1,4-Addition of Nucleophiles to -Unsaturated Carbonyl Compounds - Carbohydrates: Tools for Stereoselective Synthesis - page 247

12

1,4-Addition of Nucleophiles to α , β -Unsaturated Carbonyl
Compounds
Yolanda Díaz, M. Isabel Matheu, David Benito and Sergio Castillón

12.1
Copper-Catalyzed Reactions - Introduction

The conjugate addition reaction is a major synthetic transformation and has con-
sequently been employed in numerous total syntheses [1]. Although several soft
carbon nucleophiles such as malonates easily undergo this reaction, harder carbon
nucleophiles such as classical organometallic reagents need the presence of a
transition metal to avoid direct attack on the carbonyl group of the Michael accep-
tor. Traditionally, copper has found the broadest application, and various organo-
copper species have been widely used [2].
Four decades ago, it was already obvious that an asymmetric version of conju-
gate addition would be of great interest and, currently, the asymmetric conjugate
addition of carbon nucleophiles to -unsaturated carbonyl compounds is a

useful method for the formation of single carbon-carbon bonds and the synthesis
of chiral compounds [3]. There are several ways to tackle the problem: by func-
tional group transformation, using chiral auxiliaries or reagents, or via the intro-
duction of chiral ligands (Scheme 12.1). Until the mid-1990s, the stoichiometric
approach (methods 2 and 3) was the most successful, with diastereoselectivities
reaching

α , β

99% [3a, 4].
A catalytic approach can only be envisioned by method 4: hetero-cuprates in
combination with external chiral ligands. Copper-catalyzed conjugate addition has
its background in the first example described by Kharash, in 1941 [5]. Stoichio-
metric organocopper reagents are usually prepared by transmetalation of an orga-
nolithium or Grignard reagent. The catalytic process, however, is usually performed
with Grignard reagents since organolithium reagents are too reactive towards the
carbonyl functionality. Therefore, all of the enantioselective catalytic approaches
were based on the use of Grignard reagents as primary organometallics. However,
a prominent position in the rapid development of this process is occupied by the
copper-catalyzed, ligand accelerated, 1,4-addition of diorganozinc reagents, espe-
cially ZnEt 2 , which is a trend that was started by Alexakis [6, 7]. Trialkylaluminium

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