Stereoselective Oxidationand Reduction Reactions

Dr Simon WoodwardSchool of Chemistry, University of Nottingham

Oxidation Reactions

• Epoxidation

– Epoxide opening

• Dihydroxylation

• Aminohydroxylation

• Alcohol oxidation

“Click Chemistry: Diverse Chemical Function from a Few Good Reactions” Kolb, Finn, Sharpless, Angew. Chem. Int. Ed. 2001, 40, 2004.

Sharpless Asymmetric Epoxidation of Allylic Alcohols

Review: Katsuki and Martin, Org. React., 1996, 48, 1.

OH

R1R2

R3

(-)-DET "O"

(+)-DET "O"

Sharpless, J. Am. Chem. Soc., 1987, 109, 5765 .Mechanism: J. Am. Chem. Soc., 1991, 113, 106 and 113.

• tBuOOH, Ti(OiPr)4, DET, CH2Cl2, 4Å MS

• Hydroxamic acid ligands for Vanadium-catalysed asymmetric epoxidation of allylic alcohols: Yamamoto, J. Am. Chem. Soc. 2000, 122, 10452.

Chiral Mn(salen) Catalysts: Overview

N N

O OtBu tBu

tButBu

Mn

Cl

H H

Stoichiometric co-oxidants:Usually aq. NaOCl, CH2Cl2mCPBA / NMO (low temperature)

Preparation of catalyst: Organic Syntheses, 1998, 75, 1.Polymer supported catalyst: e.g. Janda, J. Am. Chem. Soc., 2000, 122, 6929.

Cis-Disubstituted alkenes: J. Am. Chem. Soc. 1991, 113, 7063.Trisubstituted alkenes: J. Org. Chem. 1994, 59, 4378.Tetrasubstituted alkenes: Tetrahedron Lett. 1995, 36, 5123.Cinnamate esters: Tetrahedron 1994, 50, 4323.

Review: Katsuki Coord. Chem. Rev. 1995, 140, 189.

• Poor enantioselectivities for trans-disubstituted and terminal alkenes] (but see Katsuki, Synlett, 2000, 1557)

•Via radical intermediate, so stereospecificity with respect to alkene geometry sometimes eroded. Can use to make trans-epoxides from cis-alkenes: Jacobsen, J. Am. Chem. Soc. 1994, 116, 6937.

• Asymmetric epoxidation of E-alkenes using Cr(salens): Gilheany, Org. Lett. 2001, 3, 663, and refs. therein

PhPh

O

0.04eq. (R,R)-Mn(salen)Cl

NaOCl, pH 11.3CH2Cl2, 4ºC

84% yield92% ee

Dioxiranes

R1 R1

O Oxone® (KHSO5)

R1 R2

OO

Base

Isolation of dioxiranes: neutral, anhydrous oxidantsPreparation of dimethyldioxirane (DMDO) solutions: Adam, Chem. Ber., 1991, 124, 2377.More concentrated, “acetone free” solutions: Messeguer, Tetrahedron Lett., 1996, 37, 3585.

• Electrophilic oxidants, but successful for epoxidation of electron poor alkenes: e.g. Baumstark, J. Org. Chem., 1993, 58, 7615.

In situ dioxirane formationBiphasic, CH2Cl2 / H2O: Denmark, J. Org. Chem., 1995, 60, 1391.Monophasic, CH3CN / H2O: Yang, J. Org. Chem., 1995, 60, 3887.In situ DMDO prep.: Shi, J. Org. Chem., 1998, 63, 6425.Trifluoroacetone + H2O2: Shi, J. Org. Chem., 2000, 65, 8808.

Chiral Dioxiranes: Asymmetric Epoxidation of trans-Alkenes

Shi, J. Am. Chem. Soc. 1997, 119, 11224. Review: Shi, Synthesis, 2000, 1979.

• Preparation: 2 steps from D-fructose (enantiomer available in 5 steps from L-sorbose)• Excellent enantioselectivities for epoxidation of trisubstituted and trans-disubstituted alkenes• Poor ee for cis- and terminal alkenes

• Ketone decomposes by Baeyer-Villiger reaction - cannot be recycled. High pH conditions required.

O

O

O

OO

O

PhCH3

30 mol% ketone

Oxone, K2CO3CH3CN, 0ºC

pH 10.5 buffer

PhCH3

O

93% yield; 92% ee

(Use of H2O2 as primary oxidant: Tetrahedron Lett., 1999, 40, 8721;Tetrahedron, 2001, 57, 5213.)

O

OO

OO

OO

RH

R

Other substrate types:Conjugated dienes: J. Org. Chem. 1998, 63, 2948Enynes: Tetrahedron Lett. 1998, 39, 4425.

Modified catalyst for cis-alkenes: J. Am. Chem. Soc. 2000, 122, 11551.Terminal alkenes: Org. Lett., 2001, 3, 1929.

Stable catalysts:Armstrong, Chem. Commun. 1998, 625; Tetrahedron: Asymmetry, 2000, 11, 2057. Shi, Org. Lett. 2001, 3, 715.

Oxidation of silyl enol ethers

Other methods for asymmetric oxidation of silyl enol ethers:Chiral Mn(salens):Thornton, Chem. Commun. 1992, 172; Adam, Tetrahedron Lett. 1996, 37, 6531, and refs. therein.Chiral oxaziridines: Review: Davis, Chem. Rev., 1992, 92, 919.Asymmetric dihydroxylation: J. Org. Chem. 1992, 57, 5067.

Shi, Tetrahedron Lett. 1998, 39, 7819:

Ph

OTBDMS

Ph

OCat. ketone, Oxone

CH3CN, aq. buffer

OH

80% yield90% ee

O OO

O

OO

Ketone =

OR ORO

R=Ac: 59% yield, 74% eeR=Bz: 82% yield, 93% ee

O

OBz

O

OBz

pTsOHsilica gelor YbCl3or AlMe3R=Bz

90% ee 87-91% ee

ShiJ. Am. Chem. Soc. 1999, 121, 4080.

Hydrolytic Kinetic Resolution

Jacobsen, Science 1997, 277, 936. Acc. Chem. Res. 2000, 33, 421.

O1. 0.2 mol% (salen)*Co(III)(OAc) 0.55 eq. H2O, rt, 12 hr

2. Distillation

OOH

OH

> 98% ee(44% yield)

> 98% ee(50% yield)

+

• Catalyst can be recycled (AcOH, air)

• Easily-synthesised oligomeric Co(salen) catalysts are highly active for epoxide opening by water, alcohols and phenols: J. Am. Chem. Soc. 2001, 123, 2687.

Asymmetric Epoxidation of Electron-Deficient Alkenes

R1 R2

O

R1 R2

OO

Review: M.J. Porter and J. Skidmore, Chem. Commun., 2000, 1215.

• Polyleucine, H2O2, base: e.g. Tetrahedron Lett., 2001, 42, 3741. Reviews: Tetrahedron: Asymmetry 1997, 8, 3163; 1998, 9, 1457.

• Catalytic Mg peroxides (tBuOOH, cat. Bu2Mg, cat. diethyl tartrate): R1, R2=Ph Jackson, Angew. Chem., Int. Ed. Engl. 1997, 36, 410. • Chiral phase-transfer catalysts (R2 can be alkyl): Lygo, Tetrahedron, 1999, 55, 6289; Tetrahedron Lett. 2001, 42, 1343.

• Lanthanide catalysis (BINOL, La(OiPr)3 or Yb(OiPr)3, 4Å MS, tBuOOH): R1=Ph, iPr or Me; R2=Ph, iPr, Ph(CH2)2 or Me. La-BINOL-Ph3AsO -mechanistic studies: J. Am. Chem. Soc., 2001, 123, 2725.

• Chiral hydroperoxides, KOH, CH3CN: Adam, J. Am. Chem. Soc., 2000, 122, 5654.

• Stoichiometric zinc alkylperoxides (O2, Et2Zn, R*OH): R1=Ph or tBu, R2=alkyl or aryl Enders, Angew. Chem. Int. Ed. Engl. 1996, 35, 1725; Liebigs Ann. Chem. 1997, 1101

• Chiral dioxiranes: e.g. Tetrahedron: Asymmetry, 2001, 12, 1113.

Alkene Dihydroxylation

R1

R3

R2

R4 R3 R4

OH OHR1 R2

OsO4

R3 R4

O OR1 R2

OsO O

Catalytic systems:• NMO / acetone / H2O (Upjohn procedure): Tetrahedron Lett. 1976, 23, 1973.

• Cat. Me3NO•2H2O, CH2Cl2: Poli, Tetrahedron Lett. 1989, 30, 7385.

• K3Fe(CN)6, K2CO3, tBuOH / H2O: Minato, Yamamoto, Tsuji, J. Org. Chem. 1990, 55, 766.

• NMO, PhB(OH)2, CH2Cl2: Narasaka, Chem. Lett. 1988, 1721. - Diol trapped as boronate ester - useful if diol is unstable or highly water soluble

• Selenoxides as co-oxidants: Krief, Synlett, 2001, 501.

• H2O2, cat. flavin, cat. N-methylmorpholine: Backvall, J. Am. Chem. Soc. 1999, 121, 10424; J. Am. Chem. Soc. 2001, 123, 1365.• H2O2, cat. V(O)(acac)2, NMM, acetone/water: Backvall, Tetrahedron Lett., 2001, 42, 2569.

• O2, K2[OsO2(OH)4], tBuOH / H2O: Beller, Angew. Chem. Int. Ed. 1999, 38, 3026; J. Am. Chem. Soc. 2000, 122, 10289. Wirth, Angew. Chem. Int. Ed. 2000, 39, 334.

Fe-catalysed asymmetric dihydroxylation: Que, J. Am. Chem. Soc. 2001, 123, 6722.

Directed Dihydroxylations

“Kishi rule” - dihydroxylation occurs anti- to oxygen functionality.Review: Cha, Chem. Rev. 1995, 95, 1761.

OH

But

OH

But

OH

But

OsO4, NMO, acetone / H2OOsO4, TMEDA, CH2Cl2, -78ºC

+

OH

OH

OH

OH

anti syn

7:11:24

O

H

But

OsO

N O

O

N

O

OH OH

OsO4, TMEDA

CH2Cl2, -78ºCHO

OH

Regioselectivity > 25:1

Hydroxyl-directed dihydroxylation: Donohoe, Tetrahedron Lett. 1997, 38, 5027.

• Bidentate ligand required

• Dihydroxylation directed by trichloroacetamides: Donohoe, J. Org. Chem. 1999, 64, 2980.• Catalytic directed dihydroxylation of cyclic trichloroacetamides: Donohoe, Tetrahedron Lett. 2000, 41, 4701. • Syn-selective dihydroxylation of acyclic allylic alcohols: Donohoe, Tetrahedron Lett. 1999, 40, 6881.

Sharpless Asymmetric Dihydroxylation

NNO

N

OMe

N

O

N

MeO

H

EtN

Et

H

(DHQD)2-PHAL

AD-Mix:K2OsO2(OH)4, ligand,

K3Fe(CN)6, K2CO3

Review: Sharpless, Chem. Rev. 1994, 94, 2483.

RM

H

RS

RL

"HO" "OH"

"HO" "OH"

-face

-face

slightly hindered

very!!!!!hindered

attractive area - good for aromatic

and alkyl substituents

DHQD= dihydroquinidineDHQ= dihydroquinine "pseudoenantiomers"

DHQ series

DHQD series

Sharpless AD: Recent DevelopmentsImproved ligands:• Pyrimidine (PYR) spacer for sterically congested / terminal alkenes: J.Org. Chem. 1993, 58, 3785.• Anthraquinone (AQN) spacer gives better results for almost all alkenes having only aliphatic substituents: Angew. Chem. Int. Ed. Engl. 1996, 35, 448.

Mechanism:

• Comparison of theoretical and experimental kinetic isotope effects supports [3+2]-mechanism Sharpless, Houk et al. J. Am. Chem. Soc. 1997, 119, 9907.

OOs

O

O O

[3+2]

Os O

OO

OOs O

OO

O[2+2]

OOs

O

O O

Origins of asymmetric induction:Sharpless: J. Am. Chem. Soc. 1997, 119, 1840.Corey (“enzyme like” binding pocket): J. Am. Chem. Soc. 1996, 118, 319; 11038.

Polymer supported chiral ligands: Review: Synlett, 1999, 1181. Crudden, Org. Lett. 2001, 3, 2325. Bolm, Synlett, 2001, 93 (AQN-ligands). Polymer supported Os-catalyst: Kobayashi, J. Am. Chem. Soc. 1999, 121, 11229. Org. Lett. 2001, 3, 2649.

Importance of pH control: improved rates for internal olefins at pH 12 (no MeSO2NH2); higher ee for terminal olefins at pH 10: Beller, Tetrahedron Lett. 2000, 41, 8083.

AminohydroxylationReview: O’Brien, Angew. Chem., Int. Ed. Engl. 1999, 38, 326.

R1

R2

XNClNa (X=Ts, Ms, CBz, Boc, Teoc)OR XNBrLi (X=Ac)

4 mol% K2OsO2(OH)25 mol% (DHQ)2PHAL

1:1 ROH:H2O

R1

R2R1

R2

NHX

OH

OH

NHX

+

• DHQD-ligand series generally provide opposite enantiomer.• Effect of substrate structure on regioselectivity: Janda, Chem. Eur. J. 1999, 5, 1565.

PhCO2Me

PhCO2Me

NHX

OH

X=Ts: 60% yield, 82% eeX=Cbz: 65% yield, 94% ee

Cinnamates:

Styrenes, Aryl alkenes (X=Ts, CBz, Boc, Teoc):

OH

NHBoc

70% yield98% ee

• Altering ligand spacer, solvent can reverse regioselectivity without decreasing ee!

• Aryl esters (and AQN-ligands) give opposite regioselectivity! Panek, Org. Lett. 1999, 1, 1949. • Can be run at higher concentration in presence of acetamide to suppress diol formation: Wuts, Org. Lett. 2000, 2, 2667.

Recent Developments in Asymmetric Aminohydroxylation

• Amino-substituted heterocycles as nitrogen sources: Sharpless, Angew. Chem. Int. Ed. Engl. 1999, 38, 1080.• Adenine derivatives as N-source: Sharpless, Tetrahedron Lett. 1998, 39, 7669.

N N

NH2

1. tBuOCl, EtOH, 0ºC

2. Aq. NaOH, 0ºCN N

N-Cl Na+

PhPh

5% K2OsO2(OH)46% (DHQ)2PHAL

rt

PhPh

OH

NH

N

N

45% yield97% ee

• N-bromo-N-lithio salts of primary carboxamides as N-source: Sharpless, Org. Lett. 2000, 2, 2221.• Unsaturated phosphonates as substrates: Sharpless, J. Org. Chem., 1999, 64, 8379.

Pd-Catalysed Oxidative Kinetic Resolution of Secondary Alcohols with O2

Sigman, J. Am. Chem. Soc. 2001, 123, 7475. Stoltz, J. Am. Chem. Soc. 2001, 123, 7725.

OH O OH5 mol% Pd(nbd)Cl220 mol% (-)-sparteine

3Å MS, 1 atm O2PhCH3, 80ºC

+

(±)

S = kfast/kslow = 47.1

55% conversion5.0 g 2.7 g 2.2 g, 99% ee

NaBH4, MeOH99%

Reduction Reactions

• Hydrogenation

• Transfer hydrogenation

• Boranes

• Hydride reagents

• Hydrosilylation

Asymmetric reduction of alkenes, ketones, imines…….

Monsanto synthesis of L-DOPA

CO2Me

NHAc

CO2Me

NHAc0.1% [(R,R)-(dipamp)Rh(COD)]+BF4

3 atm H2, 50°C, H2O / iPrOH

MeO OMe MeO OMe

CO2-

NH3+

HO OH

HBr

L-DOPA(anti-Parkinson's)

OMe

P P

MeO

Ph

Ph

= (R,R)-dipamp

94% ee

Rh(I)-BINAP Complexes

(S)-BINAP

PPh2

PPh2

[(S)-(BINAP)Rh(nbd)]+ClO4-

Ph NHAc

CO2R

Ph NHAc

CO2R

H2, MeOHR=Me 98%, 93% eeR=H 97%, 100% ee

[(S)-(BINAP)Rh(nbd)]+ClO4-

NHAc

CO2H

Ph NHAc

CO2H

H2, MeOH93%, 87% ee

Ph

Noyori, J. Am. Chem. Soc. 1980, 102, 7932.

Ru BINAP complexes are more general; work for e.g. simple acrylic acids. Mechanistically distinct: Tetrahedron Lett. 1990, 31, 7189.

Rh(I)-diphosphole Complexes

P P

R

RR

R

P

P

R

R

R

RR = Me, Et, Pr

(R,R)-DuPHOS(R,R)-BPE

Review: Burk, Acc. Chem. Res. 2000, 33, 363

0.05% [Rh(R,R-nPr-DuPHOS)(COD)]+TfO-

R2 NHAc

CO2Me

NHAc

CO2Me

2 atm H2, MeOH

R1=H, R2=MeR1=Me, R2=H

R1

99.6% ee99.4% ee

• sense of enantioselectivity independent of acrylamide geometry

Monodentate ligands

O

OPNMe2

O

OP O

(S)-MonoPhos

Ligand A

MonoPhos: deVries, Feringa, J. Am. Chem. Soc. 2000, 122, 11539. Ligand A: Reetz, Angew. Chem. Int. Ed. 2000, 39, 3889.Review: Angew. Chem. Int. Ed. 2001, 40, 1197.

CO2Me

CO2Me

CO2Me

CO2Men% [Rh(cod)2]BF4

2n% ligand, CH2Cl2

(S)-MonophosLigand A

n=5, 1atm H2, 0°Cn=0.1, 1.3 bar H2, rt

94.4% ee99.6% ee

NHAc

CO2Me

NHAc

CO2Men% [Rh(cod)2]BF4

2n% ligand, CH2Cl2

(S)-MonophosLigand A

n=5, 1atm H2, rtn=0.1, 1.3 bar H2, rt

99% ee95.5% ee

Asymmetric Hydrogenation of Functionalised Ketones

OXR

Ru

(S)-BINAP

(R)-BINAP

O

RX

RX

OH

R

MePhMeMe

(CH2)2CH=Me2CH2Cl

Me

X

NMe2NMe2CH2OHCO2MeCO2MeCO2Et

Br

BINAP

969598989897

92

[(Ru(S-BINAP)X2] or [Ru(R,R-iPr-BPE)Br2]

10 atm H2, MeOH

BPE

---

99.3-

76

-

ee

Ru BINAP: J. Am. Chem. Soc. 1987, 109, 5856; J. Am. Chem. Soc. 1988, 110, 629.Ru BPE: J. Am. Chem. Soc. 1995, 115, 4423.

Review: Ager, Tetrahedron Asymm. 1997, 8, 3327.

• Mixed Ru bisphosphine/diamine complexes afford much improved turnover numbers:

0.05% [Ru(R-xylBINAP)Cl2] + R-daipen

1 mol% KOtBu, 8 atm H2, iPrOHPhNMeAc

O

PhNMeAc

OH

87%. 97% ee

PAr2

Ar2P

Ru

Cl

Cl NH2

H2N

OMe

OMe

iPr

• Basic conditions allow dynamic kinetic resolution:

Noyori, J. Am. Chem. Soc. 2000, 122, 6510.

0.33% [Ru(R-xylBINAP)Cl2] + S-daipen

66 mol% KOH, 8 atm H2, iPrOH

98%, 82% ee

O

NHCO2tBu

OH

NHCO2tBu

(±)

Also for reduction of unfunctionalised ketones. Review: Noyori, Angew. Chem., Int. Ed., 2001, 40, 40.

Catalytic asymmetric hydrogenation of aminoketones

Asymmetric Transfer Hydrogenation of KetonesReduction with the aid of a hydrogen donor in the presence of a catalystReviews: Wills, Tetrahedron Asymmetry, 1999, 10, 2045; Noyori, Acc. Chem. Res. 1997, 30, 97.

MO

H

O

L L

R1

R2

Meerwein-Ponndorf-Verley type(main group or lanthanide metals)

(a) (b)

MH O

L LM

H O

L L

O

orM

H O

L L

R1R2

Metal hydride type:transition metals, iPrOH or formate as reductant

0.5% [RuCl2(hexamethylbenzene)2]

Ligand, iPrOH/KOH, 28CR

O

R

OH

X X

NHMe

OH

Ph

Ph

ligand=

XHOMeH

RMeMeEt

Yield947395

% ee927982

Aminoalcohols as ligands:

Arylalkylketones with electron rich aryl groups and benzocycloalkanones suffer from reversibility and give lower ee…but aminoalcohols are generally not compatible with the irreversible hydride donor formic acid

O

RS

NH2

N

Ph

PhRn

SO2Ar

RL

OH

RSRL

O O

MeO

O O

Ru

Cl

O OH

NH2

NH

Ph

Ph

O2S

HN

dend

J. Am. Chem. Soc., 1995, 117, 7562; J. Am. Chem. Soc., 1996, 118, 2521; Chem. Commun., 2001, 1488

iPrOH/KOH or HCO2H/Et3N

0.5%iPrOH/KOH

HCO2H/Et3N97% ee98% ee

72% ee97% ee

97% ee97% ee

91% ee99% ee

- supported and dendritic versions of the ligands have been prepared:

1 % [RuCl2(cymene)]2

1% ligand, HCO2H/Et3N

iPrOH/KOHHCO2H/Et3N

Run:

12345

% ee

96.596.796.796.495.0

conv.

9993868852

ligand:

Monotosylated diamines: formic acid-tolerant ligands for transfer hydrogenation

- monotosylated diamines give slightly less reactive catalysts than the amino alcohols but have proven to be a more useful ligand system for ruthenium based transfer hydrogenations since compatibility with the formic acid system allows efficient reduction even in readily reversible systems:

Ketone Reduction Catalyzed by Oxazaborolidines

N B

O

H PhPh

MeO

RS RS

OH

RL RL+ BH3.THF or catecholborane

(typically ca. 10% loading)

Review: Angew Chem. Int. Ed. 1998, 37, 1986

OH

X

X=HX=MeX=Cl

96.5% ee96.7% ee95.3% ee

tBu

OH

97.3% ee

OH

CO2Me

96.7% eePh

OH

Ph

97% ee

H17C6

OH

95% ee

OH

94% ee

Bu3Sn

TBSO

OH

O O

92% ee

Polymer-supported amino alcohol and in situ generation of borane

Angew. Chem. Int. Ed., 2001, 40,1109

O OH25% catalyst

NaBH4 / TMSCl

THF, reflux

HBr

MeONO2

% ee95.796.184.196.6

Yield98979799

R

R R

SO2

NOH

PhPh

Catalyst:

O

OLiAlH4 Al

H

ORLi+

OAl

O O LiH

R

O

R UnO

AlO O Li

H

R

O

Un R

R1 R2

O

R1 R2

OH

problems: stoichiometric, capricious to prepare, requires long reaction times at very low temperatures

i) (S)-BINOL

ii) ROH

(S)-BINAL-H

Un = aryl, heteroaryl, alkene, alkyne

enantioselectivity is largely electronic in origin:

_

electrostaticrepulsion

Asymmetric reduction of ketones: stoichiometric aluminium hydrides

Noyori, J. Am. Chem. Soc., 1984, 106, 6709, 6717

O

SGa

H

OR'

Li+

Un R

O

O

SGa

O

OR'

Li+ R

Un

H

Un R

OB

Ph

C-EtC

Me

Me

Me

_ _

catecholborane

Un R

Conditions:

2.5 mol% cat.,

-20oC, THF

2-furyl

PhCH=CH-

n-hexyl

Yield ee

95

76

70

60

91

81

75

63

A catalytic binapthyl-substituted hydride source based on hard-soft principles

Woodward, Angew. Chem., Int. Ed. Engl., 1999, 38, 335; Chem. Eur. J. 2000, 6, 3586.

- replacing 'hard' aluminium by 'soft' gallium, the intermediate 'hard' alkoxide can be transferred to the 'hard' borane stoichiometric co-reductant, allowing catalytic turnover:

Ph CH3

O

Ph2PO

Ph2PO OBnO

O

O

Ph CH3

OH

N

N

O

N

O

R R

N

N

O

R

[(pigiphos)Rh(COD)]+ BF4-

87% ee

83% ee1:1:1 (R,R-pybox)/[Rh(COD)Cl]2/AgBF4

or 10:1:1 (S-pymox)/[Rh(COD)Cl]2/AgBF4

Ph2SiH2 or NpPhSiH2

then H3O+ work-up

65% ee

catalyst

(S-pymox)(S,S-pybox)pigiphos

Organometallics, 1991, 10, 560;Tetrahedron:Asymm., 1991, 2, 919

Hydrosilylation of imines/ketones: an alternative to hydrogenative reduction

O OH

NR

HNR

TiF F

TiH

2% cat, 97% ee, 84% yield

0.5% cat, 91% ee, 96% yield

pre-treated catalyst

5 eq. PMHS

THF, 15oC

slow addition of MeOH

5 eq. PMHS, THF, 60oC

slow addition of iBuNH2

pre-treated catalyst

precatalyst =

catalyst =

PhSiH3, piperidine,

MeOH

R = Bn

R = Ph 2% cat, 99% ee, 63% yield

Ph Ph

Asymmetric hydrosilylation of ketones and imines using cheap siloxanes

PMHS = poly(methylhydrosiloxane)

J. Am. Chem. Soc., 1999, 121, 5640 (ketone);Angew. Chem., Int. Ed. Engl., 1998, 37, 1103, Org. Lett., 2000, 2, 713 (imine)

Me3SiO Si OSiMe3

Me

H n

OEt

O

OEt

O

OEtOOEt

O

O

O

OMe

O

O

OMe

(S)-p-Tol-BINAP, CuCl

(S)-p-Tol-BINAP, CuCl

NaOtBu, PMHS, PhCH3

NaOtBu, PMHS, PhCH3

90%85% ee

93%80% ee

(S)-p-Tol-BINAP, CuCl

NaOtBu, PMHS, PhCH3

86%92% ee

Catalytic asymmetric hydrosilylation of enones/enoates

Buchwald, J. Am. Chem. Soc., 1999, 121, 9473; J. Am. Chem. Soc., 2000, 122, 6797