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

Evgeny V Pospelov,Alexey Yu Sukhorukov,Ivan S Golovanov,Sema L Ioffe

doi:10.3390/molecules25163613

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.

Highlights

Cyclic nitronates (1,2-oxazine-N-oxides 1 and isoxazoline-N-oxides 2) are useful intermediates in the synthesis of complex nitrogen containing scaffolds due to their versatile reactivity as 1,3-dipoles and accessibility from nitroalkenes (Scheme 1a) [1,2,3,4,5,6,7,8,9,10]
Generated by the acylation of nitronate 10 may proceed without any epimerization of the C-6 stereogenic generated by the acylation of nitronate 10 may proceed without any epimerization of the C-6 center
We were able to solve the problem of site-selective C–H oxygenation of the cyclic nitronate intermediate in the asymmetric synthesis of a potent PDE4 inhibitor CMPO by using tandem acylation/(3,3)-sigmatropic rearrangement

Summary

Introduction

Cyclic nitronates (1,2-oxazine-N-oxides 1 and isoxazoline-N-oxides 2) are useful intermediates in the synthesis of complex nitrogen containing scaffolds due to their versatile reactivity as 1,3-dipoles and accessibility from nitroalkenes (Scheme 1a) [1,2,3,4,5,6,7,8,9,10]. Denmark’s group extensively exploited the inter- and intramolecular (3 + 2)-cycloaddition reactions with six-membered cyclic nitronates 1 to construct various bi- and polycyclic nitroso acetal frameworks 3, which were converted into fused pyrrolidine derivatives by an intramolecular reductive amination (Scheme 1b) [1,11]. Using this strategy, total syntheses of numerous pyrrolizidine and indolizidine alkaloids [12,13,14], as well as (5.5.5.5)- and (5.5.5.4)-azafenestanes [15,16], were accomplished. We succeeded in using this methodology in the total synthesis of some pharmaceutical molecules, in Molecules 2020, 25, 3613; doi:10.3390/molecules25163613 www.mdpi.com/journal/molecules

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Discussion

Conclusion