palladium-catalyzed asymmetric allylic alkylation

1

B. M. Trost, J. E. Schultz ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XGeorg Thieme Verlag Stuttgart · New York2019, 51, 1–30reviewen

Palladium-Catalyzed Asymmetric Allylic Alkylation Strategies for the Synthesis of Acyclic Tetrasubstituted StereocentersBarry M. Trost* 0000-0001-7369-9121 Johnathan E. Schultz 0000-0002-8261-7711

Department of Chemistry, Stanford University, 335 Campus Drive, Stanford, CA 94305, [email protected]@stanford.edu

Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue Pd

L L

R'

R

NO2

OH

EtO2C

O

O

i-PrNO O

OH

Ph O

O

CO2Me

OH

OO

OH

OPMB

OH

N O

Br

NC

OHOH

PdL L

O

NHAcMeO2CPh

CHO

F

Ph Ot-Bu

O

i-Bu NO2

Ph

O

F

CHO

OTBSO

N

O

Bu

MeO2C

Ph

NH3+OH

O

Cl–

HO

HO

Stereocontrol on prochiral electrophiles

OH

O

Ar

Stereocontrol on prochiral nucleophiles

Received: 23.10.2018Accepted: 24.10.2018Published online: 05.12.2018DOI: 10.1055/s-0037-1610386; Art ID: ss-2018-z0713-r

License terms:

Abstract Over the past 20 years, the asymmetric synthesis of acyclictetrasubstituted stereocenters by Pd-catalyzed asymmetric allylic al-kylation (Pd-AAA) strategies has seen considerable growth. Despite theinherent difficulty in accessing acyclic tetrasubstituted stereocenters,creative approaches toward this problem have resulted in high stereoin-duction on both electrophilic and nucleophilic reaction partners. Muchof this chemistry has paved the way for unique solutions in Mo-, Ir-, andRh-AAA, with many complimentary methods arising due to the uniqueregiochemical outcomes of AAA outside of Pd catalysis.1 Introduction2 Stereocontrol on Prochiral Electrophiles3 Stereocontrol on Prochiral Nucleophiles4 Temporary Cyclic Pronucleophiles5 Allylic Alkylation with Other Metals6 Conclusions and Outlook

Key words allylic alkylation, acyclic stereocontrol, tertiary alcohols, -tertiary amines, quaternary carbon stereocenters

1 Introduction

Palladium-catalyzed asymmetric allylic alkylation (Pd-AAA) stands as a unique reaction due to the high number ofstereocenters that may be created by this process.1 Argu-ably, few transition-metal-catalyzed reactions offer thesynthetic chemist the ability to form C–C, C–N, C–O, C–F,and C–S bonds by such a variety of mechanisms for asym-metric induction (Scheme 1). The development of Pd-AAAhas been reviewed elsewhere; however, a specific aspect ofPd-AAA has significantly matured over the past 20 years,namely the synthesis of acyclic tetrasubstituted stereocen-ters.2

Pd-AAA has been shown to be successful for inducingasymmetry on both electrophilic and nucleophilic partners.Consequently, this review is divided into these two classesof reactions, with an emphasis on vinyl epoxides as electro-philes and enolates as prochiral nucleophiles. We concludewith a discussion on cyclic pronucleophiles that are readilyconverted into acyclic tetrasubstituted stereocenters subse-quent to the alkylation reaction, as well as some importantadvances made with other metals.

Scheme 1 Examples of stereocenters formed in Pd-AAA reactions

2 Stereocontrol on Prochiral Electrophiles

In the case of Pd-allylic alkylation, the most commonmechanism operative involves an initial coordination of achiral Pd(0) catalyst with an olefin bearing a leaving groupat the allylic position (Scheme 2). Ionization occurs with in-version, where the η2--allyl–Pd(II) complex is situated onthe opposite face to the leaving group. Alkylation of the η3--allyl–Pd(II) complex occurs with inversion of the stereo-chemistry about Pd(II), with simultaneous regeneration ofthe chiral Pd(0) catalyst. Because both the ionization andnucleophilic addition occur with inversion, the nucleophilic

Ph

O

SO2t-Bu

PhNNBn

O

BnO

F

OH

Ph Ph

PPh2

PdLn*

R1 R2

C–FC–C

C–S C–O

C–PC–N

Ph

Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1–30

http://orcid.org/0000-0001-7369-9121

http://orcid.org/0000-0002-8261-7711

2


substitution occurs with net retention of the stereochemis-try of the leaving group. An outer-sphere attack of a nucleo-phile is the most common pathway for soft nucleophiles(pKa <25). For hard nucleophiles, the nucleophile attacksthe metal directly and undergoes an inner-sphere reductiveelimination with retention of stereochemistry about Pd(II),and overall net inversion of stereochemistry.

Nucleophiles such as ketone enolates alkylate at the -carbon, producing a stereocenter on the nucleophile. In thiscase, asymmetric induction can be difficult to achieve sincethe C–C bond forming event most commonly occurs via anouter-sphere mechanism and the nucleophile remains dis-tal to the chiral information about the metal–ligand envi-ronment. This mode of asymmetric induction will be dis-cussed in Section 3.

Alkylation of allyl electrophiles bearing substituents, al-though typically much easier substrates for obtainingasymmetric induction, operate via more complicatedmechanisms involving –– equilibration of the -allyl in-termediate (Scheme 3d). Additionally, the enantiodeter-

mining step of the reaction may occur during any step ofthe catalytic cycle, save for dissociation of the alkylationproduct. In Pd-AAA, only two mechanisms are likely to be

Scheme 2 Mechanism of regio- and stereospecific Pd-catalyzed AA

X

R

Complexation

IonizationNucleophilicAttack

ProductDissociation

Nu

R'

Pd0Ln

Pd(II)Ln

R R'

R

Pd0Ln

Nu

R'R

Pd0Ln

X

R'

Nu

R

X

R'I

III

IV

V

VI II

Biographical Sketches

Barry M. Trost was born inPhiladelphia, Pennsylvania. Heobtained a BA degree from theUniversity of Pennsylvania in1962 and Ph.D. degree justthree years later at the Massa-chusetts Institute of Technology(1965). He directly moved tothe University of Wisconsinwhere he was promoted to Pro-fessor of Chemistry in 1969 andsubsequently became the VilasResearch professor in 1982. Hejoined the faculty at Stanford asProfessor of Chemistry in 1987and became Tamaki Professor ofHumanities and Sciences in1990. In addition, he has beenVisiting Professor in Germany(Universities of Marburg, Ham-burg, Munich, and Heidelberg),Denmark (University of Copen-

hagen), France (Universities ofParis VI and Paris-Sud), Italy(University of Pisa), and Spain(University of Barcelona). He re-ceived honorary degrees fromthe Université Claude-Bernard(Lyon I), France (1994), andTechnion – Israel Institute ofTechnology, Haifa, Israel (1997).In recognition of his many con-tributions, Professor Trost hasreceived a large number ofawards, a few among which arethe ACS Award in Pure Chemis-try (1977), the Dr. Paul JanssenPrize (1990), the ASSU GraduateTeaching Award 91991), BingTeaching Award (1993), the ACSRoger Adams Award (1995), thePresidential Green ChemistryChallenge Award (1998), theBelgian Organic Synthesis Sym-

posium Elsevier Award (200),The ACS Nobel Laureate Signa-ture Award for Graduate Educa-tion in Chemistry (2002), theACS Cope Award (2004), theNagoya Medal (2008), the RyojiNoyori Prize (2013), the Interna-tional Precious Metals Insti-tute’s Tanaka DistinguishedAchievement Award (2014), theGerman Chemical Society’sAugust-Wilhelm-von-HofmannDenkmünze (2014), the Tetra-hedron Prize (2014), and theACS Linus Pauling Award(2015). Professor Trost has beenelected a fellow of the AmericanAcademy of Sciences (1982)and a member of the U.S. Na-tional Academy of Sciences(1980).

Johnathan E. Schultz grewup in the southwestern NorthDakota and west-central Minne-sota. He attended North DakotaState University in Fargo, NDwhere he graduated SummaCum Laude with a BS degree inChemistry and a minor in Math-

ematics. He conducted under-graduate research in thelaboratories of Gregory R. Cookwith research studies on thesynthesis of isoform selectivehistone deacetylase inhibitors aswell as nucleophilic allylationmethodology. He is currently

pursuing his Ph.D. studies atStanford University as a re-search assistant in the laborato-ries of Barry M. Trost. Hisresearch has focused on Pd-cat-alyzed allylic alkylation strate-gies for the synthesis of acyclictetrasubstituted stereocenters.


3



operative in the synthesis of acyclic tetrasubstituted stereo-centers on the electrophile, namely differentiation of enan-tiotopic olefin faces (Scheme 3b) and –– equilibration(Scheme 3d). In most cases, the chiral ligands employed inPd-AAA are phosphines, and a variety of scaffolds have aris-en from the many creative approaches toward acyclic ste-reocontrol in allylic alkylation (Figure 1).

Scheme 3 Modes of asymmetric induction on electrophile

Differentiation of enantiotopic termini

PdLn

R R Nu

– PdLn*

R R

Nu

Differentiation of enantiotopic leaving groups

R

X

X PdLn*

– X PdLn

R X

X

X PdLn*

– X

X

PdLn

Differentiation of enantiotopic olefin faces

Pd

R'

Nu

– PdLn*

R'

Nu

– X

π−σ−π Equilibration

PdL L

R'

R R

R'

PdLL

Ha

Hb

R

R'Pd

L

LHaHb

PdL L

R'

R

R'X

Pd R

R

R*Ln *Ln

a) b)

c) d)

Figure 1 Structures of chiral ligands used in Pd-AAA strategies toward acyclic tetrasubstituted stereocenters

HNNH

PPh2 Ph2P

O O

(R,R)-TrostL1

HNNH

PPh2 Ph2P

O O

(R,R)-TrostL2

Ph Ph

NH HNO O

Ph2PPPh2

(R,R)-TrostL3

NH HNO

PPh2

O

Ph2P

(R,R)-TrostL4

HNNH

N N

O O

(R,R)-TrostL5

PPh2

PPh2

(R)-BINAPL13

PPh2 N

O

PHOXL21

Ph

CH2OH

O

OP

O

OH

i-Pr

i-Pri-Pr

i-Pr

i-Pri-Pr(S)-TRIP L15

O

OMe

2-naphthyl

2-naphthyl

Ar2P

Me3N

NH HNO

PAr2

O

Ar2P CF3F3C

Ar = 4-CF3C6H4

(R,R)-Trost

L16

N

PPh2

(R)-QUINAPL22

PPh2 N

O

(S)-t-Bu-PHOXL19

t-Bu

P N

O

t-Bu

Di-CF3-(S)(t-Bu)-PHOX L20

CF3

F3C

CF3

PAr2 Ar2P

L17 (R,R,R)-Xyl-SKP

SNH

OH

O

MeO

F

F

F

F

O O

L18

Ar = 3,5-Me2C6H3

MeO

MeO

P

P

O

O

2

2

(R)-L7

Fe PPh2

PPh2

NMe

(R)-(S)-L9

O

N

OO

N

2

Me

FePh2P

Ph2P

N

3

O

N

O

O

Me

(S)-(R)-L10

Fe FeR

Ar2P

(S,S)-(R,R)-TRAP

Ar = 4-MeOC6H4, L11Ar = Ph, L12

HR =

Fe

N OP

Et2N

O

OH

(S,RPHOS,R)-L8

Fe

N OP

Et2N

O

OH

i-Pr(S,SPHOS,R)-L14

Ph

Ar = 4-ClC6H4

L6

4


2.1 Reactions of Isoprene Monoepoxide

The potential of achieving Pd-AAA with isoprene mon-oepoxide (1) was an attractive pursuit, due to the prospectof achieving high enantioinduction for alkylation at thebranched position (Scheme 4). The Trost group hasachieved branch-selective alkylation for carbon,3 oxygen,4,5

and nitrogen6–8 nucleophiles, affording valuable chiral acy-clic tetrasubstituted building blocks containing orthogonalhydroxymethyl and vinyl functional group handles.

Scheme 4 Pd-AAA strategy for the synthesis of acyclic tetrasubstitut-ed building blocks using electrophilic isoprene monoepoxide

These reactions constitute a dynamic kinetic asymmet-ric transformation (DYKAT), whereby racemic isoprenemonoepoxide is ionized by a palladium catalyst, with theinitially formed -allyl species bearing an opposite sense ofchirality or opposite syn/anti configuration9 (Scheme 5).Since the unbranched terminus of the -allyl contains twohydrogen substituents, the η1--Pd(II) complex allows forrotation from one stereoisomer isomer to the other withoutsyn/anti isomerization (Scheme 5a). Although –– equil-

ibration may occur at the branched carbon (Scheme 5b),this pathway is unproductive since both the -allyl stereo-chemistry and the syn/anti configuration have isomerized.

An important structural consideration for this reactionalso involves the equilibrium between syn and anti isomers(Scheme 6). Upon ionization of butadiene monoepoxide (2),diastereomeric -allyl complexes are formed. The hy-droxymethylene substituent is sterically more hinderedthan the hydrogen substituent; consequently, complex 2a isthe most favored complex due to the least amount of stericclash with the ligand environment. The regioselectivity ofnucleophilic addition runs counter to that typically ob-served for Pd-AAA, where the branched isomer is formed inhigh selectivity. The ‘wall and flap model’ shows the ap-proximate chiral environment about each terminus of theelectrophile based on chelation of a C2-symmetric ligandbearing diarylphosphines (i.e. Trost ligand, BINAP).

In the case of isoprene monoepoxide (1), the methyl andhydroxymethylene substituents are sterically very similar;however, the presence of an alkoxide from the epoxideopening renders the two electronically dissimilar (Scheme7a). Two factors dictate alkylation at the branched termi-nus, namely: 1. The alkoxide leaving group often acts as abase for the pronucleophile and engages in hydrogen bonddirected alkylation of the nucleophile. 2. Ligand and addi-tive effects can alter the most favorable trajectory of the in-coming nucleophile toward the branched product.10 The

O

(+/–)

Pd(0) cat.

L* cat

OHNu

+ NuHNu

OH+

1 linear achiralproduct

branched chiralproduct

Scheme 5 Mechanism of dynamic kinetic asymmetric transformation (DYKAT) of isoprene monoepoxide

PdL L

OHOH

PdLL

Ha

Hb

OHPd

L

LHaHb

PdL L

OH

PdL L

OHOH

Pd LL OH

Pd LL

PdL L

OH

H

syn syn

synanti

a.)

b.)

H

HH

Scheme 6 Wall and flap model as a rationale for regio- and enantioselectivity in allylic alkylation with butadiene monoepoxide

Pd Pd

Pd R

Ionize:

PdR

π−σ−π

π−σ−π

π−σ−π π−σ−π

H

O

O O

(+/–)

2

2a 2b

2c 2d

R = CH2O–


5


outer-sphere nucleophilic attack occurs with inversion ofthe stereochemistry of the -allyl, and each enantiomer ofproduct can be obtained from two of the stereoisomericcomplexes (Scheme 7b).

Scheme 7 Mechanistic pathways for Pd-AAA of isoprene monoepox-ide

Methanol was shown to alkylate at the branched carbonwith high enantioselectivity in the Pd-AAA of isoprenemonoepoxide (Scheme 8).4 The use of catalytic borane wascrucial for reactivity, as the reaction proceeded with littleconversion in its absence. Initially, stoichiometric trimethylborate [B(OMe)3] was used in the reaction, affording theproduct in 80% yield and 2% ee. It was envisioned that thestoichiometric use of borane results in too rapid a reaction,such that equilibration of isoprene monoepoxide cannotoccur prior to nucleophilic attack. Use of catalytic triethyl-borane in the presence of methanol produced diethylme-thoxyborane as catalyst, and these conditions proved opti-mal for enantioselectivity.

Because of the lower acidity of aliphatic alcohols, theiruse in Pd-AAA has remained limited; however, the kineticeffect imparted by the boron additive renders this reactionfavorable in alkylation of vinyl epoxides (Scheme 9a).4 Ad-ditionally, the unimolecular mechanism accounts for the

high selectivity for the branched product. Primary alcohols3 undergo the alkylation chemoselectively over secondaryalcohols. Additionally, the high yields indicate the productalcohol 6 is not competitive with primary alcohol substrate3, presumably due to either a slow alkylation reaction or asmall population as the alkoxydiethylborane species 4(Scheme 9b).

The reaction scope shows several primary alcohols 3were competent nucleophilic partners in this reaction(Scheme 10).4 For substrates with low enantioselectivityusing triethylborane as catalyst, it was reasoned that ether-ification was occurring faster than the required -allylequilibration. Use of the more bulky tri-sec-butylboraneproved useful for solving this problem (6b, 6d, 6g). With ahampered rate of etherification, the products were formedwith higher enantioselectivity. Spontaneous cyclization to ahemiketal (6d) or lactone (6b) occurred when the nucleop-hilic alcohol contained a pendant ketone or methyl ester re-spectively. The etherification product of 4-methoxybenzylalcohol addition 6c is a particularly useful synthetic precur-sor due to the ubiquity of PMB-protected alcohols in syn-thetic sequences.

A net addition of nucleophilic hydroxide was discoveredfor this reaction using a mixed system of triethylborane andsodium hydrogen carbonate (Scheme 11).5 Upon ionization,a borinic ester intermediate is formed that directs the al-kylation of hydrogencarbonate to the branched positionwith high enantioselectivity. The unstable carbonate prod-uct 7 undergoes decarboxylation to directly afford the ter-tiary alcohol product 8.

NuOH

Nu

OH

PdL L

OH

PdL L

PdL L

PdL L

OH

OHOH

OHNu

OHNu

A B

C D

A

B

C

D

NuOH

Nu

OH

OHNu

OHNu

+

+

+

+

a.) Diastereomeric Pd(II) allyl complexes b.) Alkylation products by Pd(II) diastereomer

Scheme 8 Optimization of allylic etherification with isoprene monoep-oxide

O(+/–)

Pd2dba3·CHCl3 (1%)(S,S)-L1 (3%)

OMe

OH

Conditions

B(OMe)3 (1 equiv)B(OMe)3 (1%), MeOH (1 equiv)

Et2B(OMe) (1 equiv)Et2B(OMe) (1%), MeOH (1 equiv)

BEt3 (1%), MeOH (1 equiv)

% ee

2495890941 6a

conditionsCH2Cl2, r.t

Scheme 9 Borane co-catalyst in Pd-catalyzed regio- and enantioselective allylic etherification of isoprene monoepoxide

PdL L

PdL L

O OBB

RO RO

Et Et Et Et

OBEt2

OR

OBEt2

OR

a.) Alkoxydiethylborane-directed allylic etherification of isoprene monoepoxide

OBEt2

OR

ROH R

OBEt2

BEt3

– C2H6

Pd(0)L* cat

1

3OH

OR

RO

BEt2+

b.) Mechanism of alkoxydiethylborane catalytic turnover

3 4 5 6 4

5 ent-5


6


Scheme 11 Pd-AAA of isoprene monoepoxide with sodium hydrogen carbonate in the presence of borane co-catalyst

In the absence of borane additive; however, the carbon-ate product 9 was isolated (Scheme 12).5 The difference inreaction outcomes was attributed to the attack of carbondioxide by the alkoxide leaving group. This system provedmore challenging for optimization due to the lability of 9 toracemization. In the presence of tetrabutylammoniumchloride, the product was isolated with high enantioselec-tivity at low conversion, but was nearly racemic upon com-pletion of the reaction. However, sodium hydrogen carbon-ate in phosphate buffer resulted in high enantioselectivityat high conversion. Under the optimized conditions, lowcatalyst loading in the absence of buffer proved effective forachieving high enantioselectivity.

Scheme 12 Pd-AAA of isoprene monoepoxide with sodium hydrogen carbonate in the absence of borane co-catalyst.

Carbon nucleophiles were successfully applied in thischemistry using nitromethane (10) or -keto esters(Scheme 13).3 These reactions were pioneering for the met-al-catalyzed synthesis of acyclic all-carbon quaternary ste-reocenters, which has been an active area of pursuit sincethe development of this chemistry.11 The product from ni-

tromethane addition 11 is particularly valuable, as the re-sulting nitromethylene substituent serves as an acyl anionequivalent, orthogonal to the two other functional grouphandles (Scheme 13a). In the case of -keto ester 12, the hy-droxymethyl group spontaneously cyclizes to form a he-miketal 13 upon allylic alkylation (Scheme 13b). A retro-aldol reaction of 13 proceeds cleanly in the presence oftetrabutylammonium fluoride (TBAF) to furnish acyclic 14.

Scheme 13 Pd-AAA of isoprene monoepoxide with carbon nucleo-philes

Isoprene monoepoxide has been successfully alkylatedby phthalimide (15) to afford the branched, -tertiary im-ide 16 (Scheme 14).7 The regioselectivity is invoked to bethe result of both hydrogen bonding and ligand-directed ef-fects. Achiral dppe afforded exclusively the linear product.The reaction with chiral ligand L2 proved to be solvent,base, and temperature sensitive. High enantioselectivitycould be achieved without exogenous base; however, thisresulted in exceedingly long reaction times. Prolonged reac-tion time after completion of the reaction resulted in ahigher proportion of branched product, likely due to re-ion-ization of 16.

Scheme 14 Pd-AAA of isoprene monoepoxide with phthalimide

Enantiopure amino esters 17 were reacted with iso-prene monoepoxide in a catalyst-controlled regio- and di-astereoselective allylic alkylation (Scheme 15).8 A subse-quent cyclization by KCN afforded 2-oxomorpholines 18with high diastereoselectivity. Although the products of thesequence are cyclic, the product of the first step of the reac-tion sequence is an acyclic -tertiary amine, demonstratingthat amines react in analogy to phthalimide with isoprenemonoepoxide. It was shown that catalyst control could dic-tate diastereodivergent pathways when using the naturalamino acids. Multiple ligands were employed, due to the

Scheme 10 Select examples of tertiary ether synthesis with isoprene monoepoxide

O

(+/–)+

Pd2dba3·CHCl3 (1%)(S,S)-L1 (3%)

1.0 equiv 1.0 equivO

OHROH

RHNNH

PPh2Ph2P

O O

(S,S)-L1

MeOOH

OOH

OPMBOH

OOH

NC

OOH

OH

O

O

OO

O

OHMe

88% yield, 94% ee(BEt3)

83% yield95% ee(BEt3)

91% yield, 94% ee(BEt3)

77% yield,98% ee(B(s-Bu)3), DMAP 5%

81% yield90% ee

(B(s-Bu)3)40 °C

63% yield85% ee1.1 d.r.(BEt3)40 °C

75% yield, 94% ee(B(s-Bu)3)

1 3 6

6a

6e

6c 6d6b

6f 6g

BR3 (1%)CH2Cl2, r.t. or 40 °C

O(+/–)

+

Pd2dba3·CHCl3 (1%)(S,S)-L1 (3%)

BEt3 (1%)CH2Cl2/H2O, 40 °C1.0 equiv 1.0 equiv

NaHCO3

OCO2–

OHdecarboxylation

– CO2OH

OH

91% yield97% ee1 7 8

HNNH

PPh2 Ph2P

O O

(S,S)-L1

O

(+/–)+

Pd2dba3·CHCl3 (0.5%)(S,S)-L1 (1.5%)

CH2Cl2/H2O, r.t.1.0 equiv 1.2 equiv

NaHCO3 O

O

O

88% yield93% ee1 9

O

(+/–)Pd2dba3·CHCl3 (1%)

(S,S)-L2 (3%)CH2Cl2

+ MeNO2NO2

OHHNNH

PPh2 Ph2P

O O

(S,S)-L251% yield97% ee

i-Pr

O O

OEt

Pd2dba3·CHCl3 (1%)(S,S)-L2 (3%)

1 (1.3 equiv)CH2Cl2

1.0 equiv

74% yield, 97% ee

O

EtO2CHO

i-Pr

TBAF

THF, r.t. EtO2C

O

O

i-Pr

97% yield

1 10 11

12 13 14

a.)

b.)

[Pd(allyl)Cl]2 (2.5%)(R,R)-L2 (7.5%)

1 (1 equiv)Cs2CO3 (5%)THF, 55 °C

1.1 equiv

HNNH

PPh2 Ph2P

O O

(R,R)-L2

NO O

OHHNO O

72% yield, 87% ee

15 16


7


presence of match-mismatch effects unique to each aminoester. Since the enantiomeric amino acids are commerciallyavailable, all four stereoisomeric products are accessible bythis route. This is a valuable feature, especially in diversity-oriented approaches to compound libraries.12

Scheme 15 Pd-AAA of isoprene monoepoxide with enantiopure ami-no esters

2.2 Applications in Complex Molecule Synthesis

Isoprene monoepoxide was successfully used in the keysteps in the synthesis of hyperolactone C (26) and (+)-biy-ouyanagin A (29) (Scheme 16).13 The nucleophilic precursor24 was accessed by dianion functionalization of methyl ace-toacetate (21) with benzaldehyde. The necessary diazo pre-

cursor 23 was synthesized in two steps from 22, and thePd-AAA pronucleophile 24 was accessed by rhodium car-bene insertion into an enol O–H bond. The two vicinal tet-rasubstituted stereocenters of 25 were formed by a regio-,enantio-, and diastereoselective Pd-AAA between 24 andisoprene monoepoxide (1). The short reaction time provedcrucial to the success of this reaction, as a host of side reac-tions occurred upon completion of the reaction. The 59%isolated yield of 25 is reflective of a modest 2.1:1branched/linear ratio; however, the product was isolated asa single enantiomer in 26:1 d.r.

Lactonization of 25 catalyzed by 4-toluenesulfonic acidproduced hyperolactone C (26) in a single step. For the syn-thesis of (+)-biyouyanagin A (29), ent-hyperolactone C wasreadily accessed by simply changing the enantiomer ofTrost L2. The efficiency of the sequence is outstanding, withthe synthesis of hyperolactone C requiring a longest linearsequence of six steps, and (+)-biyouyanagin A synthesizedby an additional photocycloaddition with zingiberene (27)in the presence of 2′-acetonaphthone (28).

In the total synthesis of (–)-terpestacin14 (Scheme 17),the key Pd-AAA reaction between a diosphenol 30 and ra-cemic isoprene monoepoxide (1) was observed to proceedrapidly and in high yield, but with low enantioselectivity(~50% ee). It was reasoned that the low enantioselectivitypotentially resulted from a short lifetime of the -allyl in-termediate due to rapid nucleophilic attack. Addition of ha-lide additives has been shown to increase enantioselectivityby increasing the rate of –– equilibration.15 Increasingthe concentration of tetrabutylammonium chloride dis-played this effect; however, slow addition of 30 provedmost effectual for increasing the lifetime of the -allyl in-termediate. Under optimized conditions, silylation of theproduct alcohol was performed in a single operation, af-fording product 31 in 93–95% yield and 88–96% ee. The chi-ral information of the newly formed stereocenter could betranslated via a [3,3]-sigmatropic rearrangement, and di-

O

(+/–)+

1) [Pd(allyl)Cl]2 (2.5%)Ligand (3.75%)

NEt3 (1 equiv), CH2Cl2, r.t.

2) KCN, THF or MeCN80 °C1.0 equiv 1.0 equiv

CO2Me

NH4Cl

RH

HN

ORH

O

HN

O

HO

HN

O

HO

HN HN

HN

O

HO

HN

O

HO

HO HO

HNNH

PPh2 Ph2P

O O

(R,R)-L2

HNNH

PPh2 Ph2P

O O

(R,R)-L1

Ph Ph

NH HNO O

Ph2PPPh2

(R,R)-L3

HN

ORH

O

+

1 17 18a 18b

Ligand

(R,R)-L1(S,S)-L1(R,R)-L2(S,S)-L2(R,R)-L3(S,S)-L3

Yield

395175755045

19a/19b

1:2.8 6.7:1

1:6.112.4:1

1:11.5 14:1 19a 19b

Ligand

(R,R)-L1(R,R)-L2(S,S)-L2(R,R)-L3(S,S)-L3

Yield

6985602859

20a/20b

1:21:54:1

1:2.83:1 20a 20b

Scheme 16 Pd-AAA of isoprene monoepoxide in the total synthesis of hyperolactone C and (+)-biyouyanagin A

Ph O

O

CO2Me

Pd2dba3·CHCl3 (1%)(R,R)-L2

(+/–)-1CH2Cl2, r.t. 10 mins

Ph O

O

CO2Me

OH

2.1:1 b/l, 26:1 d.r.99% ee, 59% yield

PTSA (20%)

CH2Cl2, r.t. Ph O

O

O

O85% yield

hyperolactone C

O

CO2Me

NaH, THF, 0 °Cthen BuLi

then PhCHO

O

CO2Me

OH

Ph

1) TsN3, NEt3, MeCN88% yield

2) DMP, CH2Cl291% yield

O

CO2Me

O

Ph

N2

[Rh2(OAc)4]

CH2Cl2, r.t.

92% yield

54% yield

Ph O

O

O

O

ent-hyperolactone C(1.0 equiv)

H

H

+O

O

O

OPh

H

H

H H

H

O

zingiberene(6.0 equiv)

2'-acetonaphthone(1.0 equiv)

43% yield(+)-biyouyanagin A

hv, CH2Cl2

5 °C, 8 h+

21 22 23

2425

26

27 ent-26 28 29


8


rect oxidation of the Claisen rearrangement product afford-ed the desired diketone 33 in 78% yield over the sequence,with 4:1 selectivity in the formation of the resultant olefin.A Sakurai allylation of 33 installed an allyl functional grouphandle to form 34. This precursor was used in the construc-tion of macrocycle 35. An additional catalyst-controlled Pd-AAA/sigmatropic rearrangement in the late stages of thesynthesis afforded 38, which was efficiently elaborated tothe target.

Scheme 17 Pd-AAA of isoprene monoepoxide in the total synthesis of (–)-terpestacin

The synthesis of tipranavir was accomplished by settingthe stereochemistry of a tetrasubstituted and tertiary ste-reocenters by Pd-AAA (Scheme 18) and Mo-AAA, respec-tively (Scheme 19).16 A propyl-substituted vinyl epoxide 41was accessed in two steps from 1-chloropentan-2-one (40).After addition of vinylmagnesium bromide, the tertiary al-cohol product was efficiently cyclized to form 41 in 86%yield over two steps. A borane co-catalyzed Pd-AAA of thevinyl epoxide with 4-methoxybenzyl alcohol proved highlyenantioselective in the construction of acyclic tertiary ether42. Synthesis of the phenethyl side chain was readily ac-

complished by Heck arylation and hydrogenation of the vi-nyl functional group handle. The hydroxymethylene func-tional group handle was homologated via an oxidation/Wit-tig olefination/hydroboration/oxidation sequence.

Scheme 18 Synthesis of acyclic tertiary ether fragment in the total synthesis of tipranavir

The tertiary stereocenter was synthesized by a branch-selective cinnamylation of dimethyl malonate sodium salt48 and 3-nitrocinnamyl electrophile 47 under chiral molyb-denum catalysis (Scheme 19). Decarboxylation of a methylester afforded nucleophilic precursor 48, which was cou-pled with the previously prepared aldehyde 46 via an esterenolate aldol reaction. Oxidation of the resulting alcohol,followed by PMB deprotection provided substrate 50 for asodium hydroxide mediated lactonization. Hydrogenationconditions afforded both nitro and olefin reduction, and theproduct 52 was completed by sulfonamide formation. Asimilar strategy was employed in the total synthesis of (–)-malyngolide.17 Additionally, synthetic studies on amphidin-olide B1,18 as well as (+)-pleuromutilin19 have employedisoprene monoepoxide in Pd-AAA for the synthesis of earlychiral building blocks.

2.3 Other Acyclic Electrophiles

In the work of the Trost group on the prenylation of ox-indoles, conditions were developed to selectively affordboth the branched and linear prenylation products (Scheme20).20 This strategy culminated in a unified approach to-ward flustramine natural products. For the reverse pre-nylated product 56, vicinal quaternary carbons are formedwhile setting the cyclic stereocenter in high enantioselec-tivity. Formation of the linear product 55 using the Trost L1was typical of most Pd-AAA; however, the unique structur-al features of Trost L2 provide the branched product. Addi-tionally, tetrabutylammonium difluorotriphenylsilicate(TBAT) as a halide additive improved the reaction outcome,due most likely to a required rate increase in –– equili-bration.

OOH

O

(+/–)

1) Pd2dba3·CHCl3 (2%)(R,R)-L1 (6%)

Bu4NCl (0.5 equiv)CH2Cl2, r.t., 6 h

2) TIPSOTf2,6-lutidine

+O

O

OTIPS

CHCl3

100 °C0.25 h

HO

O

OTIPS

Pd(OAc)2 (1 equiv)Cs2CO3 (1.5 equiv)

MeCN, r.t.

O

O

OTIPS

allylTMSMgBr2·Et2O

CH2Cl2 –78 °C to r.t.

78% yield over two stepsE/Z 4:1

1.0 equiv 2.0 equiv

93-95% yield, 88-96% ee

HO

O

OTIPS

86% yield, 5.7:1 d.r.

O

HO

OHOH

(–)-terpestacin

O

HO

OH

Pd2dba3·CHCl3 (2.5%)(S,S)-L1 (7.5%)

CH2Cl2, r.t.

OBoc

O

O

OH

1) DME, 150 °C2) PMBCl, Cs2CO3

TBAI (cat.) DMF

3) Ac2O, Py

O

PMBO

OAc

89% yield, d.r. > 15:1

steps

5 steps

69% over 3 steps

(+/–)

32 33

34

35

36

37

38

39

30 1 31

O

Cl

O

OPMB

OH1) vinylMgBrTHF, 0 °C

2) NaOHEt2O, r.t.

Pd2dba3·CHCl3 (1%)(S,S)-L1 (3%)

PMBOH (1.1 equiv)BEt3 (1%), CH2Cl2, r.t.

Pd(OAc)2 (10%)P(o-Tol)3 (40%)

NEt3, PhItoluene, reflux

OPMB

OH

Pd/C, H2

MeOH, Py25 °C

Ph

OPMB

OH

Ph

1) Dess–MartinCH2Cl2, 25 °C

2) Ph3PCH2THF reflux

OPMBPh

catechol borane(Ph3P)RhCl (1%)

THF, then

NaOH, H2O2, r.t.

OPMB

CHO

Ph

86% yield 69% yield, 98% ee

92% yield99% yield

94% yield 88% yield

40 41 42

43 44

45 46


9


An extension of this chemistry allowed for the synthesisof an acyclic quaternary carbon stereocenter when usinggeranyl-type electrophiles (Scheme 21). When using race-mic, branched electrophile 57, the linear and branched

products were formed in equal amounts, with the branchedproduct 58 formed with high enantio- and diastereoselec-tivity.

It was determined from subsequent experiments thatwhen using achiral (Z)-60, a regio-, enantio-, and diastereo-selective synthesis of vicinal quaternary stereocenters wasachieved (Scheme 22). These results indicate that ionizationof the electrophile is enantiodetermining with respect tothe acyclic electrophile, and diastereoselective alkylation bythe oxindole occurs faster than –– equilibration. Thisprocess underscores both the versatility in controlling ste-reochemical reaction outcomes and the importance of un-derstanding the underlying processes in Pd-AAA reactionoptimization.

A Pd-catalyzed enantioselective allyl-allyl cross-cou-pling protocol was reported by Morken and co-workers forthe asymmetric synthesis of acyclic quaternary stereocen-ters (Scheme 23).21 This process represents one of few Pd-catalyzed AAA reactions to occur with hard nucleophileswith high enantioselectivity. It was shown that both (E) and(Z) linear electrophiles, as well as branched racemic electro-phile 62 afforded the same enantiomer of the respectiveproduct in similar yields. This result likely indicates that

Scheme 19 A Pd- and Mo-AAA strategy for the synthesis of tipranavir

BocOMeO

ONa

CO2Me

2.0 equiv1.0 equiv

1) Mo(CO)3(C7H8) (10%)(R,R)-L5 (15%)

THF, reflux

2) NaCl, 150 °CDMSO–H2O 20:1

+

94% yield96% ee

MeO2C

NO2

(+/–)

NO2

1) NaHMDSTHF, –78 °C

then 46

2) Dess–MartinCH2Cl2, r.t.

O

R

NO2

OPMBPh

89% yield, R = CO2Me

1) CANMeCN/H2O88% yield

2) NaOHMeOH, 4 °C77% yield

OH

NO2Ph

O O

1) Pd/C, H2

2) ArSO2ClCH2Cl2, py

DMSO, –25 °C

OH

HNPh

O O

SO O

92% yieldtipranivir

HNNH

N N

O O

(R,R)-L5

47 48 49

50 51

CF3

52

Scheme 20 Regioselective Pd-catalyzed prenylation of oxindoles

N O

NC

Br

Pd2dba3·CHCl3 (2.5%)(R,R)-L2 (7.5%)

TBAT (30%)r.t., CH2Cl2 N O

Br

1.5 equiv1.0 equiv

HNNH

PPh2 Ph2P

O O

(R,R)-L2

branched/linear 18:188% yield (branched)

87% ee

OBoc(+/–)

CN

N O

NC

Br

Pd2dba3·CHCl3 (2.5%)(R,R)-L1 (7.5%)

r.t., tolueneN O

Br

1.5 equiv

1.0 equiv

HNNH

PPh2 Ph2P

O O

(R,R)-L1

branched/linear 1:3.266% yield (linear)

96% ee

OBoc(+/–)

CN

53

54

55

53

54

56

Scheme 21 A regiodivergent Pd-AAA of oxindoles using racemic branched electrophile

N O

NC

+

Br

Pd2dba3·CHCl3 (2.5%)(R,R)-L2 (7.5%)

r.t., CH2Cl2, 24 h

N O

Br

NC

1.5 equiv

1.0 equiv

N O

Br

NC

branched

linearE/Z 15:1

HNNH

PPh2 Ph2P

O O

(R,R)-L2

58/59 = 50:5046% yield (58)

>95:5 d.r.90% ee

OBoc

(+/–)

53

57

58

59


10


rapid equilibration of the -allyl intermediate occurs beforereductive elimination, and it is ligand control of the -allylstereochemistry that dictates the enantioselectivity. In thereaction optimization it was observed that -hydride elimi-nation was a significant side product. Addition of fluoridein a THF/water mixture was shown to minimize this sidereaction by acceleration of allyl transmetalation.

Scheme 23 Catalytic enantioselective branch selective allyl-allyl cross coupling

The substrate scope revealed high enantioselectivitiesfor the synthesis of acyclic benzylic quaternary stereocen-ters. High enantioselectivity was observed when placingbranched aliphatic substituents in addition to the methylgroup (64f, 64g, 64i). A modest, but appreciable enantioin-duction was observed for a geranyl-type substrate (64j).

The C–C bond-forming event is invoked to occur via a 7-membered 3,3′ inner-sphere reductive elimination ofbis(η1-allyl)Pd(II) complex 67 (Scheme 24). In this scenario,palladium is bound to the unsubstituted terminus of thetrisubstituted allyl partner. The alternative mechanismwould involve a more classical 3-membered reductive elim-ination; however, calculations place this pathway at ~15kcal/mol higher in energy.22 The source of enantioinductionin this reaction is not immediately clear. The stereocenter iscreated in the reductive elimination step to form 68; how-ever, the pre-equilibrium of the (E)- and (Z)-isomers of 66may be enantiodetermining if the Re or Si pathway is sig-nificantly favored for both isomers.

The branch-selective Pd-AAA reaction has beenachieved using ligands developed by the Hou group.23 Race-mic tertiary allylic acetates were alkylated with modest en-antioselectivity and branch/linear selectivity using dimeth-yl malonate as the pronucleophile (Scheme 25). Extensiveoptimization of ligand, solvent, additive, and base was re-quired in the process. This ligand class offers modulation ofthe BINOL, phosphorus, and oxazoline chirality for achiev-ing branch-selective Pd-AAA. The presence of high (E)-se-lectivity in the linear product 71 indicates that high syn/an-

Scheme 22 Pd-catalyzed regio-, diastereo-, and enantioselective synthesis of vicinal quaternary stereocenters

N O

NC

TrocO

+

Br

CpPd(allyl) (5%)(R,R)-L2 (7.5%)

60 °C, CH2Cl2, 36 h

N O

Br

NC

1.5 equiv

1.0 equiv

N O

Br

NC

branched

linear

HNNH

PPh2 Ph2P

O O

(R,R)-L2

58/61 = 13:192% yield>95:5 d.r.91% ee

53

60

58

61

MeO

MeO

P

P

O

O

2

2

R1

OBoc

R2

Bpin+

1.0 equiv 1.2 equiv

Pd2dba3 (2%)(R)-L7 (4%)

CsF (3 equiv)THF–H2O, 60 °C

R1R2(+/–)

(R)-MeO-furyl-biphep L7

Br Me NCl

90% yield92% ee

90% yield92% ee

76% yield92% ee

81% yield90% ee

97% yield84% ee

Et

97% yield92% ee

78% yield92% ee

45% yielda

86% ee

n-Bu

58% yield80% ee

MOMO

96% yieldb

52% ee

a) Tertiary allylic chloride electrophile was used. b) Linear geranyl electrophile was used.

62 63 64

64a 64b 64c 64d 64e

64f 64g 64h 64i 64j

Scheme 24 Mechanism of enantioselective allyl-allyl cross coupling

PdLn*

RL

RS

PdLn*

RS

RL

RL

RS PdLn*

RS

RL PdLn*

PdRS

RL

Ln*

PdRL

RS

Ln*

RLRS

RSRL

Re addition

Si addition

65 66 67 68

anti-65 (Z)-66 (Z)-67 ent-68

63

63


11


ti control is achieved in the -allyl formation. Enantioinduc-tion is achieved by facial discrimination of the stericallydifferentiated methyl and aryl substituents.

Scheme 25 Pd-catalyzed branch-selective cinnamylation of dimethyl malonate for the synthesis of acyclic quaternary stereocenters

3 Stereocontrol on Prochiral Nucleophiles

In Pd-AAA, achieving high enantiocontrol on nucleo-philes remains inherently more difficult than achieving en-antiocontrol on the electrophilic partner, due to the outer-sphere mechanism for nucleophilic addition. In the alkyla-tion event, the chiral information about the metal–ligandsphere must be successfully relayed distal to the metal inorder to observe catalyst differentiation of enantiotopic fac-es of the nucleophile. This problem is compounded by thepresence of enantioconvergent and enantiodivergent allyla-tion pathways (Scheme 26). In the case of enantioconver-gent allylation (Scheme 26a), the chiral catalyst recognizesthe substituents at the site of reaction. Although the restric-tion of controlling the enolate geometry has been removed,R1 and R2 are limited to sterically differentiable substituents(i.e. alkyl vs. aryl).

When an enantiodivergent pathway is operative(Scheme 26b), the catalyst recognizes the substituents vici-nal to the site of reaction. This pathway is desirable if R1 and

R2 are of limited steric differentiation; however, the enolategeometry must be strictly controlled in order to observehigh enantioselectivity. The enantiodivergent pathway hasan important advantage over the enantioconvergent path-way, since the identity of X can be exploited as an achiralauxiliary and a tunable parameter for reaction optimiza-tion.

As will be seen, both the substituents and the enolategeometry are commonly recognized by the catalyst in theallylation event. In this case, the presence of match-mis-match effects will be apparent when both enolate isomerscan be synthesized in geometrically pure form. The stereo-fidelity of the enolate is assumed to remain intact duringenantiodivergent allylations; however, oxygen-to-carbonmigration may provide a mechanism for erosion of the eno-late geometry if palladium enolates are formed as interme-diates (Scheme 27a). Isomerization of palladium enolateshas been exploited for the Pd-AAA DYKAT of butenolideelectrophiles with phenolic nucleophiles (Scheme 27b).24 Inthis scenario, the palladium enolate is formed on thebutenolide electrophile (Scheme 27c), and the mechanismfor isomerization of the -allyl species involves carbon-to-oxygen migration.

[Pd(allyl)Cl]2 (2%)(S,SPHOS,R)-L8 (4%)

KOAc (6%)

dimethyl malonate (3 equiv)BSA (3 equiv), Et2O, 25 °C

Fe

N OP

Et2N

OOH

(S,RPHOS,R)-L8

Ar

OAc

1.0 equiv

∗∗

Ar

CO2Me

CO2Me Ar

CO2Me

CO2Me+

(+/–)

Aromatic

Ph4-CNC6H41-Naphthyl4-MeOC6H44-MeC6H44-ClC6H4

Yield

668646319090

70/71

96:489:1176:2443:5795:595:5

%ee

737878797869

Entry

70a70b70c70d70e70f

69 70 71

Scheme 26 Structural considerations for catalyst recognition of prochiral enolates

R2

R1

O

X

Enantiodivergent allylation

X

O

R1 R2

R1

R2

O

X X

O

R2 R1

R2

R1

O

X

Enantioconvergent allylation

X

O

R1 R2

R1

R2

O

X

Catalyst differentiation of X and O–Catalyst differentiation of R1 and R2

b)a)

Scheme 27 Potential mechanism for the erosion of enolate stereochemistry

R2

R1

O

X

Pd(II)

X

O

R1

Pd(II)R2

X

O

R2

R1

Pd(II) R1

R2

O

X

Pd(II)

O to C

migration

C to O

migration

rotation

a)

b)

O OBocO+

MeO

OH

Pd2dba3 (1%)(R,R)-L1 (3%)

TBAC (30%)CH2Cl2, r.t.

1.0 equiv 1.0 equiv

O OO

MeO

74% yield, 84% ee

(+/–)

O O

LnPd

O O

PdLn

O OPdLn

O O

PdLn

O O

LnPd

c)

72 73 73 74

75 76 77

78 79 80 ent-79 ent-78


12


3.1 Intermolecular Alkylation of Prochiral Nucleo-philes

Many of the first syntheses of acyclic tetrasubstitutedstereocenters by reactions of prochiral nucleophiles werediscovered by the Ito group. In 1992, allylation of an acyclic1,3-diketone 81 (Scheme 28a) was reported in modest en-antioselectivity by employing a point and planar chiral fer-rocenyl ligand scaffold bearing an aza-crown ether.25 In1996, allylation of -nitro ester 83 was achieved by a simi-lar strategy (Scheme 28b).26 In order to enhance enantiose-lectivity upon nucleophilic attack of a -allyl palladium(II)complex, it was envisioned that linking a crown ether tochiral phosphine ligands would allow for recognition of thenucleophile counterion. In this case, the chiral informationof the catalyst could be relayed distal the site of the reac-tion, thus solving the problem of poor selectivity when us-ing prochiral nucleophiles in Pd-AAA. In both cases, signifi-cant optimization of the crown ether and counterion wasrequired to obtain the enantioselectivity.

Scheme 28 Asymmetric allylation of a 1,3-diketone and an -nitro es-ter by counterion recognition of a chiral phosphine ligand

A dual catalytic approach to Pd-AAA was achieved byexploiting chiral rhodium enolate chemistry (Scheme 29).27

It had been shown that rhodium salts form a trans bis-

phosphino complex that is bound to the nitrogen of cyano-derived enolates.28 This chemistry had been previously ap-plied to Michael additions and aldol reactions.29 Using fer-rocenyl ligands developed in the Ito group, they were ableto achieve high enantioselectivity in the allylation of cyanoester 85, cyanoamide 88, and -cyanophosphonate 90 un-der -allyl–Pd catalysis. Potentially, the ligand forms com-plexes with both rhodium and palladium, and the chiralityof each species is synergistic in the alkylation event.

Scheme 29 Dual catalytic Pd-AAA of chiral cyano-rhodium enolates

An early report on asymmetric induction utilizing acy-clic nucleophiles was provided by the Ito group30 in theirPd(0)/BINAP-catalyzed Pd-AAA of -acetamido--keto es-ters 92 (Scheme 30). High levels of enantioselectivity werereported when using potassium tert-butoxide as base. Ad-ditionally, high geometric control of the resulting olefinicproducts 94 was reported, even for commonly difficult ali-phatic allylic acetates (94g, 94h, 94i). The highest enantio-selectivities were observed for cinnamylation reactions(94c, 94d, 94e, 94f), although simple allylations proceededin good enantioselectivity.

Ph

O OPd2(dba)3·CHCl3 (0.5%)

(S)-(R)-L9 (1.1%)

1.0 equiv

(+/-)Fe PPh2

PPh2

NMe

(R)-(S)-L9

O

N

OO

N

2

Me

Ph

O

∗∗

93% yield72% ee

Ac

O2N

O

Ot-Bu

Pd2(dba)3·CHCl3 (0.5%)(S)-(R)-L10 (1%)

1.0 equiv

O

Ot-Bu

92% yield80% ee

O2N FePh2P

Ph2P

N

3

O

N

O

O

Me

(S)-(R)-L10

(+/-)

a)

b)

81 82

83 84

allyl acetate (1.5 equiv)KF (2 equiv) mesitylene

–37 °C

allyl acetate (1.5 equiv)RbF (2 equiv)

RbClO4 (1 equiv)CH2Cl2, –40 °C, 70 h

Fe FeR

Ar2P

(S,S)-(R,R)-TRAP

Ar = p-MeO-Ph

L11

HR =CO2i-PrNCRh(acac)(CO)2 (1%)(Cp)Pd(allyl) (1%)

(S,S)-(R,R)-L11 (2%)THF, –40 °C, 6 h

1.0 equiv

CN

O

Oi-Pr

93% yield99% eeO

O

O

CF3

CF3

2.0 equiv

+

Fe FeR

Ph2P

(S,S)-(R,R)-TRAP

L12

HR =

NC

Rh(acac)(CO)2 (1%)[(allyl)Pd(cod)]BF4 (1%)

(S,S)-(R,R)-L12 (2%)86 (2 equiv)

THF, –25 °C, 40 h1.0 equiv

CN

O

N

94% yield87% ee

(+/–)

O

N

OMe

Me

OMe

Me

PNC

Rh(acac)(CO)2 (1%)[(allyl)Pd(cod)]BF4 (1%)

(S,S)-(R,R)-L12 (2%)86 (2 equiv)

THF, –25 °C, 72 h1.0 equiv

∗∗ P

CN

O

91% yield, 92% ee(+/–)

O

OEtOEt

OEtOEt

a)

b)

c)

85

86 87

88 89

90 91

Scheme 30 Pd/BINAP-catalyzed allylation of -acetamido--keto esters

R1

O

CO2Me

NHAc

+R2 OAc

[Pd(allyl)Cl]2 (1%)(R)-BINAP-L13 (1.05%)

1.0 equiv 1.5 equiv

R1

O

NHAcMeO2CR2 PPh2

PPh2

(R)-BINAP-L13

O

NHAcMeO2CPh

O

NHAcMeO2C

O

NHAcMeO2Cn-Pr Ph

O

NHAcMeO2Cn-Pr Ph

O

NHAcMeO2Cn-Pr

O

NHAcMeO2C

Ph

O

NHAcMeO2CPh i-Bu

O

NHAcMeO2CPh i-Pr

O

NHAcMeO2CPh

Ph

84% yield76% ee

92% yield80% ee

96% yield87% ee

40% yield89% ee

87% yield91% ee

87% yield94% ee

71% yield95% ee

86% yield92% ee

85% yield91% ee

92 93 94

94a 94b 94c 94d 94e

94f 94g 94h 94i

KOt-Bu (1.2 equiv)toluene –30 °C


13


Curiously, the reaction outcome was largely indepen-dent of whether the branched 96 or linear (Z)-95 electro-philic substrate was used (Scheme 31). It was proposed thatany stereo- or regiochemistry present in the starting elec-trophiles is lost due to a rapid –– equilibration relativeto intermolecular nucleophilic alkylation.

Scheme 31 Independence of electrophile regio- and stereochemistry on reaction outcome

A similar catalytic system was shown to provide allyla-tion products for -acetamido--ketophosphonate nucleo-philes 97 (Scheme 32).31 A possible explanation for the highenantioselectivity in this acyclic system is control of theenolate geometry by chelation between the phosphonateand enolate oxygen atoms. The highest enantioselectivitywas observed for 3-substituted allylic electrophiles 93; al-lylation proceeded with only modest enantioselectivity.

Other work by the Ito group demonstrated acyclic con-trol in the cinnamylation of 1,3-diketones (Scheme 33).32

Two examples demonstrated cinnamylation of acyclic 1,3-diketones in good enantioselectivity. Similar levels of asym-metric induction on cyclic substrates were also reported.Cryogenic temperatures were required for high enantiocon-trol in this reaction, however, in conjunction with theirwork on -acetamido--keto esters and -acetamido--ke-tophosphonates, these reactions serve as some of the earli-est examples of Pd-AAA with stereocontrol on acyclic nu-cleophiles under simple catalyst conditions.

Scheme 33 Examples of acyclic 1,3-diketone cinnamylation

Hou and co-workers have demonstrated Pd-AAA of acy-clic diphenylamides33 using the ferrocenyl-based ligandsthat they developed (Scheme 34). In most cases, -tertiarycarbon centers were synthesized, however, the report con-tains two examples of the asymmetric synthesis of acyclictetrasubstituted stereocenters. The N,N-diphenylamide wasfound to be optimal in the initial optimization. Subsequentvariation of the chirality on the oxazoline, phosphorus, andthe BINOL moieties of the ligand proved crucial for achiev-ing high enantioselectivity.

Scheme 34 Synthesis of acyclic tetrasubstituted stereocenters by -al-kylation of N,N-diphenylamides

List and Jiang were able to demonstrate the asymmetric-allylation of -arylpropanals 107 under triple chiral ac-id/enamine/palladium catalysis (Scheme 35).34 An achiralpalladium source was used in the reaction, and asymmetricinduction was achieved by achiral amine catalyst (e.g., 106)in the presence of (S)-TRIP phosphoric acid L15. Optimiza-tion of the amine catalyst showed benzhydrylamine (106)to be differential among other achiral benzylic amines. Inaddition to allyl alcohol, more substituted alcohols 108were effective in the reaction. Although the reactionshowed impressive display of control for asymmetric qua-ternary carbon synthesis, the method was limited to -aryl-propanals, as an elongation of the aliphatic aldehyde sidechain resulted in diminished enantioselectivity (109f).

O

CO2Me

NHAc+

n-Pr

[Pd(allyl)Cl]2 (1%)(R)-BINAP-L13 (1.05%)

KOt-Bu (1.2 equiv)toluene, –30 °C1.0 equiv

1.5 equiv

O

NHAcMeO2Cn-Pr

OAc

n-Pr

OAc(+/–)

86% ee from (Z)-95

85% ee from 9694g

92g

95

96

Scheme 32 Pd-AAA of -acetamido--ketophosphonates

R1

O

P(OMe)2

NHAc+

R2 OAc

[(allyl)Pd(cod)]BF4 (0.5%)(R)-BINAP-L13 (1.1%)

KOt-Bu (1.2 equiv)toluene, –30 °C1.1 equiv 1.0 equiv

PPh2

PPh2R1

O

P(OMe)2

NHAc

O

R2

O

P(OMe)2

NHAcPh

Et

O

P(OMe)2

NHAcPh

Ph

O

P(OMe)2

NHAcPh

O

P(OMe)2

NHAcn-Pr

O

P(OMe)2

NHAc

87% yield87% ee

72% yield78% ee

78% yield88% ee

27% yield79% ee

80% yield65% ee

9397 98(R)-BINAP-L13

98a 98b 98c 98d 98e

O

O O O O O

O

+Ph OAc

[Pd(allyl)Cl]2 (0.5%)(R)-BINAP-L13 (1.05%)

1.2 equiv1.0 equiv

O

R

O O

R Ph

R = H 90% yield, 83% eeR = OMe 96% yield, 80% ee

99100

101102

KOt-Bu (1.2 equiv)toluene, –60 °C

Fe

N OP

Et2N

O

OH

i-Pr

Ph2N

O

Ph

R

OAc

[Pd(allyl)Cl]2 (1%)(S,SPHOS,R)-L14 (2%)

Ph2N

O

∗∗

Ph R

1.0 equiv

2.0 equiv

R = OPh 99% yield 93% eeR = Me 75% yield 93% ee

(S,SPHOS,R)-L14

103 104

105

LiHMDS (1 equiv)LiCl (1 equiv), THF, r.t.


14


Scheme 35 The direct -allylation of -arylpropanals with allylic alcohols

Steric elements that result in high geometric control ofthe transiently formed chiral enamine were invoked to ac-count for the stereoselectivity observed (Scheme 36a), andchiral information is transferred by hydrogen bonding bythe enamine to the chiral phosphate (Scheme 36b). Sincethis species is counterion-paired with the cationic -allyl-palladium(II) species, asymmetric induction can be realizedin the alkylation event. Additionally, it cannot be ruled outthat the phosphoric acid acts as a ligand to the -allylPd(II)species. Interestingly, under the reaction conditions, allylalcohols can be used directly, due to the activation of thehydroxyl leaving group by the phosphoric acid (Scheme36c).

Scheme 36 Proposed mechanistic feature of triple catalysis

Another dual-catalytic approach was showcased by Ooiand co-workers for the -cinnamylation of -nitro esters(Scheme 37).35 Like the system developed by List and Jiang,the phosphine ligands employed in the method are achiral.However, a linked cationic ammonium functional group al-lows for self-assembly with a chiral BINOL counterion. APd/ligand ratio of 1:2 was used, as it was believed that a C2-symmetric palladium complex would form upon cis-com-plexation of the phosphine ligands. Excellent yields and en-antioselectivities were observed for the reaction when us-

ing cinnamyl carbonate electrophiles 111, although no en-antioselectivity was observed for the simple allyl system(112d).

Scheme 37 Chiral counterion strategy for the cinnamylation of -nitro esters

The use of dual chiral palladium/chiral boron catalysiswas applied to the -allylation of carboxylic acids (Scheme38).36 A chiral boron species is generated by chelation of aboron Lewis acid with the chiral amino acid catalyst L18.Upon ionization of the allyl ester by the chiral palladiumspecies (L17), a carboxylate ene-diolate species is readilyformed, presumably due to the Lewis acidity of the coordi-nated boron catalyst and the presence of DBU as base. Al-though the enolates of carboxylic acids possess no geome-try, the large steric differences of the -aryl substituentsrender the two enantiotopic faces of the nucleophile suffi-ciently distinguishable. The ability to use two chiral cata-lysts enables excellent enantioselectivity for both allyl and

Ar CHO

R1

HO

R2

R3

+

(S)-TRIP-L15 (3%)Pd(PPh3)4 (1.5%)

5 Å MS

Ar

R2

R3R1CHO

O

OP

O

OH

i-Pr

i-Pri-Pr

i-Pr

i-Pri-Pr

Ph

NH2

Ph

40 mol%

1 equiv

2 equiv

(S)-TRIP-L15

CHO CHO CHO CHO CHO

MeO Cl97% yield97:3 e.r.

95% yield97:3 e.r.

98% yield95:5 e.r.

94% yield96:4 e.r.

F

94% yield96:4 e.r.

Me

EtCHO

77% yield81:19 e.r.

CHO

96% yield94:6 e.r.

CHO

96% yield99:1 e.r.

CHO

66% yield96:4 e.r.

CHO

95% yield94:6 e.r.

Ph

Ph

106

107

108

109

109a 109b 109c 109d 109e

109f 109g 109h 109i 109j

toluene, 40 °Cthen 2N HCl

OH O

PO

OR*

OR*

Pd

Pd(0)

Ar

NH

Ph

Ph

OP

O

*ROOR*

H

Acid-catalyzedalcohol activation

Phosphate-mediatedpreorganization

Ar

N

H

Ph

Ph

H

Ar

N

H

Ph

Ph

H

Steric control of enamine geometry

a) b) c)

CO2t-BuO2N

R1

R2 OCO2Me

+

Pd2dba3 (2.5%)L16 (5%)

R2 Ot-Bu

O

R1 NO2

OOMe

2-naphthyl

2-naphthyl

Ar2P

Me3N

L16

PhAr - 4-ClPh

Ph Ot-Bu

O

Et NO2

97% yield93% ee

Ph Ot-Bu

O

i-Bu NO2

96% yield97% ee

Ph Ot-Bu

O

Bn NO2

94% yield97% ee

Ot-Bu

O

NO2

91% yield1%< ee

Ot-Bu

O

NO2

90% yield90% ee

Cl

Ot-Bu

O

NO2

99% yield93% ee

MeO

Ot-Bu

O

NO2

94% yield91% ee

S

110

111112

112a 112b 112c 112d

112e 112f 112g

toluene/H2O(20:1)


15


3-substituted allyl systems. The scope of the reaction waslargely limited to -aryl substrates, although and -benzylsubstrate gave 114b with 80% ee.

The DAAA of cyclic -fluoro--keto esters proceedswith high enantioselectivity.37 Acyclic systems affordedproducts with high efficiency, although the enantioselectiv-ities were low. More promising enantioselectivities wereobtained when generating geometrically pure (Z)-lithiumenolates (Scheme 39).38 These species were obtained bydeprotonation of -fluoropropiophenones by LiHMDS at 0°C, and the transient species were subjected to Pd-AAA con-ditions to provide -allyl--fluoropropiophenones with60–90% ee.

3.2 Decarboxylative Allylic Alkylation Strategies

Unlike intermolecular allylic alkylation reactions, Pd-catalyzed decarboxylative allylic alkylations occur via alargely unimolecular reaction pathway (Scheme 40).39 That

is, upon ionization of an allyl moiety, the Pd–-allyl speciesis counterion-paired to its pronucleophile. Upon a decar-boxylation event, alkylation occurs via an outer-sphere at-tack of the nucleophile on the reactive Pd–-allyl species,effectively furnishing the desired product and the regener-ated chiral Pd(0) species.

The question of whether this reaction occurs via an in-ner- or outer-sphere mechanism is complicated by differ-ences in the experimental outcomes of these reactions andthe computed lowest energy pathway.40 It is worth notingthat computational work is for phosphino-oxazoline(PHOX) ligands, and experimental work is with structurallydifferent bisphosphino Trost ligands. Experimental workshowed that enol carbonate 118 underwent Pd-DAAA withkinetic resolution of the enantiomeric starting material(Scheme 41). The alkylation product 119 was formed withnet retention of the stereochemistry, indicating an outer-sphere mechanism.

Scheme 38 Select examples in chiral Pd-AAA/chiral borane-catalyzed -allylation of carboxylic acids

O

O

R1

R2

R3

[Pd(allyl)Cl]2 (2.5%)(AcO)4B2O (10%)(R,R,R)-L17 (5%)

(+/–)

OH

O

R3

R1 R1

PAr2 Ar2P

(R,R,R)-L17Ar = 3,5-Me2C6H3

SNH

OH

O

MeO

FF

FF

O O

L18

OH

O

Ph

91% yield90% ee

OH

O

Et Ph

69% yield99% ee

OH

O

Ph

93% yield87% ee

OH

O

Ar1

60% yield93% ee

OH

O

93% yield80% ee

Ph

OH

O

MeO Ph

65% yield84% ee

OH

O

AcHN Ph

54% yield84% ee

OH

O

Ar2

96% yield92% ee

OH

O

Ar3

45% yield99% ee

Ar2 = 3-ClC6H4 Ar3 = 2-ClC6H4Ar1 = 3-thienyl

113 114

114a 114b 114c 114d

114e 114f 114g 114h 114i

L18 20%, DBU (1.5 equiv)toluene, r.t., 12 h

Scheme 39 Pd-AAA of -fluoropropiophenones

PPh2 N

O

(S)-t-Bu-PHOXL19

t-Bu

O

F

LiHMDS (1.2 equiv)THF 0 °C, then

R2

OCO2Me

1.0 equiv

1.1 equiv

(+/–)R1

O

∗∗

FR1

R2

O

F

O

F

O

F

O

FMeO

86% yield78% ee

84% yield88% ee

88% yield73% ee

74% yield77% ee

O

F

O

F

O

F

O

F

91% yield84% ee

44% yield90% ee

93% yield85% ee

30% yield60% ee

F3C

Ph

Br

115

116 117

117a 117b 117c 117d

117e 117f 117g 117h

[Pd(allyl)Cl]2 (1.25%)(S)-L19 (3.1%)NaOAc (10%)

THF, 0 °C to r.t.


16


It was observed by the Trost group in work on the -al-lylation of acyclic ketones that control of the enolate geom-etry was crucial for high asymmetric induction (Scheme

42).41 It was shown that opposing enolate geometries di-verged to opposite enantiomers of product, with matchedand mismatched cases. This problem was easily overcomein the case of -tertiary ketone formation, since either eno-late isomer could be synthesized by judicious choice ofbase. However, the synthesis of acyclic tetrasubstituted ste-reocenters would prove more difficult, due in large part tothe small steric differences in the -substituents.

The Trost group developed Pd-DAAA reactions for thesynthesis of acyclic tetrasubstituted stereocenters by thesynthesis of protected -tertiary hydroxyaldehydes.42 Theallyl carbonate precursors were synthesized with high geo-metric purity (Scheme 43). A highly flexible route to sub-strates allowed for -hydroxy 122 or -bromo ketones 124to be used as substrates. Either regioisomer could be syn-thesized using hard or soft enolization conditions. Undersoft enolization using TBSOTf and triethylamine, acyl trans-fer was suppressed, presumably due to the absence of anyenolate formed, and 127a was isolated with high regiose-lectivity. Under hard enolization with sodium hexameth-yldisilazanide, acyl transfer occurs to form the more stablealdehyde enolate. Trapping with TBSCl allows for synthesisof the opposite regioisomer 128a.

A DAAA reaction proceeds smoothly with high regio-and enantioselectivity when the alcohol protecting groupcan undergo alkoxide transfer (Scheme 44). The processwas found to be regioconvergent; that is, either regioiso-meric starting material afforded the tertiary aldehyde prod-uct with nearly identical enantioselectivities. When analkoxide transfer is not required (substrate 127a), the prod-uct was formed in 15 minutes in 93% yield compared to a 1hour reaction for the regioisomeric enol carbonate 128a.

Scheme 44 A regioconvergent Pd-DAAA strategy toward -tertiary hydroxyaldehydes

Scheme 40 Mechanism of the Pd-catalyzed decarboxylative allylic al-kylation

CO2

Nu

Complexation& Ionization

Decarboxylation

ReductiveElimination

ProductDissociation

Pd0Ln

NuPd0Ln

Nu

ONu

O

Pd(II)LnNu O

O

Pd(II)Ln

I

II

III

IV

V

VI

Scheme 41 Experimental evidence for an outer-sphere mechanism

Pd2dba3·CHCl3 (2.5%)(R,R)-L4 (5.5%)

39% yield99% ee

O O

O

Ph

(+/–)

O

H H

H H

PhO O

O

PhH H

37% yield99.5% ee

+118

119 (R,R)-118

dioxane, r.t., 12 h

Scheme 42 Enantiodivergent allylations of (E)- and (Z)-enol carbon-ates

O

O

O

Pd2dba3·CHCl3 (2.5%)(R,R)-L4 (5.5%)

dioxane, r.t., 16 h

O

72% yield, 60% ee

O

O

OPd2dba3·CHCl3 (2.5%)

(R,R)-L4 (5.5%)

dioxane, r.t., 2 h

O

94% yield, 97% ee

(Z)-120

(E)-120

NH HNO

PPh2

O

Ph2P

(R,R)-L4

(S)-121

(R)-121

Scheme 43 An efficient regiodivergent synthesis of Pd-DAAA substrates

Ph

O

OH Cl

O

O

pyridine, CH2Cl2, 0 °C85% yield

Ph

O

BrNaO

O

O

DMF, r.t.60% yield

Ph

O

OCO2allyl

TBSOTf, NEt3CH2Cl2, –78 °C to r.t.

83% yield

NaHMDS, THF–78 °C, then

TBSCl83% yield

Ph

OTBS

OCO2allyl

Ph

OCO2allyl

OTBS

122

123

124

125126

127a

128a

Ph

OTBS

OCO2allyl

Pd2dba3·CHCl3 (2.5%)(R,R)-L4 (5.5%)dioxane, 23 °C

Ph CHO

OTBS

Ph

OCO2allyl

OTBS 1 h, 86% yield, 91% ee

0.25 h, 93% yield, 92% ee

NH HNO

PPh2

O

Ph2P

(R,R)-L4

127a

128a

129a


17


The substrate scope revealed aromatic, vinyl, andalkynyl substituents provided the product with high enan-tioselectivity (Scheme 45). High yields and a rapid reactionrate were achieved by employing substrates 127 with a tert-butyldimethylsiloxy group at the benzylic position, as thesesubstrates undergo Pd-AAA without silyl transfer. Addition-ally, decarboxylation likely occurs more rapidly with theseregioisomeric substrates, since the resulting aldehyde eno-late is more stabilized than the initially formed ketone eno-late when using the regioisomeric substrate.

Scheme 45 A Pd-DAAA strategy toward -tertiary hydroxyaldehydes

This strategy was applied to the synthesis of a protected-hydroxy ketone 132 (Scheme 46). Displacement of the al-kyl bromide 130 occurred smoothly in 87% yield. Underhard enolization conditions, acyl transfer was not observeddue to the trans relationship of the oxygen atoms. This iso-mer 131 was observed to be the major one, and it was sepa-rated from the minor isomeric products in 67% yield. ThePd-DAAA proceeded smoothly with regiospecificity in 94%yield and 80% ee.

Scheme 46 Synthesis and reaction of ketone-derived -alkoxy enol carbonate

Additionally, electrophiles bearing stereochemistrycould be subjected to the reaction conditions to produce al-kylation products with high diastereoselectivity. This strat-egy was applied to the formal synthesis of (S)-oxybutynin(Scheme 47). The sodium carbonate of 133 was formed bytreatment with sodium hydride, followed by carbon dioxide

capture. The transiently formed species was then treatedwith 2-bromoacetophenone and was subsequently con-verted into DAAA substrate 135 by regioselective silylation.Although the starting enol carbonate 135 existed as a mix-ture of enantiomers, the stereochemistry about the electro-phile was lost upon ionization, as the -allyl species be-comes symmetrical. The DAAA reaction proceeded smooth-ly in 18 hours to afford the hydroxyaldehyde 136 in 99%yield and 11:1 d.r. For substrate 135, the tert-butyldimeth-ylsilyl protecting group transfer occurred efficiently, as in-dicated by the high yield in the DAAA reaction. Hydrogena-tion of the olefin afforded product 137 with 84% ee, reflect-ing the stereoselectivity about the tetrasubstituted carbon.Upon desilylation of 137 and Pinnick oxidation, hydroxyacid 139 was obtained as a single isomer after a single re-crystallization, completing the formal synthesis of (S)-oxy-butynin.

Scheme 47 Formal synthesis of (S)-oxybutynin by Pd-DAAA

A method for the synthesis of acyclic quaternary stereo-centers by DAAA was investigated by Tunge and Ariyarath-na.43 Racemic 141 was used with the hope that stereoin-duction would be observed, even in the absence of enolatecontrol (Scheme 48). In this system, the two -substituentsare of considerable steric difference, and it could be imag-ined that this could result in stereocontrol of the formedenolate. Under conditions of catalyst control, only modestenantioselectivity could be observed, with Trost Ligand L4affording the product with the highest enantioselectivity.

Scheme 48 Synthesis of quaternary stereocenters by Pd-DAAA of acy-clic allyl -oxo esters

R

OTBS

O O

O

Pd2dba3·CHCl3 (2.5%)(R,R)-L4 (5.5%)

dioxane, 23 °C

CHO

OTBS

R CHO

OTBS NH HNO

PPh2

O

Ph2P

(R,R)-L4

CHO

OTBS

CHO

OTBS

MeO

CHO

OTBS

NO2

CHO

OTBS

CHO

OTBS

Me

CHO

OTBS

CHO

OTBS

Ph

O

93% yield92% ee

94% yield92% ee

92% yield85% ee

89% yield98% ee

69% yield79% ee

93% yield98% ee

81% yield93% ee

76% yield89% ee

127

129a

129

Me129b 129c 129d

129e 129f 129g 129h

Ph

O

Br

1. sodium allylcarbonateDMF, r.t.

2. NaHMDS, THF–78 °C, then

TBSCl

Ph

OTBS

OCO2allyl58% yield

over two steps

Pd2dba3·CHCl3 (2.5%)(R,R)-L4 (5.5%)

dioxane, 23 °C

O

TBSO Ph

94% yield80% ee

(+/–)

130 131 132

OHNaH, CO2THF, then

PhCOCH2Br

Ph

O

O

O

ONaHMDS

TBSCl, THF

–78 °C to 23 °C Ph

O

OTBS

O

O

42% yield 83% yield

Pd2dba3·CHCl3 (2.5%)

(R,R)-L4 (5.5%)Dioxane, 23 °C

Ph

OHC OTBS

99% yield, 11:1 d.r.

H2, Pd/C

EtOH, 23 °CPh

OHC OTBS

96% yield, 84% ee

NaClO2NaH2PO4

2-methylbut-2-ene

t-BuOH, H2O

Ph

HO2C OH

95% yield(S)-oxybutynin

133 134 135

136 137

139

(+/–)

(+/–)

(+/–)

Ph

OHO

O

Et2N

Ph

OHC OH

44% yield

138

TBAF

THF, r.t.

140

N

O

PhO

O Pd2dba3 (5%)Ligand* (13%)

solvent, temp.

N∗∗

O

Ph

Ligand

Quinap L22t-Bu-PHOX-L19

Trost L4Trost L4Trost L4

Solvent

benzenebenzene

THFDME

toluene

Temp °C

25 25–40 –40–40

%Yield

9397– –

90

141 142(+/–)

% ee

115

242049

Entry

12345


18


Additionally, a series of chiral auxiliary containing sub-strates 143 were employed as mixtures of diastereomers atthe -carbonyl position (Scheme 49). Products were formedwith some level of stereoinduction observed, and one auxil-iary proved useful for recrystallization of the product in di-astereomerically pure form.

Scheme 49 Auxiliary approach for the Pd-DAA of acyclic allyl -oxo es-ters

A more elaborate method of synthesizing geometricallydefined enolates was developed by Marek and co-workers.44

An auxiliary-containing ynamide was carbometallated andoxidized to give geometrically pure enolates. This work wasoriginally employed in aldol reactions; however, Starkov,Marek, Stoltz, and co-workers demonstrated that the tran-siently formed enolate can be successfully trapped as theenol carbonate (Scheme 50).45 Two protocols were devel-oped for this reaction, due to limitations in substrate scopeusing a one-pot method when employing acyclic carbamatesubstrates. In the second method (Scheme 50b), the iodoenamide 149 was lithiated with t-BuLi, and the enol car-bonate 150 was isolated with geometric purity after oxida-tion and acylation.

Optimization with a variety of PHOX and Trost-style li-gands revealed electron-deficient Trost ligand L6 bearingthe anthracene-9,10-diamine backbone provided the prod-uct with the highest enantioselectivity (Scheme 51). Sub-strate 151a was shown to provide 152a with higher enantio-selectivity compared to substrates bearing an oxazolidi-none.

The subsequent Pd-DAAA reaction provided allylationproducts with high enantioselectivity, even in cases wherethe two -substituents are of similar steric bulk (Scheme52). This likely indicates that the chiral catalyst recognizesthe steric and electronic differences of the enolate oxygenand the achiral auxiliary as opposed to the differentiationof the -substituents. A two-step allylation/cross-metathe-sis protocol was employed to better facilitate assay of theenantioselectivity. The acrylate moiety provided products153 with higher differentiability of substituents and betterabsorptivity for UV detection.

For substrates bearing two -substituents with consid-erable steric difference (i.e., aryl vs. alkyl), high enantiose-lectivity can be achieved for aryl ketones (Scheme 53).46 Us-ing a protocol developed for the synthesis of analogous enoltosylates,47 enol carbonate 155a was synthesized with (E)selectivity. Solvent optimization with an electron-deficientPHOX ligand L20 provided high enantioselectivity with amixed hexane/toluene solvent system.

Although high geometric control could be achieved inthe enol carbonate formation, it was observed that this wasunnecessary when employing the PHOX L20, as similar lev-els of enantioselectivity were observed for a mixture ofenolate isomers and -keto ester 157 (Scheme 54). Howev-er, high levels of enantioselectivity (86% ee) were observedwhen using Trost ligand L4 for the geometrically definedenol carbonate under the optimized conditions for the

*Xc

O

PhO

OPd(PPh3)4 (10%)

benzene, 25 °C *Xc∗∗

O

Ph

N

O

PhO

O

i-Pr

N

O

PhO

O

t-Bu

N

O

PhO

O

CHPh2

N

O

PhO

O

Bn88% yield, 85:15 d.r. 83% yield, 84:16 d.r.*88% yield, 38:62 d.r. 87% yield, 26:74 d.r.

*53% yield, <5:>95 d.r. after recrystallization

143 144

144a 144b 144c 144d

Scheme 50 One-pot carbometalation/oxidation/acylation synthesis of tetrasubstituted amide enol carbonates and two-pot carbometalation/iodina-tion followed by lithiation/oxidation/acylation

N

R3

N

Cu

R4

R3

R4

(R4)2CuLi (1.2 equiv)

N

O

R4

R3

O

Oallyl1.) t-BuOOH (1.2 equiv)

–78 °C, 0.5 h

N

CO2R2

R1

R3N

R4

R3

R2O2C

R1

R4MgBr (2 equiv)CuI (1 equiv)

N

O

R4

R3

R2O2C

R1

O

Oallyl1) t-BuLi (2 equiv)

Et2O, –78 °CI

148

146

149

147

150

O

O

O

O

145

O

O

a)

b)

–30 °C to –10 °CEt2O, 0.5 h

2.) allyl chloroformate

2.) t-BuOOLi, THF3.) allyl chloroformate

–30 °C to –10 °CEt2O, then I2

Scheme 51 Optimized substrate for Pd-DAAA of tetrasubstituted amide enol carbonates

NH HNO

PAr2

O

Ar2P

(R,R)-L6

CF3F3C

Ar = 4-CF3Ph

N

O

Bu

MeO2C

O

OPd(dba)2 (4%)(R,R)-L6 (7%)

EtOAc

N

O

Bu

MeO2C

85% yield94% ee

PhPh

E/Z < 2:98151a 152a


19


PHOX system, but selectivity (50% ee) was diminishedwhen using a mixture of isomers. It was speculated thatrapid C–O equilibration of the palladium(II) enolate may ac-count for this effect when using the PHOX system. Poten-tially, optimization with the PHOX ligand resulted in condi-tions where the facial differentiability of the -substituentsdictates the stereochemical outcome of the reaction.

A reaction involving the DAAA of -acetamido--ketoesters 158 has been described for an acyclic system(Scheme 55).48 Interestingly, with little optimization, highlevels of enantioselectivity were realized in this reaction,albeit for a limited substrate scope. Potentially, there is con-trol of the enolate geometry due to hydrogen bonding be-tween the amide hydrogen and the transient enolate ion.Phenol and naphthol were found to improve the enantiose-lectivity, although the origin of this effect is not well under-stood.

A Pd-AAA of nitroalkanes has been described by Shiba-saki and co-workers (Scheme 56).49 Although most of thereactions described in the method involve stereocontrol onthe electrophile, a single example of Pd-AAA with a racemicsecondary nitroalkane 160 and allyl carbonate 161 was re-ported, albeit with low enantioselectivity.

Scheme 56 Asymmetric allylation for the synthesis of -tertiary ni-troalkanes

4 Temporary Cyclic Pronucleophiles

4.1 Reactions of Azlactones

Alkylation of azlactones directly furnishes productswith cyclic tertiary amino functionality, and the subse-quent hydrolysis of the products has proven useful for pro-ducing acyclic -tertiary amino acids (Scheme 57). Thisprovides an efficient method for the synthesis of unnaturalamino acids, as the synthesis and elaboration of azlactonescan be readily accomplished using commercially available

Scheme 52 Substrate scope of Pd-DAAA of tetrasubstituted amide enol carbonates

N

O

R4

R3

MeO2C

Bn

O

O

1. Pd(dba)2 (4%)(R,R)-L6 (7%)EtOAc or THF

2. Grubbs' II (6%)methyl acrylate

40 °C, CH2Cl2, 3 h

N

O

R4R3

MeO2C

Bn

CO2Me

X

O

n-hexCO2Me X

O

CO2Me X

O

PhCO2Me

TBSO

69% & 84% yield94% ee

76% & 79% yield94% ee

77% & 78% yield76% ee

X

O

Etn-BuCO2Me X

O

Etn-hexCO2Me X

O

n-hexCO2Me

76% & 85% yield82% ee

64% & 85% yield94% ee

56% & 84% yield76% ee

Ph

151 153

153a 153b 153c

153d 153e 153f

Scheme 53 A Pd-DAAA of stereodefined tetrasubstituted 1,2-diaryl enol carbonates

Ar1

O

R

Ar2

O

O

Pd2dba3 (0.5%)(S)-L20 (1.2%) Ar1

O

Ar2

R

R = alkyl

95–99% yield67–92% ee

21 examples

P N

O

t-Bu

Electron-Deficient(t-Bu)-PHOX

CF3

F3C

CF3

Ph

O

Et

PhPh

O

Et

Ph

O

O

> 98:2 E/Z

LiHMDS, Me2NEt

> 98:2 E/Z

(+/–)154 155a

155

156

L20toluene, 23 °C, thenallyl chloroformate

hexane–toluene(3:1), 25 °C, 12 h

Scheme 54 Independence of enolate geometry on enantioselectivity for an electron-deficient (t-Bu)-PHOX ligand

Ph

O

Et

Ph

O

OPd2dba3 (0.5%)(S)-L20 (1.2%)

hexane–toluene(3:1), 25 °C

Ph

O

Ph

Et

> 98:2 E/Z

97% yield91% ee

Ph

O

Et

Ph

O

OPd2dba3 (0.5%)(S)-L20 (1.2%)


Ph

O

Ph

Et

25:75 E/Z

95% yield90% ee

Ph

O

O

O

Ph Et (+/–)

Pd2dba3 (0.5%)(S)-L20 (1.2%)


Ph

O

Ph

Et70% yield90% ee

155a

155a

157

156a

156a

156a

Scheme 55 Pd-DAAA of -acetamido--keto esters

R1

O

AcHN R2O

O Pd2dba3·CHCl3 (2.5%)(R,R)-L2 (5%)

R1

O

AcHN R2

HNNH

PPh2 Ph2P

O O

(R,R)-L2

O

AcHN Me 79% yield87% ee

Et

O

AcHN Me 81% yield90% ee

O

AcHN Et 55% yield80% ee

O

AcHN Bn 81% yield71% ee

158 159

159a 159b 159c 159d

1-naphthol (0.5 equiv)DCE, r.t.

Pd2dba3·CHCl3 (0.5%)L21 (1.3%)NO2

Bn

NO2

Bn

94% yield, 49% ee

OBoc+ PPh2N

O

PHOX Ligand-L21

Ph

CH2OH160 161

162toluene, r.t.TBD (10%)


20


amino acids. Additionally, the identity of the carboxylicacid template may serve as a point for reaction optimiza-tion.

Scheme 57 Azlactones as precursors to acyclic -tertiary amino acids

The Trost group has shown a breadth of Pd-AAA reac-tions with azlactones for a variety of allyl electrophiles.50

Impressively, some of the first asymmetric Pd-catalyzedbenzylation reactions were developed using azlactones aspronucleophiles.51 For electron-deficient electrophiles 163,a diphenyl phosphate leaving group in conjunction with el-evated temperatures allowed for the difficult ionization tooccur (Scheme 58).

In the case of electron-rich benzyl electrophiles 166, thediethyl phosphate leaving group proved sufficient at ambi-ent temperatures. This methodology was used in a short

asymmetric synthesis of -methyl-D-DOPA (Scheme 59a).Under conditions for the asymmetric benzylation of elec-tron-rich benzylic phosphates, the key alkylation step af-forded -tertiary azlactone 167 in 83% yield and 90% ee. Thedesired acyclic target 168 was synthesized in 96% yield byhydrolysis of the azlactone. Conveniently, the methylenedi-oxy group was hydrolyzed under these conditions. Addi-tionally, triflic acid hydrolysis in the presence of methanolallows for access to the acyclic protected amino acids 171(Scheme 59b).

Similarly, allyl electrophiles allow for the installation ofa functional group handle for synthetic modification(Scheme 60).50a Interestingly, symmetrical allyl and 2-me-thallyl electrophiles yielded products with low enantiose-lectivity. However, unsymmetrical 3-substituted electro-philes and prenyl electrophiles afforded the -tertiary al-kylated products with high enantioselectivity. It isimportant to note that prenyl and cinnamyl electrophilesproduce alkylation products with an opposite sense of chi-rality.

R

NH3

O–

O1. ArCOCl

2. DCC N

O

Ar

R

Oasymmetric

alkylation N

O

Ar

R

OR'

hydrolysis

NH3

O–R

OR'

α-aminoacids

azlactonepronucleophiles

α-tertiaryazlactones

α-tertiaryamino acids

Scheme 58 Pd-catalyzed benzylation of azlactones

OP

O

OPhOPh

1.0 equiv

+

NO

O

Ph

R2

R1

1.5 equiv

(Cp)Pd(allyl) (5%)(R,R)-L3 (6%)

NEt3 (1.2 equiv)t-BuOH (5 equiv)Dioxane, 50 °C

NO

O

Ph

R2

R1

Ph Ph

NH HNO O

Ph2PPPh2

(R,R)-L3

NO

O

PhN

O

O

Ph

MeS

NO

O

Ph

F

88% yield93% ee

80% yield85% ee

74% yield94% ee

NO

O

Ph

91% yield95% ee N

O

O

Ph

MeO

79% yield78% ee

NO

O

Ph

MeO

82% yield84% ee

MeO2CCl

163 164 165

165a 165b 165c

165f165e165d

Scheme 59 Pd-catalyzed benzylation strategy for the synthesis of -methyl-D-DOPA and benzylation strategy toward acyclic -tertiary amino acids

OP

O

OEtOEt

1.0 equiv

+ NO

O

Ph

1.5 equiv

(Cp)Pd(allyl) (5%)(R,R)-L3 (6%)

Cs2CO3 (0.6 equiv)t-BuOH (5 equiv)

CH2Cl2, 25 °C

NO

O

Ph

PhOH, AcOH

6 M HCl, reflux

O

O

OO 83% yield

90% ee

NH3

OH

O

94% yield

Cl

α-methyl-D-DOPA

HO

HO

OP

O

OEtOEt

1.0 equiv

+ NO

O

Ph

1.5 equiv

(Cp)Pd(allyl) (5%)(R,R)-L3 (6%)

Cs2CO3 (0.6 equiv)t-BuOH (5 equiv)

CH2Cl2, 25 °C

NO

O

Ph

TfOH (3 equiv)

MeOH, 80 °C

90% yield96% ee

NHBzOMe

O

86% yieldMeO

MeO

MeO

166164a

164a

167

168

169

170

171

a)

b)


21


Scheme 60 Enantiodivergent alkylation with reverse prenyl and cinnamyl electrophiles

For unsymmetrical allyl systems, diastereomeric -allylcomplexes are possible (Scheme 61). This feature likely dic-tates a distinct mode of attack by the nucleophile, and inthe case of azlactones, this trajectory of approach results inbetter recognition of the prochiral faces of the incoming nu-cleophile. When the linear product is favored, it can be seenthat by placing the 3-allyl substituent under the less hin-dered flap (Scheme 61a), nucleophilic attack occurs at theterminus where chiral information is better relayed fromthe metal center.

Scheme 61 Rationale for higher enantioselectivity for alkylation of 3-substituted electrophiles

In addition to reactions that form stereochemistry onthe nucleophile, the Trost group has utilized this transfor-mation for simultaneous stereoinduction on the electro-philic partner (Scheme 62).50b A Pd-AAA with cyclic elec-trophile 177 afforded the product 178 with high diastereo-and enantioselectivity. The remarkably high level of enantio-selectivity observed in this reaction is likely a result of sta-tistical enrichment, since the Pd(0)/chiral ligand system hasbeen shown to induce high levels of asymmetric inductionon each partner independently.

A geminal diacetoxyallylic electrophile 179 was appliedto the synthesis of sphingofungin F (Scheme 63).52 In thisreaction, the stereochemistry on the electrophile resultsfrom selective ionization of enantiotopic leaving groups in-dependent of the presence of the nucleophile. The stereo-chemistry on the azlactone in 180 was additionally ob-tained with high diastereoselectivity. The relative stereo-chemistry of the amino and acetoxy functional groups wasstrategically inverted in subsequent steps in the synthesisof sphingofungin F.

HNNH

PPh2 Ph2P

O O

(R,R)-L1

OAc

+ NO

O

Ph

Bn

1.0 equiv 1.2 equiv

(R,R)-L1 (1.5%)[Pd(allyl)Cl]2 (0.5%)

NEt3toluene, r.t.

173 75% yield, 99% ee

NO

O

Ph

Bn

+ NO

O

Ph

Bn

1.0 equiv 2.25 equiv

(R,R)-L1 (7.5%)[Pd(allyl)Cl]2 (2.5%)

NEt3toluene, r.t.

176 91% yield, 90% ee

NO

O

Ph

Ph

BnPh OAc

174 15% yield, 20% ee

NO

O

Ph

Bn+

172 164b

164b175

a)

b)

Pd Pd

π−σ−π

R R

∗∗EWGR

R1 R2

∗∗ EWGR

R1R2

low enantioselectivityhigh enantioselectivity

a) b)

Scheme 62 Diastereo- and enantioselective Pd-AAA of azlactones with cyclic prochiral electrophiles

HNNH

PPh2 Ph2P

O O

(R,R)-L1

+ NO

O

Ph

(R,R)-L1 (7.5%)[Pd(allyl)Cl]2 (2.5%)

NEt3, MeCN

178 77% yield, 13:1 d.r.99% ee

NO

O

Ph

OAcH

(+/–)177 164c (+/–)

Scheme 63 A diastereo- and enantioselective synthesis of sphingofungin F

TBDPSO

OAc

OAc NO

O

Ph

+

(R,R)-L1 (1.5%)[Pd(allyl)Cl]2 (0.5%)

NaH, THF NO

O

Ph

OAc

TBDPSO

180 70% yield11:1 d.r., 89% ee

n-C6H13 CO2

OH

OH

OH

NH3Osphingofungin F

HNNH

PPh2 Ph2P

O O

(R,R)-L1

179 164a

181


22


4.2 Cyclic -Alkoxy-Bearing Substrates

A similar strategy as that used for -tertiary amino acidscould be envisioned for asymmetric -tertiary alcohol syn-thesis, whereby a cyclic template could serve to controlenolate geometry (Scheme 64). The Stoltz group haveshown that dioxanones 182 derived from 1,3-dihydroxyac-etone can be used for this purpose.53

Scheme 64 Acyclic -tertiary hydroxy ketones, acids, and esters from dioxanone

Alkylation of unsubstituted dioxanones, followed by si-lyl enol ether formation provided substrates 184 for allylicalkylation. The trimethylsilyl enol ethers proved too unsta-ble; however, the regioisomeric triethylsilyl enol ethers 183and 184 could be separated by silica gel chromatography. Inthe presence of TBAT as a desilylation reagent, allylationproceeded in high yield and enantioselectivity using sym-metrical unsubstituted and 2-substituted allyl carbonates185 as electrophiles. A 4-toluenesulfonic acid catalyzed hy-drolysis of 186 in the presence of methanol gave the acyclichydroxy ketone products 187. Periodate cleavage, followedby esterification provided -tertiary hydroxyl esters 188.This method was used in an efficient synthesis of (+)-eu-comic acid.54

A Pd-DAAA of 5- and 6-membered lactam precursorswas developed by the Stoltz group (Scheme 65).55 An -hy-droxy ester 191 was accessed by hydrolysis of the DAAAproduct 190 in the presence of catalytic methanol and sul-furic acid.56 The method additionally was also performed

using a sulfur-containing lactam, an allyl 2-methyl-3-oxo-thiomorpholine-2-carboxylate, although derivatization ofthe product to the acyclic precursor was not demonstrated.

Likewise, thiopyranones were used for the synthesis ofacyclic quaternary stereocenters (Scheme 66).57 Acylationof thiopyranone and subsequent alkylation of the resulting-keto ester provides substrates 192 for Pd-DAAA. The reac-tion proceeds with high yield and enantioselectivity inmost cases. Direct extrusion of the sulfur atom was at-tempted, but hydrogenation of the allyl olefin of 193a couldnot be avoided. A hydroboration/oxidation proved usefulfor avoiding this problem, as Raney nickel in ethanol afford-ed the desired acyclic -quaternary ketone 195 in 94% yieldover the sequence. Although this method represents an ap-plication of cyclic structure for creating acyclic stereocen-ters, it suffers from the drawback of being limited to thesynthesis of -methyl ethyl ketones only.

Scheme 66 Thiopyranones as precursors of acyclic quaternary stereo-centers

5 Allylic Alkylation with Other Metals

The first reactions within the area of allylic alkylation todemonstrate stereocontrol in the synthesis of acyclic ste-reocenters were in Pd-AAA, followed by reactions in Mo-catalyzed AAA; however, within the last few years, majoradvances have been made employing other metals, mostnotably rhodium and iridium. Copper-catalyzed allylic sub-stitution reactions58 nicely complement methods with oth-er metals due to the unique SN2′ pathway and the ability toemploy hard nucleophilic precursors. The structures of li-gands used in Mo-, Ir-, and Rh-catalyzed AAA are shown inFigure 2.

O O

O

TESCl, NaI

NEt3, MeCN O O

OTES

O O

OTES

+

R1 R1

(S)-(t-Bu)-PHOX-L19 (5.5%)Pd(dmdba)2 (5%)

TBAT (1 equiv)toluene, 25 °C, 5–10 h

O O

OR1

R2

6–15%yield

46–78%yield

R2 = H, Me, Ph, Cl

186 59–93% yield85–94% ee

TsOH·H2O

MeOH OH OH

OR1

R2

1) H5IO6THF–H2O

2) K2CO3MeI, DMF

MeO

OH

OR1

R2

80–90% yield 54–85% yield

R1 = alkyl

R1

182 183 184

187 188

O

R2

O

O

R2185

Scheme 65 Lactam precursor to -hydroxy tertiary esters

NO

O O

OBz

Pd2(pmdba)3 (5%)(S)-PHOX-L20 (12.5%)

toluene, 60 °C

NO

O

Bz H2SO4

MeOH, 65 °CMeO

O

OH

191 71% yield190 82% yield

96% ee(+/–)189

S

O

O

OR Pd2(dmdba)3 (1%)

(R,R)-Trost L4 (2.4%)

TBME, 25 °C, 12 hS

OR

R = alkyl 70–92% yield50–94% ee

NH HNO

PPh2

O

Ph2P

(R,R)-L4

S

OBn BH3.THF

cyclohexene

then NaBO3·H2OS

OBn

OHRaney Ni

EtOH, 70 °CEt

OBn

OH

94% yield over 2 steps94% ee

(+/–)192193

193a 194 195


23


Figure 2 Structures of ligands used in Mo-, Ir-, and Rh-catalyzed AAA

5.1 Molybdenum-Catalyzed AAA

The ability to selectively access branched allylic alkyla-tion products is an attractive feature for creating stereo-chemistry on electrophilic partners. Among metals thattypically afford branched products selectively (Mo and Ir),selectivity on the nucleophilic partner was first achieved inMo-AAA for azlactones59 and oxindoles.60

In the case of branch-selective azlactone alkylation,58

the reaction proceeded in excellent yield as well as diaste-reo- and enantioselectivity (Scheme 67). Similar levels ofyield and selectivity were observed when using a carbonateor phosphate leaving group; however, the use of lithiumbase was found to afford higher branch selectivity com-pared to sodium or potassium hexamethyldisilazanide. Ad-ditionally, adopting a one-pot protocol for hydrolysis of theazlactone afforded 197 in higher yield compared to thestepwise process.

The scope of the reaction showed the best results forcinnamyl methyl carbonate electrophile (197a–e), withslightly diminished enantioselectivities for heteroaromatic

as well as 2-substituted phenyl systems (197f–j). High se-lectivity was achieved for aliphatic -substituents with var-ied substitution patterns. It is important to note that linear,achiral electrophiles 196 performed better than branched,racemic allylic carbonates, presumably due to slow ––equilibration relative to nucleophilic attack. The mode ofasymmetric induction on the electrophile therefore likelyresults from differentiation of the enantiotopic faces of theelectrophile in olefin coordination and/or ionization.

With success using azlactones as precursors for acyclic-tertiary amino acids, the Trost group studied the isomer-ic oxalactims 19861 as precursors to acyclic -tertiary alco-hols (Scheme 68).

Indeed, these pronucleophiles undergo Mo-AAA withregio-, diastereo-, and enantioselectivity. In addition to thestandard cinnamyl-type electrophiles, vinyl-substitutedsystems perform as well (199c,d). An efficient hydrolysis ofthe products directly affords acyclic -tertiary hydroxy am-ides (Scheme 69).

HNNH

N N

O O

(S,S)-TrostL5

HNNH

N N

O O

(R,R)-TrostL23

MeO OMe

O

OP(OMe)

(R)-BINOL-MeOPL25

N

N

NH2

C1

N

N

NH2

C2

O

OP

(R)-L24

N

Scheme 67 One-pot Mo-catalyzed regio-, diastereo-, and enantioselective allylic alkylation of azlactones followed by hydrolysis

NO

Ph

OR2

R1 OCO2Me +

NHBz

R2i) (S,S)-L5 (15%)

Mo(CO)3C7H8 (10%)

LiHMDSTHF, 65 °C

ii) K2CO3–MeOH

R1

(+/–)

HNNH

N N

O O

(S,S)-TrostL5

CO2Me

NHBz

Ph

CO2Me

NHBz

Ph

CO2Me

SMe

NHBz

Ph

CO2Me

NHBz

i-PrPh

CO2Me

NHBz

Ph

CO2Me

92% yield97:3 d.r.99% ee

86% yield>98:2 d.r.92% ee

85% yield>98:2

96% ee

76% yield>98:2 d.r.96% ee

82% yield>98:2 d.r.97% ee

NHBz

CO2Me

84% yield96:4 d.r.91% ee

S

NHBz

CO2Me

84% yield>98:2 d.r.92% ee

O

NHBz

CO2Me

86% yield>98:2 d.r.94% ee

S

Ph

NHBz

CO2Me

82% yield>98:2 d.r.85% ee

Br

NHBz

CO2Me

90% yield>98:2 d.r.94% ee

MeO

OMe

Ph

196 164 197

197a 197b 197c 197d 197e

197f 197g 197h 197i 197j


24


Scheme 69 Conversion of oxalactim into acyclic -tertiary hydroxy amides

The synthesis of acyclic quaternary stereocenters wasachieved using -substituted -cyano esters 200 as pronu-cleophiles (Scheme 70).62 Interestingly, the process affordsacyclic quaternary carbon products in excellent enantiose-lectivity in cases where the allyl electrophile bears no ste-

reochemistry (201a,b). Both alkyl and aryl -substituentsresulted in high regio-, diastereo-, and enantioselectivity.Additionally, -tertiary ether product 201h was accessedwith good diastereo- and enantioselectivity.

Scheme 70 Mo-catalyzed regio-, diastereo-, and enantioselective allylic alkylation of acyclic -cyano esters

Scheme 68 Mo-catalyzed regio-, diastereo-, and enantioselective allylic alkylation with oxalactims

ON

Ph

OR2

R1 OCO2Me +

ON

Ph

OR2Trost L5 (15%)Mo(CO)3C7H8

LiHMDSTHF, 65 °C

R1

(+/–)

HNNH

N N

O O

(S,S)-TrostL5

ON

Ph

OMeO

OMe

ON

Ph

OBr

ON

Ph

O

ON

Ph

O

ON

Ph

Oi-Bu

ON

Ph

Oi-PrPh

S

ON

Ph

OBuPh

ON

Ph

OPh

ON

Ph

OCyPh

ON

Ph

OBnPh

82% yield12:1 b/l18:1 dr99% ee

78% yield27:1 b/l24:1 dr99% ee

54% yield12:1 b/l12:1 dr98% ee

77% yield14:1 b/l12:1 dr89% ee

89% yield14:1 b/l10:1 dr99% ee

70% yield5.5:1 b/l20:1 dr99% ee

86% yield49:1 b/l9:1 dr

99% ee

97% yield8:1 b/l10:1 dr99% ee

74% yield9:1 b/l12:1 dr99% ee

84% yield20:1> b/l7.4:1 dr99% ee

196 198 199

199a 199b 199c 199d 199e

199f 199g 199h 199i 199j

ON

Ph

Oi-Bu

S

NaOH

EtOH/H2O60 °C

OHNH2

Oi-Bu

S

86% yield

ON

Ph

Oi-Bu Trost L5 (15%)

Mo(CO)3C7H8

LiHMDSTHF, 65 °C

(+/–)OCO2Me +

S 89% yield14:1 b/l10:1 dr99% ee

O

EtNC

BocNS

t-BuO

O

OMeNC

t-BuO

O

PhNC

Ph

t-BuO

O

EtNCt-BuO

O

NC

Br NO2

99% yield99% ee

96% yield98% ee

>20:1 b/l, 16.8:1 dr93% ee, 96% yield

>20:1 b/l, 29:1 dr98% ee, 93% yield

>20:1 b/l, 20:1 dr99% ee, 95% yield

>20:1 b/l, 13.7:1 dr97% ee, 92% yield

>20:1 b/l, 11.1:1 dr92% ee, 83% yield

>20:1 b/l, 11.1:1 dr88% ee, 79% yield

>20:1 b/l, 11:1 dr97% ee, 99% yield

>20:1 b/l, 20:1 dr98% ee, 93% yield

2.2 equiv

196

200

201

201a 201b 201c 201d 201e

201f 201g 201h 201i 201j

t-BuO

O

R2

CN

R1 OCO2Me

+

Trost L23 (15%)Mo(CO)6 (10%)

NaH (10%), BSATHF, 60 °C

HNNH

N N

O O

(R,R)-TrostL23

MeO OMe

t-BuO

O R1

R2NC

t-BuO

O

NCt-BuO

O

EtNCt-BuO

O

NC

Ph

t-BuO

O

BnNC

Ph

t-BuO

O

EtNC

t-BuO


25


5.2 Iridium-Catalyzed AAA

In iridium-catalyzed allylic alkylation, the ability to con-trol stereochemistry on the nucleophilic partner simulta-neous to stereocontrol was first demonstrated by Takemotoand co-workers63 in 2003. Since that first report, enantio-and diastereoselective Ir-AAA reactions have been reportedfor several systems. This topic has been reviewed else-where,64 so we will focus on two systems that demonstratethe synthesis of acyclic quaternary carbons on the nucleo-philic and electrophilic partners, respectively.

In an impressive display of enantio- and diastereodiver-gence, Carreira and co-workers (Scheme 71)65 were able todemonstrate the ability to access all four stereoisomers inthe -cinnamylation of aldehydes to afford vicinal acyclicquaternary and tertiary stereocenters. Borrowing from thesuccess of dual-catalysis in Pd-AAA, they employed cincho-na alkaloids with chiral phosphoramidite ligands. The pseu-do-enantiomeric catalyst was employed to access the otherdiastereomer. Despite a small match-mismatch effect, allfour diastereomers can be accessed in near perfect selectiv-ity by this method.

The branch-selective Ir-AAA of trisubstituted cinnamylelectrophiles was demonstrated by the Stoltz group(Scheme 72).66 In this reaction, acyl anion equivalent 205 isused to allow for easy access to -aryl--vinyl carbonylcompounds 207. This method demonstrates a new land-mark in Ir-AAA, as more highly substituted electrophiles206 have proven difficult in Ir-AAA. In a single operation,the acyl anion was cleaved to directly afford carboxylic acid

207. Additionally, conditions were developed to obtain es-ters and primary and secondary amides directly from theallylic alkylation products.

The reaction was limited in electrophile scope, as re-placement of the methyl group with ethyl (207j), isopropyl,or butyl groups or the para- or mono-meta-substitutedphenyl group with di-meta- (207i) or ortho-substitutedphenyl groups (207l) resulted in lower, or no, reactivity, butnot lower enantioselectivity. Additionally, excess electro-phile over the acyl anion equivalent was required for highyields. Triethylborane proved to be crucial for reactivity, asno reaction proceeded in its absence, and lower yields wereobserved for lithium bromide as an additive. Presumably,triethylborane assists by Lewis acid activation in the other-wise difficult ionization reaction. The mode of asymmetricinduction of this reaction is selective ionization from enan-tiotopic faces. This was demonstrated by observing no en-antioselectivity when using the branched, racemic electro-phile.

5.3 Rhodium-Catalyzed AAA

Exploiting the stereospecificity of the Rh-allylic alkyla-tion, the Evans group was able to alkylate enantiopure ter-tiary allylic carbonates with regio- and stereospecificity(Scheme 73).67 An electron-deficient phosphite ligand wasfound to afford the product with highest enantiospecificity(denoted as es) compared to more electron-neutral phos-phite ligands.68 All ligands screened showed complete re-giospecificity in the reaction. It was reasoned that the elec-

Scheme 71 Regio-, diastereo-, and enantioselective -cinnamylation of aldehydes by dual chiral amine/chiral iridium catalysis

O

OP

(S)-L24

N

N

N

NH2

C1

N

N

NH2

C2

H

O

Ph

OH

S

+

[(Ir(cod)Cl)2] (2%)(R)-L24 (8%)

C1 (10%)Cl3CCO2H (0.5 equiv)

DCE, 25 °C

H

O

Ph

S

1.1 equiv 64% yield, dr >20:1ee >99%

H

O

Ph

OH

S

+

[(Ir(cod)Cl)2] (2%)(R)-L24 (8%)


DCE, 25 °C

H

O

Ph

S

70% yield, dr 11:1ee >99%

H

O

Ph

OH

S

+

[(Ir(cod)Cl)2] (2%)(S)-L24 (8%)


DCE, 25 °C

H

O

Ph

S

64% yield, dr 10:1ee >99%

H

O

Ph

OH

S

+

[(Ir(cod)Cl)2] (2%)(S)-L18 (8%)


DCE, 25 °C

H

O

Ph

S

70% yield, dr >20:1ee >99%

O

OP

(R)-L24

N

1.0 equiv202

1.1 equiv202

1.1 equiv202

1.1 equiv202

203

1.0 equiv203

1.0 equiv203

1.0 equiv203

204a

204b

204c

204d


26


tron deficiency of the ligand facilitated a more rapid inter-molecular alkylation event relative to –– equilibration.Additionally, more bulky ligands resulted in significantlydiminished enantiospecificity, presumably due to high co-ordinative unsaturation of the Rh complex, thus favoringthe η1-allyl species necessary for isomerization.

The reaction scope revealed high regioselectivity in allcases (Scheme 74). The stereospecificity of the reaction washigh for most substrates, although disubstituted aromaticsfor Ar1 resulted in diminished enantiospecificity. The elec-tronics of Ar2 showed high stereospecificity for electron-withdrawing substituents at the 4-position, and diminishedspecificity for electron-donating groups. This likely resultsfrom a more electrophilic -allyl species with electron-

Scheme 72 Branch selective Ir-AAA of trisubstituted electrophiles by an acyl anion equivalent nucleophile

NC

OMOM

CN Ar

R

OCO2Me+

i) BEt3 (2 equiv)[Ir(cod)Cl]2 (2%)

(S)-L24 (4.2%), TBD (10%)THF, 60 °C

ii) 6 M HCl, 80 °C1.0 equiv 2.0 equiv

HO

O

Ar R

O

OP

(S)-L24

N

HO

O

HO

O

HO

O

HO

O

HO

O

HO

O

Cl F3C77% yield95% ee

NO2

80% yield93% ee

83% yield92% ee

65% yield94% ee

93% yield87% ee

*66% yield92% ee

HO

O

HO

O

HO

O

HO

O

EtHO

O

HO

O

F

*68% yield93% ee

Br

90% yield90% ee

*32% yield85% ee

*61% yield92% ee

69% yield92% ee

0% yield

R = Me or Et

*Double the Ir and ligand loading was used.

205 206 207

207a 207b 207c 207d 207e 207f

207g 207h 207i 207j 207k 207l

Scheme 73 Regio- and enantiospecific Rh-allylic alkylation of tertiary allylic carbonates with a cyanohydrin acyl anion equivalent

OCO2Me

Ph

i) [RhCl(cod)]2 (2.5%)P(OCH2CF3)3 (10%)

ii) LiHMDS (1.8 equiv)209 (1.3 equiv)THF, –10 °C

Ph CN

OTBS+

1.0 equiv 1.3 equiv

Ph

O

PhPh

TBSO

Ph

CN TBAT

THF, r.t.

87% yield>19:1 b/l, 91% es

208 209 210211a

Scheme 74 Scope of Rh-allylic alkylation of tertiary allylic carbonates with a cyanohydrin acyl anion equivalent

OCO2Me

Ar1

i) [RhCl(cod)]2 (2.5%)P(OCH2CF3)3 (10%)

ii) LiHMDS (1.8 equiv)213 (1.3 equiv)THF, –10 °C

iii) TBAT, THF, r.t.

Ar2 CN

OTBS+

1.0 equiv 1.3 equiv

Ar2

O

Ar1

O

Ph

87% yield, b/l >19:191% es

O

Ph

80% yield, b/l >19:193% es

F

O

Ph

83% yield, b/l >19:187% es

Br

O

Ph

78% yield, b/l >19:181% es

MeO

OMe

Ph

O

Cl

Ph

O

OMe

Ph

O

F

Ph

O

Ph

O

F

76% yield, b/l >19:199% es

69% yield, b/l >19:190% es

73% yield, b/l >19:190% es

86% yield, b/l >19:193% es

80% yield, b/l >19:194% es

211212 213

211a 211b 211c 211d

211e 211f 211g 211h 211i


27


withdrawing substituents, favoring a rapid intermolecularreaction with cyanohydrin nucleophile relative to isomeri-zation.

This work was extended to vinyl acyl anion equivalent215 (Scheme 75).69 The product 217 can be chemoselective-ly reduced to afford the formal product from an aliphaticacyl anion equivalent addition, affording acyclic -quater-nary -vinyl ketone 218. This reaction was highlighted for atertiary allylic carbonate bearing two aliphatic substitu-ents, with the reaction proceeding with high regio- and ste-reospecificity.

The Evans group demonstrated the first direct asym-metric alkylation reaction of -tertiary nitriles 219 by Rh-catalyzed AAA (Scheme 76).70 The process improves step-economy in the -functionalization of nitriles by generatingthe reactive anion in situ, thus side-stepping the synthesisand isolation of racemic N-silylketenimines. The reactionwas shown to proceed smoothly in the absence of addi-tives; however, improved enantioselectivity was observedin the presence of a crown ether. High enantioselectivitywas demonstrated for substrates bearing methyl, isopropyl,and benzyl substituents.

Additionally, the Evans group have shown a direct inter-molecular Rh-catalyzed allylic alkylation of -aryl alde-hydes (Scheme 77).71 Deprotonation with lithium hexa-methyldisilazanide affords lithium enolates that undergoallylic alkylation with allyl benzoate (222) with high enan-tioselectivity. Although the reaction requires a ligand load-ing of 40 mol%, ligand L25 is conveniently accessed in onestep from BINOL.

Strangely, control experiments showed that both eno-late isomers converge to the same enantiomer of product(Scheme 78). The respective silyl enol ethers are convertedinto the lithium enolates by treatment with methyllithium.The enantioselectivity in the catalytic reaction is signifi-cantly higher. It is worth noting that the presence ofhexamethyldisilazanide is absent in the control experi-ments. The fact that both enolate isomers converge to thesame product is all the more surprising considering thesmall steric differences between the -substituents forproducts 223b, 223c, 223d, 223h, 223i, 223j. It could be en-visioned that there is electronic differentiation due to thestrong dependence of enantioselectivity on the 4-substitu-tion of the aromatic substituent.

Scheme 75 Rh-allylic alkylation of tertiary allylic carbonates with a vinyl cyanohydrin acyl anion equivalent

OCO2Me[Rh(cod)Cl]2 (2.5%)P(OCH2CF3)3 (10%)

LiHMDS (1.8 equiv)215 (1.3 equiv)THF, –10 °C

NC

OTBS

OBn

1.0 equiv 1.3 equiv

+ OBn

NC OTBS

TBAF

–40 °COBn

O

98% ee

82% yield, 92% ee

[PPh3CuH]6

benzene–H2Or.t.

OBn

O

82% yield, 92% ee

214 215216

217 218

Scheme 76 Rh-catalyzed asymmetric alkylation of secondary benzylic nitriles

R2

CN

R1

i) 15-crown-5 (1.2 equiv)LiHMDS, THF, –30 °C

ii) Rh(cod)2OTf (5%)(R)-L25 (20%)

iii) allyl benzoate (1 equiv)THF, –30 °C

R2

CN

R1

O

OP(OMe)

L25(R)-BINOL-

MeOP

CN CN CN CN CN

CN CN CN CN CN

86% yield, 92% ee 77% yield, 92% ee 81% yield, 84% ee

Ph

MeO

88% yield, 81% ee

Me

83% yield, 90% ee

Br

87% yield, 92% ee 92% yield, 95% ee

Br Br

Ph

85% yield, 92% ee

Ph


Ph

F3C F3C

219 220

220a 220b 220c 220d 220e

220j220i220h220g220f


28


Scheme 78 Effect of enolate geometry on stereochemical outcome

6 Conclusions and Outlook

An understanding of the mechanistic features of Pd-AAA has allowed for a variety of methods for the asymmet-ric synthesis of acyclic tetrasubstituted stereocenters in-cluding tertiary alcohols and ethers, -tertiary amines, andall-carbon quaternary carbons. Isoprene monoepoxide andrelated electrophiles have served as excellent precursors forforming difficult stereocenters, many of which appear innatural products. Additionally, the presence of hy-droxymethylene and vinyl functional group handles in theresulting products allow for the synthesis of highly valuablesources of chirality. Stereocontrol on other electrophiles hasbeen demonstrated in the branch-selective reverse-pre-nylation of oxindoles. This remains an exciting precedent in

control of acyclic tetrasubstituted stereocenters on electro-philes; however, reactions with other nucleophiles is stillunderdeveloped in this area of research.

Despite the difficulty of achieving asymmetric induc-tion on nucleophiles in Pd-AAA, important advances havebeen made over the past 20 years. The ability to controlacyclic geometric elements of enol carbonates has beenachieved by many well-designed substrate syntheses. Thisstrategy works well in conjunction with strategies employ-ing cyclic precursor such as azlactones, as evidenced bymethods for the synthesis of tertiary alcohols, -tertiaryamines, and all-carbon quaternary stereocenters. The addi-tion of dual and triple catalysis has enabled the chemist tointroduce new modes of stereocontrol as well as the abilityto exploit multiple chiral catalysts within the same reactionfor enhanced stereoselectivity.

Following the success of Pd- and Mo-AAA strategies forstereocontrol in the synthesis of acyclic stereocenters, re-cent advances in Ir- and Rh-AAA nicely demonstrate acyclicstereocontrol on both nucleophilic and electrophilic reac-tion partners. Undoubtedly, more efficient strategies in thisbroad area of research will continue to emerge, further en-riching the options of synthetic chemists for stereocontrolin asymmetric synthesis.

Funding Information

Funding was provided in part by the Tamaki Foundation. ()

Acknowledgment

Dr. Yu Bai is thanked for reviewing the manuscript.

Scheme 77 Rh-catalyzed asymmetric allylic alkylation of -aryl aldehydes

R2

CHO

R1

RhCl(PPh3)3 (10%)(R)-L25 (40%)

DMPU, THF, r.t., thenLiHMDS

OBz+R2

CHO

R1

O

OP(OMe)

L25(R)-BINOL-

MeOP

Et

CHO CHO CHO CHO

Et

CHO

Et

CHO

Et

CHO CHO CHO CHO

74% yield, 92% ee

Br

79% yield, 88% ee

MeO

66% yield, 94% ee

F


Br


MeO MeO

61% yield, 90% ee 64% yield, 92% ee 62% yield, 91% ee

221 222 223

223a 223b 223c 223d 223e

223f 223g 223h 223i 223j

Et

CHO

RhCl(PPh3)3 (10%)(R)-L25 (40%)

DMPU, THF, r.t., thenLiHMDS

OBz

Et

CHOMeO

MeO

79% yield, 91% ee

a.)

MeO

Et

OTMSi) MeLi, THF, 0 °C

ii) RhCl(PPh3)3 (10%)(R)-L25 (40%)

DMPU, THF, r.t.

OBz

Et

CHO

MeO

81% yield, 71% eeE/Z 94:6

MeO

Et i) MeLi, THF, 0 °Cii) RhCl(PPh3)3 (10%)

(R)-L25 (40%)

DMPU, THF, r.t.

OBz

Et

CHO

MeO

84% yield, 68% eeE/Z 7:93

b.)

c.)

OTMS

H

H

221g

222

223g

223g

223g

222

222

224

225


29


References

(1) (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.(b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.(c) Trost, B. M. J. Org. Chem. 2004, 69, 5813. (d) Trost, B. M.;Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747.(e) Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59.

(2) Although the term quaternary stereocenter is sometimes usedinterchangeably with tetrasubstituted stereocenter, for the sakeof this review, quaternary stereocenters will only be applied toall-carbon quaternary stereocenters.

(3) Trost, B. M.; Jiang, C. J. Am. Chem. Soc. 2001, 123, 12907.(4) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc. 1998,

120, 12702.(5) Trost, B. M.; McEachern, E. J. J. Am. Chem. Soc. 1999, 121, 8649.(6) Trost, B. M.; Jiang, C.; Hammer, K. Synthesis 2005, 3335.(7) Trost, B. M.; Bunt, R. C.; Lemoine, R.; Calkins, T. L. J. Am. Chem.

Soc. 2000, 122, 5968.(8) Trost, B. M.; Calkins, T. L.; Oertelt, C.; Zambrano, J. Tetrahedron

Lett. 1998, 39, 1713.(9) The -allyl complex that places the higher priority group cis to

the central hydrogen is denoted as the syn isomer(10) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.(11) Feng, J.; Holmes, M.; Krische, M. J. Chem. Rev. 2017, For a review

on metal-catalyzed synthesis of acyclic quaternary stereocen-ters: 117, 12564.

(12) For a review on diversity-oriented synthesis: Galloway, W. R. J.D.; Isidro-Llobet, A.; Spring, D. R. Nat. Commun. 2010, 1, 80;DOI: 10.1038/ncomms1081.

(13) Du, D.; Li, L.; Xie, Z. Angew. Chem. Int. Ed. 2009, 48, 7853.(14) Trost, B. M.; Dong, G.; Vance, J. A. Chem.–Eur. J. 2010, 16, 6265.(15) Fagnou, K.; Lautens, M. Angew. Chem. Int. Ed. 2002, 41, 26.(16) Trost, B. M.; Andersen, N. G. J. Am. Chem. Soc. 2002, 124, 14320.(17) Trost, B. M.; Tang, W.; Schulte, J. L. Org. Lett. 2000, 2, 4013.(18) Mandal, A. K.; Schneekloth, J. S.; Crews, C. M. Org. Lett. 2005, 7,

3645.(19) Zeng, M.; Murphy, S. K.; Herzon, S. B. J. Am. Chem. Soc. 2017,

139, 16377.(20) Trost, B. M.; Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2011,

133, 7328.(21) Zhang, P.; Le, H.; Kyne, R. E.; Morken, J. P. J. Am. Chem. Soc. 2011,

133, 9716.(22) Ardolino, M. J.; Morken, J. P. Tetrahedron 2015, 71, 6409.(23) Hou, X.-L.; Sun, N. Org. Lett. 2004, 6, 4399.(24) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543.

(b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090.(25) Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. J. Am. Chem. Soc.

1992, 114, 2586.(26) Sawamura, M.; Nakayama, Y.; Tang, W.-M.; Ito, Y. J. Org. Chem.

1996, 61, 9090.(27) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118,

3309.(28) Mizuho, Y.; Kasuga, N.; Komiya, S. Chem. Lett. 1991, 2127.(29) Sawamura, M.; Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992,

114, 8295.(30) Kuwano, R.; Ito, Y. J. Am. Chem. Soc. 1999, 121, 3236.(31) Kuwano, R.; Nishio, R.; Ito, Y. Org. Lett. 1999, 1, 837.(32) Kuwano, R.; Uchida, K.; Ito, Y. Org. Lett. 2003, 5, 2177.(33) Zhang, K.; Peng, Q.; Hou, X.-L.; Wu, Y.-D. Angew. Chem. Int. Ed.

2008, 47, 1741.(34) Jiang, G.; List, B. Angew. Chem. Int. Ed. 2011, 50, 9471.(35) Ohmatsu, K.; Ito, M.; Kurieda, T.; Ooi, T. Nat. Chem. 2012, 4, 473.

(36) Fujita, T.; Yamamoto, T.; Morita, Y.; Chen, H.; Shimizu, Y.; Kanai,M. J. Am. Chem. Soc. 2018, 140, 5899.

(37) Belanger, E.; Houze, C.; Guimond, N.; Cantin, K.; Paquin, J.-F.Chem. Commun. 2008, 3251.

(38) Wang, W.; Shen, H.; Wan, X.-L.; Chen, Q.-Y.; Guo, Y. J. Org. Chem.2014, 79, 6347.

(39) Weaver, J. D.; Recio, A. III.; Grenning, A. J.; Tunge, J. A. Chem. Rev.2011, 111, 1846.

(40) Keith, J. A.; Behenna, D. C.; Sherden, N.; Mohr, J. T.; Ma, S.;Marinescu, S. C.; Nielsen, R. J.; Oxgaard, J.; Stoltz, B. M.;Goddard, W. A. J. Am. Chem. Soc. 2012, 134, 19050.

(41) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131,18343.

(42) Trost, B. M.; Xu, J.; Reichle, M. J. Am. Chem. Soc. 2007, 129, 282.(43) Ariyarathna, J.; Tunge, J. A. Org. Biomol. Chem. 2014, 12, 8386.(44) Minko, Y.; Pasco, M.; Lercher, L.; Botoshansky, M.; Marek, I.

Nature (London) 2012, 490, 522.(45) Starkov, P.; Moore, J. T.; Duquette, D. C.; Stoltz, B. M.; Marek, I.

J. Am. Chem. Soc. 2017, 139, 9615.(46) Alexy, E. J.; Zhang, H.; Stoltz, B. M. J. Am. Chem. Soc. 2018, 140,

10109.(47) (a) Li, B. X.; Le, D. N.; Mack, K. A.; McClory, A.; Lim, N.-K.;

Cravillion, T.; Savage, S.; Han, C.; Collum, D. B.; Zhang, H.;Gosselin, F. J. Am. Chem. Soc. 2017, 139, 10777. (b) Mack, K. A.;McClory, A.; Zhang, H.; Gosselin, F.; Collum, D. B. J. Am. Chem.Soc. 2017, 139, 12182.

(48) Kuwano, R.; Naoki, I.; Murakami, M. Chem. Commun. 2005,3951.

(49) Maki, K.; Kanai, M.; Shibasaki, M. Tetrahedron 2007, 63, 4250.(50) (a) Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727.

(b) Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed. Engl. 1997, 36,2635.

(51) (a) Trost, B. M.; Czabaniuk, L. C. J. Am. Chem. Soc. 2012, 134,5778. (b) Trost, B. M.; Czabaniuk, L. C. Chem.–Eur. J. 2013, 19,15210.

(52) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 1998, 120, 6818.(53) Seto, M.; Roizen, J. L.; Stoltz, B. M. Angew. Chem. Int. Ed. 2008, 47,

6873.(54) Estipona, B. I.; Pritchett, B. P.; Craig, R. A.; Stoltz, B. M. Tetrahe-

dron 2016, 72, 3707.(55) Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S.

C.; Stoltz, B. M. Nat. Chem. 2012, 4, 130.(56) Numajiri, Y.; Jiménez-Osés, G.; Wang, B.; Houk, K. N.; Stoltz, B.

M. Org. Lett. 2015, 17, 1082.(57) Alexy, E. J.; Virgil, S. C.; Bartberger, M. D.; Stoltz, B. M. Org. Lett.

2017, 19, 5007.(58) Hartwig, J. F.; Stanley, L. Copper-Catalyzed Allylic Substitution, In

Organotransition Metal Chemistry: From Bonding to Catalysis;Hartwig, J. F., Ed.; University Science Books: Mill Valley, 2010,999–1008.

(59) Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256.(60) (a) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.

(b) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548.(61) Trost, B. M.; Dogra, K.; Franzini, M. J. Am. Chem. Soc. 2004, 126,

1944.(62) Trost, B. M.; Miller, J. R.; Hoffman, C. M. Jr. J. Am. Chem. Soc.

2011, 133, 8165.(63) Kanayama, T.; Yoshida, D.; Miyabe, H.; Takemoto, K. Angew.

Chem. Int. Ed. 2003, 42, 2054.(64) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. ACS Catal. 2016, 6,

6207.(65) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science

(Washington, D. C.) 2013, 340, 1065.


30


(66) Shockley, S. E.; Hethcox, J. C.; Stoltz, B. M. Angew. Chem. Int. Ed.2017, 56, 11545.

(67) Evans, P. A.; Oliver, S.; Chae, J. J. Am. Chem. Soc. 2012, 134,19314.

(68) Evans, P. A.; Oliver, S. Org. Lett. 2013, 15, 5626.

(69) Turnbull, B. W. H.; Oliver, S.; Evans, P. A. J. Am. Chem. Soc. 2015,137, 15374.

(70) Turnbull, B. W. H.; Evans, P. A. J. Am. Chem. Soc. 2015, 137, 6156.(71) Wright, T. B.; Evans, P. A. J. Am. Chem. Soc. 2016, 138, 15303.


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