Enantioselective a-Alkylation of Aldehydes by Photoredox Organocatalysis: Rapid Access to Pharmacophore Fragments from b- Cyanoaldehydes**

The combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective a-cyanoalkylation of aldehydes. This synergistic catalysis protocol allows for the coupling of two highly versatile yet orthogonal functionalities, allowing rapid diversification of the oxonitrile products to a wide array of medicinally relevant derivatives and heterocycles. This methodology has also been applied to the total synthesis of the lignan natural product ( )-bursehernin. The enantioselective a-alkylation of carbonyl compounds with sp-hybridized halide-bearing electrophiles has long been considered an elusive goal for practitioners of asymmetric catalysis. Indeed, the most commonly employed strategy to achieve the stereoselective construction of a-alkyl carbonyls involves the coupling of auxiliary-based metal enolates with halo or tosyloxy alkanes. A critical issue for the development of catalytic variants of this venerable reaction has been the insufficient electrophilicity of alkyl halides towards silyl or alkyl enol ether p-nucleophiles (enolate equivalents that are broadly employed in asymmetric catalysis). This limitation has mandated the use of lithium-, sodium-, or cesium-derived enolates for auxiliary controlled carbonyl a-functionalization at higher carbonyl oxidation states. Recently, however, the application of secondary amine organocatalysts has overcome several of these constraints by the direct use of aldehydes or ketones in a variety of chiral enamine a-functionalization reactions. As one example, our laboratory disclosed the synergistic merger of enamine catalysis with visible-light photoredox catalysis, wherein a ruthenium photocatalyst is used to generate highly electrophilic alkyl radicals derived from simple a-bromoesters and ketones. Since that time, the field of photoredox catalysis as applied to organic synthesis has received considerable attention and we have disclosed its successful application to the enantioselective a-trifluoromethylation, a-benzylation, and a-amination of aldehydes. Recently, we questioned whether this dual photoredoxorganocatalysis platform could be translated to the asymmetric catalytic alkylation of aldehydes using a-bromo cyanoalkyls, a protocol that would generate b-cyanoaldehydes in one step. As a critical design element, we recognized that a-bromo cyanoalkylating reagents would not be suitable electrophiles for most catalytic enolate addition pathways; however, the corresponding open-shell radicals, derived by one-electron reduction of a-bromonitriles, should readily undergo coupling with transiently generated chiral enamines. In addition, the nitrile functional group offers rapid access to a large array of carbonyl, amine, or imidate motifs, and as such, b-cyanoaldehydes can be readily translated to lactones, pyrrolidines, lactams, and cyanoalcohols—pharmacophore fragments that are ubiquitous in medicinal chemistry. Herein we report the first enantioselective a-cyanoalkylation of aldehydes via the synergistic combination of photoredox and organocatalysis (Figure 1). Furthermore, we demonstrate the application of this new dual catalysis platform to the rapid and stereoselective construction of cyclic and acyclic motifs of broad value to the chemistry of drug discovery. We envisioned that our cyanoalkylation dual catalysis mechanism would proceed as depicted in Scheme 1. SingleFigure 1. Photoredox organocatalysis a-cyanoalkylation of aldehydes. [*] E. R. Welin, Dr. A. A. Warkentin, Dr. J. C. Conrad, Prof. Dr. D. W. C. MacMillan Merck Center for Catalysis at Princeton University Washington Road, Princeton, NJ 08544-1009 (USA) E-mail: [email protected] Homepage: http://www.princeeton.edu/chemistry/macmillan/ [**] The authors are grateful for financial support provided by the NIH General Medical Sciences Grant NIHGMS (grant number R01 GM093213-01) and kind gifts from Merck, AbbVie, and Bristol