Cu-catalyzed enantioselective allylic alkylation with organolithium reagents

Abstract

This protocol describes a method for the catalytic enantioselective synthesis of tertiary and quaternary carbon stereogenic centers, which are widely present in pharmaceutical and natural products. The method is based on the direct reaction between organolithium compounds, which are cheap, readily available and broadly used in chemical synthesis, and allylic electrophiles, using chiral copper catalysts. The methodology involves the asymmetric allylic alkylation (AAA) of allyl bromides, chlorides and ethers with organolithium compounds using catalyst systems based on Cu-Taniaphos and Cu-phosphoramidites. The protocol contains a complete description of the reaction setup, a method based on H-NMR, gas chromatography-mass spectrometry (GC-MS) and chiral HPLC for assaying the regioselectivity and enantioselectivity of the product, and isolation, purification and characterization procedures. Six Cu-catalyzed AAA reactions between different organolithium reagents and allylic systems are detailed in the text as representative examples of these procedures. These reactions proceed within 1-10 h, depending on the nature of the allylic substrate (bromide, chloride, or ether and disubstituted or trisubstituted) or the chiral ligand used (Taniaphos or phosphoramidite). However, the entire protocol, including workup and purification, generally requires an additional 4-7 h to complete.

Stereospecific Ring Contraction of Bromocycloheptenes through Dyotropic Rearrangements via Nonclassical Carbocation–Anion Pairs

“…The copper-catalyzed desymmetrization of 1 by asymmetric allylic substitution 2 (AAS) with organolithium reagents 3 initially afforded the expected products 2a – e (>99:1 dr ), as observed by NMR spectroscopy of the crude reaction mixtures [see Supporting Information (SI)]. The reaction also proceeded with high enantioselectivity, as determined by chiral GC.…”