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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