9 asymmetric alkylation of enolates

Myers

Asymmetric Alkylation of Enolates

• An early milestone in the use of a chiral auxiliary for asymmetric alkylation:
Cl
H2N

OH
HO

C6H5

OEt

• Application to iterative assembly of 1,3,n-substituted carbon chains by Evans et al. in
synthesis of ionomycin:

O

KOt-Bu, CH3I

NH2

• Strongly nucleophilic prolinol amide enolates react with "-branched alkyl halides.

C6H5

CH3

CH3

N

CH3O

OH
O

LDA; EtI
2-Oxazolines as
carboxyl equivalents

C6H5

O
HO

CH3

N

Ph
CH3 CH3

Ph

I
CH3

dr 97 : 3

CH3

N

CH3O

84%

CH2CH3

N

OH
O

KH, LDA;

O

3-6 N HCl

CH3

Chem 115

83%

CH2CH3

aq. HCl, 100 °C;

latent aldehyde

NaOH

78% ee

91%
O

Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J. Am. Chem. Soc. 1976, 98, 567-576.

SO2Ph

TDSO

Ph

HO

CH3 CH3

CH3 CH3

• Prolinol amide enolates provided an important advance:
PhSO2
OH
CH3CH2COCl
NH

OH
O
N

Et3N

16
14

CH3

OTBDPS

CH3 CH3
• 3° amides
form Z-enolates
selectively

2 LDA

(S)-2-Pyrrolidinemethanol

12

O

OLi
OLi
CH3

N

H

H

H

CH3
CH3

O
HO

CH3
CH2C6H5

1 N HCl, !

BnBr

N
92%

CH3
CH2C6H5

Evans, D. A.; Takacs, J. M.; Tetrahedron Lett. 1980, 21, 4233.
Sonnet, P.; Heath, R. R. J. Org. Chem. 1980, 45, 3137.

75% yield, 76% de

O

OH

OH
Ca

OH
16

OH
O

CH3

CH3
CH3

14

O

O

O
O

12

CH3 CH3

CH3 CH3 CH3

Ionomycin Calcium Complex

Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc.
1990, 112, 5290-5313.

1


Evans Oxazolidinone Auxiliaries in Asymmetric Synthesis: Alkylations

Myers

Chem 115

Evans Oxazolidinone Auxiliaries in Asymmetric Synthesis: Alkylations
Acylation provides imides, closer to esters than amides in terms of acidity,
enolate nucleophilicity and cleavage chemistry:

As originally introduced, two enantio-complimentary reagents:
O
O

NH

n-BuLi, THF, –78˚C;
O

NH

O
CH3

(4R, 5S)-(+)-4-Methyl-5-phenyl-2-oxazolidinone

Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am Chem. Soc. 1982, 104, 1737-1739.

O

O

NH

CH2CH3

N

PrCOCl, 80-90%

CH3
H3C

Evans, D. A.; Bartroli, J.: Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127-2129.
Z-Enolates are formed with very high selectivity. Chelated geometry presumed in
ground and transition states:

O
O

O

O

O

H3C

Several oxazolidinones are now commercially available, in both enantiomeric forms:
O

NH
CH3

CH3

H3C
(S)-(!)-4-Isopropyl-2-oxazolidinone

O

O

O

O
CH2CH3

N

NH

O

LDA, THF

O

Li

O
CH2CH3

N

–78 ˚C

CH3

CH3

H3C

H3C

BnBr, –78 ˚C
(S)-(!)-4-Benzyl-2-oxazolidinone

(S)-(+)-4-Benzyl-2-oxazolidinone

O

O

O
O

92%

O

NH

O

NH

O
CH2CH3

N

Bn
CH3
H3C

(S)-(!)-4-Phenyl-2-oxazolidinone

(S)-(+)-4-Phenyl-2-oxazolidinone
O

O
O

O

O

NH

>99:1

O

NH

N

CH3

CH3

CH3

O

O

CH2CH3

LDA; BnBr
78%

O

O
CH2CH3

N

Bn
CH3

>99:1

H3C
(4S,5R)-(!)-4-Methyl-5-phenyl-2-oxazolidinone

(R)-(+)-4-Phenyl-2-oxazolidinone

Evans, D. A.; Ennis, M. D.; Mathre, D. J. . J. Am. Chem. Soc. 1982, 104, 1737-1739.

2


• Less reactive (non-allylic/benzylic) electrophiles require use of sodium enolates or triflate as
leaving group:
O

O

O
CH3

N

O

NaN(TMS)2, THF
O

–78 ˚C; EtI

O

O
CH3

N

CH3

N

O

Exercise: Why are the products configurationally stable?
O O
O

CH3
LDA, THF, –78 ˚C;
O N
CH3
EtCOCl
CH3
88%
H3C

O

Et

53%

CH3

• Highly diastereoselective acylation of imide enolates is possible:

CH3

CH3

H3C

94 : 6
Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737-1739.

Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737-1739.
O

O

• Diastereoselective hydroxylation has been demonstrated:
O

O
CH3

N

O

LDA, –78 ˚C;

O

CH3

CH3

O
O

O
SO2Ph
N
(±) 1.5 equiv

O
N

CH3

O

O

CH3 CH3

CH3

CF3SO3

• note selective enolization of imide
over ester

NaN(TMS)2 (1 equiv), THF, –78 ˚C

CH3

LDA, –78 ˚C;

• sodium enolate required
OCH3

N

<5% alkylation
I

O

O

CH3

O
OCH3

N

OH
>95% de

68%

Decicco, C. P.; Grover, P. J. Am. Chem. Soc. 1996, 61, 3534-3541.

CH3

• Auxiliary cleaved with Mg(OMe)2
with little to no epimerization

96 : 4
pure isomer: 68% yield

Evans, D. A.; Morissey, M. M.; Dorow, R. L. J. Am. Chem. Soc. 1985, 107, 4346-4348.

see also: Williams, D. R.; McGill, J. M. J. Org. Chem. 1990, 55, 3447-3459.

• Asymmetric azidation provides a route to !-amino acid derivatives:
• Titanium enolates provide a route for diastereoselective SN1-like coupling reactions:
O
O

O
N

Bn

CH3

O

TiCl4, (i-Pr)2NEt;
(CH3O)3CH
95%

O

O

O
N

Bn

O

CH3

CH(OCH3)2
99 : 1

Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc.
1990, 112, 8215-8216.

O

O
N

t-Bu

KHMDS, TrisylN3, –78 ˚C;
HOAc, –78"0 ºC
90%

O

O
t-Bu

N

N3
>99 : 1

Trisyl = 2,4,6-triisopropylbenzenesulfonyl
Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112,
4011-4030.

3


CH3

Alkylation of Pseudoephenamine and Pseudoephedrine Amides:

CH3

NHCH3

• Enolates are formed using 1.95–2.2 equiv LDA.

NHCH3

OH

• Alkylations are highly diastereoselective.

OH

(R,R)-(–)-Pseudoephedrine

• LiCl (~6 equiv) promotes a rapid, clean reaction.

(S,S)-(+)-Pseudoephedrine

• Pseudoephedrine is a commodity chemical, manufactured on multi-ton scale/annum. Its use
is highly regulated in many countries.

Mnemonic:

R

O

N
OH CH3
NHCH3

NHCH3

OH

(S,S)-(–)-Pseudoephenamine

R1

1,4-syn

R = CH3 or Ph

• Epoxides approach from the opposite enolate π-face.

• Use of pseudoephenamine is not restricted; it appears to be a superior auxiliary in many
instances.

O
R3

Morales, M.R.; Mellem, K.T.; Myers, A.G. Angew. Chem. Int. Ed., 2012, 51, 4568–4571.
Preparation of Pseudoephedrine and Pseudoephenamine Amides:
O
R1 O
R2
R1
X
N
NHCH3
OH
CH
OH
3

O

N
OH CH3 R2

2. R2X

R = CH3 or Ph

OH

(R,R)-(+)-Pseudoephenamine

R

1. LDA, LiCl
R1

OLi

R2

R1

R2

X

Yield (%)

mp (ºC)

Ph

CH3

EtCO2

88

188–191

Ph

Et

n-PrCO2

83

133–135

Ph

Bn

Cl

80

147–149

Ph

n-Bu

R'CH2CO2

70

88–90

CH3

CH3

CH3O*

89

114–115

CH3

Ph

Cl

88

145–146

CH3

Cl

Cl

90

79–81

CH3

i-Pr

Cl

92

73–74

CH3

3-pyridyl

(H3C)3CCO2

97

117.5–118.5

H

H

R1

N
H3C

OLi

R2
H

R3X

• Askin et al. reported this type of selectivity reversal for
epoxide electrophiles with prolinol amide enolates and
proposed that the Li cation coordinates and directs the
epoxide opening:

OBn
I
OTBS
H OLi
OLi

N

R

H

OBn
*Even unactivated esters react (under basic conditions), presumbly by transesterification
followed by intramolecular O!N Acyl Transfer
Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.: Kopecky, D. J.; Gleason, J. L.
J. Am. Chem. Soc. 1997, 119, 6496-6511.
Morales, M.R.; Mellem, K.T.; Myers, A.G. Angew. Chem. Int. Ed., 2012, 51, 4568–4571.

Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428.

O

Askin, D.; Volante, R. P.; Ryan, K. M.; Reamer, R. A.; Shinkai, I. Tetrahedron Lett.
1988, 29, 4245.
Kevin Mellem

4


Reduction of Alkylation Products:
Diastereoselective Alkylation Reactions:
R1

O

• Lithium amidotrihydroborate (LiH2NBH3 (LAB)), prepared by deprotonation (LDA)
of commercial, crystalline ammonia-borane complex, provides primary alcohols:
R1

1. LDA, LiCl
R2

N
OH CH3

O

N
OH CH3 R3

2. R3X

R2

CH3 O

R1

R2

R3X

temp (˚C)

crude (isol) de (%)

isol yield (%)

Ph

CH3

BnBr

0

90 (≥99)

85

Ph

CH3

EtI

0

88 (96)

96

Ph

n-Bu

CH3I

0

90 (96)

84

Ph

Bn

n-BuI

–78

≥99 (≥99)

99

CH3

CH3

BrCH2CO2t-Bu

–78

94 (96)

78

CH3

Ph

EtI

0

96 (≥99)

92

CH3

i-Pr

BnBr

0

98 (≥99)

83

CH3

t-Bu

BnBr

0

98 (≥99)

84

Cl

BnBr

–45

90 (≥99)

88

CH3

LAB, THF
OTIPS

N
OH CH3 CH3 CH3

OTIPS

HO

23 ˚C, 1 h

CH3 CH3

98%

98% de

97% ee

Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996, 37, 3623.
Myers, A. G.; Yang, B. H.; Chen, H.; Kopecky, D. J. Synlett 1997, 5, 457.
• Semi-reduction with Brown's lithium triethoxyaluminium hydride provides aldehydes directly
but it can be complicated by low yields, epimerization of the "-stereocenter, and formation of
a stable aminal intermediate:

CH3 O
N
OH CH3 Bn

n-Bu

O

LiAlH(OEt)3
hexanes-THF, 0 ˚C

Bn

82%

97% ee

≥99% de

Hydrolysis of Alkylation Products:
• Occurs under acidic or basic conditions. Both methods likely involve initial N!O acyl
transfer.
• Strongly acidic conditions are required, but are well tolerated by many simple substrates.

n-Bu

H

Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am.
Chem. Soc. 1997, 119, 6496-6511.

Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 86, 1089.
Addition of Alkyllithium Reagents to form Ketones:

O
Bn
N
OH CH3 n-Bu

O

H2SO4, dioxane
reflux

Bn

HO

93%

O
O

n-Bu
97% ee

≥99% de

• Alkaline conditions work well with many substrates, but not those susceptible to facile
epimerization ("-aryl).
CH3 O

n-Bu

N
OH CH3 CH3
≥99% de

93%

–78 ! 0 ˚C
95%

≥97% de

CH3

n-Bu

≥95% ee

O

n-Bu4NOH, t-BuOH, H2O
reflux

N
OH CH3

CH3

n-BuLi (2.4 eq), Et2O

HO

n-Bu
O

CH3
97% ee

Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am.
Chem. Soc. 1997, 119, 6496-6511.
Morales, M.R.; Mellem, K.T.; Myers, A.G. Angew. Chem. Int. Ed., 2012, 51, 4568–4571.

O
CH3
N
OH CH3 n-Bu
≥96% de

PhLi (2.4 eq), Et2O
–78 ! 0 ˚C
96%

CH3

Ph

n-Bu
≥93% ee
Kevin Mellem

5


Application to the Iterative Synthesis of 1,3,n-Substituted Carbon Chains:
>199:1

>199:1
CH3
H

O

(EtCO)2O, Et3N

N
OH CH3

CH3

X!+

95%

O

LDA, LiCl; BnBr
90%

1

LAB

Bn

X!+

90%

CH3

I

CH3

PPh3, I2, Im

Bn
CH3

98%

Bn

O

O

LAB

LDA, LiCl, 1

Bn

X!+

95%

97%

CH3 CH3

CH3 CH3

LDA, LiCl, ent-1
95%

93%

LDA, LiCl, ent-1

X!"

LAB

142:1

O
CH3 CH3 CH3

LAB

93%

CH3 CH3 CH3
"matched"

91%

LAB

66:1

Bn
CH3 CH3 CH3

60% yield, 9 steps
94.1% final de

HO

Bn

X!"

"mismatched"

70:1

HO

199:1

X!+

CH3 CH3 CH3

93%

58% yield, 9 steps
95.7% final de

94%

Bn

"mismatched"

CH3 CH3 CH3

93%
O
Bn

"matched"

Bn

LDA, LiCl, ent-1

66:1

O
CH3 CH3 CH3

HO

LDA, LiCl, 1

96%

O

LAB

97%

CH3 CH3

70 : 1

X!+

PPh3, I2, Im

Bn

I

142 : 1
Bn

CH3 CH3

"mismatched"

CH3 CH3

LDA, LiCl, 1

Bn

HO

96%

CH3 CH3

Bn

I

97%

LAB

Bn

X!"

"matched"

PPh3, I2, Im

55 : 1

58 : 1

>99:1

>99:1

HO

Bn

HO

89%

199:1
Bn

CH3 CH3 CH3
56% yield, 9 steps
92.6% final de

HO

Bn
CH3 CH3 CH3

57% yield, 9 steps
94.7% final de

Myers, A. G.; Yang, B. H.; Chen, H.; Kopecky, D. J. Synlett 1997, 5, 457-459.

6


Construction of Quaternary Centers

R1

R

LDA,
LiCl

O

N
CH3
OH CH3 CH3

THF
0 ºC

Matched
R = CH3 or Ph

OLi

X"+

O

BnBr
CH3

CH3

X"+

DMPU
–40 ºC

Z-enolate

CH3
H3C Bn

95%, 9.9:1 dr

R2

R2

Ph
Ph

O

N
R2
OH CH3R3 CH3

2. R3X, DMPU

OH CH3 CH3
R1

R1

1. LDA, LiCl, 0 ºC

N

• Pseudoephenamine and pseudoephedrine can be used to direct the formation of quaternary
centers by two methods: enolization–alkylation or conjugate addition–alkylation.

Enolization–Alkylation:

O

R3X

temp (˚C)

crude dr

isol yield (%)

CH3

BnBr

–40!0

≥19:1

85

CH3

allylBr

–40!0

≥19:1

99

≥19:1

87

Ph

n-Pr

BnBr

–40!0

Ph

Ph

allylBr

–40!0

≥19:1

82

CH3

Ph

EtI

–40

6.2:1

87

BnBr

–40

19:1

90

CH3

vinyl

Conjugate Addition–Alkylation:
R

LDA,
LiCl

O

N
CH3
OH CH3 CH3

THF
0 ºC

Mismatched

OLi
X"+

CH3

CH3
E-enolate

O

BnBr
X"+

DMPU
–40 ºC

Bn

CH3
CH3

89%, 5.2:1 dr

R = CH3 or Ph

O
N
OH CH3 CH3

1. CH3Li (1.0 eq),
LiCl, THF
–78 ºC
2. t-BuLi
–78!–40 ºC

OLi
X#–

t-Bu
CH3

Kummer, D. A.; Chain, W. J.; Morales, M. R.; Quiroga, O.; Myers, A. G. J. Am. Chem. Soc.
2008, 130, 13231–13233.

Br
–40 ºC

Mnemonic:

O
X#–
O
N

O

1. LDA, LiCl
R1

OH CH3 H CH3

2. R2X, DMPU

t-Bu
H3C

N

R1

85%, ≥19:1 dr

OH CH3 R2 CH3
• Even bulky organolithium reagents such as tert-buyllithium are suitable reagents for this
transformation.

Retention of stereochemistry.
Morales, M. R.; Mellem, K. T.; Myers, A. G. Angew. Chem. Int. Ed., 2012, 51, 4568–4571.
E. Reyes, J. L. Vicario, L. Carrillo, D. Badia, A. Iza, U. Uria, Org. Lett. 2006, 8, 2535–2538.

Kevin Mellem

7


Myers

Asymmetric Alkylation of Enolates
R1

1. CH3Li, LiCl, –78 ºC
2. R3Li, –78" –40 ºC

O

N
OH CH3 R2

O

R1

R3
N
R
R
2
4
OH CH3

3. R4X, –40 ºC

Chem 115

Addition of alkyllithium reagents to form ketones:
CH3 O
N

CH3
Bn CH3

OH CH3
R1

R2

R3

R4X

crude dr

isol yield (%)

Ph

CH3

n-Bu

BnBr

≥19:1

75

Ph

CH3

Ph

AllylBr

≥19:1

80

Ph

Et

t-Bu

CH3I

≥19:1

79

CH3I

Ph

n-pentyl

t-Bu

≥19:1

76

CH3

CH3

n-Bu

allylBr

11.1:1

72

CH3

CH3

t-Bu

allylBr

12.5:1

98

CH3

Et

t-Bu

CH3I

9.1:1

99

CH3

Et

Ph

CH3I

19:1

89

O

CH3Li, HMPA
Et2O
–78"0 ºC

H3C
Bn

CH3
CH3

93%

Reduction to form aldehydes:

Ph

CH3 O

Tf2O, pyr

CH3
N
Ph Bn
OH CH3

CH2Cl2, 0 ºC

O
H3C

N
CH3
TfO H3C Ph Bn
oxazolinium triflate
Red-Al
THF, 0 ºC;
then HCl-TFA

Transformations of !-quaternary pseudoephenamine and pseudoephedrine amides

90 % (two steps)

O

Hydrolysis of !-quaternary alkylation products:

CH3

H
CH3 O
N

CH3
Bn CH3

OH CH3

O

n-Bu4NOH
H2O/dioxane
115 ºC

Ph

HO
Bn

CH3
CH3

Bn

LAB reduction to form primary alcohols:

94%
Kummer, D. A.; Chain, W. J.; Morales, M. R.; Quiroga, O.; Myers, A. G. J. Am. Chem. Soc.
2008, 130, 13231–13233.

O

LAB
t-Bu

N
OH CH3

H3C

CH3

THF, 60 ºC

HO

t-Bu
CH3

98%

H3C

Kevin Mellem

8


Myers

Asymmetric Alkylation of Enolates
• Enders chiral hydrazone methodology:

• Helmchen camphor-derived auxiliaries:

H3C

CH3 SO2Ph
N
OH
CH3

CH3

Chem 115

H3C

CH3SO2Ph
N
O
CH3

CH3

CH3
CH3

O
CH3

O

H
CH2OCH3

84%
94% ee

O

H3C CH3

LICA, THF –78 ˚C
BnBr (95%); LiAlH4
CH2Ph
HO

N

N

t-BuLi, –78 ˚C;
BOMCl,–-100 ˚C;
aq. CuCl2

er 94 : 6

CH3

O
CH2OCH2Ph
O

O

H3C CH3

(S)-(+)-1-Amino-2-(methoxymethyl)
pyrrolidine [SAMP-Hydrazone]
Enders, D. In Asymmetric Synthesis; Morrison, J. D.; Academic Press: New York,
1984; Vol. 3, Chapter 4.

Enders, D.; Hundertmark, T.; Lazny, R. Syn. Comm. 1999, 29, 27-33.
Schmierier, R.; Grotemeier, G.; Helmchen, G.; Selim, A. Angew. Chem., Int. Ed. Engl. 1981,
20, 207-208.
• Oppolzer camphorsultam auxiliaries in asymmetric alkylation:
H3C

CH3

NaH;
NH

H3C

• An alternative oxazolidinone-based auxiliary allows !-alkylation of ketones with excellent
stereoselectivities. The ease of synthesis and removal of the auxiliary makes it a practical
alternative to the traditional RAMP/SAMP methodology:

CH3

CH3

H3C

CH3

H3C

O

CH3CH2COCl

CH3

N

O

S
O
O

S

O
O

N
H3C

(1S)-(–)-2,10-Camphorsultam

N
O

1. LDA, THF
–78 ºC
N

Br

2.

CH3

O

94%

N
O

H3C

HMPA, C6H5CH2Br

1. LDA, THF
–78 ºC
2. 4-BrC6H4CH2Br

89%

89%, dr = 97 : 3

NaN(TMS)2;

H3C

HO

O

O

O
CH3
CH2C6H5

LiOH, H2O2

O

O

CH3
CH3

N
S
O
O

CH2C6H5

p-TsOH
acetone, 23 ºC

H3C
Br

N

N

Ph
Ph
Bn

H3C

94%

Br

97% de
Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30, 5603-5606.

Lim, D.; Coltart, D. M. Angew. Chem., Int. Ed. Engl. 2008, 47, 5207–5210.

Fan Liu

9


Myers

Catalytic Methods for Asymmetric Alkylation

• An early, remarkable result from the Merck Process group:

H

N

Br –

Chem 115

• Corey and co-workers have developed catalysts that are highly enantioselective:
Br "

0.11 g
H

N+

OH
N
Cl

O

CF3

O

Cl

CH3Cl, C7H8-50% NaOH

Cl

Cl

20 ºC, 18h, 95%

H3CO

O

CH3

O

O

H3CO

0.61g

N

Ph
92% ee

N

CsOH•H2O, CH2Cl2

Ot-Bu

–78 ˚C, 24 h

Ph

• Although limited to a single example, this provided a dramatic illustration of the potential of
chiral phase-transfer catalysis for C-C bond formation.

Ot-Bu
O
O

O
CH3

O

O

Dolling, U.; David, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446-447.

N
Ph

O

Br

Ph

CH3
81%, 96% ee

1.5 equiv

• The method was adapted by O'Donnell, who had earlier developed a PT method for the
synthesis of racemic !-amino acids:

Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414-12415.
Cl –
H

N
Phosphazene bases can also be used with the catalyst above, see: O'Donnel, M. F.;

Delgado, F.; Hostsettler, C.; Schwesinger, R. Tetrahedron Lett. 1998, 39, 8775-8778.

OH
N
O
Ph

N

O

CH2Cl2 - 50% NaOH

Ot-Bu

Ph

19.2 g (65 mmol)

Ot-Bu

Ph

25 ˚C, 15 h, 95%

Ph

N

Br

64% ee

Cl

O

OTMS
MeLi - LiBr (1 equiv), C7H8, 23 ˚C;

Cl
crystallization
O
H2N

• Koga and co-workers have developed chiral additives for the asymmetric alkylation of
lithium enolates. The work has been extended to include examples that employ additives
in catalytic amounts:

(CH3)2NCH2CH2CH2N(CH3)2 (2 equiv),
BnBr (10 equiv), "45 ˚C, 18h

6N HCl, ∆

OH

16.8 g (>99% ee)

N

H
N
Ph

6.5 g, >99% ee,
50% overall

Cl

O' Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353-2355.

CH2Ph

N
CH3

76%, 96% ee

CH3
N
CH3

0.05 equiv
Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K. J. Am. Chem. Soc. 1994, 116,
8829-8830.

10