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. 2020 Aug 8;25(16):3613.
doi: 10.3390/molecules25163613.

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

Evgeny V Pospelov  1   2 , Ivan S Golovanov  1 , Sema L Ioffe  1 , Alexey Yu Sukhorukov  1   3
Affiliations

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

Evgeny V Pospelov et al. Molecules. .

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.

Keywords: C–H functionalization; PDE4 inhibitors; anchimeric assistance; epimerization; pyrrolidines; total synthesis.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Scheme 1
Scheme 1
Approaches towards modification of cyclic nitronates. (a) Synthesis of cyclic nitronates from nitroalkenes; (b) 1,3-Dipolar addition with cyclic nitronates and its application in total synthesis; (c) C-H functionalization of cyclic nitronates via N-siloxyenamines (route 1); (d) C-H functionalization of cyclic nitronates via [3,3]-rearrangement of N-acyloxyenamines (route 2).
Scheme 2
Scheme 2
Previous asymmetric synthesis of (−)-CMPO.
Scheme 3
Scheme 3
Problems associated with C-6 epimerization in the LA-assisted functionalization of cyclic nitronate 10. (a) Functionalization of cyclic nitronate 10; (b) Mechanism of epimerization at C-6; (c) Hydride reduction of 4,6-cis-1,2-oxazines.
Scheme 4
Scheme 4
Tandem acylation/(3,3)-rearrangement of nitronate 10.
Scheme 5
Scheme 5
Cyanoborohydride reduction of 3-hydroxymethyl 1,2-oxazine 13 and its pivalate 17.
Scheme 6
Scheme 6
Conversion of 1,2-oxazines 18 and 18′ into target PDE4 inhibitor (−)-CMPO.
Scheme 7
Scheme 7
Plausible mechanism of the epimerization at the C-6 position in 1,2-oxazine 18. Ar − 4-methoxy-3-cyclopentyloxyphenyl, G*—trans-2-phenylcyclohexyl. DFT calculations: MN15/Def2TZVP (AcOH, smd), LA was not included in the calculations.
Figure 1
Figure 1
Numeration of atoms in products 17–20.
See this image and copyright information in PMC

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