Page 125 - Advanced Organic Chemistry Part B - Reactions & Synthesis

Table 2.3. Summary of Stereoselectivity for Aldol Addition Reactions 97

Y β H R Z OM Y β OH O SECTION 2.1
+ 5 4 2 1 Aldol Addition and
R O R E R 1 R 3 R Condensation Reactions
X α X α E
R Z R
Aldehyde Steric Aldehyde Chelate Aldehyde Polar
(Felkin) Control TS Substituent Control

Cyclic TS
α
α X = alkoxy
α
3,4-syn for X = medium X = alkoxy 3,4-syn
β
Y = alkoxy 3,5-anti E-enolate 2,3-anti, 3,4-weak
E-enolate 2,3-anti, 3,4-syn Z-enolate 2,3-syn,3,4-anti

β
Z-enolate 2,3-syn, 3,4-anti Y = alkoxy 3,5-anti
Open TS
α
3,4-syn for X = medium

based on structural effects in the reactant aldehyde. These general principles have
been applied to the synthesis of a number of more complex molecules. Table 2.3
summarizes the relationships discussed in this section.
Scheme 2.3 shows reactions of several substituted aldehydes of varying
complexity that illustrate aldehyde facial diastereoselectivity in the aldol and
Mukaiyama reactions. The stereoselectivity of the new bond formation depends on the
effect that reactant substituents have on the detailed structure of the TS. The 3,4-syn
stereoselectivity of Entry 1 derives from a Felkin-type acyclic TS.

+
CH3 O BF 3 – CH 3 OBF 3 – O OH
Ph
Ph CH CCH Ph
TBDMSO 3 2 CH
CH 2 H H O H H 3 CH 3
CH 3

Entry 2 shows an E-enolate of a hindered ester reacting with an aldehyde
having both an -methyl and -methoxy group. The reaction shows a 13:1 preference
for the Felkin approach product (3,4-syn) and is controlled by the steric effect of
the -methyl substituent. Another example of steric control with an ester enolate
is found in a step in the synthesis of (+)-discodermolide. 99 The E-enolate of a
hindered aryl ester was generated using LiTMP and LiBr. Reaction through a Felkin
TS resulted in syn diastereoselectivity for the hydroxy and ester groups at the
new bond.

99
I. Paterson, G. J. Florence, K. Gerlach, J. P. Scott, and N. Sereinig, J. Am. Chem. Soc., 123, 9535
(2001).