Enantioselective ketone reductions convert prochiral ketones into chiral, non-racemic alcohols and are used heavily for the synthesis of stereodefined alcohols.
Introduction
Carbonyl reduction, the net addition of H2 across a carbon-oxygen double bond, is a straightforward way to generate alcohols. Stoichiometric reducing agents to accomplish this task include lithium aluminium hydride, sodium borohydride, alkoxy borohydrides, alkoxy aluminium hydrides, and boranes. Initial efforts toward enantioselective ketone reductions focused on the development of chiral, non-racemic reducing agents. Although stoichiometric chiral reducing agents often afford products with high enantioselectivity, the necessity of a stoichiometric amount of chiral material is a disadvantage of these reagents.
The catalytic, asymmetric reduction of ketones may be accomplished through the use of catalytic amounts of an oxazaborolidine catalyst in conjunction with borane or catecholborane as the stoichiometric reducing agent. Oxazaborolidines remain in common use for reductions of simple ketones.
More recently, efforts in the field of enantioselective reduction have focused on the development of transition metal catalyzed reactions, which employ cheap reductants such as hydrogen gas (H2), formic acid (HCO2H), or isopropanol ((CH3)2CHOH). The latter two reagents are used for transfer hydrogenations, which represent the formal transfer of an H2 molecule from the reductant to the substrate. Asymmetric induction in transition metal catalyzed reactions is achieved through the use of a chiral Lewis basic ligand in catalytic amounts. For ketone substrates that can chelate the metal catalyst, enantioselectivities of transition metal catalyzed reactions may be higher (and side reactions less prevalent) than the corresponding oxazaborolidine reductions.
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Mechanism and stereochemistry
Oxazaborolidine reductions
The mechanism of oxazaborolidine reductions has been supported by ab initio calculations. Coordination of borane to the oxazaborolidine nitrogen generates the complex I, which then coordinates a molecule of ketone to yield complex II. In the transition state for hydride transfer (II → III), the large substituent of the ketone is aligned inward to avoid steric interactions with the outward-pointing R group of the oxazaborolidine, which is often tethered to the nitrogen atom. After hydride transfer, complex III releases the product and coordinates a second molecule of borane. (2)
Transition metal catalyzed reductions
Transition metal catalyzed reductions may proceed by a variety of mechanisms, depending on the reductant and metal employed. Regardless of the precise mechanism, it is the spatial properties of the chiral ligand bound to the metal center that determine the sense and extent of enantioselectivity. A reliable stereochemical model has been developed for reductions employing BINAP ligands. When BINAP chelates to a transition metal such as ruthenium, the phenyl groups attached to phosphorus reside in either pseudoaxial or psudeoequatorial positions. The pseudoequatorial phenyl groups project into the region of space on the other side of the BINAP ligand and influence the preferred binding conformation of chelating ketones (such as α-amino ketones or β-keto esters). The ketone typically occupies the more open regions of space, leading to hydride delivery to a single face of the ketone. The C2 symmetry of the coordination space ensures that only a single face of the ketone will be accessible to the catalyst, no matter in which open region the ketone binds. (3)
Scope and limitations
Stoichiometric, chiral hydride reductions
Lithium aluminium hydride (LAH) modified with chiral alkoxide ligands may be used to synthesize chiral alcohols in good yield and high enantioselectivity. Chelating ligands such as BINOL are used to avoid disproportionation and background reduction by LAH. Chiral diamines and amino alcohols have also been used to modify LAH for enantioselective reductions. (4) Chirally modified borohydrides are also useful for enantioselective ketone reductions. Economical ligands derived from amino acids have been used to modify borohydrides, affording highly selective reducing agents. (5) Chiral alkylborohydrides are accessible through the diastereoselective hydroboration of chiral alkenes. Boranes derived from pinene have been used in this context for enantioselective reductions. Neutral alkoxyboranes may result from these reductions. (6)