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Catalytic, Enantioselective Ketone Reduction: The CBS Reduction Prochiral ketones are enantioselectively reduced using a chiral oxazaborolidine Catalyst derived from the amino acid proline. N B O Ph Ph H R BH 3 N B O Ph Ph H R H 3 B CBS reagent O CH 3 "Chiral hydride" HO CH 3 H ACIEE, 1998, 37, 1985. JACS, 1987, 7925 A steric differentiation of R s and R L groups is necessary; very often, R s is an alkene, alkyne, or an aryl group N B O Ph Ph B H H H R O R s R L N B O Ph Ph B H H H R O R L R S N B O Ph Ph B H H H R O R s R L N B O Ph Ph BH 2 R O R s R L H O R s R L H BH 3 The steric demand of the substituent on boron (R) influences enantioselectivity: high enantioselectivities are usually achieved when R=Bu H 2 B HO R s R L H H 3 O +

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Catalytic, Enantioselective Ketone Reduction: The CBS Reduction

Prochiral ketones are enantioselectively reduced using a chiral oxazaborolidineCatalyst derived from the amino acid proline.

NB

O

Ph

Ph

H

R

BH3

NB

O

Ph

Ph

H

RH3B

CBS reagent

O

CH3

"Chiral hydride"HO

CH3

H

ACIEE, 1998, 37, 1985.JACS, 1987, 7925

A steric differentiation of Rs and RLgroups is necessary; very often, Rsis an alkene, alkyne, or an aryl group

N

B

OPh

Ph

BH

H H

R

O

Rs

RL

N

B

OPh

Ph

BH

H H

R

O

RL

RS

N

B

OPh

Ph

BH

H H

R

O

Rs

RL

N

B

OPh

Ph

BH2

R

O

Rs

RL

H

O

Rs

RLHBH3

The steric demand of the substituent on boron (R) influences enantioselectivity:high enantioselectivities are usually achieved when R=Bu

H2BHO

Rs

RLH

H3O+

CBS Reduction: ExamplesKetone Alcohol CBS reagent %ee

O OH

R=Me 98.8

O

Br

NO2

BnO

OH

Br

NO2

BnO

94%O

BH

HN

O

R

H3C

OH

R

H3C

R=Me 99%

O

OR

S

N

OH

OR

S

N

R=Bu 99% TL, 2004, 5845

Chem Eur. J. 2004, 2759

JOC, 1993, 2880

JOC, 1998, 5280

Reductions Using Chiral Boranes: Stoichiometric

B

Cl

Ipc2BCl

Brown and Midland, JOC, 1989, 54, 159, 4504.

BH

Alpine-Hydride

BH

t-BuIpcBCl

O

Pyr

CO2Me

(Ipc)2BCl

OH

Pyr

CO2Me

87%99.5% ee JOC 1993, 3731.

Mechanism: these reagents react through a cyclic TS and regenerate an alkene

BO

H

CH3 RsRL

Cl R

OBRCl

CH3 Rs RL

H+ OH

Rs RL

H

Noyori Asymmetric HydrogenationOriginal:

H3C

O O

OCH3

H2 (100 atm)

RuCl2[(R)-BINAP] (0.05 mol%)

CH3OH, 36h, 100°C

H3C

OH O

OCH3

96%, >99%ee

JACS, 1987, 5856

Both enantiomers of BINAP are commercially available:

PPh2

PPh2

(R)-(+)-BINAP

PPh2

PPh2

(S)-(-)-BINAP

Ru

P PCl

H

RO OR

octahedral coordination at Ru

active catalyst:

Mechanism of Asymmetric Hydrogenation

[(R)-BINAP]RuCl2

2 CH3OH

[(R)-BINAP]RuCl2(CH3OH)2

+H2

-HCl

[(R)-BINAP]RuHCl(CH3OH)2

O

O

OCH3

CH3

2 CH3OH

O

O

OCH3

CH3

[(R)BINAP]HCl Ru

O

O

OCH3

CH3

[(R)BINAP](CH3OH)Cl Ru

CH3OH

[(R)-BINAP]RuCl(CH3O)(CH3OH)2

H2

CH3OH

2CH3OH

O

HO

OCH3

CH3

reduction proceeds through the keto form of !-keto-ester:Acc. Chem. Res.1990, 345

Stereochemical Rationale

P P

Ru

Cl

H

RO OR

The rigid BINAP ligand forces phenyl rings to protrude in two quadrants:

(S)-BINAP

P P

Ru

Cl

H

RO OR

(R)-BINAP

The two protruding phenyl groups allow a coordinating ligand access to only two quadrants on the accesible face of Ru(the other face is blocked by BINAP's napthyl rings)Of the two possible diastereomeric transition states for complexes with (R)-BINAP, the one leading to the (R) !-hydroxyester allows the approach of the ketone at an unhindered quadrant

Ru

P PCl

H

O O

H3C OCH3

(R)-BINAP OH O

OCH3

R-!-hydroxy ester

Ru

P PCl

H

O O

H3CO CH3

(R)-BINAPOH O

OCH3

S-!-hydroxy esterblockedquadrant

Bull. Chem. Soc. Jpn. 1995, 36

Reaction Conditions

In situ catalyst generation leads to milder reaction conditions:

[RuCl2(benzene)]2

R-BINAP

(R)-BINAP RuCl2

reaction conditions:

4 atm/100°C or 100atm/23°C

S-BINAP

(S)-BINAP RuCl2RuCl2•(COD) (50psi H2), 80°C

O O

OEt

H2 (4 atm)

Ru-(R)-BINAP (0.05 mol%)

EtOH, 6h, 100°COH O

OCH3

96%, 97-98%ee

BnO BnO

Synthesis, 1995, 1014

O O

OMe

H2 (50 psi)

Ru-(S)-BINAP (0.2 mol%)

MeOH, 6h, 80°COH O

OCH3

TL, 1991, 4227JOC, 1992, 5990

H3C

O O

Ot Bu

1atm=14.6 psi

H2 (50 psi)

Ru-(R)-BINAP (0.05 mol%)

MeOH, 8h, 40°C

H3C

OH O

Ot Bu

97%, >97%ee

JOC, 1992, 6689

t-Bu ester not cleaved

Conditions, continued

O O

OCH3

H2 (1 atm)

Ru-(S)-BINAP (2 mol%)

MeOH, 8h, 40°COH O

OCH3

100%, 99%ee

TL, 1995, 4801H3C

Atmospheric pressure reduction is possible yusing higher catalyst loading and a catalyst prepared in situ from

BINAP, (COD)Ru(2-methylallyl)2, and HBr

H3C

Kinetic Resolution:

HO

O

H2 (100 atm)

RuCl2[(R)-BINAP ]

EtOH, 8hHO

OH

HO

O

+

50.5%, 92% ee 49.5%, 92%ee

•The catalyst reacts with one enantiomer faster than the other• maximum 50% yield for eack recovered enantiomer.

Dynamic Kinetic ResolutionIf a substrate is epimerizable under the reaction conditions, and the enantiomer that does not react can beTransformed into the one that does react, then a high yield of a single diasteromer product may be obtained

O O

OCH3

H2 (100 atm)

RuBr2[(R)-BINAP ](0.4 mol%)

CH2Cl2, 15°C, 50hOH O

OCH3

Note that for yields ~100% of the desired enantiomer, kinv>>kS,R or kR,R, that is, a rapid isomerization

between the two enenatiomeric !-keto esters must occur

NHAc

kinv

O O

OCH3

NHAc

NHAc 99%, 98% ee

kS,R

H2 (100 atm)

RuBr2[(R)-BINAP ](0.4 mol%)

CH2Cl2, 15°C, 50h OH O

OCH3

NHAckR,R

JACS, 1989, 9134

However,

O O

OCH3

CH3

H2 (100 atm)

RuBr2[(R)-BINAP ](0.4 mol%)

CH2Cl2, 15°C, 50hOH O

OCH3

CH3

OH O

OCH3

CH3

+

1 : 1The stereochemistry at the "#position is substrate dependent!The stereochemistry of the 2° alcohol is determined by the choice of catalyst

Dynamic Kinetic Resolution

Examples:

O O

OCH3

H2 (100 atm)

RuBr2[(R)-BINAP ](0.4 mol%)

CH3OH, 15°C, 50hOH O

OCH3

NHAc NHAc

OH O

OCH3

NHAc

+

82 : 18

solvent change:

O O

OCH3

H2(100 atm)

[RuCl(PhH)[(R)-BINAP] Cl

(0.09 mol%)

OH O

OCH3

OH O

OCH3+

H H

99 : 1

The preference for one diastereomer over another can be rationlized by analyzing the diastereomeric transition states for reduction:

H3C

NO

OH

H3C

O

H

Ru OP

P

X

intramolecular H-Bondin this TS

HO

O

H3C

H

Ru OP

P

X

P,P=(R)-BINAPP,P=(R)-BINAP

H-bond is partially lost in MeOHdue to solvent competition JACS, 1989, 9134

JACS, 1993, 144

Other Ligands for Asymmetric Hydrogenation

PP

(R,R)-iPr-BPE

Milder conditions reported for Burk's ligand:

H3C

O O

OCH3

H2(60psi)

(R,R)-iPr-BPE-RuBr2 (0.2 mol%)

CH3OH:H2O (9:1) H3C

OH O

OCH3

100%, 99.3% ee

JACS, 1995, 4423

Merck's PHANEPHOS ligand results in extremely mild, neutral conditions for the reduction of !-keto esters:

PPh2

PPh2

S-2,2-PHANEPHOS

H3C

O O

OCH3

H2(50psi)

S-2,2-PHANEPHOS-Ru(TFA)2

(0.6 mol%)

CH3OH:H2O, -5°C, 18 h H3C

OH O

OCH3

100%, 96% ee

TL, 1998, 4441.

Alkenes have prochiral faces, also!Reagent Control

Enantioselective Hydrogenation of Alkenes

P

Ph

P

Ph

OMe

MeO

(R,R)-DIPAMP (Chiral at phosporous)

PPh2

PPh2

(S) - BINAP

CO2H

NHAc

MeO

AcO

H2

R,R-DIPAMP

Rh+

CO2H

NHAc

MeO

AcO

CO2H

NH2

HO

HO

L-DOPA

94% eeJACS, 1977, 99, 5946.

JACS, 1987, 1746

JACS, 2000, 12714

Asymmetric hydrogenation en route to amino acidsCoordinating groups on the alkene have resulted in high enantioselectivities:

Ph

CO2CH3

NHAc

H2

Rh (COD)2BF4

phosphite ligandPh

CO2CH3

NHAc

OPAr2

OPAr2

Ar substitutent %ee

4-CF3 49

4-CH3 93

4-OCH3 99

catalyst fine-tuning possible

CH3

H3C

CH3

OH

Ru(S-BINAP)(OAc)2 CH3

H3C

CH3

OH

99%ee

H3CO

OCH3

(CH2)4CH3

CO2H

Ru(R-BINAP)(OAc)2

H2

H2

H3CO

OCH3

(CH2)4CH3

CO2H

H100%

97%ee

TL, 2003, 9025COD= Hydrogenation dissociatesCOD from metal, leavingtwo open coordiantion sites