Direct enantioselective photocatalytic α-functionalization of aldehydes with nitrogen-lactam radicals

Lactams can be considered some of the most significant heterocycles in medicinal chemistry and drug discovery. They are a privileged structure, common to a large variety of natural products and drugs, to which they lend a potential therapeutic effect for the treatment of different disorders, spanning from cancer, diabetes, and infectious diseases.1 Typically, lactam rings are introduced in organic molecules by ring-closure reactions, while no example of direct introduction is reported. In this context, we report the development of a photocatalytic strategy that enables the direct stereoselective introduction of lactam rings, via nitrogen radicals (Figure 1). In the last decades, light emerged as one of the most powerful synthetic tools to assist the organic synthesis, enabling challenging transformations under mild conditions, via radical intermediates. Its combination with organocatalysis allowed us to point out a stereoselective version of the reaction, that opened the door to the synthesis of chiral molecules of synthetic interest. To the best of our knowledge, no example of nitrogen lactam radical is reported in the literature, therefore we first studied the development of a N-aminopyridinium salt as radical precursor.2 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.3 The scope of lactam rings and the one of the substrates was studied, obtaining the desired products from 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. F. Saldìvar-Gonzalez, E. Lenci, A. Trabocchi, and J. L. Medina-Franco; RSC Adv., 2019, 9, 27105-27116 2. T. W. Greulich, C. G. Daniliuc, A. Studer, Org Lett, 2015, 17, 254–257 3. G. Cecere, C. M. König, J. L. Alleva, D. W. C. MacMillan, JACS, 2013, 135, 11521–11524