Enantioselective alkylation of carbonyl compounds. From stoichiometric to catalytic asymmetric induct ion

Multinuclear organometallic species play a significant role in alkylation of carbonyl compounds. Enantioselective alkylation of aldehydes using a 1: 1 reagent/substrate stoichiometry is achievable by chirally modified lithium/magnesium binary organometallic reagents. For example, diethylmagnesium treated with di-O-lithio-(S)-2.2'dihydroxy1, 1'-binaphthyl reacts with benzaldehyde in a THFdimethoxyethane mixture a t -100 OC to give (S)1-phenyl1propanol in 92% ee. In the presence of a catalytic quantity of (4-3exo-(dimethy1amino)isoborneol (DAIB), reaction of dialkylzincs and aldehydes in nonpolar media is accelerated greatly to lead to the corresponding S alcohols in very high enantiomeric excesses (up to 99% ee). The enantioselective catalysis involves fluxional organozinc species and the product-forming dinuclear intermediate possesses DAIB auxiliary, an aldehyde ligand, and three alkyl groups, where it is the bridging alkyl group, rather than the terminal alkyls, that migrates from zinc to the carbonyl carbon. Reaction of organometallic compounds with carbonyl substrates is one of the most fundamental operations in synthetic organic chemistry. There are two major ways to provide a chiral, nonracemic environment to the organometallic reagents, leading to enantiomeric alcoholic products (ref. 1 and 2). The first is coordination of chiral solvents or neutral complexing agent(s) to the metallic center (ref. 3 and 41, and the other method is the modification of the organometallics by protic chiral auxiliaries such as alcohols or amines, giving organometallic alkoxides or amides respectively (ref. 5 and 6). Although several successful results along these lines have been reported, high enantioselectivities have been obtained only by a careful combination of carbonyl compounds and organic groups (alkyl, aryl, etc.), and a general method is still elusive. In addition, most stereoselctive reactions of organolithium or -magnesium compounds so far recorded suffer from the necessity of using excess amounts (usually 4 equivalents or more) of chiral source to carbonyl substrates, which may be associated with aggregation of the chirally modified organometallic reagents. We aimed to attain a high level of enantioselective reaction with a stoichiometric, or hopefully catalytic, amount of chiral auxiliary per organometallic or carbonyl compound. L I T H I U M / M A G N E S I U M BINARY ORGANOMETALLIC REAGENTS MODIFIED BY BINAPHTHOL We planned to create lithium/magnesium binary organometallic agents having the empirical formula 1, because (1) the requisite organometallic reagents are readily accessible, (2) such well-shaped, coordinatively saturated reagents consisting of tetrahedral lithium and magnesium metal centers could avoid the formation of complicated polymers or aggregates in ethereal solvents, and (3) the two kinds of metals