Enantioselective Addition of Organometallic Reagents to Carbonyl Compounds: Chirality Transfer, Multiplication, and Amplification

TLDR

Nucleophilic addition of organometallic reagents to carbonyls is a fundamental synthetic operation, and using chiral, nonracemic auxiliaries—especially catalytically—enables the efficient production of optically active alcohols, potentially heralding a new generation of enantioselective reactions. The alkyl transfer proceeds through a dinuclear Zn complex bearing a chiral amino alkoxide, an aldehyde ligand, and three alkyl groups. Using organozinc reagents with the chiral auxiliary (–)‑DAIB, the authors achieved catalytic enantioselective alkylation of aldehydes to secondary alcohols with up to 99 % ee, and demonstrated a pronounced nonlinear amplification effect—reaching 98 % ee from only 14 % ee of DAIB—attributable to distinct properties of homochiral versus heterochiral dinuclear complexes.

Abstract

Abstract Nucleophilic addition of organometallic reagents to carbonyl substrates constitutes one of the most fundamental operations in organic synthesis. Modification of the organometallic compounds by chiral, nonracemic auxiliaries offers a general opportunity to create optically active alcohols, and the catalytic version in particular provides maximum synthetic efficiency. The use of organozinc chemistry, unlike conventional organolithium or ‐magnesium chemistry, has realized an ideal catalytic enantioselective alkylation of aldehydes leading to a diverse array of secondary alcohols of high optical purity. A combination of dialkylzinc compounds and certain sterically constrained β‐dialkylamino alcohols, such as (–)‐3‐ exo ‐dimethylaminoiso‐ borneol [(–)‐DAIB], as chiral inducers affords the best result (up to 99% ee ). The alkyl transfer reaction occurs via a dinuclear Zn complex containing a chiral amino alkoxide, an aldehyde ligand, and three alkyl groups. The chiral multiplication method exhibits enormous chiral amplification: a high level of enantioselection (up to 98%) is attainable by use of DAIB in 14% ee . This unusual nonlinear effect is a result of a marked difference in chemical properties of the diastereomeric (homochiral and heterochiral) dinuclear complexes formed from the dialkylzinc and the DAIB auxiliary. This phenomenon may be the beginning of a new generation of enantioselective organic reactions.