Chemoenzymatic Asymmetric Synthesis of Complex Heterocycles: Dihydrobenzoxazinones and Dihydroquinoxalinones

Abstract

Chiral dihydrobenzoxazinones and dihydroquinoxalinones serve as essential building blocks for pharmaceuticals and agrochemicals. Here, we report short chemoenzymatic synthesis routes for the facile preparation of these complex heterocycles in an optically pure form. These synthetic routes involve a highly stereoselective hydroamination step catalyzed by ethylenediamine- N , N′- disuccinic acid lyase (EDDS lyase). This enzyme is capable of catalyzing the asymmetric addition of various substituted 2-aminophenols to fumarate to give a broad range of substituted N- (2-hydroxyphenyl)- l -aspartic acids with excellent enantiomeric excess (ee up to >99%). This biocatalytic hydroamination step was combined with an acid-catalyzed esterification–cyclization sequence to convert the enzymatically generated noncanonical amino acids into the desired dihydrobenzoxazinones in good overall yield (up to 63%) and high optical purity (ee up to >99%). By means of a similar one-pot, two-step chemoenzymatic approach, enantioenriched dihydroquinoxalinones (ee up to >99%) were prepared in good overall yield (up to 78%) using water as solvent for both steps. These chemoenzymatic methodologies offer attractive alternative routes to challenging dihydrobenzoxazinones and dihydroquinoxalinones, starting from simple and commercially available achiral building blocks.

Synthesis of Dihydroquinoxalinones from Biomass-Derived Keto Acids and o-Phenylenediamines

“…Among nitrogen-containing compounds, dihydroquinoxalinones, with special pharmacodynamic models, have been verified as key raw materials for the synthesis of various bioactive compounds or drugs for anti-human immunodeficiency virus (anti-HIV), antitumor, bactericidal, anti-inflammatory, and cardiovascular treatment (Scheme ). − A typical example is that the 1-non-nucleoside HIV-1 reverse transcriptase inhibitor GW420867X commercial drug contains a dihydroquinoxalinone core structure …”

Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis

“…This approach has successfully been used for the synthesis of a variety of natural products, synthetic APIs or interesting building blocks thereof and has experienced a lot of attention in the last years. [22][23][24][25][26][27][28][29][30][31][32][33][34] The concepts developed for opioid structures are exclusively based on early stage enzymatic transformations to access basic chiral synthons followed by a sophisticated chemical synthetic sequence over numerous steps (Scheme 1DI and II). [35][36][37][38][39][40][41][42][43][44][45] The biotransformations used involved either a broadly exploited toluene dioxygenase (for dihydroxylation) or a lipase (for a kinetic resolution).…”

Hot off the press

“…A one-pot, two-step chemoenzymatic method for the synthesis of pharmaceutically relevant heterocycles has been developed using ethylenediamine- N , N ′-disuccinic acid (EDDS) lyase. 35 The enzyme was shown to catalyse the asymmetric addition of 2-aminophenols and 2-aminoanilines (Scheme 6) with fumarate, and following acid-mediated cyclisation, resulted in the asymmetric synthesis of dihydrobenzoxazinones and dihydroquinoxalinones, respectively. Serine mutation of a heme-coordinating residue of myoglobin has produced an artificial metalloenzyme capable of performing atom transfer radical cyclisation reactions.…”