation of various biologically important compounds,for example for the synthesis of phosphonic acids 369, and espe-cially phosphonic analogues of glutamic acid 370.316 In generalthe reaction furnished the phosphonates in good yields and withhigh enantioselectivities with various enals, which were deriva-tives of aliphatic, aromatic, heteroaromatic a,b-unsaturatedaldehydes. The reaction provides also good results with aromatica,b-unsaturated aldehydes, such as cinnamaldehyde and its para-substituted derivates. For these substrates, the correspondingphosphonates were obtained with satisfactory yields and enanti-oselectivities of 41–88% ee (Scheme 126).

Terada et al.317–319 have used axially chiral derivatives of guani-dine 371 to catalyze the asymmetric phospha-Michael reaction.This type of organocatalyst is very convenient for asymmetricadditions of malonates318 to nitroolefins and enantioselective

P O

H

Ph

P

OHR'

Ph PhBH3

75-98% ee 366

H3 (b), 3,5-(CF3)2C6H3 (c)

NaBH4CH3CO2H

, 3-NO2C6H4, 4-ClC6H4,H2CH2, PhC(=O)CH2CH2CH2

with diphenylphosphine.

(PhO)2(O)H + RNO2

R

(PhO)2P

O

NO2

HN

NH

N

X

Ar

Ar

Ph

(PhO)2P

O

NHBoc

(R)-348, 80-97%ee

84-98%

NiCl2/NaBH4Boc2O

MeOH/CF3CH2OH

(R)-372, 91% ee

R=Ph, 77%

X = CH3 (a), PhCH2 (b), Ph2CH (c);Ar = Ph (d), 3,5-(CF3)2C6H2 (e), 3,5-t-Bu2C6H3 (f)

(R)-371

(R)-371

Scheme 127. Phospha-Michael phosphonylation of nitroalkenes catalyzed byguanidine (R)-371.

R

NR*

P(O)(OR')2

NH

R*P(O)(OR')2

O

R

R

NR*

R

NR*

P(OR')2

O R'

+

+

P(OR')3

+

Nu-R1

Nu-

c d

f

g

O

R a

e

ratedetermining

step

b

*

*

H2O H2O

Scheme 125. Mechanism of asymmetric hydrophosphination of a,b-unsaturatedadehydes.

+

R CHO

R

CHO(i-PrO)2P(O)

367c/NaI/PhCO2H

CH2Cl2, RT

368, 41-67%; 74-88% ee

Ph

(HO)2P NH2

O

370

P(Oi-Pr)3

R = Pr, Et, Ph, p-An, p-ClC6H4, p-NMe2C6H4, (Z)-n-hex-3-en,CH2CH2OTBDMS, 2-furyl, 2-thiophene

Ph

(i-PrO)2P NH2

O

369 (dr=1:1)

NaCNNH4Cl

Et2O, NH3 aq

CN

R=Ph

COOH

ref 316a

Scheme 126. Enantioselective phosphonylation of a,b-unsaturated aldehydes withtrialkylphosphites, catalyzed by diarylprolinol 367c.


amination of cyclic ketones.319 Catalyst 371 acts as a Brønsted baseand catalyzes enantioselective reactions via deprotonation of 1,3-dicarbonyl compounds. Axially chiral guanidine 371 catalyzedthe Michael addition of diphenyl phosphite to nitroalkenes withthe formation of b-nitrophosphonates 348 with enantioselectivi-ties of 87–97% ee. Increasing the volume of the N-alkyl or arylsubstituents in guanidine 371 increased the enantioselectivity ofthe catalyst at low loading (1 mol %) in step by step fashion withan increase in the steric size of the alkyl moiety X (X = a,b,c, andAr = Ph from 6% ee to 43% ee). The introduction of 3,5-substituentsonto the phenyl ring of the Ar substituents was the most effectivein enhancing both the enantioselectivity and catalytic efficiency(X = c, and Ar = d,e,f from 43% ee to 92% ee). The phospha-Michaelreaction allowed phosphonylation of aromatic, heteroaromatic,and aliphatic nitroalkenes [see below the data for (R)-372 (X = Ph2-

CH and Ar = 3,5-t-BuC6H3]. The authors showed the applicability ofthe Michael adducts for the synthesis of biologically importantb-aminophosphonates 372 (Scheme 127).317

The application of organocatalysis in the Michael asymmetricaddition of nucleophiles to vinyl-bis-phosphonates, activated byelectronegative phosphorous groups has been studied.320–322

Alexakis et al.323 have reported that the addition of aldehydes totetraethyl methylene-bis-phosphonates 373 catalyzed by chiraldiarylprolinol 367a leads to the formation of geminal bis-phospho-nates 374 (Scheme 128). The reaction was completed in 12 h atambient temperature in the presence of 20% mol. of catalyst inCHCl3 and afforded the Michael adducts 374 in a yield of 80%and with enantioselectivities of up to 90% ee. The enantioselectiv-ity decreased from 90 to 80% ee by lowering the temperature. Thedetermination of the absolute configuration of the product 374 ledto a postulate that Michael acceptor attack occurred from theSi-face of the E-enamine (Scheme 129).324

Jørgensen reported on the addition of cyclic b-ketoesters 375and 377 to ethylene-bis-phosphonate 373, catalyzed by dihydroqu-inine leading to optically active geminal bis-phosphonates 376 and378, bearing a stereocenter with a quaternary carbon atom, in goodyields and with high enantioselectivity (Scheme 130).325

Barros and Phillips synthesized chiral c-keto-bis-phosphonatesby the Michael addition of cyclic ketones to vinyl-bis-phospho-nates, catalyzed with 0.1 mol equiv of (S)-(+)-1-(2-pyrrolidinyl)-pyrrolidine 379 and benzoic acid as a cocatalyst.326 All reactionsproceeded with good enantioselectivities, with high diastereose-lectivity (cis:trans) in the case of geminal bis-phosphonate 381(dr = 1:99) and yields of up to 86%. Cyclohexanone and its deriva-tives provided monoalkylated products 380, however the reactionwith cyclopentanone led to the formation of 2,5-dialkylated prod-ucts 381 with 99% ee (Scheme 131).

An enantioselective method for the synthesis of a-methylene-d-lactones and d-lactams, catalyzed by diarylprolinol 367 was pro-posed. The methodology used the Michael addition of unmodifiedaldehydes to ethyl 2-(diethoxyphosphoryl)acrylates as a key stepwith formation of enantiomerically enriched adducts 382 thatwere transformed into compounds 383, with retention of enanti-oselectivity. The methodology allowed the preparation of opticallyactive c-substituted a-methylene-d-lactones 383, and d-lactams384 (Scheme 132).327

CH2O2Et

O

H

R

P(O)(OEt)2

CO2Et

O

R

O

HO

R

P(O)(OEt)2

CO2Et

O

R

O

(EtO)2P(O)

383, 62%, 92%ee

RCHO/367 NaBH4/MeOH

TFA/CH2Cl2 K2CO3/HCHO

382, 95-99% ee

NBn

O

384 63%, 84% ee

(EtO)2P(O)

Scheme 132. Michael addition of aldehydes to ethyl 2 (diethoxyphosphoryl)acrylates.

O

H

R+

P(O)(OEt)2

P(O)(OEt)2

O

H

R

P(O)(OEt)2

P(O)(OEt)2H

NH OH

Ph

Ph

374,373 46-97%ee

367

65-85%

R (yield, %;ee,%) = i-Pr (80, 90); Me (75, 75); t-Bu (85, 97); Pr (75, 86); i-Pr (71, 91); Bn (81, 85)

Scheme 128. Asymmetric conjugate addition (ACA) of aldehydes to vinyl bis-phosphonates.

P(O)(OEt)2

P(O)(OEt)2

toluene, -30oC+

X

Y

O

CO2t-Bu

99% ee

X

OCO2t-Bu

P(O)(OEt)2

P(O)(OEt)2

X=H, Me, OMe; Y=H, Me, OMe

373 375 (S)-376,

DHQ=dihydroquinine

DHQ

Y95-98%

+

O

CO2Me

OCO2Me

P(O)(OEt)2

P(O)(OEt)2

377(R)-378, ee=87%, [α]D = -45 (CHCl3)

76%

373DHQ

toluene, -60oC

Scheme 130. Addition of cyclic b-ketoesters 375, 377 to ethylene-bis-phosphonate 373.

NTMSO

Ph

Ph

R

P P(O)(OEt)2

O OEt

EtON

TMSO

Ph

Ph

R

P P(O)(OEt)2

O OEt

EtO

Si-face attackRe-face attack

HH

Scheme 129. Transition state for Michael acceptor attack from the Si-face of the E-enamine.

NNH

P(O)(OEt)2

P(O)(OEt)2

O

R

379 380, 40% ee

(EtO)2P(O) P(O)(OEt)2

P(O)(OEt)2

O

(EtO)2P(O)

381, 58%, dr (cis-trans) >1:99, 99% ee

Scheme 131. Synthesis of chiral c-keto-bis-phosphonates 380, 381.


(EtO)2P(O)

O

CO2RCHO

Ph

O(EtO)2P(O) CO2R

Ph

O

(EtO)2P

O

Ph

CO2R

OHCO2R

Ph

O

(EtO)2P CO2R

R Ph

R' = Ar/Aliphatic, 71-95% yielddr up to 95:5, up to 98% ee

OH

(EtO)2P

O

CO2Et

Ph

OH

(EtO)2P

O

CO2Et

Ph

+

388a, 20% yieldrecrystallisation to 90% ee

388b, 75% yield96% ee

c

ae

+

dr 95:5 b385,

390

386

387, 97% ee

367

O

dr 94-98%

-30oCCH2Cl2

yield 76%

d

O(EtO)2P(O)

Ph389

50% yield, 96% ee

Scheme 133. Synthesis of diethoxyphosphoryl-2-oxocyclohex-3-en-carboxylates 386–390. Reagents and conditions: (a) H2, 10% Pd/C, MeOH, rt, overnight; (b) K2CO3/HCHO,THF/H2O,0 �C; (c) NaBH4 (2 equiv), CaCl2 (1 equiv), MeOH, 0 �C, 2 h; (d) MSA (35 mol %), toluene, 50% yield, 96% ee; (e) PhMgBr (1.2 equiv), CuI (1.2 equiv), THF, 0 �C, 2 h.

Table 11Organocatalytic reaction of cinnamaldehyde with ethyl 4-diethoxyphosphoryl-3-oxobutanoate328

(EtO)2P

OO

CO2Et

CHO

R

+

O

R

(EtO)2P

O

CO2Et

Ar=3,5-(CF3)2C6H3

367c (10-20%)

Entry R Additives Solvent t (�C) Yield (%) ee (%) dr

1 Ph — CH2Cl2 Rt 66 94 >95:52 Ph — CHCl3 Rt 67 94 >95:53 Ph — EtOH Rt 55 96 >95:54 Ph — toluene Rt 42 94 >95:55 Ph — CH2Cl2 �30 76 98 >95:56 Ph PhCO2H CH2Cl2 �30 79 98 >95:57 4-NO2C6H4- PhCO2H CH2Cl2 �30 95 98 87:138 4-CF3C6H4- PhCO2H CH2Cl2 �30 81 98 >95:59 2-An PhCO2H CH2Cl2 �30 94 97 92:810 3-An PhCO2H CH2Cl2 �30 76 97 >95:511 biphenyl PhCO2H CH2Cl2 �30 78 98 >95:512 2-Furyl PhCO2H CH2Cl2 �30 71 97 90:1013 Ph PhCO2H CH2Cl2 �30 76 98 >95:5


Albrecht and Jørgensen et al.328 have described an enantio- anddiastereoselective Michael addition, initiated by organocatalyst367c, proceeding with formation of optically active 6-substi-tuted-3-diethoxyphosphoryl-2-oxocyclohex-3-en-carboxylates386–390 as shown in Scheme 133. The methodology used the reac-tion of ethyl 4-diethoxyphosphoryl-oxobutanoate, b-unsaturatedaldehydes that was catalyzed by chiral diarylprolinol ethers.Cyclohexencarboxylates 386–390 are especially convenient forthe preparation of functionalized tetrahydrobenzenes and cyclo-hexane derivatives, bearing four stereogenic centers and with highlevels of stereocontrol (Scheme 133 and Table 11).

Michael addition of a-nitrophosphonates to enones and toa-substituted nitroolefins initiated by bifunctional organocatalyst

391 proceeded with high diastereo- and enantioselectivitiesleading to the formation of a,c-diaminophosphonates 390, bear-ing quaternary and tertiary stereocenters (Scheme 134).329

Nitrophosphonates bearing quaternary stereocenters wereconverted into cyclic quaternary a-aminophosphonates by intra-molecular reduction-cyclization or Baeyer–Villiger oxidation,with subsequent intramolecular reduction-cyclization reactionas shown in Scheme 134.330a Cinchona based squaramide cata-lysts 391b were applied to the asymmetric Michael addition ofa-nitroethylphosphonates to acrylic acid aryl esters, resultingin high yields and enantioselectivities. The adducts were reducedto their cyclic aminophosphonates by catalytichydrogenation.330b

R P∗

O

OEt

Ph

O O

+

NH

CO2H

( 20 mol%)

R = Ph, 4-FC6H4, 4-Br-C6H4, 4-Cl-C6H4,

3-Tolyl, 4-An, Me, Et, 2-Thienyl

rt

Scheme 136. Reaction of asymmetric ketophosp

P(O)(OEt)2Me

NO2

P(O)(OEt)2

Me NO2

ArCO

390, yield 86%, 74% ee

NHR

N

N

HN

S

MeO

391a-c

Ar=3,4-(MeO)2C6H3

C5H11

P(O)(OEt)2

Me NO2

O2N

79%

392, dr=20:1, >98 ee329

CF3

CF3

R=

O O

NHBn

P(O)(OEt)2

Me NO2

PhOCO

HN O(EtO)2P(O)

(a) (b)

83-93%

393330b

394, 51%, 97% ee330b

93%, 76% eea

b

c

d

4-NO2C6H4 (c)

Scheme 134. Michael addition of a-nitrophosphonates to enones catalyzed by 391a–c. Reagents and conditions: (a) ArCOCH@CH2/391c, mesitylene/xylene, �65 �C; (b)O2NCH@CHC5H11/391a, PhCF3, �10 �C; (c) PhOCOCH@CH2/PhCF3/�10 �C; (d) H2/Pd-C.

O

R' P(O)(OR)2+

O

R"

OH

P(O)(OR)2

R'O

R"397a-d

32-94%396, 71-99% ee

NH

C(O)X X=OH (a), NH2 (b), p-TlSO2NH (c),N

NN

NH

397a-d

(d)

395

Scheme 135. Reaction of ketophosphonates 395 with ketones catalyzed by L-proline.


6.4. Addition to ketophosphonates

Proline and its derivatives 397a–d catalyze the reaction of keto-phosphonates 395 with enolizable ketones leading to the forma-tion of chiral ketophosphonates.331–335 The reaction of acetonewith methyl or isopropyl ketophosphonates 395 provides hydrox-yphosphonates 396 with the highest enantiomeric excess, howeverthe reaction of butanone or methoxyacetone with ketophospho-nates afforded phosphonates with moderate enantioselectivities(Scheme 135).

Rawal reported the enantioselective Mukaiyama aldol reactions ofN,O-ketene acetals with acyl phosphonates, catalyzed by commer-cially available taddol.336 The organocatalytic reaction of ketoneswith a-ketophosphonates having an asymmetric phosphorus atomwas also studied. However because of the stereogenic center on thephosphorus atom, the reaction led to the formation of two diastereo-mers 398 and 399 in a ratio of�1:1, which were separated by crystal-lization. The enatiomeric purity of these two diastereomers was high(81–99% ee for first and 61–91% ee for second). The absolute config-urations were defined by X-ray crystal analysis (Scheme 136).332,333

Zhang and Zhao334 recently reported that the 9-amino-9-deoxy-epiquinine derivatives 401 catalyze the cross-aldol reactionbetween aldehydes and arylketophosphonates 400 (Scheme 137).With this organocatalyst b-formyl-a-hydroxyphosphonates 402were obtained in yields of 35–75% and with an enantioselectivityof 68–99% ee. The (R)-absolute configuration of several hydrox-yphosphonates was proven by X-ray monocrystal analysis.

The reaction of diethyl formylphosphonates 403 with ketonescatalyzed by L-prolinamide 397b led to the formation of a-hydrox-

PO

O R OH

PhOEt

PO

O R OH

EtOPh

+

398, 81-99 %ee 399, 61-91%ee

honates with acetone catalyzed by proline.

O

HR1

+

O

P(O)(OR3)2R2

OH

P(O)(OR3)2

R2

OHC

R1

401, MBA

toluene, 0oC

402400

N

H2N

N

H

OMe

401

Scheme 137. Reaction of aldehydes with arylketophosphonates catalyzed by 9-amino-9-deoxy-epiquinine 401.

OH

HO P(O)(OEt)2

OR'

R"

+NH

CONH2

CH2Cl2, 0oC

OH

P(O)(OEt)2

O

R'

R"

404

397b

403

Scheme 138. Reaction of diethyl formylphosphonates with ketones catalyzed byL-prolinamide 397b.

O

R' P(O)(OR)2

+408 (5 mol %)

HO

R' P(O)(OR)2

NO2

N

N

HO

OR"

408, R" = H, Bn

406, 71-99%ee

P(O)(OR)2

OH

BzHN

Ph

Pd/C,H2/MeOHRT, 70%

BzCl/Et3N95%

407, 97%ee

CH3NO2

395

THF, rt

61-93%

R = Me, Et, i-PrR' = Me, Et, Bn, 4-XC6H4, where X = H, Me, F, Cl, Br

*

*

Scheme 140. Organocatalytic nitroaldol reactions of acylphosphonates 395 withnitromethane.


yphosphonates 404 in good yields. Various ketones reactedsmoothly under the optimal reaction conditions, to afford enantio-enriched a-hydroxyphosphonates 404 with very good enantiose-lectivity (Scheme 138). The authors proposed that the additionproceeds through transition states A and B having a nine-mem-bered chair conformation in which the phosphonate occupies apseudo-equatorial position. The Re face attack is disfavored as aresult of the unfavorable steric interaction between the large axialphosphonate group and the axial methyl group, therefore the Si-face attack is favored, which leads to the observed products(Scheme 139).335

O

R' P(O)(OR)2+ CH3NO2

P(O)(OR)2HOR'

NO2

*

NH HN

HNNHOO

Ph Ph

410

410 (5 mol%)2,4=dinitrophenol (6 mol%)

-20oC, t-BuOMePhOMe (2:1)

409, yield up to 95%ee up to 99%

R'=Alk, Ar, HetarylR=Me, Et, i-Pr

Scheme 141. Asymmetric Henry reaction of a-ketophosphonates with nitrometh-ane catalyzed by amine-amide 410.

N

O H

HN O

H

(EtO)2(O)PN

OHHN O

H

(EtO)2(O)P

OH

H

(EtO)2(O)P

O

OHH

(EtO)2(O)P

O

favored disfavored

(S)-405 (R)-405

(S)(R)

BA

Scheme 139. Stereochemistry of the reaction of diethyl formylphosphonates withketones catalyzed by L-prolinamide 397b.

Zhao et al.337 have reported on the organocatalytic and highly enan-tioselective nitroaldol reactions of a-ketophosphonates 395 withnitromethane using cupreine or 9-O-benzylcupreine 408 as the cata-lyst. Both catalysts were highly reactive and enantioselective leadingto the formation of optically active b-nitro-a-hydroxyphosphonates

406 in good yields and with high enantioselectivities (>90% ee). Thereaction was carried out with a-ketophosphonate 395 (0.5 mmol),excess nitromethane, and the catalyst (0.0125 mmol, 5 mol %) inTHF. The products 406 were converted into aminophosphonates407 with high ee (Scheme 140).

The secondary amine-amide 410 is an efficient catalyst forasymmetric Henry reactions of a-ketophosphonates under mildconditions. In the presence of 5 mol % organocatalyst 410, excellentenantioselectivities for hydroxyphosphonates 409 (up to 99% ee)and moderate to high yields were achieved for most substrates.Aryl-substituted a-ketophosphonates with various ester alkylgroups, such as Me, Et, and i-Pr, were found to be tolerable in thisreaction and good results were obtained. Additives of 2,4-dinitro-phenol and excess MeNO2 in a 2:1 mixture of t-BuOMe–PhOMeat 20 �C increased the enantioselectivity. A theoretical study onthe transition states revealed that this secondary amine amide cat-alyst could be involved in hydrogen bond interactions, which isimportant for the reactivity and enantioselectivity of this reaction.A hydrogen bond between the phosphorus oxygen and the amidemoiety contributes greatly to the stability of the transition stateleading to the formation of the major (R) product in accordancewith the experimental results (Scheme 141).338,339

O

R' P

O

OR

CH(OR)2 yield up to 81%93-98% eedr 1:1- 1.5:1

O

+L-proline OH

R' P

O

OR

CH(OR)2

O

OH

R' P

O

OR

H

O

R'P

O

OR

OR

O

TFA

TMSClROHCH2Cl2

412

413

414

411R = Me, Et;R' = Me, Ph, XC6H4, where X=4-Cl, 4-F, 4-Br, 4-Me, 3-F,

47-64%

66%

acetone, -30oC

Scheme 142. Phosphaaldol reaction of L-a-acylphosphinates with acetone, catalyzed by L-proline.

O

O

OH

YO

P(O)(OMe)2R+

O

OOH

R O

P(O)(OMe)2Y

354 (10mol%)

MeOH, DBU

415

416

O

OOH

R O

OMeY

417, 94-99% ee

CH2Cl2, 20oC

Y = H, MeO;R = Me, Et, Pr, i-Pr, Bu, i-Bu, s-BuR' = Me, Et;

58-99%

Scheme 143. Enantioselective Michael additions of 2-hydroxy-1,4-naphthoquinone 415 to a-ketophosphonates 416 catalyzed by cinchonine-based thiourea 354.


A highly enantioselective synthesis of a-hydroxyphosphinates412 was achieved based on the L-proline catalyzed aldol reactionof a-acylphosphinates and acetone. Due to the preexisting chiralityat the phosphorus center, mixtures of two diastereomers of thea-hydroxyphosphinates were obtained with high enantioselectivi-ty for both diastereomers. a-Hydroxyphosphinates 412 wereconverted into a-hydroxy-H-phosphinates 413 by treatment withtrifluoroacetic acid (TFA). An oxidation–reduction reaction ofa-hydroxyphosphinates or a-hydroxy-H-phosphinates, with theformation of phosphonates 414, was observed in the presence oftrimethylchlorosilane and alcohol as shown in Scheme 142.340

The cinchonine-based thiourea 354 effectively catalyzed thehighly enantioselective Michael addition of 2-hydroxy-1,4-naph-thoquinone 415 to b,c-unsaturated a-ketophosphonates 416 withthe formation of the corresponding ketophosphonates, which aftertreatment with DBU and MeOH were converted into b-substitutedcarboxylates 417 in good yields and with high enantioselectivities(94–99% ee) (Scheme 143).341

6.5. Catalytic asymmetric modification of P-ylides

Phosphorous ylides are capable of carrying out nucleophilicattack on activated imines with the formation of functionalizedP-ylides containing a stereogenic center.

Chen developed an organocatalytic approach to enantiomeri-cally enriched N-Boc-b-amino-a-methylenecarboxilates 421,which were earlier obtained by an aza-Morita–Baylis–Hillmanreaction.343 According to this methodology, the bis-thiourea 422

catalyzed the reaction of Mannich type reaction between ylides418 and N-Boc-imines 419 with the subsequent olefination of 420with formaldehyde. Catalyst 422 can be regenerated by flash-chromatography and reused without a reduction in its activity. Thetandem Mannich/Wittig type reaction was applied for the prepara-tion of various chiral esters of N-Boc-a-amino-a-methylenecar-bonic acids 421 (Scheme 144)

The stereoselective synthesis of cis-5-nitro-4,6-diphenylcycloh-exen-1-carbonates 425–427 was achieved by organocatalyticenantioselective cascade nitro-Michael/Michael–Wittig reactionwith evidence of a dynamic kinetic asymmetric transformation(DYCAT).344 The reaction of 418 with nitrostyrene 423 catalyzedby chiral pyrrolidine derivatives 367 provided the additionproducts 424 with enantioselectivities 92–99% ee. The addition ofcinnamaldehyde to 424 afforded the cyclohexenecarboxylates425–427 in dr 4:1:3–6:1:2. An increase in the diastereoselectivitywas achieved by the organocatalytic asymmetric conjugateaddition of phosphonium ylide 418 to nitrostyrenes 423 with thenoncovalent thiourea catalyst 410. This annulation reactionprovides a simple protocol for the stereoselective construction oftrisubstituted cyclohexenecarboxylates 425–427 containing threecontiguous stereogenic centers, with an all-cis stereochemistryand with high enantioselectivity (up to 99% ee) (Scheme 145).

The asymmetric organocatalytic Michael reaction of phospho-rus ylides 418 with nitroolefines, was catalyzed by the chiralthioureas 422 catalyzed and resulted in enantiomerically purec-a-nitro-b-aryl-a-methylene carboxylates 429 via the formationof enantioenriched P-intermediates 428. The reaction provided

Ph3PO

OEt + NO2

RR

*

O

PPh3

O2NOEt

428418

422 HCHOR

*

O

O2NOEt

429

THF, rto-xylene,-40 oC, 4Å MS

423

R=4-FC6H4 27% ee= 46%R=3-ClC6H4 26% ee= 39%R=3-FC6H4 25% ee= 35%R=4-An 35% ee= 24%R=3-Tl 35% ee= 42%R=4-Tl 35% ee= 41%R=3,5-Me2C6H3 29% ee =59%R=3,4-(OCH2O)C6H3 52% ee= 11%R’=2-Thienyl 40% ee =43%R=PhCH2CH2 60% ee =16%R=Cy 43% ee =19%

Scheme 146. Asymmetric organocatalytic Michael reaction of phosphorus ylides 418 with nitroolefins 423 catalyzed by chiral Brønsted acids 422.

Ph3POEt

O

+R

NBocO NHBoc

RPPh3

EtO

O NHBoc

REtO R = aryl, alkylup to 87% yieldup to 87% ee

NH HN

HN

SS

NH

F3C

F3C

CF3

CF3

422

422

418 419 420

421

-Ph3PO

HCHO

m-xylene, 0oC,MS 4Å

Scheme 144. Asymmetric synthesis of N-Boca-amino a-methylencarbonates 421 via a Mannich/Wittig tandem type reaction.

Ph3PO

OEt+ NO2

RR' O

PPh3

O2NOEt

CH=OPh

OR

O2NOEt

Ph

(R)-424418

NH

OTMS

Ph

Ph

OR

O2NOEt

Ph

OR

O2NOEt

Ph

425 426 427

+ +

DYKAT367

423

Scheme 145. Organocatalytic enantioselective cascade nitro-Michael/Michael–Wittig reaction.


OR

O

Ph3P + R'

O

Ph

O

R'

O

RO

Ph

N

N

NH3

OMe

432

418 430

432

∗O

R

PPh3

O

RO

Ph

431

HCH=O

R = Me, Et, i-Pr

DCE,-15 oC

(20% mol)

N

Boc

COO

2

H

THF, rt

Scheme 147. The asymmetric catalytic reaction of phosphorus ylides with a,b-unsaturated ketones.


highly functionalized c-a-nitro carbonyl compounds, which can-not be obtained by classic Morita–Baylis–Hillman (MBH) reactionof nitroolefins with acrylates (Scheme 146).345

The asymmetric catalytic reaction of phosphorus ylides 418 withketones 430 via the formation of addition products 431 resulted inthe formation of a,b-unsaturated ketones with high enantioselectiv-ity (up to 95% ee) using chiral ion-pair catalyst 432. The ion-paircatalyst 432 was synthesized by mixing of 9-amino-(9-deoxy)-epi-quinine 401 with L-proline.346 The Wittig reaction product 431was introduced into the reaction with formaldehyde, to obtain anumber of chiral a-methylene-d-ketoesters (Scheme 147).

7. Asymmetric cycloaddition reactions

One of the most useful and interesting applications of vinyl-phosphonates are cycloaddition reactions, which provide rapidaccess to highly functionalized and complex molecules.347–355

The Diels–Alder cycloaddition of vinylphosphine oxides is one ofthe most interesting cycloadditions reactions of this type ofcompound. In this case, the vinylphosphorus group can react as a

+

R

(MeO)2(O)P O

CH2

435, 10433a-d 434

OEt

N

OMe

R'

R' = Me (a), Ph (b), Bn (c), Ph (d)

Scheme 148. The hetero Diels–Alder reaction of a,b-unsatura

dienophile, or be a part of a diene. Evans used chiral Lewis acids,in particular C2-symmetric Cu(II) bis(oxazolin) complexes 435, ascatalysts. For example, the reaction of ethylvinyl ester with croto-nyl phosphonate 433 in the presence of of [Cu((S,S)-tert-Bu-box)](OTf)2 complex 435 afforded cycloadduct 436 in 89% yieldand with high stereoselectivity: an endo/exo isomer ratio of 99:1and up to 99% ee. With respect to simple b-substituted a,b-unsat-urated acyl phosphonates 433, broad substrate generality wasobserved. In particular, phenyl-, isopropyl-, and ethoxy-substitutedsubstrates all participated in high yielding, diastereoselectiveDiels–Alder reactions with ethyl vinyl ether to give dihydropyrans436 (Scheme 148).348–350

Acylphosphonate 433a was reacted with cyclopentadiene 437in the presence of complex 435 to form two products 438 and439 in quantitative yield and in a ratio of 35:65. The expectedDiels–Alder product was obtained with an endo/exo ratio of87:13, and with an enantiomeric purity of 84% ee for the endoisomer (Scheme 149).349

A number of a,b-unsaturated acyl phosphonates and b,c-unsaturated a-keto esters and amides have been successfully

O

R

(MeO)2(O)P OEt

Cl2, -78oC

mol%(2R,4R)-436a-d

CuN

O

Me

R'

2+

2X-

yield 89%

ted carbonyls with alkenes catalyzed by complexes 435.

P(O)(OEt)2

O

RO

O

P

O

P

445a,b44

4

R = Ph(a)(b)

Scheme 152. Cycloaddition between phosphonoacrylates 445

+

Me

(MeO)2(O)P O

O P(O)(OMe)2

H

Me

H

O

MeH

H(MeO)2(O)P

435b (10 mol%)

-78 oC

endo:exo 87:1384% ee

endo:exo > 95:595% ee

yield 99%,

433a

438 439

CH2Cl2437

438:439 = 35:65

Scheme 149. Cycloaddition of acylphosphonate 433a to cyclopentadiene in the presence of Cu-complex 434b.

O+

R

(MeO)2(O)P O OO

MeH

H(MeO)2(O)P

endo:exo 99:1, ee=71-97%

79- 99%433a 440

R = Me, Ph, i-Pr, OEt

435b-d, 10 mol%

CH2Cl2, -78 oC

Scheme 150. Hetero Diels–Alder reaction acylphosphonates 433a with dihydrofu-ran catalyzed by bis-oxazoline/Cu(II) complexes 435.

O

HR(EtO)2P

O

O CH2Cl2,RT

O

Me

P(O)(OEt)2

R

HO

O

Me

P(O)(OEt)2

R

O

442, 41-91% yield19-94%ee

443, 71-88%80-89% ee

HN

S SI

I

+ SiO2

PCC

CH2Cl2

441

444

I

I

444

68:32-83:17 anomericratio

Scheme 151. Hetero-Diels–Alder reaction of aldehydes with b-unsaturated a-ketophosphonates.


employed as heterodienes, while enol ethers and sulfides and cer-tain ketone silyl enol ethers have functioned as heterodieno-philes.349,350 Bicyclic adducts 440 were synthesized by thereaction of crotonyl phosphonate 433a with dihydrofuran cata-lyzed by bis-oxazoline/Cu(II) complexes 435 in good yields andwith very high enantioselectivity.349 The high diastereoselectivityfor the catalyzed hetero Diels–Alder reactions is due to frontierorbital control and/or electrostatic effects that preferentially placethe OR substituent in proximity with the heterodiene carbonyl car-bon (endo orientation). This stereocontrol element has been impli-cated in related conjugate addition reactions to unsaturated imidesand azaimides. Hanessian351 studied the effect of substituents andreaction parameters on the course of hetero Diels–Alder reactionsof vinylketophosphonates with cyclopentadiene, cyclohexadiene,and dihydrofuran (Scheme 150).

Some prolinal dithioacetal derivatives 444 were studied as cat-alysts for the inverse-electron-demand hetero-Diels–Alder reac-tion of enolizable aldehydes with b,c-unsaturated a-ketophosphonates 441. The corresponding 5,6-dihydro-4H-pyran-2-ylphosphonates 442 (as a mixture of two diastereomers in an80:20 ratio) were obtained with good ee values (up to 94% ee) asshown in Scheme 152. Product 442 was oxidized into the corre-sponding lactone derivative 443 (Scheme 151).342

2-Phosphonoacrylates 446–449 were efficiently prepared andevaluated in Lewis acid mediated Diels–Alder reactions. Under theactivation of SnCl4, all of the reactions were performed in CH2Cl2

at�65 �C to exclusively afford the endo-cycloadducts with dr’s rang-ing from 50:50 to >99:1. The best facial selectivity was obtainedfrom the substrate bearing a (�)-phenylmenthyl group, to giveadducts almost as (dr = 99:1) single diastereomers (Scheme 152).353

H

O(O)(OEt)2

H

O

O

P(O)(OEt)2

H

O

(O)(OEt)2

H

O

O

P(O)(OEt)2

+

exo

endo6

47 449

448

a and trans-piperylene under various reaction conditions.

N Oi-PrO

O

P(O)(OMe)2

CO2Me

O

P(O)(OEt)2N

Oi-PrO

O O

P(O)(OEt)2

NO

i-PrO

OP(O)(OMe)2

CO2Me92%

60%

451

450 454452 (major isomer)

453

Scheme 153. Asymmetric synthesis of b-amidophosphonocyclohexane 452, 454.

(RO)2(O)H +

NHPg

R'(RO)2P

O

79-95%ee52-95%,

N

OH

OMe

H

N

F

Et

HN

R' SO2Ar

Pg

KOH/toluene, -78oC

Ar = Ph, p = Tl; R = H, Me, Et, BnPg = Boc, Cbz ; R = Me, Et, BnR' = Me, Et, Bn, i-Bu, c-C6H11, Ph(CH2)2

HCl

NH3+ Cl-

R'(RO)2P

O

458 460

461

459

459, (5-10 mol%)

+

Scheme 155. Phosphonylation of a-amidosulphones 458 under phase-transfercatalysis conditions.


Shibuya developed the synthesis of buta-1,3-diene derivativespossessing a (diethoxyphosphinoyl) difluoromethylene group atthe terminal carbon atom with high endo/exo selectivity352

Marchand-Brynaert354 reported the [4+2] cycloaddition of enantio-merically pure 1-aminodiene 450 onto substituted phosphonodie-nophiles 451 and 453 at reflux in acetonitrile to provide chiralb- and c-amidophosphonocyclohexenes 454 and 452, respectively,with good selectivities.354 The cyclization of 453 with chiral amin-odiene 450 at reflux in toluene afforded cycloadduct 454 with highregioselectivity (95:5) and diastereoselectivity (dr 81:6:6:7)(Scheme 153).

Tomioka developed a lithiation–cyclization procedure of readilyavailable chiral and achiral a,b,c,x-unsaturated bis-phosphine oxi-des 455 for the conventional synthesis of chiral bis-phosphines456, which were useful as chiral ligands for catalytic asymmetricreactions. Upon treatment with lithium diisopropylamide, achiraland chiral a,b,c,x-unsaturated bis-phosphine oxides 455 under-went a lithiation–conjugate addition tandem cyclization to affordthe corresponding endo-a,b-unsaturated cyclic bis-phosphine oxi-des 456. Sequential stereoselective reduction of the cyclized bis-phosphine oxide 456 gave the corresponding trans- and cis-bis-phosphines 457 (Scheme 154).356

CO2Et

CO2Et

MeO

MeO P(O)Ph2

P(O)Ph2

MeO

MeO

P(O)Ph2

P(O)Ph2

MeO

MeO

MeO

MeO PPh2

PPh2

DIBAH

LiP(O)(OEt)2

P(O)Ph2

1) LiAlH4

2) HSiCl3

96%

455, 48%

456, 60% (major isomer) 457

i-Pr2NLi

benzene, 110oC

THF, -78oC

Scheme 154. Lithiation-cyclization of a,b-unsaturated bis-phosphine oxides 455.

N

R H

P(O)Ph2

+ R'CH2NO2

NH

RR'

Ph2P(O)

NO2

CF3

F3C NH

NH

S

N

57-91% yield64-76% eedr (R=Me): 73:27

CH2Cl2

462464

463

463

R = Ph, 4-Tl, 4-ClC6H4, 2-Nphth, 2-furyl, 2-Py, 2-thienyl,8-cinnamyl; R' = H, Me

Scheme 156. Aza-Henry reaction of imines 462 with nitroalkanes catalyzed bychiral thiourea 463.

8. Miscellaneous methods

The asymmetric hydrophosphonylation of a-amido sulfones458 was achieved under phase-transfer catalysis conditions.357

The best results were obtained with fluorosubstituted catalysts459, prepared from methyl hydroquinine. The reactions were per-formed at �78 �C in the presence of KOH as a base, using diethylphosphite as a phosphonylation agent. Very good stereoselectivitywas achieved in the reaction of a-amidosulphones 458 bearingR = Alk. a-Amido sulfones derived from aromatic aldehydes(R0 = Ar) gave the corresponding products in nearly racemic form,presumably due to a base-promoted racemization. After deprotec-tion of 460 a-aminophosphonic acids or monomethyl esters of the

phosphonic acid 461 with retention of the enantiomeric purity(Scheme 155).

Aza-Henry reaction of imines 462 with nitroalkanes catalyzedby chiral thiourea 463, led to the formation of b-nitroamines 464with high yields and enantioselectivities (91%-yields and 76% ee)Scheme 156).358

Solvent-free enantioselective addition of dialkylzinc toN-diphenylphosphinoylimines 462 in the presence of chiral2-morpholino-1-phenylpropan-1-ol 467 or 468 led to the forma-tion of N-diphenylphosphinoylamines 465 and 466 with up to97% ee. The reaction in a solvent-free system is faster than inorganic solvents. Me-DuPHOS monoxide (Boz-PHOS) 469 is aneffective ligand for the copper-catalyzed addition of dialkyl zincto N-phosphinoylimines 462. Good results were also obtained with

yield 80-98%89-99% ee

Cu(OTf)2/469

Lig = Me-DuPhos 4a, ee 73-90%Lig = Boz-Phos 113, ee 97%

R = Me, Et, i-Pr, BuR' = Ph, 3-Tl, 4-Tl, 4-ClC6H4, 4-BrC6H4, 4-An, 1-Nphth, 2-Npth, 2-furyl, ferrocenyl

N

R'

P(O)Ph2 HN

R

P(O)Ph2HN

RR'

P(O)Ph2

N

O

HO

MePh

N

O

HO

MePh

(R)-465 (S)-466462

Et2ZnR2Zn

Cu(OTf)2/468

PP

469 Boz-Phos

467 468

HToluene, 0oC

yield 84-98%92-98% ee

Scheme 157. Enantioselective addition of dialkylzinc to N-diphenylphosphinoyli-mines 462.

OBoc

RCOOMe +

P(O)R'2

RCOOMe

H

quinidine (20 mol%)

Na2CO3 (1.5 eq), 0oC

474 475

R'2P(O)H

Scheme 159. Morita–Baylis–Hilman (MBH) reaction of carbonates with dialkylphosphites.


oxazolines, catalyzing the asymmetric addition of diethylzinc toC@N bonds (Scheme 157).365–367

N

Ar H

BocP(OR)2Me

O

NO2

+NH

ArP(OR)2

O

Me

Boc

NO2

472

NH2

ArP(OH)2

O

Me NH2

Zn/HCl

50% HCl

84%yield

100% yield

471, 67-99% ee

H

N N

NN

HH

H

+

TfO-

472

470

48-86%

dr=2:1-10:1

R = Et, i-Pr, Bu, CHEt2, CHi-Pr2Ar = 4-ClC6H4

470 + PhSO2CH=CH2

P(O)(OR)2PhSO2

Me NO2

391b (10 mol%)

473, 97% ee

CH2Cl2, 0oC

93%

Scheme 158. Stereocontrolled additions of a-nitrophosphonates 470.

P

O

O PhP

HO

O Ph P

OH

O Ph

+Cat

476 (Sp,Rc)-477 (RpSc)-478

Cat = quinidine, cinchonine

t=20-60oC, CH2Cl2

Scheme 160. Enantioselective rearrangement of 3,4-epoxyphospholane oxides476.

N PG +

HN

PG

P(O)(OPh)2

Et2Zn (150mol%)Toluene, r.t. 12h

Pg=2-Picolinoyl

N

NXH

X=NHCOPy

480, 98% ee

481

479

481 (5 mol%)

Yield 90%

(PhO)2P(O)H

Scheme 161. Enantioselective desymmetrization of aziridines 479 withphosphites.

Stereocontrolled additions of a-nitrophosphonates 470 to imi-nes, catalyzed with chiral Brønsted acid 472 proceeded with theformation of a-substituted a,b-diaminophosphonates 471.359 TheLewis acidity of the catalysts was especially important for the ste-reoselectivity of the reactions (Scheme 159). a-Nitro-c-sulfonylphosphonates 473 with a key tetrasubstituted stereogenic a-car-bon center were also synthesized in high yield and enantioselectiv-ity through a quinine-squaramide-catalyzed conjugate addition ofa-nitro phosphonates 470 to aryl vinyl sulfones (Scheme 158).368

Quinidine initiates SN2 and SN2–SN2-Morita–Baylis–Hilmann(MBH) reactions of carbonates 474 with dialkyl phosphites. Thechoice of base allowed the suppression of the competitive SN2reaction, acceleration of enantioselective allyl substitution reac-tions and provided the addition products 475 in good yields andwith high enantioselectivities (Scheme 159).361

Cinchona alkaloids serve as effective chiral bases for the enan-tioselective rearrangement of 3,4-epoxyphospholane oxides 476

resulting in the formation of P,C-chirogenic 4-hydroxy-2-phospho-lene derivatives 477 and 478 with up to 52% ee. For the rearrange-ment of epoxy phospholene–borane, the highest enantioselectivitywas achieved with a sec-BuLi/sparteine base system as the pro-moter (Scheme 160).360

Nakamuro has developed the highly enantioselective desym-metrization of aziridines 479 with phosphites. High yields andenantioselectivities of the products were obtained for the reactionwith various aziridines, using a new type of easily accessible chiralcatalysts 481 derived from 9-amino-9-deoxy-epi-cinchona alka-loids. The authors have observed complexes based on the cinchonaalkaloid amide-Zn(II) by ESI-MS analysis. This method allowed toobtain both enantiomers of optically active b-aminophosphonates480 to be obtained in high yields and with high enantioselectivities(up to 99% ee) (Scheme 161).362

The asymmetric Mannich reaction of N-carbamoyl imines withdialkyl diazomethylphosphonates catalyzed by chiral phosphoricacids 482 is an effective method for the synthesis of chiral

O

OP

O

OH

R

R

N

Ph H

Boc

N2

P(O)(OR')2

+

N2

P(O)(OR')2

NH

Ph

Boc

*

R = H, Ph, 3,5-(CF3)2C6H3, SiPh3,9-Anthryl, 2,4,6-(i-Pr)3C6H2R' = Me, Et, i-Pr, i-Bu

482 (x mol%)

4Å MS, toluenetemp oC

482

(S)-483, yield 31-93% ee38-98% ee

Scheme 162. Reactions of dialkyl diazomethylphosphonates with N-carbamoylimines.


b-amino-a-diazophosphonates 483 and their derivatives.363

Reactions of dialkyl diazomethylphosphonates with N-carbamoylimines at a loading of catalyst 482 of 0.1 mol % proceededsmoothly and led to the corresponding b-amino-a-diazophospho-nates 483 in 97% yield and 99% ee (Scheme 162).

The enantioselective ring opening of meso-epoxides withdithiophosphorus acids catalyzed by a (salen)Ti(IV) complexgenerated in situ from Ti(Oi-Pr)4 and chiral Schiff base, led to theformation of products 485 with low to good enantioselectivities(up to 73% ee). The (salen) 484/Ti(IV) complex containing the1,2-diaminocyclohexane substituent exhibited the highest enanti-oselectivity. The substituents in the dithiophosphorus acids andthose on the salen aromatic ring have a significant influence onthe reaction. High regioselectivity was observed for the alkylsubstituted epoxides, whereas poor regioselectivity was obtainedfor the aryl substituted compounds (Scheme 163).364

9. Conclusion and future directions

The creation of highly effective catalysts based upon chiralorganophosphorus compounds, as well as the creation of chiralorganophosphorus synthons continue to be important problemsfor modern chemistry. In this review, we have considered variousversions of asymmetric catalysis and some other techniques thatgive individual organophosphorus compounds in high enantio-meric excess. It is important to note that despite the impressiveprogress achieved in the synthesis and studies of properties ofchiral organophosphorus compounds, not all problems have beensolved. The prospects of chemical modification of chiral phospho-rus compounds with the introduction of new and more complexgroups including those with a specific configuration at thephosphorus centers are far from exhausted. The problems are theresolution of enantiomers and purification of chiral tertiaryphosphines and chiral phosphine oxides. The exact absolute con-figuration can only be successfully established in limited cases.

(EtO)2P(S)SH +O

Ph

MeOH

N

Me OH

N

t-Bu t-Bu

484

484/Ti(Oi-Pr)4

75%

toluene, 25oC

Scheme 163. The enantioselective reaction of meso epoxides with d

However, only in a limited number of cases, high productivity,broad substrate scope, functional group tolerance, and cost of thecatalyst have fulfilled the requirements needed for industrial appli-cations, so that the search for new and more efficient catalyticsystems remains an active topic in the field.

The problem of the development of enantioselective methods,which give easy access to both antipodes of chiral organophospho-rus species still remains. The search for enantioselective methodsproviding rapid access to optically active phosphorus-containingacids, tertiary phosphines, and phosphine oxides remains a topicalone. In connection with this, the elaboration of highly efficientmethods of organocatalytic, enzymatic, and microbiological syn-thesis of chiral organophosphorus compounds is of particularimportance. It is easy to predict that the basic efforts in studyingthe chemistry of chiral tertiary phosphines and phosphine oxideswill be concentrated in this direction and new enantioselectivereactions are promising for solving these problems. Therefore,combining catalysis and asymmetric synthesis will give an impetusto the design of novel synthetic strategies of practical and theoret-ical importance.

From the data presented in the review it can be seen that someeffective methods of asymmetric catalysis have been successfullyused in modern organic chemistry and have found applications inorganophosphorus chemistry. Obviously, asymmetric catalysis bychiral heterocyclic carbenes (NHC) and bifunctional organocatalystscould be a very useful tool in the construction of chiral phosphorus-containing compounds with complex structures. Multi-componentsyntheses of chiral organophosphorus derivatives using asymmetriccatalytic processes present a new and important area of studies.New experimental techniques, such as immobilized chiral catalysts,catalytic ionic liquids, and fluorous methodology, can also beapplied effectively in the asymmetric chemistry of phosphorus.Organocatalysis, which has demonstrated its potential in some syn-theses of chiral phosphorus compounds, is needed in the searchesfor new catalysts and new reactions. A serious problem is a creationof chirality on the phosphorus center with the simultaneous con-struction of asymmetry on the side chain of the organophosphoruscompounds by means of asymmetric catalysts.

One can expect that catalytic methods for the synthesis of orga-nophosphorus compounds will remain the focus of intensiveresearch, especially in the field of biologically active compounds.In the future, the design of various forms of catalyst applicationtechniques, their modification and the creation of new preparativeforms of organo and biocatalysts will serve as a basis for novelbroad-spectrum asymmetric catalysts for industry. Looking intothe future, it seems that organophosphorus compounds will bethe subject of intensive studies, especially with regard to theirrange of applications as ligands for metal complex catalysts or aspotentially bioactive compounds. It is believed that the applicationof chiral organophosphorus compounds will be expanded greatlyupon.

OH

Ph

(EtO)2P(S)S OH

R'

HS[H]

485, 55%ee

ithiophosphorus acids catalyzed by (salen 484) Ti(IV) complex.


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asymmetric catalysis as a method for the synthesis of chiral organophosphorus compounds

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