Page 61 - Advanced Organic Chemistry Part B - Reactions & Synthesis

33

SECTION 1.2
Alkylation of Enolates

Fig. 1.5. Minimum energy structure of dili-
thium derivative of di-iso-propyl malate.
Reproduced from Helv. Chim. Acta, 85, 4216
(2002), by permission of Wiley-VCH.

∗
group as well as the C(3). HF/6-31G computations indicate that tricoordinate structures
are formed, such as that shown for the di-iso-propyl ester in Figure 1.5. Curiously, the
highest diastereoselectivity (19:1) is seen with the di-iso-propyl ester. For the dimethyl,
diethyl, and di-t-butyl esters, the ratios are about 8:1. The diastereoselectivity is even
higher (40:1) with the mixed t-butyl-iso-propyl ester. This result can be understood
by considering the differences in the si and re faces of the enolates. In the di-t-butyl
ester, both faces are hindered and selectivity is low. The di-iso-propyl ester has more
hindrance to the re face, and this is accentuated in the mixed ester.
favored by 19:1 favored by 7:1 favored by 4.5:1 favored by 40:1

Li O – H Me Li O - Me Me O Li O – Me Me Li – H Me
–
-
Li O – O Me Li O O Me Li O Me Li O - O O Me
O O O O O O
O H O
H Me Me
Me Me Me Me Me
Me Me Me
increased hindrance increased hindrance increased hindrance

at both faces at si face at re face
Alkylations of this type also proved to be sensitive to the cation. Good stereo-
selectivity (15:1) was observed for the lithium enolate, but the sodium and potassium
75
enolates were much less selective. This probably reflects the weaker coordination of
the latter metals.
HO HO
CO 2 CH(CH ) 2eq. base CO CH(CH )
3 2
3 2
2
(CH ) CHO C (CH ) CHO C
3 2
2
2
3 2
ArCH Br
2
base yield anti:syn OCH 3
LiHMDS 80 15:1
OCH Ph
2
NaHMDS 45 1:2
KHMDS 20 1:1
Carboxylic acids can be directly alkylated by conversion to dianions with two
equivalents of LDA. The dianions are alkylated at the -carbon, as would be expected,
because the enolate carbon is more strongly nucleophilic than the carboxylate anion. 76
75 M. Sefkow, J. Org. Chem., 66, 2343 (2001).
76
P. L. Creger, J. Org. Chem., 37, 1907 (1972); P. L. Creger, J. Am. Chem. Soc., 89, 2500 (1967);
P. L. Creger, Org. Synth., 50, 58 (1970).