The α-alkylation of ketones is a fundamental synthetic transformation. The development of asymmetric variants of this reaction is important given that numerous natural products, drugs, and related compounds exist as α-functionalized ketones or derivatives thereof. We previously reported our preliminary studies on the development of a new enantioselective ketone α-alkylation procedure using N-amino cyclic carbamate (ACC) auxiliaries. In comparison to other auxiliary-based methods, ACC alkylation offers a number of advantages and is both highly enantioselective and high yielding. Herein, we provide a full account of our studies on the enantioselective ACC ketone α-alkylation method.

A formal asymmetric synthesis of the marine natural product apratoxin D, a highly potent inhibitor of H-460 human lung cancer cell growth (IC50 value of 2.6nM), is described. The key feature of the synthesis is an advanced-stage asymmetric ACC α,α-bisalkylation of a chiral nonracemic methyl ketone to provide access to an advanced intermediate as a single diastereomer that has previously been advanced to apratoxin D.