Page 70 - Advanced Organic Chemistry Part B - Reactions & Synthesis

42 In 12 the upper face is shielded by the isopropyl group, whereas in 13 the lower face is
shielded by the methyl and phenyl groups. As a result, alkylation of the two derivatives
CHAPTER 1 gives products of the opposite configuration. The initial alkylation product ratios are
Alkylation of Enolates typically 95:5 in favor of the major isomer. Since these products are diastereomeric
and Other Carbon
Nucleophiles mixtures, they can be separated and purified. Subsequent hydrolysis or alcoholysis
provides acids or esters in enantiomerically enriched form. Alternatively, the acyl
imides can be reduced to alcohols or aldehydes. The final products can often be
obtained in greater than 99% enantiomeric purity.
A number of other types of chiral auxiliaries have been employed in enolate
alkylation. Excellent results are obtained using amides of pseudoephedrine. Alkylation
93
occurs anti to the -oxybenzyl group. The reactions involve the Z-enolate and there
is likely bridging between the two lithium cations, perhaps by di-(isopropyl)amine. 94

OLi
H LiO
H
N R
CH 3
H
CH 3
C
X
OLi
CH 3 1) LDA, O
CH 3
CH 3 LiCl
N N CH 3
OLi CH 3 2) n-BuI OH CH 3 CH 3
Both enantiomers of the auxiliary are available, so either enantiomeric product
can be obtained. This methodology has been applied to a number of enantioselective
syntheses. 95 For example, the glycine derivative 14 can be used to prepare -amino
acid analogs. 96
1) LiHMDS,
O O
CH 3 LiCl (3.2 eq.) CH 3
NH 2 .H 2 O NH 2
N N
2) CH 2 I 79%
14 OH CH 3 OH CH 3 91:9 dr
97
Enolates of phenylglycinol amides also exhibit good diastereoselectivity. A chelating
interaction with the deprotonated hydroxy group is probably involved here as well.
1)s-BuLi, Ph
Ph O O
LiCl, – 78°C
HO
HO CH 3 N CH 3
N
2) PhCH 2 Br CH 2 Ph
CH 3
CH 3
The trans-2-naphthyl cyclohexyl sulfone 15 can be prepared readily in either
enantiomeric form. The corresponding ester enolates can be alkylated in good yield
98
and diastereoselectivity. In this case, the steric shielding is provided by the naphthyl
93
A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky, and J. L. Gleason, J. Am. Chem.
Soc., 119, 6496 (1997); A. G. Myers, M. Siu, and F. Ren, J. Am. Chem. Soc., 124, 4230 (2002).
94 J. L. Vicario, D. Badia, E. Dominguez, and L. Carrillo, J. Org. Chem., 64, 4610 (1999).
95
S. Karlsson and E. Hedenstrom, Acta Chem. Scand., 53, 620 (1999).
96
A. G. Myers, P. S. Schnider, S. Kwon, and D. W. Kung, J. Org. Chem., 64, 3322 (1999).
97 V. Jullian, J.-C. Quirion, and H.-P. Husson, Synthesis, 1091 (1997).
98
G. Sarakinos and E. J. Corey, Org. Lett., 1, 1741 (1999).