Page 97 - Advanced Organic Chemistry Part B - Reactions & Synthesis

A similar preference for formation of the syn aldol is found for other Z-enolates derived 69
from ketones in which one of the carbonyl substituents is bulky. Ketone enolates
with less bulky substituents show a decreasing stereoselectivity in the order t-butyl > SECTION 2.1
i-propyl > ethyl. 2c This trend parallels a decreasing preference for stereoselective Aldol Addition and
Condensation Reactions
formation of the Z-enolate.

O OH
LDA CH 3 R H R PhCH O O OH
CH CH CR +
2
3
+ R Ph R Ph
–
–
O H O Li + CH 3 O Li +
CH 3
E:Z CH 3
2,3-anti:syn
R = C H 70:30 36:64
2 5
CH(CH ) 40:60 18:82
3 2
C(CH ) 2:98 2:98
3 3
The enolates derived from cyclic ketones are necessarily E-isomers. The enolate
of cyclohexanone reacts with benzaldehyde to give both possible stereoisomeric
products. The stereoselectivity is about 5:1 in favor of the anti isomer under optimum
conditions. 6
–
O Li + O OH O OH
H H
–78°C Ph Ph
+ PhCH O +
THF
syn 16%
anti 84%
From these and many related examples the following generalizations can be made
about kinetic stereoselection in aldol additions of lithium enolates. (1) The chair TS
model provides a basis for analyzing the stereoselectivity observed in aldol reactions of
ketone enolates having one bulky substituent. The preference is Z-enolate → syn aldol;
E-enolate → anti aldol. (2) When the enolate has no bulky substituent, stereoselectivity
is low. (3) Z-Enolates are more stereoselective than E-enolates. Table 2.1 gives some
illustrative data.
The requirement that an enolate have at least one bulky substituent restricts the
types of compounds that give highly stereoselective aldol additions via the lithium
enolate method. Furthermore, only the enolate formed by kinetic deprotonation is
directly available. Whereas ketones with one tertiary alkyl substituent give mainly the
Z-enolate, less highly substituted ketones usually give mixtures of E- and Z-enolates. 7
(Review the data in Scheme 1.1.) Therefore efforts aimed at increasing the stereo-
selectivity of aldol additions have been directed at two facets of the problem: (1)
better control of enolate stereochemistry, and (2) enhancement of the degree of
stereoselectivity in the addition step, which is discussed in Section 2.1.2.2.
The E:Z ratio can be modified by the precise conditions for formation of the
enolate. For example, the E:Z ratio for 3-pentanone and 2-methyl-3-pentanone can
be increased by use of a 1:1 lithium tetramethylpiperidide(LiTMP)-LiBr mixture for

6 M. Majewski and D. M. Gleave, Tetrahedron Lett., 30, 5681 (1989).
7
R. E. Ireland, R. H. Mueller, and A. K. Willard, J. Am. Chem. Soc., 98, 2868 (1976); W. A. Kleschick,
C. T. Buse, and C. H. Heathcock, J. Am. Chem. Soc., 99, 247 (1977); Z. A. Fataftah, I. E. Kopka, and
M. W. Rathke, J. Am. Chem. Soc., 102, 3959 (1980).