Novel nitrogen-lactam radicals in stereoselective α-functionalization of aldehydes

We report the development of a photocatalytic strategy that enables the direct stereoselective introduction of lactam rings, via nitrogen radicals. To the best of our knowledge, in the literature no example of nitrogen radical localized on lactam rings is described; we first developed a N-aminopyridinium salt as radical precursor.[1] This novel strategy enables the direct introduction of lactams, one of the most widespread heterocycles in natural products and drugs.[2] We combined photocatalysis with organocatalysis to develop a stereoselective transformation performed under mild conditions, for the synthesis of chiral molecules of synthetic interest. Inspired by a work of MacMillan and coworkers, we tested the reactivity of the radical with the nucleophilic enamine of aldehydes, obtaining good results in the α-functionalization of a wide range of substrates (Figure 1).[3] The scope of lactam rings and of the substrates was studied, obtaining the desired products in moderate to good yield and with good enantiomeric excess. In the end, the strategy was exploited for the synthesis of an orphan drug, Levetiracetam, to demonstrate the synthetic applicability of the method. [1] T. W. Greulich, C. G. Daniliuc, A. Studer, Org Lett, 2015, 17, 254–257 [2] F. Saldìvar-Gonzalez, E. Lenci, A. Trabocchi, and J. L. Medina-Franco; RSC Adv., 2019, 9, 27105-27116 [3] G. Cecere, C. M. König, J. L. Alleva, D. W. C. MacMillan, JACS, 2013, 135, 11521–11524