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Requirements for an Effective Chiral Auxiliary Enolate Alkylation
1. Xc must be low cost, and available in both enentiomeric forms
2. The cleavage of Xc from the substrate must occur under mild enough conditions
so that racemization is avoided.
3. The pi-facial selectivity of electrophile attack on the enolate will be dictated by sterics.
4. Either E or Z enolate should be formed exclusively
5. Metal ion chelation provides a rigid template and a single conformation, so that the sterics
of the auxiliary can enforce facial bias in electrophile attack on the enolate
Early examples of Chiral auxiliaries for enolate alkylation2-Oxazolines as Carbonyl Equivalents
N
OPh
OCH3
LDA
EtI N
OPh
OLi
phenyl shields top face
E+
N
OPh
OCH3
6N HCl
O
HO
78% ee
Meyers, JACS, 1976, 567.
Prolinol amides:
NH
OHO
Cl
N
OH
O2 LDA
N
O
O
Li
Li
BnBr
N
OH
O
PhTL, 1980, 4233JACS, 1990, 5290.
76% de
1N HCl/
NaHCO3
N->O acyl migration,general basecat. hydrolysis
O
CH3
Ph
HO
tertiary amides generally form Z-enolates
Evans Chiral AuxiliaryEnantiocomplementary Reagents:
O NH
O
O NH
O
O NH
O
CH3
O NH
O
CH3
O NH
O
Ph
O NH
O
Ph
Acylaton provides imides, closer to esters in terms of acidity, enolate nucleophilicity, and cleavage chemistry:
O NH
O
n-BuLi
PrCOClO N
O O
LDA
THF, -78O N
O O
Li
Z-enolates are formed with very highselectivity due to sterics; metal chelated geometry presumed in ground and transition states
JACS, 1982, 104, 1737.
BnBr
O N
O O
Ph
>99:1
O N
O O
LDA
BnBr
O N
O O
Ph
>99:1
Less Reactive Electrophiles: Use sodium enolate
O N
O
Ph
O N
O
CH3
O
NaHMDS
EtI
O N
O O
94:6
Alternatively, use triflate:
O LDA
TfO
O N
O
Ph
O
CH3 CH3>95% de
Enolate Oxidation- use Davis Oxaziridine: JACS, 1985, 4346
O N
O
CH3
O
CO2Me
NaN(TMS)2
NSO2Ph
O
O N
O
CH3
O
CO2Me
OH
Aziridination: Amino acid synthesis: JACS, 1990, 4011.
O N
O
Ph
O
tBu
KHMDS
ArSO2N3
O N
O
Ph
O
tBu
N3
PPh3O N
O
Ph
O
tBu
NH2
Pseudoephedrine as a Chiral Auxiliary
OH
N
CH3
CH3
R,R-(-)-pseudoephedrine
H OH
N
CH3
CH3
H
S,S-(+)-pseudoephedrine
cheap, commercially available chiral amino alcohols
O
XR
OH
N
CH3
CH3
O
R
1. 1.95 LDA LiCl
2. R'XOH
N
CH3
CH3
O
R
R'
1,4- syn relationship
electrophile enters from the same face as methyl group
epoxides and alkyl halides attack oppositefaces of the enolate due to lithium coordination of the epoxide O
>99% de
OLi(solvent)
NH3C
H3C
OLi(solvent)
R
H H
H
R'X
Myers, JOC, 1996, 61, 2428
Myers, JACS, 1997, 119, 6496.
Challenge:Remove Chiral Auxiliary w/o Racemization
OH
N
CH3
CH3
O
C4H9
Ph
>99%de
H2SO4
dioxane
reflux
O
C4H9
Ph
HO
nBu4NOH, tBuOH
H2O, reflux
O
C4H9
Ph
HO
basic conditions lead to facile epimerizationof !-aryl substituted carbonyls
Reduction: LiNH2BH3
OH
N
CH3
CH3
O
C4H9
Ph
LAB, THFC4H9
Ph
HO
LiAlH(OEt)3
O
C4H9
Ph
H
TL, 1996, 3623
2.4 eq. MeLi O
C4H9
Ph
H3C
JACS, 1997, 6496.
Xc
O
Bn
Xc
O
Bn
CH3
HO
Bn
CH3
I
Bn
CH3
Xc
OLi
CH3
Xc
O
CH3
Bn
CH3
Xc
O
CH3
Bn
CH3
Xd
OLi
CH3
I
CH3
Bn
CH3
I
CH3
Bn
CH3
CH3
Bn
CH3CH3
HO
CH3
Bn
CH3CH3
HO
CH3
Bn
CH3CH3
HO
CH3
Bn
CH3CH3
HO
LABLDA
CH3IPPh3, I2
imidazole
as above
as above
repeat cycle
repeat cycle
Synlett, 1997, 5, 457.
Iterative Synthesis of 1,3 n-Substituted Carbon Chains
Camphor-Based Auxiliaries
Helmchen Chiral Ester Enolate
CH3H3C
O
N
SO2Ph
O
CH3Me
NLi
THF
CH3H3C
O
N
SO2Ph
OLi
CH3
Me
E enolate
El+
CH3H3C
O
N
SO2Ph
O
CH3
MeEl
dr 99:1
CH3H3C
O
N
SO2Ph
O
CH3Me
NLi
THF/HMPA
CH3H3C
O
N
SO2Ph
OLi
CH3Me
Z enolate
El+
CH3H3C
O
N
SO2Ph
O
CH3Me
El
4:1
dr 94:6
Enolization leakage in the presence of HMPAHMPA breaks up higher orderlithium enolate aggregates!
CH3H3C
OH
N
SO2Ph
Me
ACIEE, 1981, 20, 207ACIEE, 1984, 23, 60TL, 1983, 24, 1235TL, 1983, 24, 3213
Camphor-Based Auxiliaries
Oppolzer Camphorsultam
CH3H3C
NH
S O
O
NaH
CH3CH2COCl
CH3H3C
N
S O
O
O NaN(TMS)2
CH3H3C
N
S O
O
O
Na
E+
BnBr, HMPA
CH3H3C
N
S O
O
O
CH3
Ph
LiOH
H2O2
O
CH3
Ph
HO
97% de
Oppolzer, TL, 1989, 41, 5603
no racemizationunder these hydrolysisconditions
Chiral Metalloenamines and Metallated Hydrazones
N
MeO
Bn
LDAMeI
N
O
Bn
Li
Me
N
O
Bn
Me
CH3H3O+
O
CH3
Meyers, JACS, 1981, 103, 3081.
O O
N
N
CH2OMe
t-BuLi
O O
N
N
CH2OMe
Li
BOMCl
aq. CuCl O O
O
CH2OCH2Ph
84%94% ee
Enders, Syn Comm. 1999, 29, 27.
C-2 Symmetric Amine Auxiliaries
N
OMOM
OMOM
O LDA
EtI
N
OMOM
OMOM
OLi
N
OMOM
OMOM
O
CH3
CH3
Z-enolate
O
CH3
CH3
HO
Yamaguchi, TL, 1984, 25, 857.
de>95%
1N HClreflux
Catalytic Methods for Asymmteric Alkylation
N
N
O
H
H
Br-
chiral phase-transfer catalyst
O
NOtBu
Ph
Ph
1
1, 10mol%
CsOH•H2O
+ R-X
O
NOtBu
Ph
Ph R
R= -(CH2)4Cl -(CH2)2CO2CH3 -(CH2)2COEt
%ee 99 95 91 99
O
Corey, TL, 1998, 39, 5347.
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