Page 216 - Advanced Organic Chemistry Part B - Reactions & Synthesis

188 enolate addition to acceptors with two anion-stabilizing groups. Entry 8 is noteworthy
in that it creates two contiguous quaternary carbons. Entry 9 shows an addition of
CHAPTER 2 an amide anion. Entry 10 is a case of an enolate stabilized by both the dithiane ring
Reactions of Carbon and ester substituent. The acceptor, an , -unsaturated lactam, is relatively unreactive
Nucleophiles with
Carbonyl Compounds but the addition is driven forward by formation of a new bond. The chiral moiety
incorporated into the five-membered ring promotes enantioselective formation of the
new stereocenter.
There have been several studies of the stereochemistry of conjugate addition
reactions. If there are substituents on both the nucleophilic enolate and the acceptor,
either syn or anti adducts can be formed.

O – O O R 3 O O R 3 O
R 1 + R 3 R 4 R 1 R 4 + R 1 R 4
R 2 R 2 R 2
syn anti
The reaction shows a dependence on the E-or Z-stereochemistry of the enolate.
Z-enolates favor anti adducts and E-enolates favor syn adducts. These tendencies
can be understood in terms of an eight-membered chelated TS. 299 The enone in this
TS is in an s-cis conformation. The stereochemistry is influenced by the s-cis/s-
4
trans equilibria. Bulky R groups favor the s-cis conformer and enhance the stereo-
selectivity of the reaction. A computational study on the reaction also suggested an
eight-membered TS. 300

R 4 R 4 3
O O O O R O
R 2 O Li R 2 4
R 1 R 1 R 1 R
R 3 H R 3 H R 2
H H
Z-enolate anti
R 4 R 4 R 3
O O O O
H O Li H O 1 R 4
R 1 R 1 R 2
R 3 H R 3 H R
R 2 E-enolate R 2 syn
The carbonyl functional groups are the most common both as activating EWG
substituents in the acceptor and as the anion-stabilizing group in the enolate, but several
other EWGs also undergo conjugate addition reactions. Nitroalkenes are excellent
acceptors. The nitro group is a strong EWG and there is usually no competition from
nucleophilic attack on the nitro group.
O O
1) LDA, THF, –78°C NO 2
2) CH 2 CHNO 2
3) pH4 72%
Ref. 301
299 D. Oare and C. H. Heathcock, J. Org. Chem., 55, 157 (1990); D. A. Oare and C. H. Heathcock,
Top. Stereochem., 19, 227 (1989); A. Bernardi, Gazz. Chim. Ital., 125, 539 (1995).
300
A. Bernardi, A. M. Capelli, A. Cassinari, A. Comotti, C. Gennari, and C. Scolastico, J. Org. Chem.,
57, 7029 (1992).
301 R. J. Flintoft, J. C. Buzby, and J. A. Tucker, Tetrahedron Lett., 40, 4485 (1999).