Issue 1, 2017

The stereodivergent formation of 2,6-cis and 2,6-trans-tetrahydropyrans: experimental and computational investigation of the mechanism of a thioester oxy-Michael cyclization

Abstract

The origins of the stereodivergence in the thioester oxy-Michael cyclization for the formation of 4-hydroxy-2,6-cis- or 2,6-trans-substituted tetrahydropyran rings under different conditions was investigated both computationally and experimentally. Synthetic studies showed that the 4-hydroxyl group was essential for stereodivergence. When the 4-hydroxyl group was present, TBAF-mediated conditions gave the 2,6-trans-tetrahydropyran and trifluoroacetic acid-mediated conditions gave the 2,6-cis-tetrahydropyran. This stereodivergence vanished when the hydroxyl group was removed or protected. Computational studies revealed that: (i) the trifluoroacetic acid catalysed formation of 2,6-cis-tetrahydropyrans was mediated by a trifluoroacetate-hydroxonium bridge and proceeded via a chair-like transition state; (ii) the TBAF-mediated formation of 2,6-trans-tetrahydropyrans proceeded via a boat-like transition state, where the 4-hydroxyl group formed a crucial hydrogen bond to the cyclizing alkoxide; (iii) both reactions are under kinetic control. The utility of this stereodivergent approach for the formation of 4-hydroxy-2,6-substituted tetrahydropyran rings has been demonstrated by the total syntheses of the anti-osteoporotic natural products diospongin A and B.

Graphical abstract: The stereodivergent formation of 2,6-cis and 2,6-trans-tetrahydropyrans: experimental and computational investigation of the mechanism of a thioester oxy-Michael cyclization

Supplementary files

Article information

Article type
Edge Article
Submitted
04 Aug 2016
Accepted
26 Aug 2016
First published
30 Aug 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2017,8, 482-490

The stereodivergent formation of 2,6-cis and 2,6-trans-tetrahydropyrans: experimental and computational investigation of the mechanism of a thioester oxy-Michael cyclization

K. Ermanis, Y. Hsiao, U. Kaya, A. Jeuken and P. A. Clarke, Chem. Sci., 2017, 8, 482 DOI: 10.1039/C6SC03478K

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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