Biocatalytic Synthesis of N-N and C-N Heterobiaryl Atropisomers

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

PROPOSAL SUMMARY Atropisomerism is a type of chirality that arises from restricted rotation about a bond. Introduction of atropisomerism to small-molecule drug candidates can improve potency, selectivity, and ADME (absorption, distribution, metabolism, and excretion) properties. An underexplored class of atropisomers are heterobiaryl atropisomers featuring an N–N or C–N atropisomeric axis. These classes of atropisomers have demonstrated potent pharmaceutical properties. However, as compared to C–C atropisomers, there are relatively few enantioselective methodologies for their synthesis. Most strategies rely on the derivatization of substrates already containing the N–X bond (where X = N or C). An underexplored approach is the direct coupling of two heteroarene fragments that form the N–X bond atroposelectively. However, known methods require the pre- functionalization of starting materials, thereby limiting the generality of these strategies. Nature, on the other hand, synthesizes heterobiaryl atropisomers by a direct oxidative coupling, wherein an N–H and X–H bond undergo direct conversion into an N–X bond under mild reaction conditions. Flavin- dependent aromatic hydroxylases (FDAH) are an enzyme class with demonstrated N–N and C–N coupling reactivity. The research outlined in this proposal will draw upon this known reactivity to develop general strategies for the synthesis of N–N and C–N heterobiaryl atropisomers. Towards this goal, I will employ bioinformatic techniques to develop a library of FDAH enzymes to explore this unique coupling reactivity. From the reactivity profile of this FDAH enzyme library, I will identify features of these enzymes that contribute to the site-selectivity of this oxidative coupling approach. Employing both enzyme library reactivity profiling and protein engineering, I will develop atroposelective N–N and C–N biocatalytic coupling strategies. The methods developed herein will provide access to a class of medicinally relevant atropisomers that are difficult to obtain by other approaches.