1,4-Addition of Nucleophiles to -Unsaturated Carbonyl Compounds - Carbohydrates: Tools for Stereoselective Synthesis - page 250

Copper salt is essential for high catalytic activity and high enantioselectivity.
Both copper(I) and copper(II) species have been tested. Copper(II) salts usually
have the advantage of being cheaper and easier to handle. In this case, the reduc-
tion of the copper(II) species to the true catalytic copper(I) species must take place
in situ . Although Cu(OTf) 2 has been used extensively in asymmetric addition reac-
tions, leading in most cases to high degrees of enantioselectivities, it has been
demonstrated that this Cu source can be replaced by much cheaper copper car-
boxylates, and that the Lewis acidity of the copper source, previously believed to
play an important role, is not a significant factor [9b].
The chiral ligand is the centerpiece of this reaction, with the degree of enanti-
oselectivity being entirely due to it [7]. P-donor ligands are among the most effec-
tive ligands in this reaction. They are of the phosphite and phosphoramidite type,
most of them are monodentate, but some are bidentate. Aryl phosphines have
been scarcely used in this reaction and only successfully when combined with
other coordination sites. Phosphinite-based ligands have also been less studied.
The most studied ligands are, by far, phosphites or phosphoramidites, where the
phosphorus atoms are attached to three heteroatoms. In all cases, the phosphorus
atom is incorporated in a ring formed from a diol. The chirality can be introduced
through the diol moiety or by the exocyclic alcohol/amine, or by both. In the latter
case, a matched or mismatched relationship may exist. Non-phosphorus ligands
have been comparatively less used, although very high degrees of enantio-induc-
tion have also been obtained.
With regard to substrate, recently, conjugate additions of nucleophiles to
cyclic enones have been studied extensively, as the products may be useful for
the synthesis of biologically active compounds [3b, 3d, 10]. However, relatively
few publications describing highly enantioselective additions of organometallics
to linear aliphatic enones are found in the literature. Thus, for this class of
substrate, the development of more active and enantioselective catalysts is still
needed.
In contrast, one of the main problems revealed in these investigations is the
dynamic behavior of equilibria between several species of organocopper com-
pounds in solution. If the more reactive cuprates lead to a racemic product, a loss
of enantioselectivity is unavoidable. It is, therefore, desirable to design and syn-
thesize new chiral catalysts that can react rapidly with the substrate, and therefore
suppress the undesired competing reactions. This fact justifies expanding the
range of ligands used for Cu-catalyzed additions of organoaluminium reagents to
cyclic and, more specifically, to linear substrates.
In this sense, using carbohydrate derivatives as starting materials for the syn-
thesis of chiral ligands has several advantages: (i) the raw materials are of high
optical purity and are readily available; (ii) their multifunctional property makes it
possible to design an array of ligand structures through a series of modifications
[11, 12].
This chapter covers the literature reports on enantioselective conjugate additions
using carbohydrate derivatives as chiral ligands. The chapter is organized as
follows. Section 12.2 presents the different ligands together with a brief outline of