Synthesis of Pharmaceutically Valued Molecules Enabled by Organophotoredox Catalysis

Abstract

Photoredox catalysis has emerged as the currently most powerful strategy to manipulatethe open-shell radicals for diverse chemical transformation that is impossible or difficult to accomplish using the conventional ionic pathways. This method is highlighted by the reaction mildness, biological compatibility, and broad substrates tolerance. Therefore, photoredox catalysis has been applied to total synthesis of nature products, modify the biomolecules (protein, DNA, saccharides, etc.), novel materials synthesis, etc. In the traditional polar strategy, a number of synthons such as organometal complexes are labile and/or less reactive, while the precursors of radicals (carboxylic acids, halogens, esters, amines, olefins, etc.) are usually bench stable, easily accessible, and the radicals are highly reactive, which demonstrate a quite distinct manner to construct the target molecules. Herein, we developed a series of novel approaches to constructing the pharmaceutically valued compounds using the photoredox catalysis. In the first effort, an approach for efficient synthesis of C-glycosyl amino acids is developed. Different from typical photoredox-catalyzed reactions of imines, the new process follows a pathway in which α-imino esters serve as electrophiles in chemoselective addition reactions with nucleophilic glycosyl radicals. The process is highlighted by the mild nature of the reaction conditions, the highly stereoselectivity attending C–C bond formation, and its applicability to C-glycosylation using both armed and disarmed pentose and hexose derivatives. In the second effort, a mild, versatile organophotoredox protocol has been developed for the preparation of diverse, enantioenriched α-deuterated α-amino acids. Distinct from the wellestablished two-electron transformations, this radical-based strategy offers the unrivaled capacity of the convergent unification of readily accessible feedstock carboxylic acids and a chiral methyleneoxazolidinone fragment and the simultaneous highly diastereo-, chemo-, and regioselective incorporation of deuterium. Furthermore, the approach has addressed the longstanding challenge of the installation of sterically demanding side chains into α-amino acids. While strategies involving a 2e− transfer pathway have dictated glycosylation development, the direct glycosylation of readily accessible glycosyl donors as radical precursors is particularly appealing because of high radical anomeric selectivity and atom- and step-economy. However, the development of the radical process has been challenging owing to notorious competing reduction, elimination and/or SN side reactions of commonly used, labile glycosyl donors. Toward this end,15 we introduce an organophotocatalytic strategy through which glycosyl bromides can be efficiently converted into corresponding anomeric radicals by photoredox mediated HAT catalysis without a transition metal or a directing group and achieve highly anomeric selectivity. The power of this platform has been demonstrated by the mild reaction conditions enabling the synthesis of challenging α-1,2-cis-thioglycosides, the tolerance of various functional groups and the broad substrate scope for both common pentoses and hexoses. Furthermore, this general approach is compatible with both sp2 and sp3 sulfur electrophiles and late-stage glycodiversification for a total of 50 substrates probed. Reactions that lead to destruction of aromatic ring systems often require harsh conditions and, thus, take place with poor selectivities. Selective partial dearomatization of fused arenes is even more challenging but it can be a strategic approach to creating versatile, complex polycyclic frameworks. We have developed a general organophotoredox approach for the chemo- and regioselective dearomatization of structurally diverse polycyclic aromatics, including quinolines, isoquinolines, quinoxalines, naphthalenes, anthracenes and phenanthrenes. The success of the new method for chemoselective oxidative rupture of aromatic moieties relies on precise manipulation of the electronic nature of the fused polycyclic arenes. Experimental and computational results show that the key to overcoming the intrinsic thermodynamic and kinetic unfavorability of the dearomatization process is an ultimate hydrogen atom transfer (HAT) step, which enables dearomatization to predominate over the otherwise favorable aromatization pathway. We show that this strategy can be applied to rapid synthesis of biologically valued targets and late-stage skeletal remodeling en route to complex structures.