The Cyclic Nitronate Route to Pharmaceutical Molecules: Synthesis of GSK’s Potent PDE4 Inhibitor as a Case Study

Abstract

An efficient asymmetric synthesis of GlaxoSmithKline’s potent PDE4 inhibitor was accomplished in eight steps from a catechol-derived nitroalkene. The key intermediate (3-acyloxymethyl-substituted 1,2-oxazine) was prepared in a straightforward manner by tandem acylation/(3,3)-sigmatropic rearrangement of the corresponding 1,2-oxazine-N-oxide. The latter was assembled by a (4 + 2)-cycloaddition between the suitably substituted nitroalkene and vinyl ether. Facile acetal epimerization at the C-6 position in 1,2-oxazine ring was observed in the course of reduction with NaBH3CN in AcOH. Density functional theory (DFT) calculations suggest that the epimerization may proceed through an unusual tricyclic oxazolo(1,2)oxazinium cation formed via double anchimeric assistance from a distant acyloxy group and the nitrogen atom of the 1,2-oxazine ring.

The Molecular Mechanism of the Formation of Four-Membered Cyclic Nitronates and Their Retro (3 + 2) Cycloaddition: A DFT Mechanistic Study

“…Cyclic nitronates are an important class of compounds because they pose useful intermediates in the synthesis of complex nitrogen-containing scaffolds due to their high reactivity as 1,3-dipoles and availability from nitroalkenes [ 1 , 2 , 3 , 4 ]. The main methods of obtaining cyclic four-membered nitronates are thermal and photochemical methods involving the cleavage of unsaturated nitro compounds [ 5 , 6 , 7 , 8 , 9 ].…”