New Route To α-Alkylated Ketones

A new method for asymmetrically α-alkylating ketones—adding alkyl substituents to carbons adjacent to ketone groups to give chiral products—is simpler and more amenable to scale-up than current approaches, according to Duke University's Daniel Lim and Don M. Coltart, the researchers who devised the procedure (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200800848). In the reaction, a ketone is combined with a chiral N-amino cyclic carbamate (ACC, red) to generate a hydrazone, which is then alkylated by an alkyl halide (purple) to yield chiral products and the original ACC. This approach also makes it possible for the first time to α,α-bisalkylate ketones asymmetrically. The technique could prove useful for modifying and synthesizing alkylated ketone structures found in many natural products and drugs. The method works at temperatures between −40 and 0 °C, and the ACC chiral auxiliaries used can be directly recycled to save costs. Both of these factors make scale-up more practical. In previous asymmetric ketone α-alkylations, colder reaction temperatures (−110 to −78 °C) were required and the chiral auxiliaries used were more difficult to recycle.