advances in asymmetric hydrogenation and hydride reduction of organophosphorus compounds

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Advances in Asymmetric Hydrogenationand Hydride Reduction ofOrganophosphorus CompoundsOleg I. Kolodiazhnyiaa Institute of Bioorganic Chemistry and Petrochemistry, NationalAcademy of Sciences of Ukraine, Murmanska Str., 1, Kiev, UkraineAccepted author version posted online: 18 Jun 2014.Publishedonline: 04 Aug 2014.

To cite this article: Oleg I. Kolodiazhnyi (2014) Advances in Asymmetric Hydrogenation and HydrideReduction of Organophosphorus Compounds, Phosphorus, Sulfur, and Silicon and the Related Elements,189:7-8, 1102-1131, DOI: 10.1080/10426507.2014.905778

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Phosphorus, Sulfur, and Silicon, 189:1102–1131, 2014Copyright C© Taylor & Francis Group, LLCISSN: 1042-6507 print / 1563-5325 onlineDOI: 10.1080/10426507.2014.905778

ADVANCES IN ASYMMETRIC HYDROGENATIONAND HYDRIDE REDUCTION OF ORGANOPHOSPHORUSCOMPOUNDS

Oleg I. KolodiazhnyiInstitute of Bioorganic Chemistry and Petrochemistry, National Academyof Sciences of Ukraine, Murmanska Str., 1, Kiev, Ukraine

GRAPHICAL ABSTRACT

Abstract This article describes the asymmetric synthesis of chiral organophosphorus com-pounds using methods of enantioselective hydride reduction and hydrogenation of corre-sponding unsaturated compounds. Many applications in stereoselective synthesis with ref-erence to updated literature findings as well as the author’s original research are discussed.The uses of chiral organophosphorus compounds in some asymmetric transformations lead-ing to the formation of phosphorus analogues of important natural compounds were alsopresented.

Keywords Asymmetric catalysis; hydrogenation; hydride reduction; chiral phosphoruscompounds

1. INTRODUCTION

Chiral phosphorus compounds play an important role in many areas of science in-cluding biologically active pharmaceuticals, agrochemicals, and ligands for transition metalcomplexes.1–5 Many methods were used to prepare enantiomerically pure organophos-phorus compounds including classical resolution via diastereoisomers, chemical kineticresolution, enzymatic resolution, chromatographic resolution, and asymmetric catalysis.Asymmetric synthesis and asymmetric catalysis have been, and remain, a primary researchfield of chemistry.6–8 Therefore, methods for the asymmetric synthesis of organophospho-rus compounds have been extensively studied in many academic and industrial research

Received 20 January 2014; accepted 29 January 2014.Dedicated to Professor Dr. Louis D. Quin on the occasion of his 86th birthday.Address correspondence to O. Kolodiazhnyi, Institute of Bioorganic Chemistry and Petrochemistry, National

Academy of Sciences of Ukraine, Murmanska Str., 1, Kiev, Ukraine. E-mail: [email protected]

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ASYMMETRIC HYDROGENATION AND HYDRIDE REDUCTION 1103

laboratories. Over the last few years, enormous success has been achieved in the asym-metric synthesis of organophosphorus compounds, primarily with phosphine ligands forcatalyzed asymmetric hydrogenation reactions, and many articles devoted to the synthesisof chiral organophosphorus compounds have been published.7–12

Various versions of asymmetric metallocomplex, organo- and biocatalysis, devoted tothe synthesis of separate classes of organophosphorus bonds were discussed in the chemicalliterature.7–12 The presented review discusses methods for asymmetric metallorganic andorganocatalysis in the synthesis of chiral organophosphorus compounds on a basis both therecent literary data, and researches of authors. This account describes asymmetric catalytichydrogenation and the hydride reduction of unsaturated compounds. Researches in thisfield progress intensively and a large array of experimental data has been accumulated. Theresults obtained seem to be quite interesting and require generalization; this is the reasonfor the present review to appear.

2. ASYMMETRIC CATALYTIC HYDROGENATION

Asymmetric hydrogenation is a chemical reaction that adds two atoms of hydrogento a target (substrate) molecule with three-dimensional spatial selectivity.13–15

Homogeneous asymmetric hydrogenation with chiral complexes of transition metalsis one of the most important industrial methods for the preparation of enantiomericallypure organic moleculas.16 Asymmetric hydrogenation of prochiral aminophosphonates, ke-tophosphonates, and ketoiminophosphonates is one of the most effective, practical, andeconomic synthetic methods for the preparation of chiral organophosphorus compounds.7

For the last few years, various chiral complexes of transition metals, bearing chiral phos-phine ligands, were used as catalysts for asymmetric hydrogenation of unsaturated phos-phorus compounds. For asymmetric catalytic hydrogenation of phosphonates containingC=C, C=O, or C=N bonds, Rhodium, Ruthenium, Iridium complexes with chiral bis-phosphine ligands were used.16–19 Nojori published first works concerning application ofBINAP-Ru catalysts for asymmetric hydrogenation of ketophosphonates.19–21 Asymmet-ric catalytic hydrogenation of unsaturated phosphonates is widely used in the synthesis ofaminophosphonates and aminophosphonic acid representing practical value, as biologicallyactive compounds, therefore many publications were dedicated to the development of thismethod.22–43

Hydrogenation of C=C bonds. The first works devoted to asymmetric synthesis ofaminophosphonates by catalytic hydrogenation of unsaturated phosphonates were pub-lished about 30 years ago. Schollkopf et al.22 in 1985 reported that asymmetric hydro-genation of N-[1-(dimethoxyphosphoryl)-ethenyl]formamide, using the rhodium catalystwith (+)-DIOP chiral ligand, afforded the (1-aminoethyl)phosphonate L-3 in good yieldsand 76% ee enantioselectivity. The initially formed formamides L-3 was hydrolyzed withconc. hydrochloric acid to give the aminophosphonic acid. The crystallization from wa-ter/methanol allowed increasing the optical purity of L-19 up to 93% ee (Scheme 1).

Afterwards the hydrogenation of α-enamidophosphonates attracted interest of sev-eral chemical groups as a method for the synthesis of chiral aminophosphonates anda number of articles were published on this subjects. Oehme at al.23 reported that chiralRh(I)complexes with BPPM ligands 7 or PROPRAPHOS 8 are active catalysts for the asym-metric hydrogenation of (E)-phenylenamidophosphonates possessing high reaction ratesand relatively high stereoselectivities. For example, the hydrogenation of amidovinylphos-phonates 5 catalyzed by the BPPM(7)/Rh complex afforded the α-aminophosphinates

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1104 O. I. KOLODIAZHNYI

Scheme 1 Asymmetric catalytic hydrogenation of unsaturated phosphonates.

6 with 96% ee. Since PROPRAPHOS 8 is available in both configurations, (R)- and(S)-α-aminophosphonic acid 6 could be obtained with enantioselectivities of 88–96% ee(Scheme 2).

Burk and coworkers24 proposed cationic rhodium complexes of the C2 symmetricDuPHOS 13а,b and BPE 14a,b ligands as effective catalysts for asymmetric hydrogenationof N-aryl and N-benzyloxycarbonyl-enamido phosphonates 10 (Scheme 4). The catalystEt-DuPHOS/Rh(СOD) provided a good enantioselectivity for both types of substrates 10(95% and 94% ee, correspondingly). The reaction was completed for 12 h in methanolat room temperature and at a pressure of 4 atm to result in the aminophosphonates withenantioselectivities up to 95% ee.24 The similar results were earlier obtained by Beletskaya,Gridnev, and others with catalyst Rh/(R,R)-t-Bu-BisP∗ 12 (Table 1).25–27

Wang, et al.28 applied readily available and inexpensive chiral phosphine-aminophosphine ligands 17 to the enantioselective hydrogenation of various α-enol esterphosphonates and α-enamido phosphonates. The phosphine-aminophosphine ligands 17exhibited superior enantioselectivity to that obtained with BoPhos analogues 18. Very good

Lig= (2S,3S)-DIOP 2, ee=83% (S)Lig= (2S,4S)-7, ee=96% (S)Lig=(R)-8 ee=89% (R) Lig= (S)-8 ee=92% (S)Lig= (4R,5R)-9, ee=63% (S)

Scheme 2 Asymmetric hydrogenation of vinylphosphonates 21 in the presence of rhodium catalysts.

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Table 1 Enantioselective hydrogenation of enamidophosphonates 10 catalyzed by Rh complexes bearingBisP 12, DuPhos 13a,b, and BPE 14a,b ligands

R Lig Conv,% ee,% Conf Refs

Ac, (R,R)-12 100, 90 (R)-(−) 25

Ac, (S,S)-13a 100, 93 R-(−) 24

Ac, (S,S)-13b 100, 95 R-(−) 24

Ac, (S,S)-13c 90 68 R-(−) 24

Cbz, (S,S)-14a 88 88 R-(−) 24

Cbz, (S,S)-13a 72 90 R-(−) 24

Cbz, (S,S)-13b 100 94 R-(−) 24

Cbz, (S,S)-14c 100 81 R-(−) 24

Cbz, (R,R)-14b 93 57 S-(+) 24

enantioselectivities (93–97% ee) were achieved in the hydrogenation of various substratescatalyzed by (S)-17/[Rh(COD)]BF4 complex, demonstrating the high potential of theseligands 17 in the preparation of optically active α-aminophosphonates 16a,b (Scheme 3).

Asymmetric hydrogenation of β-enamidothiophosphonates catalyzed by iridiumcomplex followed by desulfidation offers a new approach to chiral N,P-ligands. Oshimaet al. developed a convenient method for the synthesis of chiral phosphine sulfides 21.19

The chiral iridium complexes containing chiral ferrocene ligand 20 catalyzed enantios-elective hydrogenation of alkenthiophosphonates 19 with formation of optically active

Scheme 3 Hydrogenation of a- enamidophosphonates 15 catalyzed by Rh/(S)-17 complex.

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Scheme 4 Enantioselective hydrogenation of vinylphosphonates 28 with iridium complexes.

(E)-2-amino-1-thiophosphinylalkanes 21 in high yields and high ee. The subsequent desul-fidation of phosphine sulfides 21 led to the formation of 2-amino-1-phosphinoalkanes 22and optically active phosphines 23a,b, that can serve as ligands in asymmetric reactions(Scheme 4).

Boerner et al. showed that the Rh-catalyzed asymmetric hydrogenation of prochiralβ-N-acetylamino-vinylphosphonates leads to the formation of chiral β-N-acetylamino-phosphonates with excellent yields (up to 100%) and with high enantioselectivities (89–92%ee) (Scheme 5). The reaction was dependent on the chiral bidentate phosphorus ligand andthe solvent was employed. In some cases, an inversion of the induced chirality was observedby using the corresponding E- or Z-isomeric substrates.30 Catalysts were generated in situby mixing [Rh(СOD)2]BF4 with equimolecular amount of bidentate phosphorous ligand.The phosphines 27,28,30 were the most effective among 240 chiral ligands. The highestenantioselectivity was achieved in dichloromethane or THF, at room temperature and athydrogen pressure of 4 bar. The optical purity of hydrogenation products was defined byHPLC, however, absolute configurations of products were not reported.30

Doherti et al.31 have reported that rhodium complexes with (R,S)-JOSIPHOS 30 or(R)-Me-CATPHOS 28 ligands are effective catalysts for the asymmetric hydrogenation of(E)- and (Z)-β-aryl-β-(enamido)phosphonates. At the same time well-known ligands suchas TangPhos 29, PHANEPHOS 31, and DuPhos 13 were ineffective. These complexes,Rh/16 and Rh/28, form the complementary pair of catalysts for the efficient asymmet-ric hydrogenation of (E)- and (Z)-β-aryl-β-(enamido)phosphonates, respectively. In themajority of cases, the hydrogenation with these catalysts afforded phosphonates in goodyields (72–97%) and with very good enantioselectivity (99% ee). Authors reported opticalrotations of products, however, absolute configurations were not determined (Table 2).

Phosphine–phosphinites and phosphine–phosphites are examples of nonsymmetricligands that differ in the electronics and the sterics of their respective binding groups.32a–c

Numerous phosphine–phosphinite and phosphine–phosphite ligands were described for thelast few years.

The P-OP ligands studied in the asymmetric hydrogenation encompass diverse carbonbackbones and stereogenic elements between the two phosphorus functionalities, and manyof them provide a highly stereodifferentiating environment around the catalytic rhodiummetal center. The hydrogenation of various functionalized alkenes catalyzed by Rh/P-OP

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Scheme 5 Asymmetric hydrogenation of b-N-N-vinylphosphonates with rhodium complexes.

complexes led to the formation of products with high enantioselectivities even at lowloadings of the catalyst.

For example, Pizzano et al. studied the hydrogenation of β-(acylamino)vinylphospho-nates 34 with Rh/P-OP catalysts 36 leading to the formation of β-acyliminophosphonates 35with enantioselectivities up to 99% ee.32a The analysis of the obtained results showed that the

Table 2 Enantioselective hydrogenation of (E)-/(Z)-β-aryl- β-(enamido) phosphonates with rhodium complexescontaining ligands (R, S)-JOSIPHOS 30 and (R)-Me-CATPHOS 2818

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

(R,S)-30 Z 4-Me 77 99 (+)(R,S)-30 Z H 72 97 (+)(R,S)-30 Z 4-F 66 96 (+)(R,S)-30 Z 4-Cl 81 94 (+)(R,S)-30 Z 4-Br 79 99 (+)(R,S)-30 Z 4-MeO 82 99 (+)(R)-28 E 4-Me 94 99 (+)(R)-28 E H 97 99 (+)(R)-28 E 4-F 78 99 (+)(R)-28 E 4-Cl 80 99 (+)(R)-28 E 4-Br 87 99 (+)(R)-28 E 4-MeO 79 99 (+)

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Scheme 6 Hydrogenation of b-(acylamino)vinylphosphonates.

catalysts containing electron-donating groups P(i-Pr)2 are more active and enantioselectivecompared to the PPh2 substituted catalysts. The NMR studies, about the interaction betweenvinylphosphonates with the catalyst, indicated the formation of chelates with the olefin cisto the phosphite group of Rh(P-OP)+ fragment. In all cases, the catalyst containing (S)-P-OP ligands afforded (R)-enantiomers and, on the contrary, the catalysts with (R)-P-OPligands led to the formation of (S)-hydrogenated products (Scheme 6).The significant attention was given to asymmetric hydrogenation of α- and β-enolphosphonates, as a method for the synthesis of chiral hydroxyphosphonates which,as well as aminophosphonates, reveal diverse and interesting biological and biochemicalproperties. Chiral phosphinic ligands—1,2-bis(alkylmethylphosphino)ethanes (BisP)12 and bis(alkylmethylphosphino)methanes (MiniPHOS) 39—have also displayed ahigh enantioselectivity in hydrogenation of vinylphosphonates 38 catalyzed by rhodiumcomplexes.25,32–35 An important feature of these ligands is that a bulky alkyl group and thesmallest alkyl group (methyl group) are bound to each phosphorus atom. These ligandsform five- or four-membered C2-symmetric chelates, therefore the imposed asymmetricenvironment ensure the high enantioselectivity in catalytic asymmetric reactions. Forexample, the asymmetric hydrogenation of diethyl benzoyloxyethenphosphonate 37catalyzed by Ru/(R,R)-t-Bu-BisP∗complexes was performed in methanol at 4 bar pressureof H2 to result in (S)-α-benzoyloxyethylphosphonates 38 with 93% ee (Scheme 7). Thehydrogenation of enolphosphonates 40 catalyzed by rhodium complexes bearing chiralP-OP ligands 36, as well as in the case of acyliminophosphonates, proceeded with goodenantioselectivity.35 Complexes [Rh(COD)(41)]BF4 show fluxional behavior in solution,consistent with backbone oscillation around the coordination plane (Figure 1). In depends

Scheme 7 The asymmetric hydrogenation of dimethyl benzoyloxyethenphosphonate 37.25

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Figure 1 Stereochemical sense of the asymmetric hydrogenation of 37.35

on steric characteristics of ligands and of substrate, the hydrogenation catalyzed with thesecomplexes provides the products with enantioselectivity >90% ee. A detailed studies ofthe phosphane–phosphite ligands 36 demonstrated an influence of steric characteristicson the enantioselectivities: 98% ee were thus obtained with substrates bearing an alkylsubstituent in the β-position, while for their aryl counterparts values of up to 92% ee wereachieved (Scheme 8).

40

Scheme 8 35

It was reported that Rh/P-OP complexaes are excellent catalysts for enantioselective hy-drogenation of β-(acyloxy)vinylphosphonates (Scheme 9). For example, the hydrogenationof substrates 42 catalyzed by complex [Rh(COD)[(S)-36a,b] BF4 led to the formation ofchiral phosphonates 43 with good yields and enantioselectivities of 95–99% ee.32 Theβ-alkyl substrates are more reactive than β-aryl, and reacted for a short time with fullconversion. The phosphonates 43 were transformed without racemization into correspond-ing alcohols. For example, the deprotection of a phosphonate 43, gives easy access toβ-hydroxy-γ -aminophosphonic acid 44 which are precursors of biologically interestingphosphono-Gabob. The magnitude of coupling constants of the 31P nuclei in NMR spectraof P-OP ligand indicated a cis olefin coordination to the phosphite (Figure 2).32

Wang et al. developed an enantioselective method for the synthesis of α-benzyloxyphosphonates by hydrogenation of enolphosphonates 37, including β-aryl-,β-alkoxy-, and β-alkylsubstitutes substrates, in the presence of rhodium complexescontaining unsymmetrical phosphin–phosphoramidite ligand 17a or THNAPhos 45.As a result of asymmetric hydrogenation, the phosphonates 46 were prepared withvery high enantioselectivities up to 99.9% ee (Scheme 10).36 Rhodium complexes withphosphine-aminophosphine ligands 17а also displayed good enantioselectivity that attained

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R=Me, i-Pr, Bu, 4-MeC6H4, 4-MeOC6H4, 4-BrC6H4, 2-naphthyl, CH2NHBoc; R’=Ph, t-Bu

Scheme 9

Figure 2 The coordination mode of vinylphosphonates for a complex {Rh(42)[(S)-36b]}BF4.

97% ee in asymmetric hydrogenation of dimethyl α-benzoylooxyetenphosphonates 46,containing α-aryl, α-alkyl, and α-alkoxy substituents. Besides the enantioselectivity ofphosphine-aminophosphine ligands 17a was higher than this one of well-known BoPhozand DuPhos ligands (Table 3).

Hydrogenation of enolphosphonates 37 in the presence of cationic rhodium catalystsLig/Rh(COD) OTf containing C2-symmetric ligands (Lig= BPE 14a, b or DuPHOS 13a-d) occurred with good ee at room temperature and low pressure of hydrogen. The higheststereoselectivity for the unsubstituted enolphosphonates 37 was obtained with Et-DuPHOS-Rh catalyst. Alkyl-substituted enolbenzoate substrates 37 were reduced with optimum ee’susing the less bulky Me-DuPHOS-Rh as shown in Scheme 11.24

Chiral phosphine–phosphoramidite ligand 47, (S)-HY-Phos, which was preparedby simple two-step method from 1-naphthylamine and BINOL-phosphite, was success-fully applied for the Rh-catalyzed asymmetric hydrogenation of functionalized olefins,including α-(acetamido) cinnamates, enamides, and enolphosphonates, with 98–99%

Scheme 10 Asymmetric hydrogenation of a-enolphosphonates.

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

Entry Lig R Solvent yields (%) ee (%) (config) Refs

1 14a Ph CH2Cl2 96 92 182 45 Ph CH2Cl2 — 99.4 263 45 p-FC6H4 iPrOH — 99.9 264 45 p-ClC6H4 iPrOH — 99.9 265 45 p-An iPrOH — 99.9 266 45 m-An iPrOH — 99.8 267 45 m-ClC6H4 iPrOH — 99.3 268 45 o-ClC6H4 iPrOH — 99.9 269 45 1-nphth iPrOH — 99.2 2610 13 2-thienyl CH2Cl2 — 99.3 2612 17a p-FC6H4 CH2Cl2 99 96 (+) 1813 17a p-ClC6H4 CH2Cl2 98 94 (+) 1814 17a p-BrC6H4 CH2Cl2 95 97 (+) 1815 17a p-NO2C6H4 CH2Cl2 99 95 (+) 1816 17a p-An CH2Cl2 99 95 (S) 1817 17a m-An CH2Cl2 98 96 (+) 1819 17a 1-nphth CH2Cl2 98 95 (+) 1820 17a 2-thienyl CH2Cl2 98 95 (+) 1821 17a H CH2Cl2 94 93 (S) 1822 17a Me CH2Cl2 99 96 (S) 1823 17a Et CH2Cl2 99 96 (S) 1824 17a (CH2)9CH3 CH2Cl2 97 96 (S) 1825 17a OMe CH2Cl2 99 94 (S) 1826 17a OEt CH2Cl2 99 93 (+) 1811 17a Ph CH2Cl2 98 96 (S) 1827 17b Ph CH2Cl2 97 85 (S) 18

ee (Scheme 12).42,43 It was also reported asymmetric hydrogenation of vinylphospho-nates 45 catalyzed by rhodium complexes, containing (R,R)-TADDOL or (S)-BINOL-phosphite derivatives of indole. By means of these catalysts, enantiomerically enriched(S)-phosphonates 46 with yields of 32–82% ee were obtained.47

Rhodium complexes containing ClickFerrophos II 50 and (R)-MonoPhos 51 ligandswere used as catalysts for the hydrogenation of various unsaturated phosphonates.38–41Thehydrogenation of α, β-unsaturated phosphonates 48 in the presence of Rh/ClickFerrophoscatalysts including β-alkyl, aryl-, and β-dialkylphosphonates, (Z)-β-enolphosphonates,α-phenylethylphosphonates, allowed to prepare corresponding chiral phosphonates in

37

Scheme 11 Asymmetric hydrogenation of vinylphospho- 192 nates 45 catalyzed by rhodium complexes.

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R=H, Me, Et, n-C10H21, Ph, p-FC6H4, p-O2NC6H4, p-An, m-An, m-ClC6H4, o-ClC6H4, EtO, i-PrO

Scheme 12 Asymmetric hydrogenation of α- or β-acyloxy α,β-unsaturated phosphonates 45.

Scheme 13 Asymmetric hydrogenation of phosphonates 48.

good yields and with high enantioselectivities (up to 96% ee). Zhang49 reported thatRh(I) complexes of monodentate phosphoramides bearing primary amines (DpenPhos)52 effectively catalyze asymmetric hydrogenation of α- or β-acyloxy α,β-unsaturatedphosphonates 45,48, providing the corresponding biologically important chiral α- or β-hydroxyphosphonates 46,49 with high enantioselectivities (93–96% ee) (Scheme 13).

Asymmetric hydrogenation of alkenephosphonates represents attractive method forthe preparation of chiral alkylphosphonates and chiral tertiary phosphine oxides that canbe used as new potent drugs or new chiral ligands. Genet and Beletzskaya26,27 reported in2001 enantioselective hydrogenation of vinylphosphonates 53 catalyzed by complexes ofiridium containing phenyloxazoline ligands 55−57. Effectiveness of chiral iridium catalysts(70–94% ee) was proved on a number of substrates. For example, the optically active 1-arylethylphosphinates 54е, that are phosphorous analogues of Naproxen [Ar=2-(6-MeO-Nphth)] were synthesized with 92–95% ee by hydrogenation of vinylphosphonates in

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Scheme 14 Hydrogenation of unsaturated phosphonates catalyzed by rhodium and iridium complexes.

methylene chloride, at room temperature. or weak heating and H2 pressure 5–60 bar(Scheme 14).

A number of chiral alkylphosphonates 59 bearing a β-stereogenic center were syn-thesized by catalytic hydrogenation of corresponding β-substituted α, β-unsaturated phos-phonates 58 using the rhodium complexes, with ferrocene-based monophosphoramiditeligands 60 (Scheme 15). Under the mild hydrogenation conditions, the hydrogenation pro-ceeded with 100% conversion to give products with high enantioselectivities: 99.5% ee incase of (E)-substrates, and 98.0% ee in case of (Z)-substrates. The hydrogenation with theRh/(Rc, Sc)-FAPhos catalyst led to the formation of compounds 59 with (R)-absolute con-figuration,42 though in other cases the absolute configurations of products were not defined.Asymmetric hydrogenation of β,γ -unsaturated phosphonates catalyzed by Rh/(Rc,Sc)-FAPhos-Bn complex led to the formation of chiral β-substituted alkaneposphonates 61with 98% ее (Scheme 16).43

Scheme 15

Scheme 16 Enantioselective catalytic hydrogenation of vinylphosphonates.

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Scheme 17 Asymmetric hydrogenation of carboxyethylvinylphosphonates.

Diphenylvinylphosphine oxides and di- and trisubstituted vinylphosphonates 62 were em-ployed as substrates in asymmetric hydrogenations catalyzed by iridium complex 64. Com-plete conversions and excellent enantioselectivities (up to and above 99% ee) were observedfor a range of substrates with both aromatic and aliphatic groups at the prochiral carbon.The big number of compounds 63 with high enantioselectivities were described. The hy-drogenation of electron-deficient carboxyethylvinylphosphonates was also carried out withstereoselectivity up to 99% ee (Scheme 17).44

Chiral 1-aryl- or 1-alkyl-substituted ethylphosphonates 66 were synthesized with enantiose-lectivities of 92–98% ee and very good yields by asymmetric hydrogenation of correspond-ing 1-aryl or 1-alkyletenylphosphonates in the presence of rhodium complexes containingP-chiral aminophosphine-phosphine BoPhoz-type ligands 37. Authors reported that this cat-alyst is especially effective for the asymmetric hydrogenation of 1-aryletenylphosphonates.Indeed, a number of substrates were hydrogenated with this catalyst with enantioselectivityup to 98% ee. Hydrogenation proceeded under soft conditions (room temperature, 10 barH2, and 0.2 mole% of catalyst) to provide the best result in catalytic asymmetric synthesisof chiral 1-aryl or 1-alkylsubstituted ethylphosphonates 66 (Scheme 18).45, 46

Hydrogenation of C=О bonds. Chiral complexes of transition metals catalyze hydro-genation of prochiral ketones.47,48 From the practical point of view, catalytic asymmetrichydrogenation of ketophosphonates is one of convenient methods for the synthe-sis of chiral hydroxyphosphonates.16–20 Asymmetric catalytic synthesis of α-aminoand α-hydroxyphosphonates 69 attracts a great interest because of pharmaceutical

Scheme 18 Asymmetric hydrogenation of substrates 65 with catalyst Rh/(SC, RFe, RP)-67.

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Scheme 19 Catalytic asymmetric hydrogenation of ketophosphonates.

activity of such compounds. The described synthetic approaches are based on theasymmetric hydrogenation using various catalysts, in particular Ru(II)–BINAP com-plexes.50 Noyori and coworks19–21 in 1995–1996 disclosed that Ru(II)–BINAP (1 mol%[RuCl2(R)-BINAP](dmf)n) complexes catalyze the enantioselective hydrogenation ofβ-ketophosphonates 68 in methanol under low pressure hydrogen and at 30◦C withformation of corresponding β-hydroxyphosphonates in very high yields and with 97%ee. The hydrogenation with a (S)-BINAP-Ru(II) catalyst afforded predominantly the(R)-products, while the (R)–BINAP complexes formed the (S)-enriched compounds(Scheme 19).

Racemic α-acetamido-β-ketophosphonates 70 in the presence of (R)-BINAP-Rucatalyst were hydrogenated to (1R,2R)-hydroxyphosphonates 71 with high diastereose-lectivity (syn:anti=97:3) and with enantioselectivity of 98% ee (Scheme 20). Then theproduct (1R,2R)-70 was successfully transformed into enantiomerically pure (1R,2R)-phosphothreonine 72 in 92% yield (Scheme 23).19 The hydrogenation of racemic, con-figurationally labile rac-70 led to the formation of four diastereomeres (1R,2R)-, (1R,2S)-,(1S,2R)-, and (1S,2S) -71. The optimization of reaction conditions and high stereoselec-tivity of (R)-BINAP ligand allowed to obtain predominantly (1R,2R)-α-amido hydrox-yphosphonates 71 with high enantio- and diastereo selectivity (98:2 dr and 95% ee forsyn-isomer). The acid hydrolysis of 71 afforded phosphothreonine in good yield.20 By thismethod, phosphaalanine, phosphaethylglycine, and phosphaphenylalanine were obtainedwith high enantiomeric purity. It was noticed that (E)-alkenes are more reactive than their(Z)-isomers.21

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Scheme 20

Scheme 21

Noyori developed a method for the synthesis of antibiotic fosfomycin 74 usingasymmetric hydrogenation catalyzed by BINAP-Ru complex. The fosfomycin 74 wasobtained in 84% yield, with 98% ee and with syn:anti ratio—90:10, starting from racemicβ-keto-α-bromphosphonate rac-72 (Scheme 21).20

Genet in 1996 reported the asymmetric hydrogenation of ketophosphonates catalyzedby chiral (S)-BINAP-Ru 68 and (R)-MeO-BIPHEP 76 complexes and obtained hydrox-yphosphonates 75 with high yields and enantioselectivities up to 99% ee (Scheme 22).51,52

Authors used chiral Ru(lI) catalysts for hydrogenation of a number of β-ketophosphonatesand β-ketothiophosphonates, including compounds bearing heterocycles. Asymmetric hy-drogenation of diethyl 2-oxopropylphosphonate at atmospheric pressure and 50◦C with(S)-Binap led to the formation of β-hydroxyphosphonates 75 with a complete conversionand with 99% ee.

Dynamic kinetic resolution of α-amido-β-ketophosphonates 70 by asymmetric hy-drogenation in the presence of atropoisomeric ruthenium catalysts 78,79 containing Sun-Phos ligands led to the formation of corresponding β-hydroxy-α-amidophosphonates 77with high diastereoselectivities (up to 99:1 dr) and enantioselectivities (up to 99.8% ee).Catalysts were prepared using atropoisomeric (S)-SunPhos ligands and [RuCl2(benzol)]2.Hydrogenation was carried at hydrogen pressure 10 bar, 50◦C in methanol to result in chiralphosphonates 77 with 98.0% ee and sin/anti ratio of 97:3 (Scheme 23).49,54

Scheme 22 The asymmetric hydrogenation of ketophosphonates catalyzed by chiral (S)-BINAP-Ru 68 and(R)-MeO-BIPHEP 76 complexes.

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Scheme 23 Dynamic kinetic resolution of a-amido-b-ketophosphonates 70 via asymmetric hydrogenation cat-alyzed by ruthenium complexes.

Hydrogenation of methyl, ethyl, and isopropyl (2-oxo-2-phenylethyl)phosphonatesled to the formation of alcohol 81 with 99.7, 95.5, and 90.0% ee, correspondingly. It wasfound that additives increase diastereo- and enantioselectivities of reaction. For example,the addition of catalytic amounts of CeCl3.7H2O raised the stereoselectivity of reactionto 99:1 dr and 99.8% ee.53 Electron-donating groups in para-position of phenyl group ofketophosphonates increased yields and ee values of products, while electron-withdrawinggroups reduced chemical yields (Scheme 24).

Scheme 24 Hydrogenation of β-ketophosphonates 80 with Ru-(S)-SunPhos catalyst 79.

Goulioukina and coworks55 reported the reduction of ketophosphonates catalyzed by pal-ladium catalyst, with BINAP or (R)-MeOBIPHEP ligands leading to the formation ofhydroxyphosphonates with high yields and moderate enantioselectivities (30–55% ee).

3. ASYMMETRIC CATALYTIC HYDRIDE REDUCTION

Enantioselective reduction of prochiral ketophosphonates is one of important meth-ods for the preparation of enantioenriched hydroxyphosphonates that are important biologi-cally active compounds and initial reagents for the synthesis of many enantiopure products,including natural compounds.12,55 Various methods for the enantioselective reduction ofketo- and ketiminophosphonates were developed, including reduction with chirally modi-fied boranes, complex metal hydrides, biocatalytic reduction, and others. A number of enan-tioenriched hydroxyphosphonates and aminophosphonates were prepared by this method.Biocatalytic reduction was also developed in the last years.

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One of the best methods for asymmetric catalytic reduction of ketophosphonates isreduction with chiral-modified borohydrides. Besides the borohydride anion (BH4

−) canbe modified by chiral counterion, hydrides can be substituted by chiral alcohol, carboxylicacids, alcoholic acids, and hydroxy amines. Chiral-modified borohydrides immobilized ona polymere were also applicable for reusing. Asymmetric CBS (Cory, Bakshi, Shibata)catalytic reduction (enantioselective reduction using borane and a chiral oxazaborolidineas CBS catalyst) represents an effective method for the preparation of various chiral alco-hol.56,57

Reduction of C=О bonds. Using the reduction of α-ketophosphonates 82 with thecatecholborane as a reducing reagent and the oxazaborolidine 84 as a catalyst, enantiomer-ically enriched hydroxyphosphonates 85 were synthesized with good enantioselectivities(Scheme 25).58–61 Enantioselective reduction of α-ketophosphonates led to the formationof α-hydroxyarylmethylphosphonates 86–88 with enantioselectivities from moderate togood (up to 80% ee). Mayer investigated the mechanism of catalytic reduction by ab initioМО calculations (Figure 3).58 According to Corey’s model, the carbonyl group of the α-ketophosphonates 82 is complexed to the boron atom of the (S)-2-n-butyloxazaborolidine84c in such a way that the hydride from the borane complexed to the nitrogen atom attacksthe carbon atom from the Re face. This leads to the differentiation of the two residues flank-ing the carbonyl group: the phosphoryl group is the “large” substituent, whereas the aromaticsystem is the “small” group. The co-ordination of borohydride with oxazoborolidine nitro-gen atom increases acidity of intracyclic boron atom to facilitate the reduction of ketone 82.

Scheme 25 Enantioselective reduction of ketophosphonates 82 by catecholborane 83.

The reduction of diethyl α-ketophosphonates 89 with borane catalyzed by chiral (S)- or (R)β-butyloxazoborolidines (Cat) yielded the diethyl (S)- or (R)-1-hydroxyalkylphosphonates90 in good yields and moderate enantiomeric excesses (53–83% ee) (Scheme 26). The

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

reduction of α-ketophosphonates 89 with (S)-oxazaborolidine-catecholborane led to theformation of (S)-1-hydroxylkylphosphonates (S)-90 and, correspondingly, the reductionwith the (R)-oxazaborolidine-catecholborane afforded (R)-1-hydroxylkylphosphonates 90with the same stereoselectivity.

Cat=β-butyloxazoborolidine, R=Me, Et, (1R,2S,5R)-Mnt; R’=Et, Bu, i-Bu, Ph

Scheme 26 Reduction of α-ketophosphonates 89 with (S)-oxazaborolidine-catecholborane.

Enantiopure carboxylic acids of natural origin were applied for chiral modifications ofborohydrides.62–75 In particular, chiral reductant NaBH4-Pro 92 obtained from NaBH4 andL-proline reduced ketophosphonates 89 with 50–70% ee. This reducer was applied for thesynthesis of a number of hydroxyphosphonates 91 (Scheme 27).62, 63

Interesting method is enantioselective reduction of ketophosphonates by borohydridesin the presence of tartaric acid.64–67 Natural (R,R)-(+)-tartaric acid and borohydride formchiral complex that is a convenient stereoselective reagent for reduction of ketophospho-nates.67,70 Reduction of ketophosphonates 94 with this complex was performed at coolingto −30◦C in THF. Reduction of diethyl α-ketophosphonates 94b with the NaBH4/(R,R)-TAchiral complex yielded diethyl (1S)-α-hydroxybenzylphosphonates 93 with optical purityup to 60%, whereas reduction of dimenthyl ketophosphonates 94c led to formation of(1S)-α-hydroxybenzylphosphonates 95c with purity up to 80–93% de. The stereoselectiv-ity of reduction of ketophosphonates 94 containing chiral menthyl groups at phosphorusatom with NaBH4/(R,R)-TA was higher than in case of ketophosphonates containing atphosphorus achiral methyl or ethyl groups (Table 3 and Scheme 28). Higher stereoselectiv-ity of reduction in the case of dimenthyl arylketophosphonates were explained by doubleasymmetric induction.68–76

Reduction of chiral di-(1R,2S,5R)-dimenthyl ketophosphonates 94b with chiral complex(R,R)-TA/NaBH4 proceeded under control of a double asymmetric induction to affordthe (S)-β-hydroxyphosphonates 95 with more high enantioselectivity, than in the case ofreduction of diethyl 2-ketophosphonates 96a (Table 4).77

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Scheme 27 Reduction of acylphophonates with NaBH4-Pro 92.

Examination of the lowest energy conformations for β-ketophosphonates, applyingthe PC MM+ method for the geometry minimization and energy assessment, showed thatthe nucleophilic attack of the hydride may occurs via the less hindered Si face, leadingto the corresponding (S)-β-hydroxyphosphonate as the major. The stereoselectivity of β-ketophosphonate reduction is considerably higher than that of α-ketophosphonates becausewith NABH4/TA they form more stable intermediate complex a, than b (compare the Figures4a and 4b).

For example, stereoisomers of dimenthyl 2-hydroxy-3-chloropropylphosphonate (S)-and (R)-97b were prepared with optical purity of 96% ee.70 These compounds rep-resent useful chiral synthons (chirons) for the synthesis of enantiomerically pure β-hydroxyphosphonates (Scheme 29).69–78

By means of chirons 97, several biologically important derivatives of chiral β-hydroxyphosphonates were obtained: 2-hydroxy-3-azidopropylphosphonates, phosphono-Carnitin 103, γ - amino-β-hydroxypropylphosphonic acid (phosphono-GABOB), and 101in multigram quantities.69

The 2-hydroxy-3-aminobutyric acid (GABOB) is an important amino acid, acting asan antimimetic and hypotensive drug, and is an agonist of γ -aminobutyric acid (GABA).

Scheme 28 The reduction of ketophosphonates 94 with NaBH4/(R,R)-or (S,S)-TA.

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Table 4 Asymmetric reduction of ketophosphonates to hydroxyphosphonates

Entry R R′ n Yield (%) A Configee

(%)

1 Ph Mnt 0 90 L-Pro S 52.62 2-F-C6H4 Mnt 0 90 L-Pro S 79.23 2-An Mnt 0 90 L-Pro S 60.63 Ph Mnt 0 95 L-TA R 92.44 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

Scheme 29 Stereoisomers of dialkyl 2-hydroxy-3-chloropropylphosphonate (S)-and (R)-97a,b.

As a neuromodulator, it is effective in managing a variety of clinical conditions includ-ing schizophrenia, epilepsy, and other character-based disorders.79–83 For these reasons,many synthetic routes to GABOB analogues have been developed.84–87 The enantiose-lective synthesis of (S)-phospho-GABOB was achieved using a Baker’s yeast-mediatedbio-reduction of diethyl 2-oxo-3-azidopropylphosphonate.85 Wroblewski reported the syn-thesis of phospho-GABOB by means of the regioselective opening of the oxirane ring ofdiethyl (S)-2,3-epoxypropylphosphonate with tritylamine, followed by hydrogenolysis ofthe trityl group and hydrolysis of the ester group.86,87

The efficient approach to enantiomerically pure (R)-2-hydroxy-3-aminopropylphosp-honic acid P-GABOB was attained by reduction of β-ketophosphonates with chiralcomplex (R,R)-TA/NaBH4. In the first step, optically pure dimenthyl (S)-2-hydroxy-3-chloropropylphosphonate 97b was treated with K2CO3 in acetonitrile in the presenceof KI to afford the optically pure epoxide (R)-98 in good yield. Then the epoxide ring

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Figure 4 Stereochemical model of the reduction of α-ketophosphonates (a) and β-ketophosphonates (b) with theNaBH4/(R,R)-TA.

in the phosphonate 98 was opened regioselectively with N,N-dibenzylamine at C-3 toyield the crystalline dimenthyl (R)-2-hydroxy-3-(N,N-dibenzylamino)propylphosphonate99 (Scheme 30). The 2-hydroxy-3-aminophosphonate (R)-99 was hydrolyzed on heatingwith hydrochloric acid in dioxane to yield 2-hydroxy-3-aminopropylphosphonic acid (R)-100 and without further purification was treated with hydrogen under Pd/C in methanolat 20 ◦C to afford the crystalline (R)-γ -amino-b-hydroxypropylphosphonic acid (R)-101in 74% yield and with 99% ee, that is the phosphonic analogue of naturally occurringGABOB.69

Scheme 30 Synthesis of (R)-2-hydroxy-3-aminopropylphosphonic acid P-GABOB.

The phosphocarnitine, which is phosphonate analogue of natural L-carnitine, playsan important role in the transport of fatty acids into the mitochondrial matrix.88–90

The synthesis of phosphocarnitine was also performed by an chemoenzymatic method,91,92

starting from glycine,93 and other methods.94 The β-hydroxypropylphosphonates 97were treated with Me3SiBr/EtOH or hydrolyzed with HCl in dioxane to afford theβ-hydroxypropylphosphonic acids (S)-102. The free phosphonic acid 102 was reactedwith water solution of trimethylamine to yield the trimethylammonium salt. The reactionmixture was purified by column chromatography with silica gel to give optically

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Figure 5 The conformational analysis of β-hydroxyphosphonates: (a) Newman projection relatively to Сα−Сβ

bond, (b) Newman projection relatively to Сβ−Сγ bond.

pure (R)-phosphocarnitine (R)-103 in high yield.85 The (R)-phosphocarnitine 103 is ahygroscopic crystalline compound, which decomposes on heating (>250◦C). The opticalpurity of compounds was determined by NMR in the presence of chiral solvating agentcinchonidine (Scheme 31).95

Scheme 31 Synthesis of phosphocarnitine.

The stereoselectivity observed was rationalized with the Felkin–Anh97 model for theaddition of hydride to the free carbonyl group. Diastereoisomeric 2-hydroxypropyl-phosphonates 97,103 exist preferentially as anti-conformers (Figure 4). Modeling of amolecule by means of MM+ calculations allows obtaining values of dihedral angles in themost energetically favorable conformations of hydroxyphosphonates 97,103 (Figure 5).These theoretical values coincide with experimental data of dihedral angles obtained on thebasis of NMR spectra by means of Karplus equation that confirms the conclusions

The epoxide 98 was converted consequently into azide 104 and aziridine 105. Thediethyl (2R)-2,3-epoxypropylphosphonate (R)-98 reacted readily with sodium azide inthe presence of ammonium chloride in methanol to afford dialkyl (2R)-2-hydroxy-3-azidopropylphosphonate 103 (Scheme 32). The reaction of azidophosphonates 103 withtriphenylphosphine at room temperature proceeded via the formation of unstable interme-diate A bearing pentacoordinated phosphorus. In 31P NMR spectra of the intermediate twosignals were found: δP 55.1 (pentacoordinated phosphorus) and +26.9 ppm (tetracoordi-nated phosphorus) according to the structure of this compound. Upon heating, 104 convertsinto triphenylphosphine oxide (δP 30.2 ppm) and aziridinophosphonates 105 (δP 29 ppm),which were isolated in good yield. The aziridinophosphonate (S)-105a was purified bydistillation under vacuum and isolated as colorless liquid (Scheme 32).69

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Scheme 32 Synthesis of aziridinophosphonate (S)-105.

Corbett and Johnson98 recently described a method for selective dynamic kinetic resolu-tion of α-aryl acylphosphonates 106, providing β-stereogenic α-hydroxy phosphonic acidderivatives. The reduction of acylphosphonates 106 with formic acid and triethylamine, cat-alyzed by RuCl[(S,S)-TsDPEN] (p-cymene) complex containing chiral aminosulfonamideligand 108, led to the formation of (R)-hydroxyphosphonates 107 with high diastereo- andenantioselectivities up to 99% eе. The absolute configurations of products were establishedas (1R,2R) via X-ray crystallographic analysis, confirming the anti-orientation of the OHand Ar groups (Scheme 33).

Barko et al.99 described the diastereoselective borohydride reduction of β-phthalimido-α-ketophosphonates 109 catalyzed by chiral oxazoborolidines leading tothe formation of β-amino-α-hydroxyphosphonates 110. The reduction of 109 withborohydride–dimethylsulfide complex in THF led to the formation of (S,S)- and(S,R)-diastereomeric mixture 110 (dr = 8:1–10:1), at the same time the reduction ofketophosphonates 109 with catecholborane and oxazoborolidine 84а (12 mol%) in toluene,at −60 ◦C provided only single (S,S)-diastereomer 110 in good yield (Scheme 34).99

Scheme 33 Selective dynamic kinetic resolution of α-aryl acylphosphonates 106.

Reduction of C=N bonds. One of interesting examples of enantioselective reductionof iminophosphonates was reported by Mikołajczyk.100 The CBS catalytic reduction of1-imino-2,2,2-trifluoroethylphosphonates led successfully to the formation of aminophos-phonates. The reduction of 111 with catecholborane (catBH) catalyzed by methyloxaz-aborolidine 84а allowed to obtain aminophosphonates 110 and aminophosphonic acids

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(S, R)-111(s, s)-110

(s, s)-110a-d

Scheme 34 The reduction of ketophosphonates 109 with catecholborane and oxazoborolidine 84a.

Scheme 35 Asymmetric reduction of iminophosphonates 109.

Scheme 36 Synthesis of enantiomerically enriched β-aminophosphonates 115.

111 in 92–98% yields and with 72% ee. Evidently, the starting iminophosphonates 109activated with electron-withdrawing CF3 group are able to coordinate the reagent/catalystcomplex allowing addition of weakly nucleophilic iminophosphonates (Scheme 35).

Palacios and coworks described recently the method for asymmetric synthesis of 2H-azirine-2-phosphonates 113 (Scheme 36).101 The key step of method is a base-mediatedNeber reaction of p-toluenesulfonyloximes derived from phosphonates. Alkaloids andsolid-phase bound chiral amines were used as catalysts. The best results were obtained

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Scheme 37 Borohydride reduction of β-enaminophosphonates 116.

with quinidine (up to 72% ee). In other cases, the stereoselectivity was low or moder-ate. The subsequent reduction of 2H-azirines 119 with sodium borohydride in ethanol gavecis-aziridine-phosphonates 113 with moderate ee (up to 72% ee). The ring opening of enan-tiomerically enriched N-substituted aziridine 113 by catalytic transfer hydrogenation withammonium formate and palladium on carbon led to the formation of enantiomerically en-riched β-aminophosphonates 115. The absolute configuration of β-amino phosphonates 115was established by chemical correlation with enantiomerically pure β-aminophosphonatesprepared by the Karanewsky method from γ -amino alcohols. This correlation also allowedestablishing the absolute configuration of aziridines 113 (Scheme 36).102

R = Ph, 2-An, 3-An, 4-An, 4-BrC6H4, 4-ClC6H4, 4-F-C6H4, 4-NO2-C6H4 3-ClC6H4, Nphth, 2-thienyl

Scheme 38 Reduction of β-enaminophosphonates 116.

Reduction of C=C bonds. Diethyl methylphosphonate was treated by butyllithiumin THF, after which it was reacted with nitriles to form β-enaminophosphonates 116 inhigh yields. Then β-enaminophosphonates 116 were reduced with NaBH4/CaCl2 in theTHF–isopropanol mixture to give β-aminophosphonate 117 as racemates in high yieldor with NaBH-/TA reactant in THF to give β-aminophosphonates with moderate ee. Theaminophosphonates 117 were obtained as hydrochlorides. Free aminophosphonates 117were isolated after the reaction mixture was neutralized with alkali. Aminophosphonates117 were purified by vacuum distillation, and they were isolated as colorless viscous liquids(Scheme 37).103,104

A wide range of 3-aryl-4-phosphonobutenoates 118 were reduced with PMHS in thepresence of (S)-Segphos/Cu(OAc)2 H2O catalyst 119 (1–5% mol) and tert-butanol withenantioselectivities up to 94% ee to give chiral phosphonates 120. Various silanes werescreened (PMHS, PhSiH3, 1,1,3,3-tetramethyldisiloxane) with similar results, althoughPMHS was superior with respect to enantioselectivity. The reduction was influenced by

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steric and electronic effects of the substrates. The substrates having an electron-withdrawinggroup at the para-position of phenyl ring were reduced in higher ee value than those withan electron-donating group (Scheme 38).105

4. CONCLUSIONS

It is hoped that this account devoted to asymmetric reduction of organophosphoruscompounds will be useful to chemists interested in various aspects of organic chemistryand stereochemistry.

It is necessary to note that despite the impressive progress achieved in the synthesisand studies of properties of chiral organophosphorus, not all problems have been solved.The problem of the development of enantioselective methods giving easy access to bothoptical antipodes of phosphonates still remains. The creation of highly effective catalysts forthe asymmetric reduction of ketophosphonates is an important problem, which is currentlywaiting a solution.

FUNDING

This work was financially supported by the State Foundation for Basic Research ofUkraine and the Russian Foundation for Basic Research (joint Project No. F53.3/016).

Abbreviations:

Ac acetylAn anisylAr arylBINOL 1,10-bi-2-naphtholBn benzylBoc tert-butoxycarbonylBu butylBz benzoylcat catalystCOD cyclooctadienCy cyclohexylDBU 1,8-diazabicyclo[5.4.0]undec-7-enede diastereomeric excessDMF N,N′-dimethylformamidedmpe 1,2-Bis(dimethylphosphino)ethaneDMSO dimethylsulfoxideee enantiomeric excessEt ethylFu furanylHex hexylHept heptylL ligandMe methylMes mesylMnt (1R,2S,5R)-menthyl

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MTBE methyl tert-butyl etherNphth naphtylOct octylPent pentylPh phenylPhth phthalimidoPiv pivaloylPMHS polymethylhydrosiloxanePMP p-methoxyphenylPNBA p-nitrobenzoic acidi-Pr isopropylPr propylpy pyridylQ quinineQN quinidineHQN hydroquinidineTA tartaric acidTBDPS tert-butyldiphenylsilylTBS tert-butyldimethylsilylTf triflateTHF tetrahydrofuranTol tolylTIPS triisopropylsilylTFA trifluoroacetic acidTMS trimethylsilylTs 4-toluenesulfonyl (tosyl).

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advances in asymmetric hydrogenation and hydride reduction of organophosphorus compounds

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