61st Annual Report on Research 2016

Synthetic methods that selectively functionalize unactivated aliphatic C–H bonds hold significant promise in streamlining the synthesis of complex targets and offer attractive tools for late-stage functionalization. Despite this potential, few practical transformations of aliphatic C–H bonds of preparative value exist. We have developed an approach to the selective halogenation of unactivated C–H bonds using N-haloamides and nitrogen-centered radicals. During the past grant period, we have developed an aliphatic C–H chlorination using readily prepared N-chloroamides. While the chlorination of aliphatic C–H bonds is commonly a poorly selective process owing to the promiscuity of chlorine free radical, the high levels of electronic and steric selectivity characteristic of the amidyl radical produced in this system enable the selective chlorination of C–H bonds in an array of complex molecules. This practical, site-selective reaction uses N-chloroamides and visible light with substrate as limiting reagent in all cases, which bodes well for future applications in complex synthesis.

In collaboration with the Vanderwal group we have also developed the first synthesis of natural products in the lissoclimide/haterumaimide family using the C–H chlorination as a key step. The synthesis begins with a gram-scale selective chlorination of (+)–sclareolide, which delivers a single product in 82% yield. This compound forms the basis of a short synthesis of this important family of natural products. In the upcoming grant period, new aliphatic C–H transformations will be pursued in addition to further efforts to increase reaction site selectivity in complex settings.

We thank the ACS PRF for their generous support of this work, which has played an instrumental role in our nascent efforts towards the development of practical, selective methods for intermolecular aliphatic C–H functionalization.