the growing impact of asymmetric catalysis - aldrichimica acta vol. 40 no. 3

T h e G r o w i n G i m p a c T o f a s y m m e T r i c c aT a ly s i s

VOL. 40 , NO. 3 • 2007

Palladium-Catalyzed Dynamic Kinetic Asymmetric Allylic Alkylation with the DPPBA Ligands

Development and Applications of C2-Symmetric, Chiral, Phase-Transfer Catalysts

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DABAL-Me3

Trimethylaluminum is a versatile methylation reagent in organic synthesis. However, because of its pyrophoric nature, it cannot be handled in open air. Developed by the Woodward group (University of Nottingham, U.K.), DABAL-Me3 is a free-flowing solid adduct of trimethylaluminum and DABCO® that can be manipulated without the need for an inert atmosphere.1 This bench-stable reagent has been employed in numerous reactions including methylations of aldehydes and imines,1,2 methylation of aryl and vinyl halides,3 conjugate additions to enones,4 and amide-bond formation.5 In the presence of the appropriate chiral ligand and catalyst, many of these reactions can be performed asymmetrically.

(1) Woodward, S. Synlett 2007, 1490. (2) Mata, Y. et al. J. Org. Chem. 2006, 71, 8159. (3) Cooper, T. et al. Adv. Synth. Catal. 2006, 348, 686. (4) Alexakis, A. et al. Chem. Commun. 2005, 2843. (5) Novak, A. et al. Tetrahedron Lett. 2006, 47, 5767.

Bis(trimethylaluminum)–1,4-diazabicyclo[2.2.2]octane adduct (DaBal-me3)682101

N N AlMe3Me3Al

1 g[137203-34-0]C12H30Al2N2

5 g

FW: 256.34

White Catalyst for Allylic C–H OxidationProfessor Christina White’s group (University of Illinois) recently reported selective allylic C–H oxidation reactions catalyzed by a Pd(II)–bis-sulfoxide system that furnishes branched allylic esters from α-olefins and carboxylic acids.1 These reactions can be performed in an inter- or intramolecular fashion, the latter being capable of yielding highly functionalized, large-ring macrolactone products.2 Finally, the catalyst system allows for a one-pot sequential allylic oxidation–C–H arylation to afford the E arylated allylic ester from the corresponding olefin, carboxylic acid, and arylboronic acid.3

(1) Chen, M. S. et al. J. Am. Chem. Soc. 2005, 127, 6970. (2) Fraunhoffer, K. J. et al. J. Am. Chem. Soc. 2006, 128, 9032. (3) Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128, 15076.

White Catalyst684821

S S PhPhOO

•Pd(OAc)2

250 mg[858971-43-4] C18H20O6PdS2

1 g

FW: 502.90

TarB-NO2 Reducing ReagentsIn conjunction with NaBH4, Singaram’s chiral TarB-NO2 boronic esters rapidly reduce prochiral ketones to optically active secondary alcohols with enantiomeric excesses as high as 99%.1-3 The reagents cleanly reduce aromatic ketones with high enantioselectivity and, in many cases, aliphatic ketones can be reduced with a similar degree of selectivity. Typically, TarB-NO2 reagents perform as well as, or better than, existing hydridic asymmetric reduction methods such as those employing DIP-Chloride™ or the CBS reagents.

(1) Kim, J.; Singaram, B. Tetrahedron Lett. 2006, 47, 3901. (2) Kim, J. et al. Org. Process Res. Dev. 2006, 10, 949. (3) Cordes, D. B. et al. Eur. J. Org. Chem. 2005, 5289.

3-Nitrophenylboronic acid d-tartaric acid ester, 1 M in THF (d-TarB-no2)682748

B

NO2

O

O

CO2H

CO2H

5 mLC10H8BNO8 25 mL

FW: 280.98

3-Nitrophenylboronic acid l-tartaric acid ester, 1 M in THF (l-TarB-no2)682713

B

NO2

O

O

CO2H

CO2H

5 mL[467443-01-2] C10H8BNO8

25 mL

FW: 280.98

N-tert-ButylbenzenesulfenamideIn the presence of NCS, N-tert-butylbenzenesulfenamide catalyzes the selective oxidation of a variety of primary and secondary alcohols to the corresponding aldehydes and ketones in high yield and under mild conditions.1,2 The catalytic oxidation tolerates various functional groups including silyl ethers, epoxides, urethanes, esters, and olefins. The reaction is particularly useful for the preparation of labile or easily epimerized aldehydes.

(1) Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590. (2) Matsuo, J.-i. et al. Tetrahedron 2003, 59, 6739.

N-tert-Butylbenzenesulfenamide, 97%681792

SNH

1 g[19117-31-8] C10H15NS

5 g

FW: 181.30

New Products from Aldrich R&DSigma-Aldrich Is Pleased to Offer Cutting-Edge Tools for Organic Synthesis

S S PhPhOO

•Pd(OAc)2

(10–20 mol %)

benzoquinone air, 45 °C

R + R'CO2H

or

R

OC(O)R'

H

CO2H

or

O

O

PMPO

O MeMe

OH

SNH (5 mol %)

NCS (1.1 equiv)PMP

O

O MeMe

CHOK2CO3, 4 Å MS, 0 °C

CH2Cl2, 1.5 h

94%

THF, rt, 30 min

L-TarB-NO2 (1 equiv)NaBH4 (2 equiv)

O OH

84%, 97% ee

DABCO is a registered trademark of Air Products and Chemicals, Inc. DIP-Chloride is a trademark of Sigma-Aldrich Biotechnology, L.P.

N N AlMe3Me3Al

enone

O

Me

cross-coupling

Me

RNH2

R'CO2Et

R' NHR

O

70–99%

79–99%

RCHOR Me

OH

89–95% ee

imine

R Me

HN

75–90%

P

82% eeDABAL-Me3

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57

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VOL. 40, NO. 3 • 2007

“PLEASE BOTHER US.”

Professor Carsten Bolm of RWTH Aachen University, kindly suggested that we make 2-(trimethylsilyl)ethanesulfonyl chloride (SES-Cl). This reagent is employed to protect an amine in the form of its sulfonamide. In contrast to the harsh conditions sometimes needed to deprotect tosyl-protected amines, the SES group is readily cleaved under mild conditions using a fluoride ion source, regenerating the parent amine along with volatile byproducts. We have also prepared SES-NH2, a useful reagent for the introduction of a protected nitrogen atom into a substrate.1,2

(1) Weinreb. S. M. et al. Tetrahedron Lett. 1986, 27, 2099. (2) Ribière, P. et al. Chem. Rev. 2006, 106, 2249.

SiS

Cl

OOH3C

CH3H3C

SiS

NH2

OOH3C

CH3H3C

681334 2-(Trimethylsilyl)ethanesulfonyl chloride 1 g (SES-Cl) 5 g

681326 2-(Trimethylsilyl)ethanesulfonamide 1 g (SES-NH2)

Naturally, we made these useful reagents. It was no bother at all, just a pleasure to be able to help.

Do you have a compound that you wish Aldrich could list, and that would help you in your research by saving you time and money? If so, please send us your suggestion; we will be delighted to give it careful consideration. You can contact us in any one of the ways shown on this page and on the inside back cover.

TABLE OF CONTENTSPalladium-Catalyzed Dynamic Kinetic Asymmetric Allylic Alkylation with the DPPBA Ligands ..............................................................................................................................................................................................................................................59Barry M. Trost* and Daniel R. Fandrick, Stanford University

Development and Applications of C2-Symmetric, Chiral, Phase-Transfer Catalysts ..........77Takashi Ooi and Keiji Maruoka,* Kyoto University

ABOUT OUR COVEROarsmen at Chatou (oil on canvas, 81.2 × 100.2 cm) was painted in 1879 by the French impressionist painter, Pierre Auguste Renoir (1841–1919), on the river Seine west of Paris. His use of light fresh colors in this painting and throughout his career was the result of his love of paintings from the Rococo period and of his training in a porcelain factory as a young man.

Rowing was the foremost attraction at Chatou. The man in this boat—wearing the typical costume of a short jacket and a straw hat—may be the artist’s brother, Edmond. The man standing on the bank, similarly attired, is probably the painter Gustave Caillebotte, a devoted rowing enthusiast and a friend of Renoir. The woman is most likely Aline Charigot, who was his favorite model and later became his wife.

The painting captures the brilliance of sun and water, summer and youth. In the water, strong blues and white alternate. Their shimmering intensity is enhanced by the equally strong presence of orange in the boat’s reflection and the scarlet accent of Aline’s bow. Renoir has put into practice the principle of simultaneous contrast: colors are perceived stronger when juxtaposed with their opposites—orange with blue, for example, or green with red. The silky texture of Renoir’s feathery brushstrokes mirrors the languid and leisurely scene.

This painting is a gift of Sam A. Lewisohn to the National Gallery of Art, Washington, DC.

Joe porwoll, president aldrich chemical co., inc.

Photograph © Board of Trustees, National Gallery of Art, Washington.

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Trost Ligands for Asymmetric Allylic Alkylationasymmetric allylic alkylation is a versatile catalytic reaction allowing access to a diversity of chiral molecules. This transformation converts both enantiomers of the substrate into the same enantiomer of the product, allowing theoretical yields of 100% of one enantiomer. professor Trost developed a series of ligands based on diphenylphosphinobenzoic acid (DppBa) and used them with a variety of palladium complexes for the asymmetric allylic alkylation. These ligands perform with a high degree of enantioselectivity and high yields.

O O

MeO2CO

+ NHNs

(R,R)-DACH-PhPd2dba3•CHCl3 (1 mol %)

NEt3, THF O O

NNs

N

OH

OH

H

93% yield99% ee

DACH-Naphthyl Trost Ligands

OCO2Me

+HN NH

O

O O

HN NH

O

O O

(S,S)-DACH-Nap (5 mol %)Pd2dba3•CHCl3 (2.5 mol %)

(n-Bu)4NCl, CH2Cl2

85% yield91% ee

NH HNO O

PPh2 Ph2P

NH HNO O

PPh2 Ph2P

(R,R)-DACH-Phenyl Trost Ligand692808

(S,S)-DACH-Phenyl Trost Ligand692794

DACH-Phenyl Trost Ligands

(R,R)-DACH-Naphthyl Trost Ligand692778

(S,S)-DACH-Naphthyl Trost Ligand692786

For more information, see Professor Trost’s review in this issue.

Sold in collaboration with DowPharmaSM for research purposes only. US Patent 5739396 applies.

DACH-Pyridyl Trost LigandsHNNH

N

O

N

O

(R,R)-DACH-Pyridyl Trost Ligand692751

(S,S)-DACH-Pyridyl Trost Ligand692743

692808

692778

692743

Ovaa, H. et al. Chem. Commun. 2000, 1501.

Trost, B. M.; Schroeder, G. M. J. Org. Chem. 2000, 65, 1569.

Ph OCO2CH3 + NaHC(CO2CH3)2

Ph

HH

H3CO2CCO2CH3

+ PhH

CO2CH3

CO2CH3

(R,R)-DACH-pyridyl (15 mol %)(C2H5CN)3Mo(CO)3 (10 mol %)

THF, rt

4970% yield99% ee (major)

: 1

Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104.









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Outline1. Introduction2. DYKATthroughConversionofaRacemicSubstrate intoa

MesoIntermediate 2.1. AcyclicSubstrates 2.2. CyclicSubstrates 2.3. ConduritolBSubstrates3. DYKATthroughEnolizationoftheNucleophile 3.1. StabilizedEnolates 3.2. NonstabilizedEnolates 3.3. Azlactones4. DYKAT through Rapid p–s–p Interconversion of

Intermediates 4.1. VinylEpoxidesandAziridinesasSubstrates 4.2. Baylis–HillmanAdductsasSubstrates 4.3. AcyloxyenoatesasSubstrates 4.4. AllenesasSubstrates5. OtherDYKATProcesses6. ConclusionsandOutlook7. Acknowledgment8. References

1. IntroductionThesynthesisofchiralmoleculesisaprominentthemeinorganicchemistry.Thesyntheticcommunityhascomeunder increasedpressuretopreparesyntheticbuildingblocksinanenvironmentallybenignor“green”manner.Tominimizewaste,synthesesshouldbedesignedascatalytictransformationsandshouldtakeplaceinanefficientandatom-economicalfashion.1Asymmetriccatalysishasenabledthecost-effectivepreparationofthesebuildingblocks.Onesuchgeneralmethodisthepalladium-catalyzedasymmetricallylicalkylation(AAA).Themethodologyhasdemonstrateditsabilitytoaffordchiralitythroughnumerousenantiodiscriminatingevents.2AlthoughseveralreviewshavebeenpublishedonAAA,3,4nonehas focusedon themanypalladium-catalyzeddynamickineticasymmetrictransformations(DYKATs)thathavebeendeveloped.Toourknowledge,theonlypalladium-catalyzedDYKATs,whereinasymmetricinductionresultsfromthechiralityofthepalladium

ligand,arethosethattakeplacethroughAAAs.Thisreviewwillfocusonthescopeandsyntheticutilityofthepalladium-catalyzeddynamickineticAAAwithourdiphenylphosphinobenzoicacid(DPPBA)andrelatedfamilyof ligands(Figure 1).Thesebasicligands are constructed with o-diphenylphosphinobenzoic ornaphthoicacidmoieties tetheredbyachiraldiaminebackbone.Themostcommonoftheseligandsarethestandard(LS),naphthyl(LN),stilbene(LST),andanthracene(LA)ones.Theformertwoarecommerciallyavailable.

Thereareseveralgeneralmechanismsforasymmetricinductionin catalyzed transformations. The most common one deriveschiralityfromaprochiralsubstrate,typicallythroughdifferentiationoftheenantiotopicpfaces(Scheme 1).Otherasymmetricprocessesutilizearacemicsubstrate.Inthesecases,thetransformationcanproceedthrougheitherakineticresolutionorDYKAT.5Akineticresolution(KR)resultswhentheenantiomersofaracemicsubstrateareconvertedtothechiralproductsatdifferentrates(Scheme 2).Numerouscatalyticandenzymatic transformationshaveshownhighenantioselectivityforsuchaprocess.Inthebest-casescenario,onlyonesubstrateenantiomerreactsforatheoreticalmaximumyieldof50%,inadditiontothe50%ofrecoveredstartingmaterial.Assuch,thisprocessisnomoreefficientthanaphysicalresolution.Toovercomethislimitation,severalprocessescommonlyknownas dynamic kinetic resolutions (DKRs) have been developedwhereinbothenantiomersofthesubstrateareconvertedintothesameenantiomeroftheproduct.Thisallowsforatheoretical100%yield.Aresolutionimpliesseparationofaracemicsubstrateintoitsenantiomers.Therefore,wepreferthe phrasedynamickineticasymmetrictransformation(DYKAT)6ratherthandynamickineticresolution,sincetheseprocessesarenotresolutionsasthelatterphraseimplies.Currently,therearethreegeneralprocessesforaDYKAT.Inthefirstonethesubstraterapidlyracemizesunderthereactionconditionsandthesubsequenttransformationisselectivefor one substrate enantiomer (Scheme 3).The secondDYKATconvertsthesubstrateintoamesooraprochiralintermediate,andthesubsequentasymmetricinductionresultsfromdifferentiationoftheenantiotopicterminiorfacesofthisintermediate(Scheme 4).TopreventaKR,bothsubstrateenantiomersmustbecompletelyconverted into the meso intermediate. The third DYKAT is

Palladium-Catalyzed Dynamic Kinetic Asymmetric Allylic Alkylation withthe DPPBA Ligands

Barry M. Trost* and Daniel R. FandrickDepartment of ChemistryStanford UniversityStanford, CA 94305-5080, USAEmail: [email protected]

ProfessorBarryM.Trost Dr.DanielR.Fandrick

60

Palla

dium

-Cat

alyz

ed D

ynam

ic K

inet

ic A

sym

met

ric A

llylic

Alk

ylat

ion

with

the

DPP

BA L

igan

dsV

OL.

40,

NO

. 3 •

200

7

Figure 1. The most commonly Used DppBa ligands.

HNNHOO

PPh2Ph2P

HNNHOO

PPh2Ph2P

HNNHOO

PPh2Ph2P

NH N

H

OO

PPh2 Ph2P

(S,S)-LS (S,S)-LN

(S,S)-LST (S,S)-LA

accomplished througha rapid interconversionof intermediates,andasymmetricinductionresultsfromaselectivereactionwithoneintermediate(Scheme 5).Consideringthatenantioselectivityresults from a kinetic reaction of one intermediate, the thirdDYKAT requires a Curtin–Hammett condition be establishedwhereintheenantioselectivityisnotdependent,inprinciple,uponthethermodynamicratiooftheintermediates.

Palladium-catalyzed dynamic kinetic AAAs have beenaccomplishedprimarilybyusingthelattertwoDYKATprocesses.Morespecifically,DYKATshavebeenachievedthroughconversionofthechiralsubstratesintoapseudo-mesoorprochiralintermediate,orthrougharapidp−s−pinterconversionbetweentheenantiotopicfacesofthep-allylPd(II)intermediate.

2. DYKAT through Conversion of a Racemic Substrate into a Meso IntermediateThe most general type of palladium-catalyzed DYKAT proceedsthrough a pseudo-meso-π-allylPd(II) intermediate. In this process, oxidativeadditionofeachenantiomeraffordsdifferentunsymmetricalp-allylPd(II)complexes,whichrequiresequilibrationtoaneffectivelysymmetrical complex for high enantioselectivity. Asymmetricinduction subsequently results from enantiodiscrimination of thetermini(Scheme 6).Duetothechiralcatalyst,thetwoenantiomericsubstrates undergo oxidative addition with palladium at differentrates. Therefore, for a successful DYKAT, complete substrateconversion into the π-allylPd complex is required. Two basic types ofallylicsubstrateshavebeenemployedinthiskindofDYKAT.Theπ-allylPd complexes of acyclic substrates adopt the preferred syn,syn conformation and, due to conformational restrictions, the π-allylPd complexes of cyclic substrates adopt the anti,anti conformation(Figure 2).7Althoughthesecomplexesarestructurallydistinct,theirreaction scopes and efficiencies are similar.3,4AAA of the acyclicsystemspreferentiallygeneratesthetransallylicproductsasaresultoftheformationofthefavoredsyn,synintermediates.

2.1. Acyclic SubstratesThe most common palladium-catalyzed DYKAT involves theasymmetric allylic alkylation of 1,3-diphenyl-3-acetoxypropene(1)(eq 1).8EarlyresultsshowedonlymoderateenantioselectivitieswiththesodiumsaltofthenucleophileandBINAP(R1=Me;81%,50%ee)orBINAPO(R1=Me;75%,68%ee) ligands.However,this reactionhasbecome thestandard test fornew ligands.3,4Asaresult,extensiveresearchhasbeenfocusedonthedevelopmentofalargenumberofdiversechiralligandsforthistransformation.9Highenantiomericexcesseshavebeenobtainedwithmanytypesofchiralligands such as chiraphos (3) (R1=AcNH;98%,86%ee),10P–Nligand4(R1=H;99%,99%ee),11sparteine(5)(R1=H;77%,75%ee),12 isosparteine (6) (R1 =AcNH; 90%, 92% ee),13 and Evans’sP–S ligand7 (R1=H;97%,98%ee).14Auseful extension to thefluorous ligand 8hasenabledhighselectivity(R1=Me;96%,90%ee) for an easily recyclable catalyst.15 However, substrate 1 is theleastsensitiveindeterminingtheasymmetricinductionabilityofthechiralcatalyst.

AlthoughtheDPPBAligandstypicallyaffordlowconversionsandenantioselectivitiesfortheparentsubstrate,1,theseligandshave demonstrated high levels of asymmetric induction withthe more challenging carbonate, 9. This discrepancy has beenrationalized by the DPPBA ligands encountering unfavorablestericinteractionswiththelargersubstrate1.However,duetothisstericallyrestrictivechiralenvironment,DPPBAsaresomeofthemostgeneralligandsforthepalladiumcatalyzedAAA.Forexample,highenantioselectivityandyieldfortheDYKATwithcarbonate9

Scheme 1. Typical asymmetric induction.

S product

R product

k1

k2

k1 >> k2prochiral substrate

Scheme 2. Kinetic resolution (Kr).

S product

R product

k1

k2

k1 >> k2racemic

substrate

Scheme 3. DyKaT through racemization of the substrate.

S product

R product

k1

k2

k1 >> k2

S substrate

R substrate

Scheme 4. DyKaT through conversion to a meso or prochiral intermediate.

S product

R product

k1

k2

k1 >> k2

S substrate

R substrate

meso orprochiral

intermediate

k1'

k2'

Scheme 5. DyKaT through the rapid interconversion of intermediates.

S product

R product

k1 >> k2

S substrate

R substrate

S intermediate

R intermediate

k1

k2

Scheme 6. DyKaT of symmetrical allylic substrates.

R R

LG

R R

LG

R R

Pd(II)Ln

k1'

k2'

k1

k2

R R

Nu

R Rk2k1

R R

NuNu≡

61

Barr

y M

. Tro

st*

and

Dan

iel R

. Fan

dric

kV

OL.

40,

NO

. 3 •

200

7

havebeenachievedbyutilizingthestandarddiaminocyclohexyl(DACH)ligandLS(eq 2).16

These initial results revealed the need for establishing asymmetrical π-allylintermediateforasymmetricinductionoronethatbecomestheequivalentofasymmetricalspeciesbecauseofrapidlyequilibratingnonsymmetricalstructures.Ourgroupalsoobserved that theenantioselectivityof theAAAfor theacyclicsubstrate9 wasdependentuponthesizeofthecountercationofthenucleophile.16Withthesodiumsaltofmalonate,only29%eewasobtained,buttheenantioselectivityincreasedto92%asthesizeofthe cation increased with the use of the cesium salt. The π-allylPd(II) intermediate from the initial oxidative addition is proposed tobe a tight ion pair, which requires relaxation to the necessarysymmetrical intermediate forhighasymmetric induction.17Theexactnatureoftheasymmetrymayderivefromtheconformationsofthemetal-boundligand,althoughotherexplanationshavealsobeenproffered.Reactionswithscalemicsubstratesanddifferentenantiomers of the ligand demonstrated a moderate memoryeffect supporting the requirement forequilibration.Thehigherenantiomericexcessobtainedwithcesiumwassuggestedtoderiveinpartfromaslowerrateofalkylationwithaneffectivelylargernucleophile that allowed for sufficient relaxation of the π-allylPd(II) intermediate.Additionally,thecesiumnucleophilemayalsoafforda less tight ion pair and lead to a faster equilibration. FurthersupportforthisrequirementforrelaxationwasobtainedwhenaderivativeoftheTrostligand withdipodalarms,13,furnishedhighenantioselectivityandreactivityintheAAAwiththepreviouslysluggishsodiumsaltofthemalonatenucleophile(eq 3).18Apossibleexplanationrelatestoafasterequilibrationbycoordinationofthecationtothepolyethersidechainoftheligand.AsimilarbaseandcountercationeffectontheenantioselectivitywasobservedwithBINAP-basedligands.19

Othercarbonnucleophiles,inanalogytomalonate,undergothistypeofDYKATwithhighasymmetricinduction.Thestandardligand,LS,alsoaffordshighdiastereoselectivityfortheadditionofnitroethane(eq 4).20Thisexampledemonstratestheabilityofthe catalyst to simultaneously discriminate between both theenantiotopicterminioftheallylligandandtheenantiotopicfacesoftheenolizednucleophile.

BarbituratesarealsoeffectiveandusefulsoftcarbonnucleophilesforDYKAT.21Utilizationofthestandardligand,LS,andafluorideadditive to slightly improve the ee (vide infra), led to goodenantioselectivityintheAAA(Scheme 7).Simplehydrogenationoftheinitialproductcompletedtheconcisesynthesisofpentobarbital,asedativeandhypnoticagent.

SimilartootherAAAs,numeroussoftheteroatomnucleophilescanbeemployedforDYKAT.InanextensionoftheGabrielaminesynthesis,highenantioselectivitywasachievedfortheasymmetricallylicalkylationwiththestandardligand,LS,andphthalimideasthenucleophile(Scheme 8).16,22Inthisexample,DYKATtoleratedtheunprotectedalcoholfunctionality,andtheproductprovidedausefulbuildingblockforthepreparationofpolyoxamicacid,thenovelaminoacidinseveralantifungalagents.16

2.2. Cyclic SubstratesSimilartoacyclicelectrophiles,palladium-catalyzeddynamickineticAAAsofcyclicsubstratesaffordexcellentenantioselectivitiesforabroad rangeof softnucleophiles. In thebasicalkylation,excellentenantioselectivities were achieved with malonate and phthalimidenucleophilesfor5-,6-,and7-memberedsubstrates(Scheme 9).23Asinthecaseoftheacyclicsubstrates,thenatureofthecountercationandmalonatenucleophilehadadramaticeffectontheenantioselectivity,which again emphasizes the importance of equilibration to the

Figure 2. coordination Geometries for acyclic and cyclic

p-allylpd complexes.

R R

Pd+

acyclicsyn,syn

conformation

R RPd+

cyclicanti,anti

conformation

eq 1

Ph Ph

OAc

Ph Ph

R2O2C CO2R2R1R2O

O

OR2

OM

Pd(0), ligand*

rac-1 2

PPh2 N

O

PhN N

N N

Ph2PPPh2

PO

i-Prt-BuS

Ar

Ar NPPh2MeO

N OR

RO

3chiraphos

4 5sparteine

6isosparteine

7Ar = 1-naphthyl

8R = CO(CF2)10CF3

R1

Ref. 8,10–15

eq 2

OCO2MeMeO2C CO2Me

[η3-C3H5PdCl]2 (2.5 mol %)CH2(CO2Me)2

Cs2CO3, CH2Cl2rac-9

(R,R)-LS (7.5 mol %)

1098%, 92% ee

Ref. 16

eq 3

BnO2C CO2Bn

[η3-C3H5PdCl]2 (0.2 mol %)CH2Cl2

BnO

O

OBn

ONa

Ar = O OO

HNNHO O

PAr2 Ar2P

rac-9 +

11 1268%, 90% ee

(R,R)-13 (0.6 mol %)

(R,R)-13

Ref. 18

eq 4

OCO2Me NO2

Pd2dba3•CHCl3 (0.25 mol %)BSA, CH2Cl2, (n-Bu)4NCl

NO2H

MeH

(S,S)-LS (0.75 mol %)

14 15 1671%, 11:1 dr, 97% ee

+

BSA = N,O-bis(trimethylsilyl)acetamide

Ref. 20

Scheme 7. DyKaT with Barbiturates and application to the

synthesis of pentobarbital.

Pd2dba3•CHCl3 (2.5 mol %)CH2Cl2, TBAT

(R,R)-LS (5 mol %)HN NH

O O

O

HN NH

O O

O

H2, Pd/C

HN NH

O O

O

rac-9 +

17 1896%, 72% ee

pentobarbital99%

MeOH

TBAT = tetra-n-butylammonium triphenyldifluorosilicate

Ref. 7

Ref. 21

62

Palla

dium

-Cat

alyz

ed D

ynam

ic K

inet

ic A

sym

met

ric A

llylic

Alk

ylat

ion

with

the

DPP

BA L

igan

dsV

OL.

40,

NO

. 3 •

200

7equivalent of a symmetrical meso-π-allylPd(II) intermediate. The additionoftetrahexylammoniumbromide(THABr)increasedtheeefrom38%to82%inTHF.Afurtherincreaseintheenantioselectivityto98%wasobtainedbyutilizingmethylenechlorideasthesolvent.Reetzetal.observedthattetra-n-butylammoniummalonateexistsasadimerinpolarsolvents,24andattributedtheeffectsoftheadditiveandsolventtovariationsinthenatureofthenucleophileandsubstrateion pairs in solution. Therefore, tetraalkylammonium malonateis effectively larger than the sodium counterpart and, by analogyto the acyclic substrates, allows the equilibration of the initiallyformed π-allylPd(II) intermediate to the effectively symmetrical complex.17,18

The DYKAT of cyclic substrates with nitromethane25 andbarbiturates21affordsexcellentenantioselectivitieswiththestandardandnaphthylligands(Scheme 10).Inthelatterexample,theAAAprovidedaconciseandefficientsynthesisofcyclopentobarbital,asedativeandhypnoticagent.

The dynamic kinetic asymmetric addition of oxygennucleophilestoracemicsubstratesisoneofthemoresyntheticallyusefulDYKATsforthesynthesisofcomplexnaturalproducts.ThesimplestreactionistheformalderacemizationofallylicalcoholsbythedynamickineticAAAwithcarboxylatenucleophiles.26Inorder toobtainhighenantioselectivities,both thematchedandmismatchedoxidativeadditionof thesubstratemusteffectivelycompetewithionizationoftheproduct,otherwisetheproductwillequilibratetotheracemate.Theutilizationofthecarbonateleavinggroupandacarboxylatenucleophilehasprovedeffective,providinghighenantioselectivitiesforthetypicalcyclicsubstrate32withavarietyofcarboxylicacidnucleophiles(eq 5).Themethodologywasappliedsuccessfullytotheracemicallyliccarbonate35,whichfurnishedpivalate37inhighyieldandeetoconstituteaformalsynthesisoftheantitumoragentphyllanthocin(Scheme 11).27

Extendingouruseofcarbonateandbicarbonatenucleophiles,28Gais and co-workersdevelopedanotherpracticalmethod for asimilarderacemizationofallyliccarbonates.29Inthisprocedure,thereactionproceedsinhighenantioselectivitythroughalkylationwithbicarbonateandsubsequent in situdecarboxylation to thechiralallylicalcohol(eq 6).AnattractivefeatureofthisAAAisthathydrolysisoftheionizedcarbonateleavinggroupinsitugeneratesthebicarbonatenucleophile.Thereactionisgeneralforbothacyclicandcyclicsubstratesandrequirestheuseofallyliccarbonates.

One of the most synthetically useful alkylations is with2-halophenols.AfterAAAwiththesenucleophiles,asubsequentintramolecularHeckreactioncanconstructthedihydrobenzofurancoreofnumerousbiologicallysignificantnaturalproducts.Inthepresenceofthestilbeneligand,LST,carbonate40providedefficientlyand highly enantioselectively 41, an intermediate in the totalsynthesisof(–)-galanthamine30and(–)-morphine31(Scheme 12).TheDYKATbetween39and40 illustratesthetolerancebythecatalystofarylbromidesandfunctionalityinthe2positionoftheelectrophile.

Similarly, AAA with sulfonamide nucleophiles furnishedsynthetically valuable protected amines.32 An interestingexampleofthisalkylationisthehighlyenantioselectivereactionof cyclopentene 42 (Scheme 13).33 Due to the inversion in theoxidativeaddition,34 thepalladiumcatalyst ispositionedon thesamefaceofthecyclopenteneastheacetonidesubstituentwhich,by this example, did not hinder the AAA. Ring-closing–ring-openingmetathesisandsubsequenttransformationsoftheDYKATproduct43quicklyfurnishedausefulentryintothesynthesisofindolizidinealkaloids.

Additionally, modification of the standard ligand, LS, wasrequired toobtainhighenantioselectivity in the intramolecular

Scheme 8. DyKaT with phthalimide and application to the

synthesis of polyoxamic acid.

NPd2dba3•CHCl3 (2.5 mol %) Cs2CO3 (10 mol %), THF

OH HN

O

OHO OH

O O

+

HO

O

OHNH2

OH

OH19 20 21

87%, 82% ee

polyoxamic acid

(R,R)-LS (7.5 mol %)O

Ref. 16

Scheme 9. Dynamic Kinetic aaa of cyclic substrates with

malonate and phthalimide nucleophiles.

[η3-C3H5PdCl]2 (2.5 mol %)Hex4NBr, CH2Cl2, 0 oC

OAc

n

OMe

ONa

MeO

O

+

n = 1; 81%, 98% een = 2; 86%, 96% een = 3; 99%, 93% ee

NK

O

O

+

n

NO

O

n = 1; 87%, 94% een = 2; 95%, 97% een = 3; 84%, 98% ee

OCO2Me

n

n

CO2MeMeO2C

(R,R)-LS (7.5 mol %)

22 23 24

25 26 27

[η3-C3H5PdCl]2 (2.5 mol %)Hex4NBr, CH2Cl2, 0 oC

(R,R)-LS (7.5 mol %)

Ref. 23

Scheme 10. DyKaT of cyclic substrates with nitromethane and

Barbiturates.

HN NH

O O

O

HN NH

O O

OOCO2Me

+

O

O(S,S)-LS (6 mol %)

Pd2dba3•CHCl3 (2 mol %)

(n-Bu)4NCl, BSA, CH2Cl2then CH2N2

CO2Me

NO2+ MeNO2

rac-28 2974%, 99% ee

rac-30 31 cyclopentobarbital85%, 91% ee

(S,S)-LN (5 mol %) Pd2dba3•CHCl3 (2.5 mol %)

(n-Bu)4NCl, CH2Cl2

Ref. 21,25

eq 5

[η3-C3H5PdCl]2 (2.5 mol %)Hex4NBr, CH2Cl2

OCO2Me O

O(R,R)-LS (7.5 mol %)

rac-32 33 3491%, 98% ee

+ EtCO2Na

Ref. 26

Scheme 11. application of the Deracemization of allylic

carbonates to the formal synthesis of phyllanthocin.

CO2Me

OCO2Me

CO2Me

O t-Bu

O

O CO2Me

H

H

O

O

rac-35 36

3798%, 93% ee(+)-phyllanthocin

+ t-BuCO2Na[η3-C3H5PdCl]2 (2.5 mol %)

Hex4NBr, CH2Cl2

(R,R)-LS (7.5 mol %)

O

PhO

Ref. 27

63

Barr

y M

. Tro

st*

and

Dan

iel R

. Fan

dric

kV

OL.

40,

NO

. 3 •

200

7

eq 6

Pd2dba3•CHCl3 (2 mol %)CH2Cl2, H2O

OCO2Me OH(R,R)-LS (8 mol %)

rac-32 3894%, 99% ee

Ref. 29

Scheme 12. DyKaT with phenols and its synthetic applications.

OHMeO Br

CHOCO2Me

TrocOCO2Me

OBr

OHC

OMe

O

OHH

N

OH

[η3-C3H5PdCl]2 (1 mol %) Et3N, CH2Cl2

(S,S)-LST (3 mol %)

O

OMe

OH

N

39 40 4172%, 88% ee

(–)-galanthamine (–)-morphine

+

Ref. 30,31

cyclizationleadingtotheazabicyclo[4.2.1]noneneDYKATproduct,47(Scheme 14).35Standardtransformationsof47furnishedthe“veryfastdeathfactor”anatoxin-a.TwoexplanationsarepossibleforthedifferentresultsobtainedwithLSand45.Asdiscussedpreviously,for high asymmetric induction to occur, the initial p-allylPdintermediatemustequilibrateinordertofunctionasameso-likeintermediatepriortoalkylation.Previousexamplesdemonstratedthat the larger nucleophiles afford a slower alkylation, whichallowsthenecessaryequilibrationtotakeplace.Inthisexample,andbecausethealkylationoccursintramolecularly,thecyclizationisfastandcompeteswiththeequilibration.Thiseffect is likelyoccurringwiththestandardligand,LS.Duetocoordinationtothepyridinefragmentofthemodifiedligand45, theelectrophilicityof the p-allylPd(II) complex is decreased thereby slowing thealkylationandallowingtherequiredequilibrationtotakeplace.Analternativeexplanationisthatabackgroundreactionmaycompetewiththemetal-catalyzedprocess.Usingastericallylesshinderedandamoreelectron-richPd(0)complexthatwouldformwiththepyridylligand45,afasteroxidativeadditionmaythenallowthemetal-catalyzedprocesstoout-competethebackgroundreaction.

Heterocycles are also effective nucleophiles in DYKAT.Applicationofthetypicalconditionswiththestandardligand,LS, andCs2CO3allowedthepreparationofindolocarbazoleproaglyconswithhighenantioselectivity(eq 7).36Additionally,themoreacidicindolewasselectivelyalkylated.

BurgerandTungereportedaninterestingexample,whereintheallylicalkylationwasperformedwithaketoneenolateforaformalasymmetric Claisen reaction.37 In this case, decarboxylation38oftheinitiallyformedβ-ketocarboxylatep-allylPd(II)complexafforded the reactive enolate nucleophile, 53 (eq 8). Good-to-excellentenantioselectivitieswereachieved forbothcyclicandacyclicsubstrates.Interestingly,thereactionproceededthroughcoordinationofthecarboxylatetothepalladium(II)intermediateor, namely, through a covalently bonded “ion pair” which hassufficientabilitytoequilibrate.Nocrossoverwasobservedinatestreaction,suggestingalackofsignificantdissociationoftheionpairpriortoalkylation.However,theasymmetricinductionobservedisconsistentwithalkylationoccurringonthefaceoftheallylligandoppositethepalladium.

In summary, the current technology has achieved highenantioselectivities in thedynamickineticAAAofacyclicandcyclicsubstratesthataffordasymmetricalallylicintermediate.Forasymmetricinductiontooccur,andinadditiontousingachiralcatalyst,conditionsmustbeemployedthatallowrelaxationofthesubstratestotheeffectivemesop-allylintermediate.

2.3. Conduritol B SubstratesA valuable cyclic substrate for the dynamic kineticAAA is tetra-acylatedconduritolB,55.Forthissystem,oxidativeadditionoftheracemicsubstratewiththePdcatalystfurnishesamesointermediate,56,inwhichasymmetricinductionoccursbytheselectivealkylationof one terminus (Scheme 15).39 For a successful DYKAT, bothenantiomers of 55 must completely ionize to the symmetricalintermediate, albeit at different rates.Dialkylationof the substratecanalsooccurbyionizationoftheinitialproduct,57,followedbyanother regio- and enantioselective alkylation. In both cases, fourstereocenters are established in one asymmetric transformationthroughaDYKATofracemicconduritolB.

In the AAA of tetraacetate 62 with a pivalate nucleophile,a kinetic resolution was observed with good regio- andenantioselectivity (eq 9).40 This result demonstrates the differentrates of the oxidative addition. Utilization of the more activatedtetracarbonatesubstrate66andsodiumbenzoateasthenucleophile

Scheme 13. DyKaT with carbonate 42.

Pd2dba3•CHCl3(1 mol %)Et3N, THF

O O

MeO2CO

NHNsO O

NNs

NH

OH

OH

(R,R)-LS

rac-42 4393%, 99% ee

44

+

Ref. 33

Scheme 14. intramolecular asymmetric cyclization of racemic carbonate 46.

TsHN

OCO2Me

CO2Me

NTs

MeO2CHN

O

HNNHO O

NPPh2

Pd2dba3•CHCl3 (2.5 mol %) CH2Cl2

45 (7.5 mol %)

rac-46 4790%, 88% ee

anatoxin-a

Ref. 35

eq 7

Pd2dba3•CHCl3 (1 mol %) Cs2CO3, THFN

HNH

HN

OO

NNH

HN

OO

H

OAc

+

rac-48 49 5099%, 79% ee

(S,S)-LN (3 mol %)

Ref. 36

64

Palla

dium

-Cat

alyz

ed D

ynam

ic K

inet

ic A

sym

met

ric A

llylic

Alk

ylat

ion

with

the

DPP

BA L

igan

dsV

OL.

40,

NO

. 3 •

200

7

eq 8

Pd2dba3•CHCl3 (0.2 mol %)benzene, reflux

O

O

O

Pd(II)O

OO Pd(II)

O

O

51 52 53

5475%, 94% ee

(R,R)-LS (0.4 mol %) – CO2

Ref. 37

Scheme 15. DyKaT mechanism with conduritol B substrates.

OCOR

OCOROCOR

OCOR

OCOR

OCOROCOR

OCOR

OCOR

OCOR

OCOR

LnPd(II)OCOR

OCORNu

OCOR

OCOR

OCOROCOR

Nu

OCOR

OCORNu

Ln(II)Pd

OCOR

OCOR

Nu

Ln(II)Pd

OCOR

OCORNu

Nu

OCOR

OCORNu

Nu OCOR

OCORNu

NuOCOR

OCOR

NuNu

matched ionization

mismatchedionization

matchedattack

mismatchedattack

matched ionization

mismatchedionization

mismatchedattack

matchedattack

matchedattack

55 ent-55

56

57 ent-57

58 59

60 61 ent-60 ent-61

Ref. 39

enabled complete consumption of the mismatched enantiomerand ultimately good enantioselectivity for the dynamic kineticasymmetric di(allylic substitution) (Scheme 16).39 The fourstereocenters in aminocyclohexitol 68 of hygromycin A wereefficientlyestablishedbyuseofthisDYKAT.41

Thechoiceofnucleophileofferscontrolforeithermono-orpolyalkylation.SoftnucleophilessuchasMeldrum’sacid,(phen-ylsulfonyl)nitromethane,andphthalimideaffordmonoalkylationwith good enantioselectivity. Notably, these monoalkylationsdemonstrate how, under the appropriate conditions, themismatchedionizationofthesubstratecansuccessfullycompetewiththematchedionizationofthemonoalkylatedproduct.Thesulfonylnitromethane DYKAT product has been applied tothe efficient synthesis of the HIV inhibitor (–)-cyclophellitol(Scheme 17).42

3. DYKAT through Enolization of the NucleophilePalladium-catalyzedAAAshavedemonstratedauniqueability tonot only afford enantiodiscrimination of the π-allyl electrophile, but also to effectively differentiate the enantiotopic faces of anucleophile. This property opened a new avenue for palladium-catalyzedDYKATs(Scheme 18).For this typeof transformation,the racemic nucleophile is enolized into the active achiralenolate, wherein asymmetric induction results from the catalystdiscriminatingbetweentheenantiotopicfacesoftheenolate.Duetotheconversionoftheracemicsubstrateintotheprochiralnucleophileoccurringwithoutinvolvementofthechiralcatalyst,therateoftheenolizationforbothenantiomersshouldbeidenticalandcircumventany possible memory effect. Asymmetric alkylations of racemicenolizable nucleophiles are typically not considered DYKATs.However,aDYKAToccurswhenbothenantiomersofthesubstrateareconvertedintooneenantiomeroftheproductwithatheoreticalyieldof100%.Ifoneconsiderstheoverallalkylationofaracemicnucleophile, reactionswherein thenucleophile isconverted intoaprochiralenolateorintermediateeveninaprevioustransformationaretechnicallyDYKATs.

3.1. Stabilized EnolatesThe most common palladium-catalyzed AAA wherein chiralityis established at the nucleophile is with substrates that afford astabilizedprochiralenolate.Becauseofthisstabilization,onlymildconditionsarenecessarytogeneratetheactivenucleophile.Inthepalladium-catalyzedAAA,thechiralligandispositionedonthesideofthemetaloppositetheallylligandinasquare-planargeometry.The low-to-moderate enantioselectivities observed with typicalchiralbidentateligands(suchasDIOPandtheP–Noxazolidinone)43havebeenattributedtothedistantchiralenvironmentnoteffectivelydifferentiatingbetweentheenantiotopicfacesofthenucleophile.Inanefforttoextendthechiralenvironmenttothenucleophile,severalgroups developed a series of chiral ferrocenylphosphine ligands,whichincorporateatetheredfunctionalgroup,tointeractwiththenucleophile and enhance the interaction between the nucleophileandligand.44Incontrast,theDPPBAligandshaveshownexcellentasymmetricinductionforthecreationofchiralityatthenucleophilewithout the requirement of an appendant functional group. Forexample, the asymmetric allylation of β-keto ester 71 proceededinhighyieldandenantioselectivitywithuseofthenon-ionicbaseN,N,N’,N’-tetramethylguanidine(TMG)(Scheme 19).45Theutilityofthisalkylationwasdemonstratedinthesynthesisofnitramine,abiologicallyactivespiroalkaloid.Witharacemicelectrophile,thereactionachievedexcellentdiastereoselectivity,againdemonstratingthecatalyst’sabilitytosimultaneouslydiscriminatetheenantiotopicfacesofthenucleophileandterminioftheelectrophile(eq 10).45

eq 9

OAc

OAcOAc

OAc

[η3-C3H5PdCl]2 (1 mol %) (n-Bu)4NBr, CH2Cl2, H2O

OAc

OAc

OAc

OAc

OAc

OAcOAc

O

t-Bu

O

OAc

OAcO

O

t-Bu

O

t-Bu

O

t-BuCO2Na(R,R)-LS (3 mol %)

rac-62 6350%, 83% ee

(unreacted ent-62)

6444%, 97% ee

651%

++

Ref. 40

Scheme 16. DyKaT of conduritol B Tetracarbonate (66).

OTroc

OTrocOTroc

OTroc

[η3-C3H5PdCl]2 ( 2.5 mol %) Hex4NBr, CH2Cl2, H2O

OTroc

OTrocOCOPh

OCOPhNH2

OHOCOPh

OH

O

O

PhCO2Na(S,S)-LS (7.5 mol %)

rac-66 6790%, >99% ee

68

Ref. 39,41

Scheme 17. DyKaT of conduritol B with sulfonylnitromethane.

OTroc

OTrocOTroc

OTroc

(R,R)-LS (7.5 mol %)Pd2dba3•CHCl3 ( 2.5 mol %)

Cs2CO3, THF

OTroc

OTrocOTroc

NPhO2SONa

O–

+

PhO2S NO2

OH

OHOH

OH

O

rac-69 7081%, 88% ee (–)-cyclophellitol

Ref. 42

65

Barr

y M

. Tro

st*

and

Dan

iel R

. Fan

dric

kV

OL.

40,

NO

. 3 •

200

7

Thechiral3-substitutedindolineand3H-indolestructuralmotifsarepresentinnumerousbiologicallyactivecompounds.Asymmetricallylic alkylations of racemic oxindoles provide a valuable andefficiententryintothepreparationoftheseimportantheterocycles.Becauseofthearomaticstabilizationobtainedthroughenolizationofoxindoles,onlymildconditionsarenecessaryto generatetherequirednucleophileinsitu. TheDYKATof3-aryloxindolesproceededinhighenantioselectivityfor thepreparationofaquaternarystereocenterwithout the addition of a base (eq 11).46 Since the catalyst mustdiscriminatebetweentheenantiotopicfacesofthenucleophile,theenantioselectivityshowedamoderatedependenceuponthesubstratesubstitution.Thehighestenantioselectivity,97%,wasachievedwitha3-(ortho-substituted)arylgroup.

3.2. Nonstabilized EnolatesTheasymmetricallylicalkylationsofnonstabilizedenolateshavealsobeen successful.These examples demonstrate how high asymmetricinduction can also be achieved by stoichiometrically converting theketone into the enolate or enol ether prior to alkylation. Using thestandardligand,lithiumenolate,andatinadditive,theallylicalkylationof 2-methyl-1-tetralone proceeded with high enantioselectivity(eq 12).47 The extent of the nucleophile aggregation showed asignificant effect upon the enantioselectivity, and optimal results were obtainedwithtwoequivalentsoftheamidebase.48Whileadditionofa trialkyltin chloride gave the highest ee, only a very small loss (afewpercent)ineeoccurredinitsabsence.Arelatedenolate-structureeffectonbothdiastereoselectivityandenantioselectivitywasobservedby Braun and co-workers with BINAP ligands.47b–d The asymmetricinductionobservedwith thesehardernucleophiles is consistentwithanintermolecularalkylation,inwhichalkylationoccursonthefaceoftheallylmoietyopposite themetal, inanalogy toAAAwith typicalsoftnucleophiles.Theproductsof thismethodologyhavehadbroadsynthetic applications. One particular example involves the AAAof cyclopentanone 81, which efficiently establishes the absolute stereochemistryforthesynthesesofhamigeranB48andallocyathinB2

(Scheme 20).49

Modifying the arms of the standard ligand with ferrocenylcomplexeshasalsoenabledhighenantioselectivity,95%ee,intheAAAofthetetralonesubstrate78(eq 13).50

One of the main limitations of the above methodologies isenolateequilibration.Accordingly,theaboveexamplesutilizeketonesubstratesthataffordonlyonepossibleenolateintermediate.Aneffectivesolutionistheregio-andenantioselectiveallylicalkylationofunsymmetrically substitutedketonesbyuseof their allyl enolcarbonate derivatives. The reaction proceeds after ionization ofthe allylic ester throughapalladium-promoteddecarboxylation38to theenolatenucleophile.Useof theanthracene ligand,LA,hasenabledhighenantioselectivityfortheformalDYKATofracemic2-methylcyclohexanone (eq 14).51 Due to the neutral conditionsemployedinthereaction,thealkylationefficientlyestablishestertiarystereocentersinbothcyclicandacyclicsubstrateswithoutracemizationoftheproduct(Scheme 21).52ThesyntheticutilityoftheprocesswasdemonstratedbyapplicationtotheAAA/Stork–Danheiseradditionsequencefortheformationofchiralγ,γ-disubstitutedcycloalkenones(Scheme 22).53

3.3. AzlactonesThe asymmetric allylic alkylation of azlactones offers an efficient processforthepreparationofquaternaryaminoacids,astructuralmoietypresent in numerous biologically significant molecules. The azlactones provide sufficient stabilization so that enolization can be conducted in situ.Asymmetricprenylationofazlactone94withthestandardligand,LS, proceeded in moderate yield and excellent enantiomeric excess

Scheme 18. DyKaT through enolization of the nucleophile.

OR1

H

O

R1H

OMR1

Pd(II)Ln

OR1

O

R1

enolization

k1

k2

Scheme 19. asymmetric allylic alkylation of β-Keto esters with the standard ligand.

[η3-C3H5PdCl]2 (0.5 mol %) TMG, PhMe

O

OEt

O O

OEt

O

HN

OH

allyl acetate(R,R)-LS (1.2 mol %)

71 7286%, 86% ee

nitramine

TMG = N,N,N',N'-tetramethylguanidine

Ref. 45

eq 10

O

OBn

O

OAc

+

CO2BnO

H

73 rac-48 7487%, 99:1 dr, 96% ee

[η3-C3H5PdCl]2 (0.4 mol %) TMG, PhMe

(R,R)-LS (1.2 mol %)

eq 11

NO

OMe

NO

OMe

75 7772%, 97% ee

allyl acetate (76)(R,R)-LA (5 mol %)

[η3-C3H5PdCl]2 (2.5 mol %)t-BuOH, PhMe, 4 oC

Ref. 46

eq 12

O O

78 8099%, 88% ee

76, LDA, then(S,S)-LS (5 mol %)

[η3-C3H5PdCl]2 (2.5 mol %)Me3SnCl (79), DME

Ref. 47

Scheme 20. application of the Dynamic Kinetic aaa of nonstabilized enolates to the Total synthesis of hamigeran B and allocyathin B2.

t-BuO

O

t-BuO

O

OH OO

H

OH

OH

81 8277%, 93% ee

hamigeran Ballocyathin B2

76, LDA, thenLS (1 mol %)

[η3-C3H5PdCl]2 (0.5 mol %)79, t-BuOH, DME

Br

Ref. 48,49

Ref. 45

66

Palla

dium

-Cat

alyz

ed D

ynam

ic K

inet

ic A

sym

met

ric A

llylic

Alk

ylat

ion

with

the

DPP

BA L

igan

dsV

OL.

40,

NO

. 3 •

200

7(Scheme 23).54The chiral product, 96, served as a useful substratefor the preparation of α-methylaspartic acid (97).Asdemonstratedinseveralpreviousexamples,thechiralcatalystcansimultaneouslydiscriminatebetweentheenantiotopicfacesofthenucleophileandenantiotopic termini of the racemic electrophile.This asymmetrictransformationaffordedgooddiastereoselectivityandhigheewiththeracemicacetate99(eq 15).55Thepalladium-catalyzedAAAhasalso efficiently discriminated between enantiotopic geminal leaving groups.56Extensionofthemethodologywithazlactonestogeminalacetate101providedausefulprocessfor thepreparationofchiralvicinal amino alcohols and an efficient entry into the total synthesis ofsphingofunginsEandF(Scheme 24).57

4. DYKAT through Rapid p−s−p Interconversion of IntermediatesAnothereffectiveprocessforapalladium-catalyzeddynamickineticAAA relies on the rapid interfacial exchange of the allyl ligandthrough a π−σ−π interconversion. Oxidative addition with inversion of each substrate enantiomer initially forms two diastereomeric π-allylPd(II) intermediates (Scheme 25).2,3,4Withachiralcatalyst,aratedifferenceintheoxidativeadditionisexpected,andaDYKAToccurs with complete consumption of the mismatched substrate.Asymmetric induction results from the preferential alkylationof one diastereomeric intermediate over the other. Accordingly,highenantioselectivityisachievedwhen,inadditiontoaselectivealkylation (k1 >> k2), a Curtin–Hammett condition is establishedwherein interconversion is rapid and successfully competes withnucleophilicaddition.AnotherrequirementforthistypeofDYKATistheexistenceofidenticalgeminalsubstituentsononesideoftheallyl ligand. Ifone terminusof theallyl ligand is substitutedwithdifferent geminal groups, then the π−σ−π interconversion will result in a geometrical isomerization of the allyl ligand. Theseπ-allylPd(II) intermediates cannot “racemize” through a π−σ−π mechanism(Scheme 26).Furthercomplicatingthealkylationwithunsymmetricalsubstratesisalkylationatthedifferenttermini,whichleadstoregioisomers(Scheme 27).RegioselectivityintheAAAhasbeenachievedbybothsubstrateandcatalystcontrol.Althoughthechiral catalyst provides a significant preference for a regioselective alkylation of one diastereomeric intermediate, optimization ofthe reaction conditions is often necessary to establish the Curtin–Hammettsituationforasymmetricinduction.

4.1. Vinyl Epoxides and Aziridines as SubstratesA versatile substrate for the palladium-catalyzed dynamic kineticAAAisvinylepoxide,which,duetotheringstrain,promotestheoxidativeadditionandconsumptionofthemismatchedenantiomerrequired for a DYKAT. Suitable vinyl epoxides have geminalhydrogens or other identical geminal substituents on the olefin terminus, enabling a Curtin–Hammett condition to be establishedthrough a rapid π−σ−π interconversion. In the π-allylPd(II) intermediates, thealcoholoralkoxidecandirect thealkylationforthebranchedproducttypicallythroughhydrogenbondingorothercovalentinteractionwiththeincomingnucleophile(eq 16).

AlthoughBINAP-basedligandshavebeenexaminedfortheDYKAT of vinyl epoxides,58 high enantioselectivities for theintermolecularadditionofnucleophilestovinylepoxidestypicallyrequiredtheuseoftheDPPBAligands.Thesereactionsallowedtheuseofabroadrangeofnucleophilesandenabledapplicationofthisapproachtonumeroustotalsyntheses.TheAAAwithphthalimide59provided the corresponding vinylglycinol derivative in highenantio-andregioselectivity(Scheme 28).60Ourinitialproposalwasthatahydrogen-bondinginteractionbetweenthealkoxideofthep-allylPd(II) intermediateandthenucleophilewoulddirect

eq 13

HNNHO O

Fe

Fe

83

O O

78 8093%, 95% ee

allyl ethyl carbonateLDA, then

83•2H2O (7.5 mol %)

[η3-C3H5PdCl]2 (2.5 mol %)THF

PPh2 Ph2P

Ref. 50

eq 14

O O

O

O

Pd2dba3•CHCl3 (2.5 mol %)PhMe

(R,R)-LA (5.5 mol %)

84 8588%, 85% ee

Ref. 51

Scheme 21. formation of Tertiary stereocenters by the Dynamic Kinetic aaa of allyl enol carbonates.

O O

O

MeO

O

MeO

Ph

O

O

O Ph

O

8690%

8790%, 99% ee

8991%

9094%, 94% ee

O

MeO

Ph

O

n-Pr

88

Pd2dba3•CHCl3(2.5 mol %)

dioxane

(R,R)-LA(5.5 mol %)


PhMe

(R,R)-LA(5.5 mol %)

O Cl

O

then

NaHMDSTMEDA

THF, –78 oC

O Cl

O

then

NaHMDSTHF, –78 oC

Ref. 51,52

Scheme 22. The stork–Danheiser application of DyKaT with allyl enol carbonates.

PhS

O O

O

PhS

O

O

91 9275%, 99% ee

93


dioxane

(R,R)-LA(5.5 mol %)

Ref. 53

Scheme 23. asymmetric allylic alkylation (aaa) with azlactones.

+OAc

NO

O

Ph

NO

O

Ph

OH

OHO

O NH3Cl

94 95 9653%, 98% ee

97

[η3-C3H5PdCl]2(2.5 mol %)Et3N, PhMe

(R,R)-LS(7.5 mol %)

Ref. 54

eq 15

+N

O

Oi-Bu

Ph

NO

O

Ph

OAci-Bu

H

98 rac-99 10077%, 13:1 dr, 99% ee

[η3-C3H5PdCl]2(2.5 mol %)Et3N, MeCN

(R,R)-LS(7.5 mol %)

Ref. 55

67

Barr

y M

. Tro

st*

and

Dan

iel R

. Fan

dric

kV

OL.

40,

NO

. 3 •

200

7

thealkylation.Reactionswith triphenylphosphine still favoredthebranchedproductwithaslightlylowerregioselectivity(4:1B/L).Withoutdirectingeffects,thelinearproductisfavoredduetoalkylationattheleaststericallyhinderedposition.Therefore,boththesubstrateandcatalystcontributetothehighregioselectivityobservedin theDYKAT.Thevinylglycinolderivativeobtainedbythismethodologyprovidedavaluablesyntheticbuildingblockforthepreparationofseveralbiologicallysignificantcompoundsincluding ethambutol, vigabatrin,61 DMDP, bulgecinine, andbroussonetineG.62

Alcoholsaretypicallypoornucleophilesforthealkylationofp-allylPd(II)complexesand,accordingly,requireactivationforreactivity.Ausefulstrategy toactivate thealcoholnucleophileanddirectthealkylationistoemployaboraneco-catalystforthedynamickineticasymmetricadditionstovinylepoxides.63InthisAAA,thealkoxideofthep-allylPd(II)intermediatecoordinatestotheborontoforman“ate”complex,therebyactivatingthealcoholforanintramolecularalkylation.Theprocessgivestheglycolinhighyieldwithexcellentenantio-andregioselectivity(eq 17).63ThismethodologyisoneofthemostsyntheticallyusefuloftheDYKATs,andhasbeenappliedto theasymmetricsynthesisofnucleosides,64malyngolide,65tipranavir,66andintermediate111intheformalsynthesisofLY333531(Scheme 29).67

Carbonatesarealsoeffectivenucleophileswithvinylepoxides,providinganadditionalefficientsynthesisofchiralvinylglycidols.Underbiphasicconditions,thereactionofisoprenemonoepoxideandbicarbonateaffordsthedioxolanonein88%yieldand93%ee(Scheme 30).28Thegoodyieldandregioselectivityobtainedareattributedtoanintramolecularalkylationstep.Thealkoxideoftheinitialp-allylPd(II)intermediateisproposedtoattacktheinsitugeneratedcarbondioxidetoform113,whichsubsequentlycyclizesto the dioxolanone. The high enantioselectivity results from arapidp−s−pequilibrationoccurringeitherpriortotheadditiontocarbondioxideand/orpriortothecyclization.ComplementingthisDYKAT, theuseofaboronco-catalyst (Et3B)andsodiumcarbonateasnucleophileallowsforadirectalkylationwiththecarbonatenucleophilewithoutcyclizationtothedioxolanone.Inthiscase,theintermediatecarbonate,115,undergoesafacileinsitu decarboxylationtovinylglycidol116inhighyieldandee.

Theasymmetricalkylationwithstabilizedcarbonnucleophileshas shown high regio- and enantioselectivity in the DYKATwith isoprene monoepoxide. Under optimized conditions, thedynamic kinetic AAA of isoprene monoepoxide with β-ketoestersaffordsgoodregioselectivity for thebranchedalkylationproduct and furnishes the corresponding tetrahydrofuran withhighenantiomericexcess(eq 18).68Theregioselectivityislowerin theabsenceof thefluorideadditive, tetra-n-butylammoniumtriphenyldifluorosilicate(TBAT).Thiseffect isattributedtoanintermolecular alkylation, and formation of the linear productis due to the alkylation competing with the necessary p−s−pinterconversion. The asymmetric induction obtained in theallylicalkylationswiththeDPPBAligandsisrationalizedbythepreferentialionizationandalkylationoccurringunderaflapinthe“nun’shat”model.69Thematchedalkylationofthemismatchedintermediatewould favor the linearproduct, and thematched-intermediatematchedalkylationwouldfavorthebranchedproduct(Scheme 31).Halideadditivesincreasetherateofthenecessaryinterconversion,70andimprovetheregioselectivitybypromotingthenecessaryCurtin–Hammettcondition,thusallowingforthepreferredmatchedalkylationof thematched intermediate.Theutilityofthemethodologyhasbeendemonstratedbyapplicationtothesynthesisofthehighlysubstitutedcyclopentylcore,124,ofviridenomycin(Scheme 32).71

Scheme 24. aaa of allylic Geminal acetates with azlactones.

TBDPSOOAc

OAcTBDPSO

OAc

NO

O

Ph

n-C6H13

O

OH

OH

OHCO2

–

NH3+

94 +

101 10270%, 11:1 dr, 89% ee

X = OH, sphingofungin EX = H, sphingofungin F

[η3-C3H5PdCl]2(0.5 mol %)NaH, THF

(R,R)-LS(1.5 mol %)

X

Ref. 57

Scheme 25. DyKaT through a p−s−p interconversion.

R

LG

R

LG

R

Pd(II)L*

R

Pd(II)L*

R Pd(II)L*

Pd(0)L*

k1'

k2'

Pd(0)L*

+

+

+

Nu–

k1

k2

R

Nu

R

Nu

π–σ

π–σ

Nu–

Ref. 2–4

Scheme 26. p−s−p interconversion of 1,3-Disubstituted allylpd(ii) complexes.

R1

Pd(II)L*

R1 Pd(II)L*

+

+R2

R2

R1

L*Pd(II) R2+

Scheme 27. regioselective alkylation of Unsymmetrical allyl complexes.

R1

+Pd(II)L*

R2

Nu–

R1 R2 R1 R2

Nu Nu

Nu–

eq 16

OXNu

Pd(II)

OHNu

Ref. 55

Scheme 28. Dynamic Kinetic aaa of Vinyl epoxide with phthalimide.

O NH

O

O

+

HO

N

O

ONH3Cl

CO2H

OH

NH

NHOH

HN

OHHO

OH

O

O

OH

LN (1.2 mol %)[η3-C3H5PdCl]2 (0.4 mol %)Na2CO3, CH2Cl2

103 104

10598%, 96% ee vigabatrinethambutol

(+)-broussonetine G

HN

OHHO

OHOH

DMDP

HN

HO

CO2H

OH

(–)-bulgecinine

Ref. 60–62

68

Palla

dium

-Cat

alyz

ed D

ynam

ic K

inet

ic A

sym

met

ric A

llylic

Alk

ylat

ion

with

the

DPP

BA L

igan

dsV

OL.

40,

NO

. 3 •

200

72-Vinylaziridinesarealsocompetentsubstratesforthedynamic

kinetic asymmetric cycloaddition with isocyanates to furnishsynthetically useful chiral imidazolidinones (Scheme 33).72 Inthisexample,theuseofaceticacidasaco-catalystsignificantlyimproves the enantioselectivity. This effect is rationalized byprotonationofthenitrogentetheredtothep-allylPd(II)intermediateandslowingoftheacylationbytheisocyanate,therebyallowingthenecessaryp−s−pinterconversiontoeffectivelycompetewithproductformation.Thechiralvicinaldiaminemoietyispresentinnumerousbiologicallyimportantnaturalproducts,73andtheutilityofthismethodologyhasbeendemonstratedbyapplicationtotheconcisetotalsynthesisofpseudodistominD.74

4.2. Baylis–Hillman Adducts as Substrates Asyntheticallyuseful substrate for thedynamickineticAAA is aBaylis–Hillmanadduct.Similar to theDYKATofvinyl epoxides,asymmetricinductionresultsinthiscasefromthekineticalkylationof one diastereomeric π-allylPd(II) intermediate in a mixture of rapidly interconverting complexes through a π−σ−π mechanism (Scheme 34).75InatypicalAAA,thesynpathwayisnormallystronglypreferred.7However,intheDYKATwithBaylis–Hillmanadducts,the presence of a substituent at the 2 position of the allyl ligandincreasestheimportanceoftheantipathway.Forhighasymmetricinductionandregioselectivity,thecatalystmustdiscriminatebetweentheterminioftheallylligandandaffordaselectivealkylationofaspecific geometrical isomer of the intermediate.

ThedynamickineticAAAofBaylis–Hillmanadductswithalcohol nucleophiles provides a useful strategy for the formalderacemizationofthereadilyavailablesubstrates.Underoptimizedconditions,highenantioselectiviesareobtainedintheDYKATofboth2-cyano-and2-carboethoxy-substitutedadducts(Scheme 35).76Anexaminationoftheminor,linearproductsprovidesanindicationofthepreferredallylgeometryoftheintermediates.ExclusiveZdouble-bondgeometryoftheminor,linearproductwasobservedfrom the cyano substrate 127, and exclusive E geometry wasobtainedforthelinearproductfromtheestersubstrate131.Thischangeinallylconformationwasrationalizedbystericinteractionswithinthep-allylPd(II)intermediates.Forthecyanosubstrate,thepreferredallylcomplexesaresynduetominimizationofthetypicalA1,3 strain associated with allyl ligands. In the ester substrate,the larger ester group increases the unfavorable 1,2 repulsionandoverridestheA1,3straintofavortheantiallylintermediates.Additionally,similareffectshavebeenobservedwiththerespectivelinearachiralsubstratestosupporttheconclusionthatthestrongpreferenceforeitherthesynorantipathwayisdependentonthesubstituentinthe2positionoftheallylintermediate.Accordingtotheabovemechanism,intermediatesAandD(seeScheme34)should favor different product enantiomers, contrary to theasymmetricinductionobserved.However,furtherstereochemicalanalysiswithothersubstrateshasrevealedthattheesterandcyanosubstratespreferdifferentcantsofthep-allylPd(II)intermediates.Oppositecantsorallylgeometriesofthep-allylPd(II)intermediateinvert the sense of asymmetric induction to generate oppositeenantiomersoftheproduct.Theestersubstratefavorstheanti allylcomplexwithaforwardcant,andthecyanosubstratefurnishesthesynallylintermediatewiththetypicalbackwardscant.Bothof these intermediates, therefore, favor thesameenantiomerofthe product. In addition to establishing the necessary Curtin–Hammettcondition, theDYKATwithBaylis–Hillmanadductsaffordsremarkableselectivityforspecificconformationsof thep-allylPd(II)intermediates,andresultsinhighenantioselectivitiesforthealkylation.Overall,onlypreliminarystudiesonthesubstrateandnucleophileshavebeenreported.

eq 17

O Pd2dba3•CHCl3 (1 mol %)(s-C4H9)3B (1 mol %), CH2Cl2

OHOMeH

Pd(II)L*

OBO

RR

+

103 106 10782%, 89% ee

MeOH(R,R)-LN (1.2 mol %)

–

Ref. 63

Scheme 29. synthetic applications of the asymmetric addition of alcohols to Vinyl epoxides.

OOH

OR2R1

OHON

N

N

N

Cl

OH

n-C9H19

HO

O

R1

O O

OH

Ph

HNS

N

OO

CF3

HN OO

N N

OOH

R2OH, LN

108 109

110

(–)-malyngolide tipranavir

111

Pd2dba3•CHCl3(s-C4H9)3B, CH2Cl2

Ref. 64–67

Scheme 30. Dynamic Kinetic aaa of isoprene monoepoxide with Bicarbonate.

O

+ Pd(II)L*

O–O

O

OO

O

OH

OHOH

OCO2–Pd2dba3•CHCl3

(1 mol %)Et3B (1 mol %)H2O, CH2Cl2

112

112

113 11488%, 93% ee

115 11691%, 97% ee

NaHCO3(S,S)-LS (1.5 mol %)

NaHCO3 (S,S)-LS (3 mol %)


H2O, CH2Cl2

Ref. 28

eq 18

Pd2dba3•CHCl3(1 mol %)

TBAT (1 mol %)PhH

70%, 79:21 B/L, 96% ee

O

OHEtO

O

CO2Et

OOH

n

OCO2Et

112(S,S)-LST (3 mol %)

117 118branched

119linear

n = 1,2

+

Ref. 68

Scheme 31. rationalization of the regioselectivity in the alkylation with the DppBa ligands.

O

O

π–σ–π

OROO

matched acetoacetate

k1

OH

CO2R

O

OH

(R)-112

(S)-112

120branched

121linear

ionization

mismatched

ionization

acetoacetate

k2

Pd

+

OH

Nu

Pd

+

HO

Nu

Ref. 68b,69

69

Barr

y M

. Tro

st*

and

Dan

iel R

. Fan

dric

kV

OL.

40,

NO

. 3 •

200

7

The synthetic utility of the DYKAT with Baylis–HillmanadductswasdemonstratedbyapplicationtothetotalsynthesesoffuraquinocinE77andhippospongicacidA(Scheme 36).76Withthe long chainpresent in thehippospongic acid substrate, fullconversionwasinhibited.Thus,theobservedeeevolvesfromacombination of a kinetic resolution and a DYKAT associatedwith the largechain inhibiting the ionization.Accordingly, theDYKATwiththesmallersubstrate136proceededinhighyieldandenantioselectivity.

4.3. Acyloxyenoates as SubstratesFor typical DYKATs with a π−σ−π mechanism, one terminus of the allylintermediatemustbesubstitutedwithidenticalgroups.However,inacyloxyenoatesthatdonotabidebytheaboverequirement,highenantioselectivities have been achieved through an alternativeequilibration process. In this case, asymmetric induction is due toa rapid π−σ−π interconversion, wherein equilibration between the enantiotopicfacesoccursthroughanachiralO-palladium(II)enolate(Scheme 37).78Highenantiomericexcesswasachievedwithphenol-basednucleophiles(eq 19), and a halide additive showed a significant effectontheasymmetricinduction.DuringoptimizationstudieswithCs2CO3, an ee of 24% was obtained without tetrabutylammoniumchloride(TBACl),andincreasedto75%with30mol%ofTBACl.Thiseffectwasattributedtothehalideadditiveincreasingtherateofthe π−σ−π interconversion to promote the necessary Curtin–Hammett condition.3,4,70Slowingthealkylationratebyremovingthebasefurtherincreased the ee to 84% (74% yield). The methodology efficiently providedtheabsolutestereochemistryforthetotalsynthesesof(+)-aflatoxin B1

79and(+)-brefeldinA(Scheme 38).80Asdemonstratedbytheseexamples,theeefortheDYKATsurpassed95%byutilizinganaphtholorhighlysubstitutedphenolnucleophile.

In addition to the cyclic γ-butenolide substrates, highenantioselectivitieshavealsobeenachievedinanefficientAAAthat results in thederacemizationofacyclicacyloxyenoatesandrelated electrophiles (eq 20).29Asymmetric induction for theseacyclic substratespresumably results fromananalogousp−s−pinterconversionwithaprochiralPd(II)intermediate.

4.4. Allenes as SubstratesInadditiontotheprevioustransformationswhereinastereogeniccenteris created, palladium-catalyzed dynamic kinetic AAAs of racemicalleneshaveshownhighasymmetricinductionfortheestablishmentofaxialchirality.Inthismechanism,theCurtin–Hammettconditionresults from a rapid π−σ−π interconversion through a vinylPd(II) intermediate (Scheme 39).81 Using the standard ligand, LS, highenantioselectivitiesandyieldswereobtainedforthedynamickineticasymmetric addition of malonates and amines to racemic 2,3-alkadienyl acetates (Scheme 40).82 Similarly to the addition ofmalonatenucleophiles tocyclicandacyclic substrates (vida supra),thecountercationofthenucleophileorbasehadapronouncedeffectontheasymmetricinductionforbothtypesofnucleophiles.However,theobservedpattern,whereindifferentcountercationswerenecessaryforoptimalenantioselectivity,lithiumwithmalonatesandcesiumwithamines,isnotconsistentwiththepreviouslyobservedcountercationeffects(videsupra).Adetailedrationalizationforthisdiscrepancyhasyet to be formulated.The malonate products with a tethered dienefunctionalitywereappliedtoaRh(I)-catalyzed[4+2]cycloaddition,in which the axial chirality was efficiently transferred to multiple stereogenic centers and exocyclic olefin geometry.

5. Other DYKAT ProcessesSeveral DYKATs have been reported wherein the asymmetricinduction cannot be rationalized by the previously described

Scheme 32. application of the DyKaT of isoprene mono-epoxide with β-Keto esters to the synthesis of the cyclopentyl core of Viridenomycin.

Pd2dba3•CHCl3(1 mol %)CH2Cl2

O

OHEtO

O

OCO2Et

PhS

SPh

MeO

TBSOOTBS

CO2Et

OMe

112(S,S)-LS (3 mol %)

122 12371%, 94% ee

124

Ref. 71

Scheme 33. Dynamic Kinetic asymmetric cycloaddition of 2-Vinylaziridines with isocyanates.

NDMB

NN

DMB

DMB

O

(S,S)-LN (6 mol %)[η3-C3H5PdCl]2 (2 mol %)

DMB-NCO10% AcOH, CH2Cl2

NH

OHH2N

125 12680%, 94% ee

(+)-pseudodistomin D

DMB = 2,4-dimethoxybenzyl

Ref. 72,74

Scheme 34. p−s−p interconversion of Baylis–hillman adducts.

EWG

R

X

EWGR

X

EWG

R Pd(II)+

EWG

R Pd(II)+

EWG

Pd(II)+

R

EWG

Pd(II)+

R

EWG

R

Nu

EWGR

Nu

EWGR

Nu

EWG

R

Nu

R

EWGNu

EWGNuR

M M MM MM

M

MM

MMMMMM

M

MMπ–σ–π π–σ–π

M = matched; MM = mismatched

A B

C D

Anti Pathway Syn Pathway

Ref. 75

Scheme 35. DyKaT of Baylis–hillman adducts.

n-PrCN

OCO2Me

n-PrCO2Et

OCO2Me


n-PrCN

OPMPHCN

n-Pr

OPMP

CO2Et

OPMPn-Pr

CO2EtOPMPH

n-Pr

PMP-OH (128)(R,R)-LST (3 mol %)

rac-127 12971%, 93% ee

13015%

rac-131 13264%, 92% ee

13318%


+

+

PMP-OH (128)(R,R)-LST (3 mol %)

PMP = p-methoxyphenyl

Ref. 76

70

Palla

dium

-Cat

alyz

ed D

ynam

ic K

inet

ic A

sym

met

ric A

llylic

Alk

ylat

ion

with

the

DPP

BA L

igan

dsV

OL.

40,

NO

. 3 •

200

7mechanisms.Furthermore,themechanismsthataffordtheobservedenantioselectivitiesforthesesubstratesmayalsobeoperatinginthepreviously described reactions and contributing to the previouslyobservedhighlevelsofenantioselectivityinthesecasestoo.Hobergandco-workers83andGaisandco-workers29reportedhighee’sfortheDYKATofunsymmetricalacyclicsubstrateswiththestandardLS and BINAP ligands (Scheme 41). Due to the unsymmetricalnatureoftheelectrophile,whichaffordsanallylintermediatewithdifferentgeminalgroupsonbothterminioftheligand,theDYKATcannotproceedthroughthepreviouslydescribedmesointermediateor π−σ−π mechanism. Other processes such as interfacial exchange throughantiadditionviaasecondequivalentofthePd(0)catalyst84andracemizationofthesubstratemayaccountfortheasymmetricinduction. Another possibility is that either the ionization of thecarbonateornucleophilicattackproceedswithretentionintheso-calledmismatchedsituationforanoverall inversionmechanism.85Interestingly,onlythecarbonatesubstrateshaveaffordedaDYKAT,whileacetatesubstrateshavefurnishedaselectiveKR.

6. Conclusions and OutlookInconclusion,thepalladium-catalyzeddynamickineticasymmetricallylic alkylation with the DPPBA ligands is a versatile and

Scheme 36. synthetic applications of the DyKaT of Baylis–hillman adducts.

CNOCO2Me


I

O

OCN

CN

O

OH

O

O

OHMeO

MeO2COAc

HO ORO2C

[η3-C3H5PdCl]2 (2 mol %)Hex4NCl (30 mol %)

dioxane55% conv, 50% y, 91% ee

100% conv, 65% ee R = Me 135

R = H(+)-hippospongic acid A

rac-134

rac-136

(R,R)-LST (6 mol %)

2-I-1,3-(OH)2C6H3 (137)(R,R)-LST (2.7 mol %)

13897%, 92:8 dr furaquinocin E

LiOH98%

Ref. 76,77

Scheme 37. DyKaT mechanism for γ-Butenolides.

OO

LG

OO

LG

OO

+Pd(II)

OO

+Pd(II)

OO

+Pd(II)

π-σ

π-σ

OO

Nu

OO

Nu

k1

k2

Ref. 78

eq 19

OO

BocO OO

OH

MeO

Pd2dba3•CHCl3 (1 mol %)(n-Bu)4NCl (30 mol %), CH2Cl2

(R,R)-LS (3 mol %)

rac-139 14074%, 84% ee

4-MeOC6H4OH

Ref. 78

Scheme 38. synthetic applications of the DyKaT with γ-Butenolides.

OO

OH


(n-Bu)4NCl (30 mol %)CH2Cl2

HO HO

H

H

H

O

OH

HO

OEtO2C

O

MeO OH

I

OO

HO

OEtO2C

O

MeO

IO

O

MeO

O

O

O

H

H

141 14284%, 96% ee

143 14489%, >95% ee

(+)-brefeldin A

(+)-aflatoxin B1

rac-139(R,R)-LS (7.5 mol %)


(n-Bu)4NCl (30 mol %)CH2Cl2

rac-139(R,R)-LS (7.5 mol %)

Ref. 79,80

eq 20

R

OCO2Me

R

OH

Pd2dba3•CHCl3 (2 mol %)KHCO3, H2O, CH2Cl2racemic

(R,R)-LS (4 mol %)

SM

145147149151

R

EtO2CPhO2S

CN(MeO)2(O)P

Prd

146148150152

Yield

87%87%87%83%

ee

99%93%61%69%

Ref. 29b

Scheme 39. DyKaT mechanism for allenes.

LnPd(0)

Nu Nu–k1 k2

R

HH

RLG

H

HLG

Pd(II)LnR

H

Pd(II)LnRH

Pd(II)Ln

R +++

RH Nu

R

H NuH H

k1 > > k2

LnPd(0)

–

Ref. 81

Scheme 40. DyKaT of allenes.

H CO2Me

CO2MeH

Pd2dba3•CHCl3 (2.5 mol %)Cs2CO3, THF

Hex4NCl (5 mol %), rt

BnNHMe(S,S)-LS (7.5 mol %)

BnO HO

Ac

BnO

HO

Ac

H

H

+

CO2Me

CO2Me

BnO

HN

Bn

H

BnO

[(C10H8)Rh(cod)]SbF6

CH2Cl2, rt, 0.5 hCO2Me

CO2MeH

H

BnO

153

ent-153 15497%, 90% ee

15589%, 91% ee

15698%, 95% ee

rac-153

Pd2dba3•CHCl3 (2.5 mol %)LiHMDS (1.1 equiv), THF

Hex4NCl (5 mol %), rt

(S,S)-LS (7.5 mol %)

Ref. 82

Scheme 41. DyKaT of Unsymmetrical acyclic substrates.

Ph

OCO2Et

OTBS Pd2dba3•CHCl3 (3 mol %)Cs2CO3, THF

PhOH(S)-BINAP (8 mol %)

Ph

OPh

OTBS

Ph

OCO2Me

Pd2dba3•CHCl3 (2 mol %)KHCO3, H2O, CH2Cl2

Ph

OH

rac-157 15894%, 92% ee

rac-159 16085%, 85% ee

(R,R)-LS (4 mol %)

Ref. 29b,83

71

Barr

y M

. Tro

st*

and

Dan

iel R

. Fan

dric

kV

OL.

40,

NO

. 3 •

200

7

synthetically useful technology. Currently, the predominantDYKATprocesses for asymmetric inductionare (i)discriminationof enantiotopic termini of a π-allylpalladium intermediate, (ii)discrimination of enantiotopic faces of a meso or prochiralintermediate, and (iii) kinetic alkylation of one diastereomericintermediate of rapidly interconverting π-allylPd(II) complexes. Additionally,DYKAThasbeenaccomplishedwithseveralsubstrateswherein the reaction proceeds through alternative processes.These alternative mechanisms may also be operating in the otherDYKATs and contribute to the high enantioselectivities observed.Asdemonstrated,awidevarietyofsubstratesandnucleophilesaretoleratedinDYKAT,andhaveprovidedchiralbuildingblocksforthesynthesisofnumerouscomplexnatural compounds,validating theversatility and flexibility of the methodology. Further development is necessary to broaden the nucleophile and substrate scopes.Furthermore, mechanistic studies are required to further elucidatethesenseofasymmetricinductionobservedinmostreactionsand,accordingly,unravelthefullpotentialofthissyntheticallyenablingmethodology.

7. AcknowledgmentWe thank the National Institutes of Health (GM-13598 and GM-33049) and the National Science Foundation (CHE-0455354) fortheirgeneroussupportofourprograms.

8. References(1) (a)Trost,B.M.Science1991,254,1471.(b)Trost,B.M.Acc. Chem. Res.

2002,35,695.(2) Trost,B.M.Chem. Pharm. Bull. 2002,50,1.(3) (a)Trost,B.M.;vanVranken,D.L.Chem. Rev. 1996,96,395.(b)Trost,

B.M.Acc. Chem. Res.1996,29,355.(4) Trost,B.M.J. Org. Chem.2004,69,5813.(5) ForreviewsonDKR,see:(a)Ward,R.S.Tetrahedron: Asymmetry 1995,

6,1475.(b)Cook,G.R.Curr. Org. Chem. 2000,4,869.(c)Pellissier,H.Tetrahedron 2003,59,8291andreferencestherein.

(6) AgeneraltermforaDKRiskineticasymmetrictransformation:Eliel,E.L.Stereochemistry of Carbon Compounds;McGraw-Hill:NewYork,1962;Chapter4.

(7) (a)Faller,J.W.;Thomsen,M.E.;Mattina,M.J.J. Am. Chem. Soc. 1971,93,2642.(b)Faller,J.W.;Tully,M.T.J. Am. Chem. Soc. 1972,94,2676.

(8) Trost,B.M.;Murphy,D.J.Organometallics 1985,4,1143.(9) Forrecentdevelopmentsofchiralligands,see:(a)Jansat,S.;Gomez,M.;

Philippot,K.;Muller,G.;Guiu,E.;Claver,C.;Castillon,S.;Chaudret,B.J. Am. Chem. Soc. 2004,126,1592.(b)Tokuda,R.;Matsunaga,H.;Ishizuka,T.;Nakajima,M.;Kunieda,T.Heterocycles 2005,66,135.(c)Nemoto,T.;Masuda,T.;Matsumoto,T.;Hamada,Y.J. Org. Chem. 2005,70,7172.(d)Braga,A.L.;Paixão,M.W.;Marin,G.Synlett 2005,1675.(e)Okuyama,Y.;Nakano,H.;Saito,Y.;Takahashi,K.;Hongo,H.Tetrahedron: Asymmetry 2005,16,2551.(f)Laurent,R.;Caminade,A.-M.;Majoral,J.-P.Tetrahedron Lett. 2005,46,6503.(g)Jin,M.-J.;Takale,V.B.;Sarkar,M.S.;Kim,Y.-M.Chem. Commun. 2006,663.(h)Mikhel,I.S.;Bernardinelli,G.;Alexakis,A.Inorg. Chim. Acta 2006,359,1826.(i)Kloetzing,R.J.;Knochel,P.Tetrahedron: Asymmetry 2006,17,116.

(10) Yamaguchi,M.;Shima,T.;Yamagishi,T.;Hida,M.Tetrahedron Lett. 1990,31,5049.

(11) (a)VonMatt,P.;Pfaltz,A.Angew. Chem., Int. Ed. Engl. 1993,32, 566.(b)Sprinz,J.;Kiefer,M.;Helmchen,G.;Reggelin,M.;Huttner,G.;Walter,O.;Zsolnai,L.Tetrahedron Lett. 1994,35,1523.(c)Constantine,R.N.;Kim,N.;Bunt,R.C.Org. Lett. 2003,5,2279.

(12) Togni,A.Tetrahedron: Asymmetry 1991,2,683.(13) Kang, J.;Cho,W.O.;Cho,H.G.Tetrahedron: Asymmetry 1994,5,

1347.

(14) Evans,D.A.;Campos,K.R.;Tedrow,J.S.;Michael,F.E.;Gagne,M.R.J. Org. Chem. 1999,64,2994.

(15) Mino,T.;Sato,Y.;Saito,A.;Tanaka,Y.;Saotome,H.;Sakamoto,M.;Fujita,T.J. Org. Chem. 2005,70,7979.

(16) Trost,B.M.;Krueger,A.C.;Bunt,R.C.;Zambrano,J.J. Am. Chem. Soc. 1996,118,6520andreferencestherein.

(17) Trost,B.M.;Bunt,R.C.J. Am. Chem. Soc. 1996,118,235.(18) Trost,B.M.;Radinov,R.J. Am. Chem. Soc. 1997,119,5962.(19) Kinoshita,N.;Kawabata,T.;Tsubaki,K.;Bando,M.;Fuji,K.Tetrahedron

2006,62,1756.(20) Trost,B.M.;Surivet,J.-P.J. Am. Chem. Soc. 2000,122,6291.(21) Trost,B.M.;Schroeder,G.M.J. Org. Chem. 2000,65,1569.(22) Powell,M.T.;Porte,A.M.;Reibenspies,J.;Burgess,K.Tetrahedron

2001,57,5027.(23) Trost,B.M.;Bunt,R.C.J. Am. Chem. Soc. 1994,116,4089.(24) Reetz,M.T.;Huette,S.;Goddard,R.J. Am. Chem. Soc. 1993,115,

9339.(25) Trost,B.M.;Surivet,J.-P.Angew. Chem., Int. Ed. 2000,39,3122.(26) Trost,B.M.;Organ,M.G.J. Am. Chem. Soc. 1994,116,10320.(27) Trost,B.M.;Kondo,Y.Tetrahedron Lett. 1991,32,1613.(28) Trost,B.M.;McEachern,E.J.J. Am. Chem. Soc. 1999,121,8649.(29) (a)Lüssem,B.J.;Gais,H.-J.J. Am. Chem. Soc. 2003,125,6066.(b)Gais,

H.-J.;Bondarev,O.;Hetzer,R.Tetrahedron Lett. 2005,46,6279.(30) Trost,B.M.;Toste,F.D.J. Am. Chem. Soc. 2000,122,11262.(31) Trost,B.M.;Tang,W.;Toste,F.D.J. Am. Chem. Soc. 2005,127,14785.(32) Mori,M.;Kuroda,S.;Zhang,C.-S.;Sato,Y.J. Org. Chem. 1997,62,

3263.(33) (a) Ovaa, H.; Stragies, R.; van der Marel, G. A.; van Boom, J. H.;

Blechert,S.Chem. Commun. 2000,1501.(b)Trost,B.M.;Sorum,M.T.Org. Process Res. Dev. 2003,7,432.

(34) (a)Trost,B.M.;Verhoeven,T.R.J. Am. Chem. Soc.1976,98,630.(b)Trost,B.M.;Verhoeven,T.R.J. Am. Chem. Soc. 1980,102,4730.(c)Hayashi,T.;Hagihara,T.;Konishi,M.;Kumada,M.J. Am. Chem. Soc. 1983,105,7767.

(35) Trost,B.M.;Oslob,J.D.J. Am. Chem. Soc. 1999,121,3057.(36) Trost,B.M.;Krische,M.J.;Berl,V.;Grenzer,E.M.Org. Lett. 2002,4,

2005.(37) Burger,E.C.;Tunge,J.A.Org. Lett. 2004,6,4113.(38) (a)Tsuda,T.;Chujo,Y.;Nishi,S.;Tawara,K.;Saegusa,T.J. Am. Chem.

Soc. 1980,102,6381.(b)Tsuji,J.Pure Appl. Chem. 1982,54,197.(c)Tsuji,J.;Yamada,T.;Minami,I.;Yuhara,M.;Nisar,M.;Shimizu,I.J. Org. Chem. 1987,52,2988.

(39) Trost,B.M.;Patterson,D.E.;Hembre,E.J.J. Am. Chem. Soc. 1999,121,10834.

(40) Trost,B.M.;Hembre,E.J.Tetrahedron Lett. 1999,40,219.(41) Trost,B.M.;Dudash, J., Jr.;Hembre,E. J.Chem.—Eur. J. 2001,7,

1619.(42) Trost,B.M.;Patterson,D.E.;Hembre,E.J.Chem.—Eur. J. 2001,7,

3768.(43) (a)Fiaud,J.C.;deGournay,A.H.;Larcheveque,M.;Kagan,H.B.J.

Organomet. Chem. 1978,154,175.(b)Genet,J.P.;Ferroud,D.;Juge,S.;Montes,J.R.Tetrahedron Lett. 1986, 27,4573.(c)Genet,J.-P.;Juge,S.;Achi,S.;Mallart,S.;Montes,J.R.;Levif,G.Tetrahedron 1988,44,5263.(d)Genet,J.-P.;Juge,S.;Montes,J.R.;Gaudin,J.-M.J. Chem. Soc., Chem. Commun. 1988,718.(e)Baldwin,I.C.;Williams,J.M.J.Tetrahedron: Asymmetry 1995,6,679.

(44) (a) Ito, Y.; Sawamura, M.; Matsuoka, M.; Matsumoto, Y.; Hayashi,T. Tetrahedron Lett. 1987, 28, 4849. (b) Hayashi, T.; Kanehira, K.;Hagihara,T.;Kumada,M.J. Org. Chem. 1988,53,113.(c)Sawamura,M.;Nagata,H.;Sakamoto,H.;Ito,Y.J. Am. Chem. Soc. 1992,114,2586.(d)Sawamura,M.;Nakayama,Y.;Tang,W.-M.;Ito,Y.J. Org. Chem. 1996, 61,9090.(e)Kaneko,S.;Yoshino,T.;Katoh,T.;Terashima,S.Tetrahedron: Asymmetry 1997,8,829.(f)He,X.-C.;Wang,B.;Bai,D.

72

Palla

dium

-Cat

alyz

ed D

ynam

ic K

inet

ic A

sym

met

ric A

llylic

Alk

ylat

ion

with

the

DPP

BA L

igan

dsV

OL.

40,

NO

. 3 •

200

7Tetrahedron Lett. 1998,39,411.(g)He,X.-C.;Wang,B.;Yu,G.;Bai,D.Tetrahedron: Asymmetry 2001,12,3213.

(45) Trost,B.M.;Radinov,R.;Grenzer,E.M.J. Am. Chem. Soc. 1997,119,7879.

(46) Trost,B.M.;Frederiksen,M.U.Angew. Chem., Int. Ed. 2005,44,308.(47) (a)Trost,B.M.;Schroeder,G.M.J. Am. Chem. Soc. 1999,121,6759.

(b)Braun,M.;Laicher,F.;Meier,T.Angew. Chem., Int. Ed. 2000,39,3494.(c)Braun,M.;Meier,T.Synlett2005,2968.(d)Braun,M.;Meier,T.Angew. Chem., Int. Ed. 2006,45,6952.

(48) Trost,B.M.;Pissot-Soldermann,C.;Chen,I.Chem.—Eur. J. 2005,11,951.

(49) (a)Trost,B.M.;Dong,L.;Schroeder,G.M.J. Am. Chem. Soc. 2005,127,2844.(b)Trost,B.M.;Dong,L.;Schroeder,G.M.J. Am. Chem. Soc. 2005,127,10259.

(50) You,S.-L.;Hou,X.-L.;Dai,L.-X.;Zhu,X.-Z.Org. Lett. 2001,3,149.(51) Trost,B.M.;Xu,J.J. Am. Chem. Soc. 2005,127,2846.(52) Trost,B.M.;Xu,J.J. Am. Chem. Soc. 2005,127,17180.(53) Trost,B.M.;Bream,R.N.;Xu, J.Angew. Chem., Int. Ed. 2006,45,

3109.(54) Trost,B.M.;Ariza,X.J. Am. Chem. Soc. 1999,121,10727.(55) Trost,B.M.;Ariza,X.Angew. Chem., Int. Ed. Engl. 1997,36,2635.(56) (a)Trost,B.M.;Lee,C.B.J. Am. Chem. Soc. 2001,123,3671.(b)Trost,

B.M.;Lee,C.B.J. Am. Chem. Soc. 2001,123,3687.(57) (a)Trost,B.M.;Lee,C.B.J. Am. Chem. Soc. 1998,120,6818.(b)Trost,

B.M.;Lee,C.J. Am. Chem. Soc. 2001,123,12191.(58) (a)Hayashi,T.;Yamamoto,A.;Ito,Y.Tetrahedron Lett. 1988,29,99.(b)

Larksarp,C.;Alper,H.J. Am. Chem. Soc. 1997,119,3709.(59) Trost,B.M.;Bunt,R.C.Angew. Chem., Int. Ed. Engl. 1996,35,99.(60) Trost,B.M.;Bunt,R.C.;Lemoine,R.C.;Calkins,T.L.J. Am. Chem.

Soc. 2000,122,5968.(61) Trost,B.M.;Lemoine,R.C.Tetrahedron Lett. 1996,37,9161.(62) (a)Trost,B.M.;Horne,D.B.;Woltering.M.J.Angew. Chem., Int. Ed.

2003,42,5987.(b)Trost,B.M.;Horne,D.B.;Woltering.M.J.Chem.—Eur. J.2006,12,6607.

(63) Trost,B.M.;McEachern,E.J.;Toste,F.D.J. Am. Chem. Soc. 1998,120,12702.

(64) Trost,B.M.;Brown,B.S.;McEachern,E.J.;Kuhn,O.Chem.—Eur. J. 2003,9,4442.

(65) Trost,B.M.;Tang,W.;Schulte,J.L.Org. Lett. 2000,2,4013.(66) Trost,B.M.;Andersen,N.G.J. Am. Chem. Soc. 2002,124,14320.(67) Trost,B.M.;Tang,W.Org. Lett. 2001,3,3409.(68) (a)Trost,B.M.;Jiang,C.J. Am. Chem. Soc. 2001,123,12907.(b)Jiang,

C.Ph.D.Dissertation,StanfordUniversity,Stanford,CA,2005.(69) Trost,B.M.;Toste,F.D.J. Am. Chem. Soc. 1999,121,4545.(70) Burckhardt,U.;Baumann,M.;Togni,A.Tetrahedron: Asymmetry 1997,

8,155.(71) Trost,B.M.;Jiang,C.Org. Lett. 2003,5,1563.(72) Trost,B.M.;Fandrick,D.R.J. Am. Chem. Soc. 2003,125,11836.(73) Lucet,D.;LeGall,T.;Mioskowski,C.Angew. Chem., Int. Ed. 1998,37,

2580.(74) Trost,B.M.;Fandrick,D.R.Org. Lett. 2005,7,823.(75) Trost,B.M.;Tsui,H.-C.;Toste,F.D.J. Am. Chem. Soc. 2000,122,

3534.(76) Trost,B.M.;Machacek,M.R.;Tsui,H.C.J. Am. Chem. Soc. 2005,127,

7014.(77) (a)Trost,B.M.;Thiel,O.R.;Tsui,H.-C.J. Am. Chem. Soc. 2002,124,

11616.(b)Trost,B.M.;Thiel,O.R.;Tsui,H.-C.J. Am. Chem. Soc. 2003,125,13155.

(78) Trost,B.M.;Toste,F.D.J. Am. Chem. Soc. 1999,121,3543.(79) Trost,B.M.;Toste,F.D.J. Am. Chem. Soc. 2003,125,3090.(80) (a)Trost,B.M.;Crawley,M.L.J. Am. Chem. Soc. 2002,124,9328.(b)

Trost,B.M.;Crawley,M.L.Chem.—Eur. J. 2004,10,2237.(81) (a)Ogasawara,M.;Ikeda,H.;Hayashi,T.Angew. Chem., Int. Ed. 2000,39,

1042.(b)Ogasawara,M.;Ikeda,H.;Nagano,T.;Hayashi,T.J. Am. Chem. Soc.2001,123,2089.(c)Imada,Y.;Ueno,K.;Kutsuwa,K.;Murahashi,S.-I.Chem. Lett.2002,140.(d)Ogasawara,M.;Ueyama,K.;Nagano,T.;Mizuhata,Y.;Hayashi,T.Org. Lett.2003,5,217.(e)Ogasawara,M.;Nagano,T.;Hayashi,T.J. Org. Chem. 2005,70,5764.

(82) Trost,B.M.;Fandrick,D.R.;Dinh,D.C.J. Am. Chem. Soc. 2005,127,14186.

(83) Dong,Y.;Teesdale-Spittle,P.;Hoberg,J.O.Tetrahedron Lett. 2005,46,353.

(84) ForevidenceofaPd–Pddisplacementmechanism,seeGranberg,K.L.;Bäckvall,J.-E.J. Am. Chem. Soc. 1992,114,6858.

(85) Forevidenceofa reductiveeliminationofanallylPd(II)acetate, seeLofstedt,J.;Franzen,J.;Bäckvall,J.-E.J. Org. Chem. 2001,66,8015andreferencestherein.

About the AuthorsBarry M. Trost wasbornin1941inPhiladelphia,Pennsylvania,wherehebeganhisuniversitytrainingattheUniversityofPennsylvania(B.A.,1962).HeobtainedaPh.D.degreeinchemistryjustthreeyearslaterattheMassachusettsInstituteofTechnology(1965).HethenmovedtotheUniversityofWisconsin-Madison,wherehewaspromotedtoProfessorofChemistryin1969and,in1982,becametheVilasResearchProfessor.In1987,he joined the faculty atStanfordUniversity asProfessorofChemistry,andbecametheTamakiProfessorofHumanitiesandSciencesin 1990. In addition, he has beenVisiting Professor of Chemistry inGermany(UniversitiesofMarburg,Hamburg,andMunich),Denmark(UniversityofCopenhagen),France(UniversitiesofParisVIandParis-Sud),Italy(UniversityofPisa),andSpain(UniversityofBarcelona).In1994,hewaspresentedwithaDocteur Honoris CausaoftheUniversitéClaude-Bernard (LyonI,France)and, in1997,aDoctor Scientiarum Honoris CausaoftheTechnion,Haifa,Israel.In2006,hewasappointedHonoraryProfessoroftheShanghaiInstituteofOrganicChemistry.

ProfessorTrost’sworkhasbeencharacterizedbyaveryhighorderofimagination,innovation,andscholarship.Hehasrangedovertheentirefield of organic synthesis, particularly emphasizing extraordinarily novel methodologies. In recognition of his many contributions, ProfessorTrosthas receivedanumberofawards, including theACSAward inPureChemistry(1977),theACSAwardforCreativeWorkinSyntheticOrganicChemistry(1981),theBaekelandAward(1981),theArthurC.CopeScholarAward(1989),theGuentherAwardintheChemistryofEssentialOilsandRelatedProducts(1990),theDr.PaulJanssenPrize(1990),theASSUGraduateTeachingAward(1991),theBingTeachingAward(1993), theACSRogerAdamsAward(1995), thePresidentialGreenChemistryChallengeAward(1998),theHerbertC.BrownAwardforCreativeResearchinSyntheticMethods(1999),theBelgianOrganicSynthesisSymposiumElsevierAward(2000),theNicholsMedal(2000),theYamadaPrize(2001),theACSNobelLaureateSignatureAwardforGraduateEducationinChemistry(2002),theACSCopeAward(2004),andtheJohnScottAwardofthecityofPhiladelphia(2004).ProfessorTrosthasbeenelectedafellowoftheAmericanAcademyofSciences(1992)andamemberoftheNationalAcademyofSciences(1990).Hehas published two books and over 790 scientific articles.

Daniel R. Fandrick received his B.S. degree with a major inchemistryin2001fromtheUniversityofCalifornia,SanDiego.Duringhisundergraduatestudiesunder theguidanceofProfessor JosephM.O’Connor,hecontributedtothesynthesisofastrainedcyclicferrocenylenediyne complex. In 2006, he received his Ph.D. degree in organicchemistry at Stanford University under the supervision of ProfessorBarry M. Trost. His graduate studies focused on the developmentof several palladium-catalyzed dynamic kinetic asymmetric allylicalkylations and their applications in total synthesis.After graduation,hejoinedthechemicaldevelopmentgroupatBoehringerIngelheiminRidgefield, Connecticut.^

sigma-aldrich.com

Accelerate Asymmetric Catalysisasymmetric catalysis is playing an ever-increasing role in the production of enantiomerically pure compounds for pharmaceutical, agrochemical, and industrial applications. sigma-aldrich is pleased to offer a growing portfolio of “privileged ligands”, as well as innovative new classes of chiral ligands, to accelerate your research success in asymmetric catalysis.

DuPhos/BPE

DuPhosR R,R S,SMethyl 665258 665266*Ethyl 668494 668486*Isopropyl 668524 668176*

BPER R,R S,SMethyl 665231 665207*Ethyl 668478 668451*Isopropyl 668443 668435*Phenyl 667811 667854*

Ferrocelane™

R R,R S,SMethyl 675601 675598*Ethyl 680990 681008*Isopropyl 684309 684406*

RajPhos™

R R,R S,SMethyl 677043 677035*Ethyl 677051 677078

BozPhosR R,R S,SMethyl 678635 678562*

DuPhos/BPE Ligands I Kit 687774*Denotes Kit Components

DuPhos, BPE, Ferrocelane™, RajPhos™ and BozPhos are “Sold in collaboration with Kanata Chemical Technologies Inc. for research purposes only. These Compounds were made and sold under license from E.I. duPont de Nemours and Company, which license does not include the right to use the Compounds in producing products for sale in the pharmaceutical field.”

Bidentate bis(phospholane) ligands are very useful in asymmetric hydrogenation reactions. The versatility of these ligands used with Rhodium has been demonstrated for various transformations such as the synthesis of amino acid derivatives.1,2,3 The modular nature of these ligands allows for variation of both phosphane substituent and backbone structures, leading to an extensive library of ligands for enantioselective catalytic reactions.1

Aldrich is offering a series of DuPhos, BPE, Ferrocelane™, RajPhos™, and BozPhos ligands and their derivatives.

R1

R2N(H)COR3

CO2R4

CO2Me

N(H)Ac

CO2Me

O N(H)Boc CO2MeN

N(H)Cbz

CO2Me

O

AcO OAc

OAcAcOCO2Me

N(H)Boc

NOMe

O

C7F15CO2Me

N(H)CbzCO2Me

N(H)Cbz

F

CO2Me

N(H)Boc

(1) Burk, M. J. Acc. Chem. Res. 2000, 33, 363. (2) Burk, M. J. et al. J. Am. Chem. Soc. 1998, 120, 657. (3) Burk, M. J. et al. J. Org. Chem. 2003, 68, 5731.

P PR

RR

R

PP

R R

R R

Fe

P

P

R

R

R

R

PPO

R

RR

R

PO

OR

R




























Landis Diazaphospholane LigandsRecently, there has been an increased interest in the asymmetric hydroformylation reaction. This transformation gives access to versatile chiral building blocks that are of high interest to the pharmaceutical and fine chemicals industries. Landis and co-workers reported the synthesis of chiral diazaphospholane ligands for the asymmetric hydroformylation of a variety of terminal alkenes using a Rh catalyst. This new class of ligands has turnover frequencies of up to 9000 h-1 with 96% ee and 100% conversion.1, 2 Sigma-Aldrich is pleased to offer this new class of useful ligands.(1) Clark, T. P.; Landis, C. R. J. Am. Chem. Soc. 2003, 125, 11792. (2) Clark, T. P. et al. J. Am. Chem. Soc. 2005, 127, 5040.

RR

O H

P PNNN

N

NH

NH

HN

HN

OO

OO

CH3CH3

CH3 CH3

OO

OO

R Yield (%) ee (%) Ph 100 82CN 100 87OAc 100 96

(0.024 mol%)/ Rh (0.02 mol%)

150 psig CO:H2 (1:1), 80 °C

Reetz Diphosphonite LigandsReetz and co-workers developed a new generation of BINOL-derived diphosphonite ligands for the asymmetric hydrogenation of ketones and β-keto esters,1,2 and the asymmetric conjugate addition of arylboronic acid derivatives to α,β-unsaturated carbonyls.3 Used with a RuCl2(p-cymene)2 complex, (R,R)-Reetz X-Diphosphonite converts a variety of ketones into secondary alcohols with yields and ee’s up to 100% and 98% respectively.1 Sigma-Aldrich exclusively offers this new family of ligands.(1) Reetz, M. T.; Li, X. J. Am. Chem. Soc. 2006, 128, 1044. (2) Reetz, M. T.; Li, X. Adv. Synth. Catal. 2006, 348, 1157. (3) Reetz, M. T. et al. Org. Lett. 2001, 3, 4083.

O

O OP

O OP

H3C CH3

O

O OP

O OP

(R,R)-Reetz X-Diphosphonite 682977

(S,S)-Reetz X-Diphosphonite 682869

(R,R)-Reetz D-Diphosphonite 682993

(S,S)-Reetz D-Diphosphonite 682985

NN

P

O

O

NN

P

O

O

NH

O

Ph

CH3

HN

O

Ph

CH3

NH

O

Ph

CH3

HN

O

Ph

CH3

NN

P

O

O

NN

P

O

O

NH

O

Ph

CH3

HN

O

Ph

CH3

NH

O

Ph

CH3

HN

O

Ph

CH3

Bis[(R,R,S)-DiazaPhos-SPE] 685232

Bis[(S,S,S)-DiazaPhos-SPE] 685259

N

O

N

O

P Ph

O

NH

CH3

Ph

O

HN

CH3

Ph

N

O

N

O

P Ph

O

NH

CH3

Ph

O

HN

CH3

Ph

(R,R,S)-DiazaPhos-PPE 685089

(S,S,S)-DiazaPhos-PPE 685240

DiazaPhos-SPE and DiazaPhos-PPE are sold in association with DowPharmaSM, a business unit of The Dow Chemical Company. DiazaPhos-SPE and DiazaPhos-PPE are sold for R&D purposes only, and use by the end user in the manufacture of products of commerce is not permitted.

O

O OP

O OP

H3C CH3

R

O

CH3 R CH3

OHRuCl2(p-cymene)2 (0.5 mol%)

iPrOH, base (10 mol%)

(1.25 mol%)

R Yield (%) ee (%)Ph 93 98m-MeOC6H4 91 93m-BrC6H4 100 96p-ClC6H4 96 96p-BrC6H4 98 95









sigma-aldrich.com

FeSulPhos Ligand for the Enantioselective 1,3-Dipolar Cycloaddition

Reference: Cabrera, S. et al. J. Am. Chem. Soc. 2005, 127, 16394.

Ph N CO2Me N

O

O

CH3+

(R)-FeSulPhos ( 3 mol %)Cu(CH3CN)4ClO4 (3 mol %)

NEt3 (18 mol %)CH2Cl2, rt

N

NH

CO2MePh

OO

Me

97% yield>99% ee

(RP)-FeSulPhos 687561

Sulfoximine Ligands for Asymmetric Aldol Reactions

Reference: Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 482.

OSiMe3Me

OMeO

O

OMeO Me OH

O

sulfoximine ligand (10 mol %)Cu(OTf)2 (10 mol %)

THF, rt

+

99% yield93% ee

(R)-S-Methyl-S-phenyl-N-[2-(2,4,6-triisopropylbenzylamino)-phenyl]sulfoximine669857

(S)-S-Methyl-S-phenyl-N-[2-(2,4,6-triisopropylbenzylamino)-phenyl]sulfoximine669970

Fe

S-t-Bu

PPh2

The asymmetric 1,3-dipolar cycloaddition reaction is of the utmost importance for the enantioselective synthesis of five-membered-ring heterocycles. Cabrera et al. introduced a new family of ligands consisting of a planar-chiral P,S-ligand, named FeSulPhos, for the 1,3-dipolar cycloaddition of azomethine ylides. The catalytic reaction is carried out with the FeSulPhos ligand, a copper salt, and triethylamine in methylene chloride. This new catalytic system demonstrated complete enantiocontrol (ee >99%) with conversions up to 97%. Sigma-Aldrich is pleased to offer this new ligand for asymmetric synthesis.

Chiral sulfoximine ligands have been studied for the past 15 years for use in catalytic asymmetric reactions. Bolm’s group developed a new class of sulfoximine used with copper salts for asymmetric aldol reactions. Using these bidentate ligands, Bolm and co-workers reported up to 93% ee’s and 99% yields for the Mukaiyama-type aldol reaction of 1-phenyl-1-(trimethylsilyloxy)ethane and methyl pyruvate. This new class of ligands is offered exclusively by Sigma-Aldrich.

N HNSO

H3C

H3C

H3C

H3CCH3

H3CCH3

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PPh2

PPh2

FePh2P

N

PPh2

CH3

CH3

Boc-l-Ala Ligand for the Enantioselective Reduction of Ketones

O OH

90% yield96% ee

Boc-l-Ala (1.1 mol %)RuCl2(p-cymene)2 (0.5 mol %)NaOH (5 mol %)

2-propanol, rt

Reference: Bøgevig, A. et al. Chem.—Eur. J. 2004, 10, 294.

H3CNH

OCH3

HN OHBoc

Boc-l-alanine (2S)-2-hydroxypropylamide 684414

8 Chiral Quest Ligands for Asymmetric Hydrogenation

BoPhoz and PhanePhos* for Asymmetric Hydrogenation

(S)-Me-f-KetalPhos 685674

(R)-PhanePhos 682144

(S)-PhanePhos 682136

* Sold in collaboration with Johnson Matthey for research purposes only. US5874629 and any patents arising therefrom apply.

Chemists extensively use the enantioselective reduction of ketones to secondary alcohols. This reaction gives access to important functionalities for the synthesis of natural products. Adolfsson and co-workers reported a novel class of ligands, based on pseudo-dipeptides, for the efficient reduction of ketones. The ligand is used with RuCl2(p-cymene)2 in the presence of NaOH in 2-propanol. Yields of up to 90% with 96% ee have been reported. This new ligand is now part of the Sigma-Aldrich ligand library for asymmetric transformations.

Fe

PP

H3C

H3C

CH3

CH3O

O

CH3

CH3O

OH3CH3C

(S,S)-f-Binaphane 685925

P

P

Fe

P

P

H3C CH3

CH3

CH3CH3

CH3

CH3H3C

(R)-Methyl-BoPhoz 682322

(S)-Methyl-BoPhoz 682314

(R)-Xylyl-PhanePhos 682306

(S)-Xylyl-PhanePhos 682292

Chiral Quest Ligands Kit*

Chiral Quest ligands are some of the most potent for asymmetric hydrogenation. This new kit includes 7 ligands with 100 mg of each for rapid screening of chiral catalysts. The Chiral Quest ligands Kit I includes (R)-C3-TunePhos, (R)-Binaphane, (S,S’,R,R’)-TangPhos, (1R,1’R,2S,2’S)-Duan-Phos, (S)-Binapine, (S)-Me-f-KetalPhos, and (S,S)-f-Binaphane.

* Sold in collaboration with Chiral Quest for research purposes only. U.S. Patent: 6,828,271; 6,525,210; and additional patents pending.










77

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Outline1. Introduction2. Alkylation 2.1. Asymmetric Synthesis of α-Amino Acids and Their

Derivatives 2.1.1. Monoalkylation of Schiff Bases Derived from

Glycine 2.1.2. Dialkylation of Schiff Bases Derived from

α-Alkyl-α-aminoAcids 2.1.3. AlkylationofPeptidesActivatedbyaSchiffBase 2.2. OtherAlkylations3. TheMichaelAddition4. TheAldolandRelatedReactions5. TheDarzensCondensation6. TheNeberRearrangement7. Epoxidation8. Cyanation9. Conclusions10.Acknowledgements11.ReferencesandNotes

1. IntroductionTheevolutionofphase-transfercatalysis(PTC)wasledmainlybythedemandfromindustryinthemid-1960sforatrulyeffectiveprocedurefor transferringhydrophilicanionstoorganicmedia.Withitssimpleexperimentaloperations,mildreactionconditions,inexpensiveandenvironmentallybenignreagentsandsolvents,andthepossibilityofconductinglarge-scalepreparations,PTChassincebeenrecognizedasaversatilemethodologyfororganicsynthesisinbothindustrialandacademiclaboratories.1AsymmetricPTC,thatisbasedontheuseofstructurallywell-definedchiral,nonracemiccatalysts,hasbecomeatopicofgreatscientificinterestinthepasttwodecades.Recent,enormouseffortshaveresulted innotableachievements,makingitfeasibletoperformvariousbond-formingreactionsundermildphase-transfer-catalyzedconditions.2Thisreviewwillfocusonrecentadvancesinasymmetricreactions—whichareenabledbyC2-symmetric,chiral,phase-transfercatalysts

and reported between 2000 and 2006—and will showcase thevariationsintheirdesignsandapplications.OtherasymmetricPTCs,withcinchona-alkaloid-derived,chiralquaternaryammoniumsaltsandchiralcrownetherslackingC2-symmetry,arenotcoveredduetospacelimitation,andtheirrelevantreferencesarecitedonlyinconjunctionwith related reactions.Other, excellent reviewsonasymmetricphase-transfercatalysishavealsobeenpublished.2

2. Alkylation2.1. Asymmetric Synthesis of α-Amino Acids and Their Derivatives2.1.1. monoalkylation of schiff Bases Derived from GlycineIn1989,theresearchgroupledbyMartinO'Donnellsuccessfullyutilized chiral quaternary ammonium salts, prepared fromnaturallyoccurringalkaloids,for theasymmetricsynthesisofα-amino acids by using glycinate Schiff base 1asakeysubstrate(eq 1).3Theasymmetricalkylationof1proceededsmoothlyundermild phase-transfer conditions with N-(benzyl)cinchoniniumchloride (3a)ascatalyst togive thealkylationproduct (R)-2ain good yield and moderate enantioselectivity. This practicalasymmetric alkylation procedure has been strengthened intoanevenmorevaluableprotocol through thedevelopmentofanew class of cinchona-alkaloid-derived catalysts bearing anN-anthracenylmethylfunction.In1997,Lygo’sgroupdesignedN-anthracenylmethylammonium salts 3b and 4a and appliedthem to the asymmetric phase-transfer alkylation of 1 tosynthesize α-amino acids with much higher enantioselectivities.4At thesame time,Coreyandco-workerspreparedO-allyl-N-anthracenylmethylcinchonidiniumbromide(4b),andachievedhighasymmetricinductionintheenantioselectivealkylationof1bythecombineduseofsolidCsOH•H2Oatverylowtemperature.5These reports helped generate a great deal of interest inasymmetric phase-transfer catalysis, and the enantioselectivefunctionalizationof1,particularlyalkylation,hasbeenextensivelyutilizedasabenchmarkreactiontoevaluatetheefficienciesofnewlydevisedcatalystsincludingC2-symmetricones.

Development and Applications of C2-Symmetric, Chiral, Phase-Transfer Catalysts

Takashi Ooi† and Keiji Maruoka*Department of ChemistryGraduate School of ScienceKyoto UniversitySakyo, Kyoto 606-8502, JapanEmail: [email protected]

ProfessorTakashiOoi ProfessorKeijiMaruoka

78

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007

Dev

elop

men

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2-Sy

mm

etric

, Chi

ral,

Phas

e-Tr

ansf

er C

atal

ysts

N+

Ar

Ar

Br–

N+

Ar

Ar

N+

R1

R1

R2

R2

N+

Ar

Ar

Ar

Ar

(S,S)-5a, Ar = 3,4,5-F3C6H2c, Ar = 3,5-(3,5-(t-Bu)2C6H3)2C6H3d, Ar = 3,5-(CF3)2C6H3e, Ar = 3,5-(3,5-(CF3)2C6H3)2C6H3f, Ar = 3,5-(3,4,5-F3C6H2)2C6H3g, Ar = 6-CF3-naphthalen-2-ylh, Ar = 4-CF3C6H4

(R,R)-5b, Ar = 3,5-Ph2C6H3

N+

Ar

Ar

Ar

Ar Ar

Ar

Ar

Ar

(S)-9R1 = 3,5-Ph2C6H3, R2 = Ph

(S,S)-6Ar = 3,5-Ph2C6H3

(S,S)-7Ar = 3,5-Ph2C6H3

N+

R'R'

R' R'

R'R'

R'R'

(R,R)-8R' = SiMe2(CH2CH2C8F17)

Br–

Br– Br–

Br– Br–

eq 1

Ph2C NO

Ot-Bu + BnBr Ph2C NO

Ot-BuH Bn

N

N

HX–

OR

2a

N

H R

Cl–OH

N

+

+

*

1

3a, R = Bn3b, R = (9-anthracenyl)CH2

4a; X = Cl, R = H 4b; X = Br, R = allyl

Cat.a

3a3b4a4b

Base

50% NaOH (aq)50% KOH (aq)50% KOH (aq)

CsOH•H2O

a Catalyst loading = 10 mol %.

Solvent

CH2Cl2PhMePhMe

CH2Cl2

Temp

20 oC20 oC20 oC

–78 oC

Time

9 h18 h18 h23 h

Yield

75%63%68%87%

ee

66% (R)89% (R)91% (S)94% (S)

Ref.

3a4a4b5

eq 2

Ph2C NO

Ot-Bu + RX Ph2C NO

Ot-BuH R

1

catalyst(mol %)

*

2

basesolvent, temp

Figure 1. chiral, c2-symmetric, phase-Transfer alkylation catalysts.

In 1999, our group reported the structurally rigid, chiralquaternaryammoniumsaltsoftype5a—derivedfromcommerciallyavailable (S)-or (R)-1,1’-bi-2-naphthol—asnewC2-symmetric,chiral,phase-transfercatalysts,whichweresuccessfullyappliedtothehighlyefficient,catalytic,andenantioselectivealkylationof1undermildphase-transferconditions (eq 2, Figure s 1–2,Table 1).6Thearomaticsubstituents(Ar)atthe3and3'positionsofonebinaphthylsubunitofthecatalysthadasignificanteffectontheenantiocontrollingabilityofthecatalyst,and5awasthecatalystofchoiceforthepreparationofavarietyofessentiallyenantiopureα-amino acids by this transformation.

To fully exploit the potential catalytic activity of chiralammoniumsalts suchas5b, binaryphase-transfer catalysis—usinganappropriateachiralco-catalyst—hasbeendeveloped.Forinstance,thephase-transfer-catalyzedbenzylationof1undertheinfluenceof (R,R)-5b (0.1mol%)and18-crown-6(0.1mol%)proceededsmoothlytofurnish(S)-2a in98%yieldand98%ee[4%yield(92%ee)without18-crown-6asco-catalyst].7

Withthecriticalroleofthe3,3’-diarylsubstituentsof5inmind,ourgroupalsoexaminedtheeffectofthe4,4’and6,6’substituentsofonebinaphthylsubunitonthestereoselectivityofthealkylationof1 throughthepreparationof(S,S)-6.8Wealsoassembledthesymmetrical phase-transfer catalyst 7, which exhibited highcatalyticandchiralefficiencies.9Thesymmetricalstructuralmotifin7ledustothedevelopmentoffluorous,chiral,phase-transfercatalyst8.Afterthealkylationreaction,8waseasilyrecoveredbysimpleextractionwithFC-72(perfluorohexanes)asafluoroussolventandwasusedforthenextrunwithoutanylossofreactivityorselectivity.10

Althoughtheconformationallyrigid,N-spirostructurecreatedbytwochiralbinaphthylsubunitsrepresentsacharacteristicfeatureof5andrelatedcatalysts(suchas6),italsoimposeslimitationsoncatalystdesignduetotheimperativeuseofthetwodifferentchiral binaphthyl moieties. Accordingly, our group developedthe C2-symmetric chiral quaternary ammonium bromide 9,incorporatingaconformationallyflexibleyeteasilymodifiableachiral biphenyl subunit, which exerted chiral efficiencies ashighas thoseof a seriesof conformationally rigidhomochiralcatalysts.11

Our group also undertook efforts to substantially enhancethereactivityofN-spiro,chiral,quaternaryammoniumsaltsandsimplify their structures for thepurposeofdevelopinga trulypractical method for the asymmetric synthesis of α-amino acids and theirderivatives.Ourinitialattemptwastodesignpolyamine-basedchiralphase-transfercatalystswiththeexpectationofamultipliereffectoftheattachedchiralauxiliaries.Gratifyingly,catalyst(S)-10,bearinga3,4,5-trifluorophenylgroupatthe3and3’positionsofthechiralbinaphthylmoieties,gaveriseto95%ee.12Thisobservationledtothediscoverythatchiralquaternaryammoniumbromide(S)-11,possessingflexiblestraight-chainalkylgroupsinsteadofrigidbinaphthylmoieties,functionsasanunusuallyactivechiralphase-transfercatalyst.13Thereactionof1withvariousalkylhalidesproceededsmoothlyandwithexcellentenantioselectivitiesundermildconditionsinthepresenceofonly0.01–0.05mol%of(S)-11.Furthermore,ourgroupsucceededinassemblingahighlyreactivecatalyst, (S)-12, from the readily available, gallic acidderived(S)-4,4’,5,5’,6,6’-hexamethoxybiphenyldicarboxylicacid.14

The usefulness of other chiral sources for the moleculardesignofC2-symmetricphase-transfercatalystshasrecentlybeendemonstratedinquiteanattractivemanner(Figure 3, Table 1).Inconnectionwiththeintensiveinvestigationoftheabilityofchiralmetal–salencomplexesaschiralphase-transfercatalysts in thesynthesis of α,α-dialkyl-α-amino acids from α-substituted α-amino

NNN+

N+Br–

Br–

+Nn-Bu

n-Bu

Ar

ArOMe

MeO

MeO

MeO

MeO

OMe

+N

Ar

Ar

n-Bun-Bu

(S)-10, Ar = 3,4,5-F3C6H2

(S)-12, Ar = 3,4,5-F3C6H2(S)-11, Ar = 3,4,5-F3C6H2

Ar

Ar

Ar

ArAr

Ar

Ar

Ar

Br– Br–

Figure 2. chiral, c2-symmetric, phase-Transfer alkylation catalysts.

79

Taka

shi O

oi a

nd K

eiji

Mar

uoka

*V

OL.

40,

NO

. 3 •

200

7

+N N+

2 Br–+N

i-Pr

OH

HO

OH

i-Pr

i-Pr

Ph

TfO–

N

NNO O

HHMe MeBF4

–NH

N

NH OO

OMe

H

Me

MeO

H

MeCl–

NCu

N

O O

N+

N+O

O

Ar

Me Ar

ArMe

ArR

R'2 X–

18

O O

n-Bu

20

n-Bu

15

N+

+

N+Me

+

Me2 TfO–

1413

(S,S)-16a; R = Me, R' = t-Bu, Ar = p-An, X = Ib; R = Me, R' = t-Bu, Ar = p-An, X = BF4c; R = R' = n-Pr, Ar = p-Tol, X = Id; R = R' = n-Pr, Ar = p-Tol, X = BF4e; R = R' = p-FC6H4CH2CH2, Ar = p-Tol, X = BF4

O

O

OO

O

O

17

(S)-19

Figure 3. chiral, c2- and c3-symmetric, phase-Transfer alkylation catalysts.

N+

N

H

O

Br–

Q Q

Br–

HQ HQF

N+

N

H

OHQ =

HQ HQ

Q

Q

21 22 24

25(PF6

–)

Q

Q

Q

23

N

N

N

N

Q26

Q

Q =

Figure 4. chiral, c2- and c3-symmetric, phase-Transfer alkylation catalysts.

acids,Belokon’sgroupreportedontheeffectivenessof13 intheasymmetricmonoalkylationof1.15

Nagasawaandco-workersreportedaC2-symmetricchiralcyclicguanidine of type 14 for the asymmetric alkylation of 1.16 Thestructurallyrelated15wasalsoevaluatedasachiralphase-transfercatalystbyMurphyandco-workers.17

Shibasaki’sgroupdesigneda tartrate-derivedbis(ammoniumsalt),16,basedontheconceptoftwo-centerasymmetriccatalysis,andsystematicallyoptimizedthereactionparametersforachievinghighenantioselectivity.18 Bycombiningatartratederivativeand2,5-dimethylpyrroline,MacFarland’sgroupprepareddiastereomericbis(ammoniumsalts)17,andtestedthemaschiralphase-transfercatalysts.19

The structurally unique, spiro-type bis(ammonium salt) 18wassynthesizedandsuccessfullyapplied tosimilarasymmetricalkylations of 1 by Sasai and co-workers.20 His group alsopreparedthechiralcrownether(S)-19,whichgaverisetomoderateenantioselectivityinthebenzylationof1inthepresenceofKOH.21

TheC3-symmetric,amine-based,chiralphase-transfercatalyst20hasbeendevelopedbyTakabe’sgroup.22Thehydroxylgroupsareexpectedtoplayanimportantroleashydrogen-bonddonorsintheformationofchiralionpairs.

ThedevelopmentofC2-andC3-symmetriccatalystsbyusingnaturallyoccurringalkaloidsaschiralunitshasalsobeenpursuedbyseveralresearchgroups(Figure 4, Table 1).ThegroupofJewandParkdesigneddimericandtrimericcinchona-alkaloid-derivedcatalysts 21,23 22,24 and 23,25 which substantially enhanced theenantioselectivityofthealkylationof1andexpandedthescopeofusablealkylhalideswhencomparedtotheirmonomericcounterparts.Moreover,thesameworkersinvestigatedtheidealaromaticspacerforoptimaldimericcatalystsandfoundthatcatalyst24,derivedfrom2,7-bis(bromomethyl)naphthaleneandtwocinchonaalkaloidunits, exhibited remarkable catalytic and chiral efficiencies.26Nájera’sgroupalsopreparedadimericsalt,25,whichincorporatesadimethylanthracenylbridgeasaspacer.27Inaddition,SivaandMuruganutilizedacyclictetraamineasaspacerfortheassemblyof26,whichexhibitedanextremelyhighperformanceaschiralphase-transfercatalyst.28

Thesedevelopments,togetherwiththeemergenceofotherchiralphase-transfercatalysts,29haveledtoimportant,enantiomericallyenriched α-amino acids and their derivatives being readily prepared by the asymmetric alkylation (Figure 5).30–35 These α-amino acidsandderivativeshavebeenemployedinthetotalsynthesisofbiologicallyactivecompounds.

2.1.2. Dialkylation of schiff Bases Derived from α-alkyl-α-amino acidsNonproteinogenic, chiral α,α-dialkyl-α-amino acids possessing stereochemically stable quaternary carbon centers have beensignificantsynthetictargets,notonlybecausetheyoftenareeffectiveenzymeinhibitors,butalsobecausetheyareindispensablefortheelucidation of enzymatic mechanisms. Accordingly, numerousstudieshavebeenconductedtodeveloptrulyefficientmethodsfortheirpreparation,36andphase-transfercatalysishasmadeuniquecontributions.

OnthebasisofO’Donnell’spioneeringstudyoftheasymmetricalkylationofthealdimineSchiffbasederivedfromalanineunderphase-transferconditions,37,38Belokonetal.demonstratedthat(R,R)-TADDOL(28)39 and thecopper(II)–salencomplex,13,15,40wereemployablefortheenantioselectivealkylationofalanine-derivedimines27and29(Scheme 1).

Ourgroupdevelopedaone-pot,highlyenantioselectivedoublealkylation of glycine-derived aldimine 30 by utilizing chiral

quaternaryammoniumbromide(S,S)-5a(Scheme 2).41Thisprovidesanattractiveandpowerfulstrategyfortheasymmetricsynthesisofstructurally diverse α,α-dialkyl-α-amino acids.

Sincethestereochemistryofthenewlycreatedquaternarycarboncenterwasapparentlydeterminedinthesecondalkylationprocess,thecoreofthismethodshouldbeapplicabletotheasymmetricalkylationofaldimineSchiffbase32 derived from the corresponding α-alkyl-α-amino acids. This approach was pursued by our group,41aswellasShibasaki’s18bandMaeda’s,42byusingC2-symmetricquaternaryammoniumsaltsascatalysts(Scheme 3).dl-Alanine-,phenylalanine-,leucine-,andphenylglycine-derivedimines32a–dwerealkylatedsmoothlywith (S,S)-5a and (S,S)-16b under similar conditions,affordingthedesirednoncodeddialkylaminoacidesters31withexcellent asymmetric induction. This powerful quaternizationmethod has also allowed the catalytic asymmetric synthesis ofquaternaryisoquinolinederivatives30and4-hydroxy-2-phenylprolinederivatives42from32c.

The efficient phase-transfer-catalyzed alkylation strategythatutilizes(S,S)-5awassuccessfullyappliedbyJewandPark’sgroup to the asymmetric synthesis of α-alkylserines starting with phenyloxazolinederivative33a.Thereactionisgeneralandpractical,and leads to a variety of optically active α-alkylserines after acidic hydrolysis(Scheme 4).43

80

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0, N

O. 3

• 2

007

Dev

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men

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2-Sy

mm

etric

, Chi

ral,

Phas

e-Tr

ansf

er C

atal

ysts

NO

ORPh

Me

H3N+O

OH

O

O OHOH

Ph Ph

PhPh

NO

OMe4-ClC6H4

R2. AcCl, MeOH

1. (R,R)-28 (10 mol %), R1Br NaOH or NaH, PhMe, rt

H2NO

OMe

27a, R = Me27b, R = i-Pr27c, R = t-Bu

<82% eeR1 = Bn, allyl

(R,R)-TADDOL(R,R)-28

1. (R,R)-13 (2 mol %), R'Br NaOH, PhMe, rt

29

R1 Me

R’ R

2. HCl–H2O Cl–

R

EtEt

i-Bu

R'

BnallylBna

Yield

91%46%54%

ee

82%80%55%

a 10 mol % of 13 was used.

Scheme 1. effectiveness of 28 and 13 as phase-Transfer-alkylation catalysts.

Ref. 39,40c

4-ClC6H4 NO

Ot-Bu

H2NO

Ot-Bu

H2NO

Ot-Bu

30

(S)-31a 74%, 92% ee

(R)-31a 80%, 98% ee

Ph

Ph

1. H2C=CHCH2Br

3. 10% citric acid, THF

2. PhCH2Br3. 10% citric acid, THF

(S,S)-5a (1 mol %)CsOH•H2O, PhMe

–10 to 0 oC

1. PhCH2Br2. H2C=CHCH2Br

Scheme 2. highly enantioselective, one-pot, Double alkylation of 30.

Ref. 41

4-ClC6H4 NO

Ot-BuR

H2NO

Ot-BuR1R

31

abcde

R

Bni-BuMePhMe

R1

allylallylallylallylBn

Yield

71%70%73%77%83%

ee

97%93%98%91%89%

3132

1. R1Br (S,S)-5a (1 mol %) CsOH•H2O, PhMe

2. Hydrolysis

Note

aaabc

Notes: a At –20 oC to 0 oC. Hydrolysis with 10% citric acid in THF. b At –40 oC. Hydrolysis with H2SO4 in MeOH at 50 oC. c (S,S)-16b (10 mol %) and BnBr in PhMe–CH2Cl2 (7:3) at –70 oC under argon. Hydrolysis with 0.2 M citric acid in THF.

Scheme 3. efficient syntheses of Dialkylamino acids 31 by the asymmetric phase-Transfer alkylation of 32.

Ref. 18b,41,42

+ RXO

NPh

CO2t-Bu

O

NPh

CO2t-BuR

33a

(S,S)-5a(2.5 mol %)

(S)-34a

HO

H2N CO2HR

98% (R = Bn)

KOH, PhMe0 °C, 3–20 h

Yield

98%87%48%

RX

BnBrC3H5Br

EtI

ee

>99% 97% 93%

6 N HClEtOH, reflux

Scheme 4. catalytic, asymmetric synthesis of α-alkylserines.

Ref. 43a

NH

OH

i-BuN

O

HN

NH

OH

HO

HHO

NH2

NH

HOO

NO

HN

Me

Men-Bu

OMeMeO

MeO

N

H

NH

CO2t-Bu

NCO2t-Bu

aeruginosin 298-ARef. 32

H2N CO2t-Bu

H

OH

OH

levobupivacaineRef. 34

(–)-antofineRef. 33

L-dopa esterRef. 6d,31Ref. 30 Ref. 6d

Ac

Figure 5. important α-amino acids and Their Derivatives synthesized enantioselectively with the assistance of chiral, phase-Transfer catalysts.

Table 1. mild, catalytic, and enantioselective phase-Transfer alkylation of 1 as Depicted in equation 2.

Catalyst

Cat. Mol %

RX

Base

Solvent

Temp

2

R/S Yield ee Ref.

(S,S)-5a 1.0 BnBr 50% KOH(aq) PhMe 0 °C R 90% 99% 6

(S,S)-5a 1.0 C3H5Br 50% KOH(aq) PhMe 0 °C R 80% 99% 6

(S,S)-5a 1.0 EtI CsOH(sat) PhMe –15 °C R 89% 98% 6

(R,R)-5ba 0.1 BnBr 50% KOH(aq) PhMe 0 °C S 98% 98% 7

(R,R)-5ba 0.1 C3H5Br 50% KOH(aq) PhMe 0 °C S 87% 85% 7

(R,R)-5ba 0.5 EtI 50% KOH(aq) PhMe 0 °C S 63% 94% 7

(S,S)-6 1.0 BnBr 50% KOH(aq) PhMe 0 °C R 88% 96% 8

(S,S)-6 1.0 C3H5Br 50% KOH(aq) PhMe 0 °C R 92% 88% 8

(S,S)-6 1.0 EtI 50% KOH(aq) PhMe 0 °C R 18% 71% 8

(S,S)-7 1.0 BnBr 50% KOH(aq) PhMe 0 °C R 87% 97% 9

(S,S)-7 1.0 C3H5Br 50% KOH(aq) PhMe 0 °C R 76% 93% 9

(S,S)-7 1.0 EtI 50% KOH(aq) PhMe 0 °C R 12% 88% 9

(R,R)-8 3.0 BnBr 50% KOH(aq) PhMe 0 °C S 82% 90% 10

(R,R)-8 3.0 EtI CsOH•H2O PhCF3 –20 °C S 83% 87% 10

(S)-9 1.0 BnBr CsOH(sat) PhMe –15 °C R 87% 94% 11

(S)-9 1.0 C3H5Br CsOH(sat) PhMe –15 °C R 85% 93% 11

(S)-9 1.0 EtI CsOH(sat) PhMe –15 °C R 61% 93% 11

(S)-10 3.0 BnBr 50% KOH(aq) PhMe 0 °C S 76% 63% 12

(S)-11 0.05 BnBr 50% KOH(aq) PhMe 0 °C R 98% 99% 13

(S)-11 0.05 C3H5Br 50% KOH(aq) PhMe 0 °C R 87% 98% 13

(S)-11 0.1 EtI CsOH•H2O PhMe –20 °C R 67% 99% 13

(S)-12 0.1 BnBr 50% KOH(aq) PhMe 25 °C R 96% 97% 14

(S)-12 0.5 C3H5Br 50% KOH(aq) PhMe 0 °C R 99% 96% 14

(S)-12 0.1 EtI 50% KOH(aq) PhMe 25 °C R 80% 94% 14

13 2.0 BnBr NaOH(s) PhMe 25 °C R >95% 80% 15

13 2.0 C3H5Br NaOH(s) PhMe 25 °C R >90% 81% 15

14 30.0 BnBr KOH (1 M) CH2Cl2 0 °C R 55% 90% 16

14 30.0 C3H5Br KOH (1 M) CH2Cl2 0 °C R 61% 81% 16

15 10.0 BnBr NaOH (2 M) CH2Cl2 0–25 °C R >97% 86% 17

(S,S)-16a 10.0 BnBr CsOH•H2O PhMe–CH2Cl2 –70 °C R 87% 93% 18

(S,S)-16a 10.0 C3H5Br CsOH•H2O PhMe–CH2Cl2 –70 °C R 79% 91% 18

17 5.0 BnBr CsOH CH2Cl2 –45 °C R 73% 30% 19

17 5.0 C3H5Br CsOH CH2Cl2 –45 °C R 75% 28% 19

18 20.0 BnBr 50% KOH(aq) CH2Cl2 0 °C R >95% 95% 20

(S)-19 5.0 BnBr KOH(s) PhMe 0 °C S 79% 50% 21

20 1.0 BnBr 50% KOH(aq) PhMe 0 °C S 55% 58% 22

21 5.0 BnBr 50% KOH(aq) PhMe–CHCl3 –20 °C S 94% 95% 23

21 5.0 C3H5Br 50% KOH(aq) PhMe–CHCl3 –20 °C S 86% 94% 23

21 5.0 EtI 50% KOH(aq) PhMe–CHCl3 –20 °C S 50% 92% 23





24 1.0 BnBr 50% KOH(aq) PhMe–CHCl3 0 °C S 95% 97% 26

24 1.0 C3H5Br 50% KOH(aq) PhMe–CHCl3 0 °C S 95% 97% 26

24 1.0 EtI 50% KOH(aq) PhMe–CHCl3 0 °C S 83% 97% 26

25 5.0 BnBr 50% KOH(aq) PhMe–CHCl3 0 °C S 62% 84% 27

25 5.0 C3H5Br 50% KOH(aq) PhMe–CHCl3 0 °C S 70% 90% 27

26 1.5 BnBr 20% KOH(aq) PhMe–CH2Cl2 –10 °C S 98% 94% 28

26 1.5 C3H5Br 20% KOH(aq) PhMe–CH2Cl2 –10 °C S 98% 97% 28a Using 18-crown-6 (0.1 mol %) as co-catalyst.

81

Taka

shi O

oi a

nd K

eiji

Mar

uoka

*V

OL.

40,

NO

. 3 •

200

7

eq 3

Ph2C NO

NH

O

Ot-BuBn

Ph2C NO

NH

O

Ot-BuBn

Bn

Ph2C NO

NH

O

Ot-BuBn

Bn

DL-36

(S,S)-5c (2 mol %)PhCH2Br (1.1 equiv)

PhMe–50% KOH(aq)0 °C, 6 h

97%, 97% de35

LL-36

>>

Ref. 44

O

CO2t-Bu

O

R

CO2t-Bu(S,S)-5d (1 mol %)

RBr (1.2 equiv)

PhMe, CsOH•H2O–40 to –60 °C, 2.5–9 h

NHBn

R

CO2t-BuOH

R

CO2t-Bu

37

3890% (dr = 86:14)(R = Bn, 97% ee)

L-Selectride®

THF, –78 °C

3998% (dr = 84:16)(R = Bn, 97% ee)

R = Bn; 94%, 97% eeR = PhCH=CHCH2; 80%, 92% ee

BnNH2NaBH3CN, AcOH

4 Å MS, MeOH65 °C

Scheme 5. asymmetric phase-Transfer alkylation of β-Keto esters for the construction of Quaternary stereocenters, and the stereoselective conversion of the intermediates into β-hydroxy and β-amino esters.

Ref. 46

N

O

CO2t-Bu

1-NpN

O

CO2t-Bu

1-Np

CO2Et

CO2H

+ 1-NpCO2H

H2N

OHCO2H

6 N HCl

(S,S)-5a (2.5 mol %)H2C=CHCO2Et

93%, 97% ee

95% 98%

33b1-Np = 1-naphthyl

BEMP (1.25 equiv)CH2Cl2, –60 °C, 20 h

Scheme 6. asymmetric synthesis of (2s)-α-(hydroxymethyl)-glutamic acid.

Ref. 52

eq 4

OO

O

OOO

OO

OO

OO

OO

Ph2C NO

Ot-Bu

O

Y

N+

R

R R

RBr–

Ph2C NO

Ot-Bu

H (CH2)2COY

+

1

40R = 4-CF3C6H4CH2O 42

41R = 4-CF3C6H4CH2OR' = CH2N+Et3 Br–

Cat.

16c16d40414242

Cat.Mol %

101010 12020

Y

OEtOBn

Ot-BuMeEta

OEta

Base

Cs2CO3

Cs2CO3

CsOH•H2OCs2CO3

t-BuOKt-BuOK

Solvent

PhClPhCl

t-BuOMePhCl

CH2Cl2CH2Cl2

Temp

–30 oC–30 oC–60 oC–30 oC–78 oC–78 oC

Time

26 h 10 h 26 h114 h 0.3 h 24 h

Yield

71% 84% 73%100% 65% 76%

ee

82%81%77%75%96%87%

Ref.

18b18b49505151

R

R'

R'

R

a Ph2C=NCH2CO2Et was used instead of 1.

2.1.3. alkylation of peptides activated by a schiff BaseOurgrouphasfoundthatPTCwithC2-symmetricchiralquaternaryammonium salts of type 5 can be successfully applied to thestereoselectiveN-terminalalkylationofsmallpeptidessuchasGly-l-Phederivative35.Forinstance,thebenzylationof35with(S,S)-5c—possessingstericallyhinderedaromaticsubstituentsatthe3and3’positionsofthebinaphthylmoiety—underbiphasicconditions proceeded with almost complete diastereocontrol(eq 3).44Thismethodcanbeextendedto thediastereoselectivealkylationofSchiffbaseactivatedtripeptidesandtetrapeptides.

2.2. Other AlkylationsDue to the relatively high acidity of the α-methine proton, α-substituted β-keto esters are considered to be suitable substrates foralkylationunderphase-transferconditions.45Highefficienciesandenantioselectivitieshavebeenattainedintheconstructionofquaternary stereocenters on β-keto esters by such alkylation in the presenceofthesuitablymodifiedchiralquaternaryammoniumbromide5d.Thisreactionsystemhasabroadscopewithrespectto the β-keto esters and alkyl halides that can be used. The resulting alkylationproducts37 canbe readily converted intothe corresponding β-hydroxy esters 38 and β-amino esters 39(Scheme 5).46,47

3. The Michael Addition The asymmetric Michael addition of active methylene ormethine compounds to electron-deficient olefins, particularlyα,β-unsaturated carbonyl compounds, represents a fundamental approachforconstructingfunctionalizedcarbonframeworks.Thecombination of glycinate Schiff bases with α,β-unsaturated esters and ketones as electrophiles offers a practical route to various α-aminoacidshavinganadditionalcarbonylfunctionality.48

In this regard, the researchgroupsofShibasaki,18AraiandNishida,49,50 and Akiyama51 have carried out the asymmetricMichaeladditionofglycinederivative1 toacrylatesandvinylketones in thepresenceofC2-symmetric chiral phase-transfercatalystssuchaschiralquaternaryammoniumsalts16,40,and41,andachiralcrownether,42(eq 4).

Jew,Park,andco-workersachievedthehighlyenantioselectivesynthesis of (2S)-α-(hydroxymethyl)glutamic acid, a potent metabotropic receptor ligand, through theMichael additionof2-(naphthalen-1-yl)oxazoline-4-carboxylic acid tert-butyl ester(33b)toethylacrylateinthepresenceof(S,S)-5aascatalystandBEMPasbase(Scheme 6).52

Nitroalkanesarevaluableactivemethylenecompounds,53andourgroupdevelopedadiastereo-andenantioselectiveconjugateaddition of nitroalkanes to alkylidenemalonates54 and cyclicα,β-unsaturated ketones55undermildphase-transferconditions.In this transformation, the nature of the 3 and 3’ aromaticsubstituentsofthecatalystwascriticalforattainingahighlevelofstereoselectivitywitheachelectrophile(Scheme 7).

The structurally related chiral phase-transfer catalyst 5denables the enantioselective Michael addition of β-keto esters to α,β-unsaturated aldehydes and ketones, leading to the construction ofquaternarystereocentershavingthreedifferentfunctionalitiesofcarbonylorigin(Scheme 8).46Itisworthmentioningthattheuseofthefluorenylestergreatlyimprovedtheenantioselectivityofthereaction.

In conjunction with our research effort to design effectivecatalysts for the asymmetric epoxidation of α,β-unsaturated ketones(seeScheme11),ourgrouphasaddressedtheimportanceofdual-functioningchiralphase-transfercatalystssuchas46afor

82

VO

L. 4

0, N

O. 3

• 2

007

Dev

elop

men

t an

d A

pplic

atio

ns o

f C

2-Sy

mm

etric

, Chi

ral,

Phas

e-Tr

ansf

er C

atal

ysts

n-PrNO2

PhCO2i-Pr

CO2i-Pr

O2N *

*

99% (anti/syn = 86:14)97% ee (anti isomer)

O

NO2

* *

99% (anti/syn = 4:96)91% ee (syn isomer)

PhCH=C(CO2i-Pr)2(S,S)-5e (1 mol %)

PhMe, Cs2CO30 °C, 2.5 h

(S,S)-5f (1 mol %)PhMe, Cs2CO3

–20 °C, 6 h

O

Scheme 7. michael addition of nitroalkanes to alkylidene-malonates and α,β-Unsaturated Ketones.

Ref. 54,55

O

CO2R

O O

OCO2R

O

OCO2R

O

O

43

45 (R = 9-fluorenyl)>99%, 97% ee

(S,S)-5d (2 mol %)K2CO3 (10 mol %)

cumene

44a (R = t-Bu)84%, 79% ee

44b (R = 9-fluorenyl)92%, 90% ee

H2C=CHC(O)Me (2 equiv)–78 °C, 5 min

then –40 °C, 8 h

1. H2C=CHCHO (2 equiv) –78 oC, 5 min then –40 to –35 oC

2. p-TsOH (cat.), rt

Scheme 8. asymmetric michael addition of β-Keto esters to acrolein and methyl Vinyl Ketone.

Ref. 46

eq 5

Ph

O

Ph Ph

O Ph

X

X

N+

R

R

OH

OH

Ar Ar

Ar Ar

Br–

(S)-46a (3 mol %)

*

X = CO2Et (–20 °C)99%, 90% ee (R)

X = CN (–50 °C)98%, 81% ee (R)

(S)-46a, Ar = R = 3,5-Ph2C6H3b, Ar = 3,5-Ph2C6H3, R = H

K2CO3 (10 mol %)PhMe

+ CH2X2

Ref. 56

NO

Ot-BuPh2C

O

Ot-BuRNH2

OH

O

OEtHN

t-BuONH2

O4-An

1

47anti/syn = 96:4

4-An

NHBocCO2t-Bu

NCPh2

1. (R,R)-5e (2 mol %) RCHO (2–5 equiv)

1% NaOH(aq) (15 mol %) NH4Cl (10 mol %) PhMe, 0 °C2. 1 N HCl, THF

48, 88%syn/anti = 82:18

91% ee (syn)

49, 95%syn/anti = 95:582% ee (syn)

R

Ph(CH2)2

Me(CH2)4

(i-Pr)3SiOCH2

MeCya

Yield

82%79%73%54%83%

ee

98%97%98%99%98%

a CPME used as solvent.

1. (R,R)-5a (2 mol %) 4-AnN=CHCO2Et

17% NaOH(aq) MesH, –20 °C, 6 h2. 1 N HCl, THF

(S,S)-16e (10 mol %)4-AnC=NBoc

Cs2CO3 (2 equiv)PhF, –45 °C, 48 h

Scheme 9. highly Diastereo- and enantioselective Direct aldol and mannich reactions of a Glycine Derivative.

Ref. 58b,60,61

achievingahighlyenantioselectiveMichaeladditionofmalonatesormalononitriletochalconederivatives(eq 5).56,57

4. The Aldol and Related ReactionsAlthoughthephase-transfer-catalyzed,enantioselectivedirectaldolreactionofaglycinedonorwithaldehydeacceptorscouldprovide an ideal method for the simultaneous constructionof the primary structure and stereochemical integrity ofβ-hydroxy-α-amino acids—extremely important chiral units forpharmaceuticalchemistry—theexamples reported todateareverylimited.Accordingly,ourgrouprecentlydevelopedanefficientandhighlydiastereo-andenantioselectivedirectaldolreactionofglycinateSchiffbase1withawiderangeofaliphaticaldehydesundermildphase-transferconditionsemployingchiralquaternaryammoniumsalt5easakeycatalyst(Scheme 9).58,59The highly enantioselective phase-transfer-catalyzed, directMannich reactionof1with imineswasaccomplishedbyourgroup60 and the group of Ohshima and Shibasaki61using thestructurally related chiral ammonium bromide (R,R)-5a andthetartrate-derivedbis(ammoniumsalt)(S,S)-16eascatalysts,respectively(Scheme 9).

5. The Darzens CondensationTheDarzensreactionrepresentsoneofthemostpowerfulmethodsfor the synthesis of α,β-epoxy carbonyl and related compounds. Arai’sgroupsynthesizedanewquaternarybis(ammoniumsalt),50,from(S)-1,1’-bi-2-naphthol,andutilizeditforthepreparationof optically active α,β-epoxy amides as a mixture of cis and transisomers,52and53,throughreactionofhaloamides51 withaldehydes(eq 6).62

6. The Neber RearrangementThe Neber rearrangement of oxime sulfonates into α-amino ketones proceeds via a nitrene or an anion pathway. If thelattermechanism isoperating, theuseof a chiral base couldresult in the discrimination of two enantiotopic α protons to furnish optically active α-amino ketones. Verification of this hypothesiswasprovidedby thesuccessfulasymmetricNeberrearrangementofsimpleoximesulfonate55,generatedinsitufromtheparentoxime(Z)-54.Underphase-transferconditions,andusingC2-symmetricchiralquaternaryammoniumbromide5gor5h as catalyst, the corresponding protected α-amino ketone 56wasisolatedinhighyieldandmoderateenantiomericexcess(Scheme 10).63

7. EpoxidationSince the first reportbyWynberg’sgroupon theasymmetricepoxidationofelectron-deficientolefinsunderphase-transferconditions,64anumberofusefulcatalyst–oxidantcombinationshave been elaborated particularly for the epoxidation ofchalconederivatives.65Alongthisline,Murphyandco-workerspreparedtetracyclicC2-symmetricguanidiumsaltsof type15 from(S)-malicacid,andapplied themto theenantioselectiveepoxidationofchalconederivatives(eq 7).17

Ourgroupdesignedanew,dual-function,andhighlyefficientchiral quaternary ammonium salt, 46, for the asymmetricepoxidationofvariousenonesubstrates (Scheme 11).66 In theX-ray structure of the PF6 salt of 46a, the exceedingly highasymmetricinductionisascribabletothemolecularrecognitionabilityofthecatalyst towardenonesubstratesbyvirtueoftheappropriatelyalignedhydroxylfunctionalityaswellasthechiralmolecularcavity.Indeed,theobservedenantioselectivityhighlydependsonthesizeandtheelectronicpropertiesofArandRin

83

Taka

shi O

oi a

nd K

eiji

Mar

uoka

*V

OL.

40,

NO

. 3 •

200

7

eq 6

OPh

H

CONPh2

HX

NPh2

O OH

Ph

CONPh2

H

N

N

2 Br

52

PhCHO50 (2 mol %)

51 53

+

+

+

_

50

X

ClBr

Yield

81%81%

52:53

3.5:12.3:1

52

52%58%

53

51%63%

ee

RbOH•H2OCH2Cl2, rt

Ref. 62

Bn

N

Ar

OH

Ph

N

Ar

OTs

HH

Ph

N

ArH

PhO

ArNHBz

(Z)-54Ar = 4-FC6H4

p-TsCl (1.2 equiv)5 (5 mol %), MeOH (10 equiv)

PhMe–50% KOH(aq)0 °C

56(S,S)-5g; 95%, 50% ee(S,S)-5h; 90%, 63% ee

B*_

55

1. BzCl, Py CH2Cl2

2. 6 N HCl

Scheme 10. The asymmetric neber rearrangement of oxime sulfonate 55.

Ref. 63

eq 7

Ph

O

R Ph R

OO

N

NNO O

HHMe MeBF4

–

(R,R)-15 (5 mol %)

8% NaOCl, PhMe0–25 °C R = Ph, 93% ee

R = C6H13, 91% ee

(R,R)-15

+

Ref. 17

R1

O

R2 R1 R2

OO

Ph

O

Ph

OO

(S)-46 (3 mol %)

13% NaOClPhMe, 0 °C

91%, 99% ee

(S)-46a (3 mol %)

13% NaOClPhMe, 0 °C

R1

Pht-But-Bu

R2

PhPhCy

Cat.

(S)-46a(S)-46b(S)-46b

Yield

99%99%80%

ee

96%92%96%

Scheme 11. Dual-functioning catalyst, 46, for asymmetric epoxidations.

Ref. 66

46.ThegroupofJewandParkdemonstratedthatthecombineduse of a surfactant such as Span® 20 and dimeric cinchona-alkaloid-derivedphase-transfercatalyst57enabled thehighlyefficientandenantioselectiveepoxidationofchalconederivativesusing30%aqueoushydrogenperoxideasoxidant(eq 8).67

8. CyanationThe phase-transfer-catalyzed and highly enantioselectivecyanationofaldiminederivatives58withaqueousKCNhasbeenrealizedbyourgroupbasedonthechiralquaternaryammoniumiodide(R,R,R)-60,whichpossessesastereochemicallydefinedtetranaphthylbackbone.Awide rangeof aliphatic aldiminesincluding those having α-tert-alkylsubstituentsaretoleratedbythissystem(Scheme 12).68 The use of α-amide sulfones 59 asprecursorsofthereactiveimines58wasfoundtoenhanceboththechemicalyieldsandtheenantioselectivitiesinthepresenceofonlyaslightexcessofKCN(1.05equiv).69,70ThisstudyrepresentsanessentiallynewapproachtowardtheasymmetricStrecker-typereactions.Itharnessesthedistinctsyntheticadvantagesofchiralphase-transfercatalysistoprovideatrulypracticalrouteto various unusual, optically pure α-amino acids.

9. ConclusionsThe development of C2-symmetric, chiral, phase-transfercatalystslargelyreliesonthemoleculardesignofpurelysyntheticchiralquaternaryammoniumsalts.Thesesaltsoftendelivernotonly a higher reactivity and stereoselectivity but also create

eq 8

N+

N

H

OH

F

57

OMe

N+

HON

OMeH

R

O

Ph R Ph

OO

30% H2O2 (10 equiv)50% KOH (1 equiv)

i-Pr2O, rt, 4 h

57 (1 mol %)Span® 20 (1 mol %)

R

Ph4-FC6H4

4-MeC6H4

Yield

95%94%96%

ee

>99% 98% 97%

2 Br–

Ref. 67

R H

NSO2Mes

R CN

HNSO2Mes

NMe

Me

Ar

Ar

Ar

Ar

I–

R SO2p-Tol

HNSO2Mes

(R,R,R)-60 (1 mol %)KCN(aq) (1.5 equiv)

R

(R,R,R)-60Ar = 4-CF3C6H4

H

NSO2Mes

59

58

+

From

5858585959

R

Ph(CH2)2Cy

PhMe2CPh(CH2)2

Cy

Yield

81%89%95%99%99%

ee

90%95%98%94%97%

PhMe, 0 °C2–8 h

(R,R,R)-60 (1 mol %)KCN(aq) (1.05 equiv)

PhMe, 0 °C, 2 h

Scheme 12. The phase-Transfer-catalyzed asymmetric strecker reaction of aldimines and α-amide sulfones with (r,r,r)-60.

Ref. 68,69

newsyntheticopportunities,thusexpandingtheapplicabilityofasymmetricphase-transfercatalysisinmodernorganicsynthesis.Efforts need to continue to be made toward understandingthe relationship between catalyst structure, activity, andstereocontrollingability.Thesystematicaccumulationofsuchknowledgewould allowus to conduct an evenmore rationalcatalystdesignforpursuingselectivechemicalsynthesis inareliableandpracticalmanner.

10. AcknowledgementsWethankourcolleaguesatHokkaidoandKyotoUniversities,whosenamesappearinthecitedreferences,fortheirpersonalandscientificcollaborations.Withouttheirenthusiasmfororganicchemistry,ourresearchonthedevelopmentandapplicationofC2-symmetric,chiral,phase-transfercatalystswouldnothavebeenachieved.

84

VO

L. 4

0, N

O. 3

• 2

007

Dev

elop

men

t an

d A

pplic

atio

ns o

f C

2-Sy

mm

etric

, Chi

ral,

Phas

e-Tr

ansf

er C

atal

ysts 11. References and Notes

(†) Current address: Department of Applied Chemistry, GraduateSchoolofEngineering,NagoyaUniversity,Chikusa,Nagoya464-8603,Japan.

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(24) Park,H.-g.;Jeong,B.-S.;Yoo, M.-S.; Lee,J.-H.;Park,B.-s.;Kim,M.G.;Jew,S.-s.Tetrahedron Lett.2003,44, 3497.

(25) (a)Park,H.-g.;Jeong,B.-S.;Yoo,M.-S.;Park,M.-k.;Huh,H.;Jew,S.-s.Tetrahedron Lett.2001,42, 4645.(b)Forarelatedstructure,seeSiva,A.;Murugan,E.Synthesis2005,2927.

(26) Park,H.-g.;Jeong,B.-S.;Yoo,M.-S.;Lee,J.-H.;Park,M.-k.;Lee,Y.-J.;Kim,M.-J.;Jew,S.-s.Angew. Chem., Int. Ed.2002,41, 3036.

(27) Chinchilla,R.;Mazón,P.;Nájera,C.;Ortega, F. J.Tetrahedron: Asymmetry2004,15, 2603.

(28) Siva,A.;Murugan,E.J. Mol. Catal. A: Chem.2005,241,111.(29) For recent representative contributions with non-C2-symmetric

catalysts: (a)Belokon,Y.N.;Kochetkov,K.A.;Churkina,T.D.;Ikonnikov,N.S.;Larionov,O.V.;Harutyunyan,S.R.;Vyskocil,S.;North,M.;Kagan,H.B.Angew. Chem., Int. Ed.2001,40,1948.(b)Nakoji,M.;Kanayama,T.;Okino,T.;Takemoto,Y.Org. Lett.2001,3, 3329.(c)Chinchilla,R.;Mazón,P.;Nájera, C.Tetrahedron: Asymmetry2002,13, 927.(d)Mazón,P.;Chinchilla,R.;Nájera,C.;Guillena,G.;Kreiter,R.;KleinGebbink,R.J.M.;vanKoten,G.Tetrahedron: Asymmetry2002,13, 2181.(e)Jew,S.-s.;Yoo,M.-S.;Jeong,B.-S.;Park,I.Y.;Park,H.-g.Org. Lett. 2002, 4,4245.(f)Nakoji,M.;Kanayama,T.;Okino,T.;Takemoto,Y.J.Org. Chem.2002,67, 7418.(g)Guillena,G.;Kreiter,R.;vandeCoevering,R.;KleinGebbink,R.J.M.;vanKoten,G.;Mazón,P.;Chinchilla,R.;Nájera,C.Tetrahedron: Asymmetry2003,14, 3705.(h)Lygo,B.;Allbutt,B.;James,S.R.Tetrahedron Lett.2003,44,5629.(i)Lygo,B.;Allbutt,B.Synlett2004,326.(j)Yoo,M.-S.;Jeong,B.-S.;Lee,J.-H.;Park,H.-g.;Jew,S.-s.Org. Lett. 2005, 7,1129.(k)Elango,S.;Venugopal,M.;SureshandEni,P.S.Tetrahedron2005,61,1443.(l)Kumar,S.;Sobhia,M.E.;Ramachandran,U.Tetrahedron: Asymmetry2005,16,2599.(m)Andrus,M.B.;Ye,Z.;Zhang,J.Tetrahedron Lett. 2005,46,3839.(n)Kumar,S.;Ramachandran,U.Tetrahedron 2005,61,4141.(o)Kumar,S.;Ramachandran,U.Tetrahedron2005,61,7022.

(30) Ooi,T.;Takeuchi,M.;Maruoka,K.Synthesis2001,1716.(31) Ooi,T.;Kameda,M.;Tannai,H.;Maruoka,K.Tetrahedron Lett.

2000,41,8339.(32) (a) Ohshima, T.; Gnanadesikan, V.; Shibuguchi, T.; Fukuta, Y.;

Nemoto,T.;Shibasaki,M.J. Am. Chem. Soc.2003,125,11206.(b)Fukuta,Y.;Ohshima,T.;Gnanadesikan,V.;Shibuguchi,T.;Nemoto,T.;Kisugi,T.;Okino,T.;Shibasaki,M.Proc. Natl. Acad. Sci. U.S.A. 2004,101,5433.

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(33) Kim,S.;Lee,J.;Lee,T.;Park,H.-g.;Kim,D.Org. Lett.2003,5,2703.

(34) Kumar,S.;Ramachandran,U.Tetrahedron Lett.2005,46,19.(35) For other representative examples: (a) Lygo, B.; Crosby, J.;

Peterson,J.A.Tetrahedron2001,57,6447.(b)Nitz,M.;Mezo,A.R.;Ali,M.H.;Imperiali,B.Chem. Commun.2002,1912.(c)Boeckman,R.K.,Jr.;Clark,T.J.;Shook,B.C.Org. Lett.2002,4,2109.(d)Lygo,B.;Humphreys,L.D.Tetrahedron Lett.2002,43,6677.(e)Castle,S.L.;Srikanth,G.S.C.Org. Lett.2003,5,3611.(f)Lygo,B.;Andrews,B.I.Tetrahedron Lett.2003,44,4499.(g)Lygo,B.;Andrews,B.I.;Slack,D.Tetrahedron Lett.2003,44,9039. (h)Lemaire,C.;Gillet,S.;Guillouet,S.;Plenevaux,A.;Aerts,J.;Luxen,A.Eur. J. Org. Chem.2004,2899.

(36) (a)Cativiela,C.;Diaz-de-Villegas,M.D.Tetrahedron: Asymmetry1998,9, 3517. (b)Schöllkopf,U.Top. Curr. Chem.1983,109,65.

(37) O’Donnell,M.J.;Wu,S.Tetrahedron: Asymmetry1992,3,591.(38) For related contr ibutions with cinchona-alkaloid-derived

catalysts:(a)Jew,S.-s.;Jeong,B.-S.;Lee,J.-H.;Yoo,M.-S.;Lee,Y.-J.;Park,B.-s.;Kim,M.G.;Park,H.-g.J. Org. Chem.2003,68,4514.(b)Seealsoreference29f.

(39) Belokon,Y.N.;Kochetkov,K.A.;Churkina,T.D.;Ikonnikov,N.S.;Chesnokov,A.A.;Larionov,O.V.;Singh,I.;Parmar,V.S.;Vyskočil, Š.; Kagan, H. B. J. Org. Chem.2000,65,7041.

(40) (a)Belokon,Y.N.;Davies,R.G.;North,M.Tetrahedron Lett.2000, 41, 7245. (b) Belokon, Y. N.; Davies, R. G.; Fuentes, J.A.;North,M.;Parsons,T.Tetrahedron Lett.2001,42,8093.(c)Belokon,Y.N.;Bhave,D.;D’Addario,D.;Groaz,E.;North,M.;Tagliazucca,V.Tetrahedron2004,60,1849.(d)Belokon,Y.N.;Fuentes,J.;North,M.;Steed,J.W.Tetrahedron2004,60,3191.

(41) Ooi,T.;Takeuchi,M.;Kameda,M.;Maruoka,K.J. Am. Chem. Soc.2000,122,5228.

(42) Maeda, K.; Miller, R. A., Jr.; Szumigala, R. H.; Shafiee, A.;Karady, S.; Armstrong, J. D., III Tetrahedron Lett. 2005, 46,1545.

(43) (a)Jew,S.-s.;Lee,Y.-J.;Lee,J.;Kang,M.J.;Jeong,B.-S.;Lee,J.-H.;Yoo,M.-S.;Kim,M.-J.;Choi,S.-h.;Ku,J.-M.;Park,H.-g.Angew. Chem., Int. Ed.2004,43, 2382. (b)With cinchona-alkaloid-derived catalyst, see: Lee, Y.-J.; Lee, J.; Kim, M.-J.;Kim,T.-S.;Park,H.-g.;Jew,S.-s.Org. Lett.2005,7,1557.

(44) (a) Ooi, T.; Tayama, E.; Maruoka, K. Angew. Chem., Int. Ed.2003,42,579.(b)Maruoka,K.;Tayama,E.;Ooi,T.Proc. Natl. Acad. Sci. U.S.A.2004,101,5824.

(45) For recent exampleswithcinchona-alkaloid-derivedcatalysts,see:(a)Dehmlow,E.V.;Düttmann,S.;Neumann,B.;Stammler,H.-G.Eur. J. Org. Chem.2002,2087. (b)Park,E.J.;Kim,M.H.; Kim, D. Y. J. Org. Chem. 2004, 69, 6897. (c) Bella, M.;Kobbelgaard,S.;Jørgensen,K.A.J. Am. Chem. Soc.2005,127,3670.

(46) (a)Ooi,T.;Miki,T.;Taniguchi,M.;Shiraishi,M.;Takeuchi,M.;Maruoka,K.Angew. Chem., Int. Ed.2003,42,3796. (b)Forasimilar enantioselective alkylation of cyclic α-amino-β-ketoesters, see Ooi, T.; Miki, T.; Maruoka, K. Org. Lett. 2005, 7,191.

(47) For recent examples of other alkylations using C2-symmetriccatalysts, see: (a)Kumar,S.;Ramachandran,U.Tetrahedron: Asymmetry 2005,16,647.(b)Ooi,T.;Fukumoto,K.;Maruoka,K.Angew. Chem., Int. Ed.2006,45,3839.

(48) For recent examples: (a) Belokon, Y. N.; Bespalova, N. B.;Churkina,T.D.;Cisarová,I.;Ezernitskaya,M.G.;Harutyunyan,S.R.;Hrdina,R.;Kagan,H.B.;Kocovsky,P.;Kochetkov,K.A.;Larionov,O.V.;Lyssenko,K.A.;North,M.;Polásek,M.;Peregudov, A. S.; Prisyazhnyuk, V. V.; Vyskočil, Š. J.Am. Chem.

Soc.2003,125,12860.(b)Siebum,A.H.G.;Tsang,R.K.F.;vanderSteen,R.;Raap,J.;Lugtenburg,J.Eur. J. Org. Chem. 2004,4391.(c)Lygo,B.;Allbutt,B.;Kirton,E.H.M.Tetrahedron Lett.2005,46,4461.(d)Ramachandran,P.V.;Madhi,S.;Bland-Berry,L.;RamReddy,M.V.;O’Donnell,M.J.J. Am. Chem. Soc.2005,127,13450.

(49) Arai,S.;Tsuji,R.;Nishida,A.Tetrahedron Lett.2002,43,9535.(50) Arai,S.;Tokumaru,K.;Aoyama,T.Chem. Parm. Bull.2004,52,

646.(51) Akiyama,T.;Hara,M.;Fuchibe,K.;Sakamoto,S.;Yamaguchi,

K.Chem. Commun.2003,1734.(52) Lee,Y.-J.;Lee,J.;Kim,M.-J.;Jeong,B.-S.;Lee,J.-H.;Kim,T.-

S.;Lee,J.;Ku,J.-M.;Jew,S.-s.;Park,H.-g.Org. Lett.2005,7,3207.

(53) For examples of conjugate addition under phase-transferconditionswithcrown-ether-derivedcatalysts,see:(a)Novák,T.;Tatai,J.;Bakó,P.;Czugler,M.;Keglevich,G.;Tõke,L.Synlett2001, 424. (b) Novák, T.; Bakó, P.; Keglevich, G.; Dobó, A.;Vékey,K.;Tõke,L.J. Inclusion Phenom. Macrocyclic Chem.2001,40,207.(c)Bakó,T.;Bakó,P.;Szöllõsy,Á.;Czugler,M.;Keglevich,G.;Tõke,L.Tetrahedron: Asymmetry2002,13,203.(d)With cinchona-alkaloid-derived catalyst, seeZhang,F.-Y.;Corey,E.J.Org. Lett.2004,6,3397.

(54) Ooi,T.;Fujioka,S.;Maruoka,K.J. Am. Chem. Soc.2004,126,11790.

(55) Ooi,T.;Takada,S.;Fujioka,S.;Maruoka,K.Org. Lett.2005,7,5143.

(56) Ooi,T.;Ohara,D.;Fukumoto,K.;Maruoka,K.Org. Lett.2005,7,3195.

(57) For relatedreactionswithnon-C2-symmetriccatalysts,see: (a)Zhang,F.-Y.;Corey,E.J.Org. Lett.2000,2,1097.(b)Perrard,T.;Plaquevent,J.-C.;Desmurs,J.-R.;Hébrault,D.Org. Lett.2000,2, 2959. (c)O’Donnell,M. J.;Delgado,F.;Domínguez,E.; deBlas,J.;Scott,W.L.Tetrahedron: Asymmetry2001,12,821.(d)Kim,D.Y.;Huh,S.C.;Kim,S.M.Tetrahedron Lett.2001,42,6299. (e)Dere,R.T.;Pal,R.R.;Patil,P.S.;Salunkhe,M.M.Tetrahedron Lett.2003,44,5351.(f)Donnoli,M.I.;Scafato,P.;Nardiello,M.;Casarini,D.;Giorgio,E.;Rosini,C.Tetrahedron2004,60,4975.

(58) (a)Ooi,T.;Taniguchi,M.;Kameda,M.;Maruoka,K.Angew. Chem., Int. Ed. 2002, 41, 4542. (b) Ooi, T.; Kameda, M.;Taniguchi,M.;Maruoka,K.J. Am. Chem. Soc.2004,126,9685.

(59) For the additionofdiazoacetate to aldehydesusing cinchona-alkaloid-derivedcatalysts,seeArai,S.;Hasegawa,K.;Nishida,A.Tetrahedron Lett.2004,45,1023.

(60) Ooi,T.;Kameda,M.;Fujii,J.-i;Maruoka,K.Org. Lett.2004,6,2397.

(61) Okada,A.;Shibuguchi,T.;Ohshima,T.;Masu,H.;Yamaguchi,K.;Shibasaki,M.Angew. Chem., Int. Ed.2005,44,4564.

(62) Arai,S.;Tokumaru,K.;Aoyama,T.Tetrahedron Lett.2004,45,1845.

(63) Ooi,T.;Takahashi,M.;Doda,K.;Maruoka,K.J. Am. Chem. Soc.2002,124,7640.

(64) Helder,R.;Hummelen,J.C.;Laane,R.W.P.M.;Wiering,J.S.;Wynberg,H.Tetrahedron Lett.1976,17,1831.

(65) For recent examples with non-C2-symmetric catalysts, see:(a) Adam, W.; Rao, P. B.; Degen, H.-G.; Saha-Möller, C. R.Tetrahedron: Asymmetry2001,12,121. (b)Lygo,B.;To,D.C.M.Tetrahedron Lett.2001,42,1343.(c)Adam,W.;Rao,P.B.;Degen,H.-G.;Levai,A.;Patonay,T.;Saha-Möller,C.R.J. Org. Chem.2002,67,259.(d)Arai,S.;Tsuge,H.;Oku,M.;Miura,M.;Shioiri,T.Tetrahedron2002,58,1623.(e)Lygo,B.;To,D.C.M.Chem. Commun. 2002,2360.(f)Ye,J.;Wang,Y.;Liu,R.;Zhang,

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(g)Ye,J.;Wang,Y.;Chen,J.;Liang,X.Adv. Synth. Catal. 2004,346,691. (h)Bakó,P.;Bakó,T.;Mészáros,A.;Keglevich,G.;Szöllõsy,A.;Bodor,S.;Makó,A.;Tõke,L.Synlett2004,643.(i)Bakó,T.;Bakó,P.;Keglevich,G.;Bombicz,P.;Kubinyi,M.;Pál,K.;Bodor,S.;Makó,A.;Tõke,L.Tetrahedron: Asymmetry2004,15,1589.(j)Geller,T.;Gerlach,A.;Krüger,C.M.;Militzer,H.-C.Tetrahedron Lett.2004,45,5065.(k)Geller,T.;Krüger,C.M.;Militzer,H.-C.Tetrahedron Lett.2004,45,5069.

(66) Ooi,T.;Ohara,D.;Tamura,M.;Maruoka,K.J. Am. Chem. Soc.2004,126,6844.

(67) Jew,S.-s.;Lee,J.-H.;Jeong,B.-S.;Yoo,M.-S.;Kim,M.-J.;Lee,Y.-J.;Lee,J.;Choi,S.-h.;Lee,K.;Lah,M.S.;Park,H.-g.Angew. Chem., Int. Ed. 2005,44,1383.

(68) Ooi,T.;Uematsu,Y.;Maruoka,K.J. Am. Chem. Soc.2006,128,2548.

(69) Ooi,T.;Uematsu,Y.;Fujimoto,J.;Fukumoto,K.;Maruoka,K.Tetrahedron Lett.2007,48,1337.

(70) For a similar asymmetricStrecker synthesiswith a cinchona-alkaloid-derived catalyst, see Herrera, R. P.; Sgarzani, V.;Bernardi, L.; Fini, F.; Pettersen, D.; Ricci, A. J. Org. Chem.2006,71,9869.

l-Selectride is a registered trademark of Sigma-AldrichBiotechnology, L.P. Span is a registered trademark of ICIAmericas,Inc.

About the AuthorsTakashi Ooi receivedhisPh.D.degree in1994fromNagoyaUniversityunderthedirectionofProfessorHisashiYamamoto,and then joined the group of Professor Julius Rebek, Jr., atMITasapostdoctoralfellow(1994–1995).HewasappointedassistantprofessoratHokkaidoUniversityin1995andpromotedtolecturerin1998.In2001,hemovedtoKyotoUniversityasanassociateprofessor,andbecameafullprofessoratNagoyaUniversity in 2006. He was awarded the Chugai Award inSynthetic Organic Chemistry (Japan, 1997), the ChemicalSocietyofJapanAward forYoungChemists (1999),and theThiemeJournalAward(2006).Hiscurrentresearch interestsare focusedon thedevelopmentofnewandusefulsyntheticmethodologies by designing organic molecular catalystsincludingC2-symmetric,chiral,quaternaryammoniumsalts.

Keiji Maruoka received his Ph.D. degree in 1980 fromthe University of Hawaii with Prof. Hisashi Yamamoto. Hewas appointed assistant professor at Nagoya University in1980,andpromotedtoassociateprofessorin1990.HemovedtoHokkaidoUniversity as a fullprofessor in1995, andhasbeenaprofessoratKyotoUniversitysince2000.HisresearchinterestsarefocusedonorganicsynthesiswithbidentateLewisacidsanddesignerchiralorganocatalysts.Hisawardsincludethe Japan Synthetic Organic Chemistry Award (2003), theNagoyaSilverMedal(2004), theGSCAward(2006),andtheChemicalSocietyofJapanAward(2006).^

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Asymmetric Alkylation Phase-Transfer Catalystschiral quaternary ammonium salts derived from c2-symmetric amines or cinchona alkaloids are powerful phase-transfer catalysts for the preparation of optically active molecules. Both types of phase-transfer catalysts allow for the stereocontrolled monoalkylation of glycine-derived schiff bases with alkyl halides to afford protected α-alkyl-α-amino acids. catalysts developed by maruoka effect these reactions with a high degree of enantioselectivity at exceptionally low catalyst loadings (<0.1 mol %).

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For further application information, see Professor Maruoka’s review article

in this issue.

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Corey, E. J. et al. J. Am. Chem. Soc. 1997, 119, 12414.

O'Donnell, M. J. et al. J. Am. Chem. Soc. 1989, 111, 2353.

Lygo, B.; Wainwright, P.G. Tetrahedron Lett. 1997, 38, 8595.

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View table of contents, search, browse, or order from our entire library at sigma-aldrich.com/books.

Chemical Synthesis

The Sigma-Aldrich Library is your guide to finding new and

best-selling chemistry books.whether your interest includes Drug Discovery,

chemical synthesis, materials science, or a wide range of other areas of interest, we can help you find the right book.

Z730203Palladium in Heterocyclic Chemistry A Guide for the Synthetic Chemist, 2nd EditionJ. J. Li and G. W. Gribble, Elsevier, 2007, 658 pp. Softcover.

Z704113Asymmetric Organocatalysis – From Biomimetic Concepts to Applications in Asymmetric SynthesisA. Berkessel and H. Gröger, Wiley-VCH, 2005, 454 pp. Hardcover.

Z703354Side Reactions in Organic Synthesis: A Guide to Successful Synthesis DesignF. Z. Dörwald, Wiley-VCH, 2005, 389 pp. Softcover.

Z705284Handbook of Chiral Chemicals, 2nd EditionD. Ager, Ed., CRC Press, 2006, 664 pp. Hardcover.

Z706043Chiral AnalysisK. W. Busch and M. A. Busch, Eds., Elsevier, 2006, 720 pp. Hardcover.

Z730181The Pilot Plant Real Book, 2nd EditionF. X. McConville, FXM Engineering, 2006, 320 pp. Softcover.

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the growing impact of asymmetric catalysis - aldrichimica acta vol. 40 no. 3

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