Stereoselective Ammonium-Directed Epoxidation in the Asymmetric Syntheses of Dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3

Solange Da Silva Pinto; Stephen G. Davies; Ai M. Fletcher; Paul M. Roberts; James E. Thomson

doi:10.1055/s-0036-1590948

Synthesis, Table of Contents

Synthesis 2018; 50(01): 64-83
DOI: 10.1055/s-0036-1590948

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Stereoselective Ammonium-Directed Epoxidation in the Asymmetric Syntheses of Dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3

Solange Da Silva Pinto

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK Email: steve.davies@chem.ox.ac.uk

,

Stephen G. Davies*

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK Email: steve.davies@chem.ox.ac.uk

,

Ai M. Fletcher

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK Email: steve.davies@chem.ox.ac.uk

,

Paul M. Roberts

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK Email: steve.davies@chem.ox.ac.uk

,

James E. Thomson

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK Email: steve.davies@chem.ox.ac.uk

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Abstract

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Abstract

Epoxidation of racemic trans-2-(N,N-dibenzylamino)cyclohex-3-en-1-ol, upon treatment with Cl₃CCO₂H then m-CPBA, proceeded with poor diastereoselectivity (ca. 60:40 dr), whilst epoxidation of racemic trans-2-(N-benzylamino)cyclohex-3-en-1-ol under the same conditions proceeded with high diastereoselectivity (>95:5 dr) and was followed by completely regioselective and stereospecific ring-opening in situ to give, after methanolysis of the intermediate trichloroacetate ester, (1RS,2SR,3SR,4SR)-2-(N-benzylamino)cyclohexane-1,3,4-triol. Use of aq HBF₄ as the acid protecting agent gave the amino triol directly. The differing diastereoselectivities of these epoxidation reactions may be due to a predilection towards formation of an intramolecular hydrogen-bond in the former substrate disrupting the ability of the in situ formed ammonium moiety to act as a directing group for the incoming oxidant; the presence of two potential hydrogen-bond donors (i.e., two N–H bonds) in the latter substrate circumvents this limitation. With the criterion for a highly diastereoselective (ammonium-directed) epoxidation in this system established, a synthesis of enantiopure trans-2-(N-benzylamino)cyclohex-3-en-1-ol (>99% ee) was developed and the ammonium-directed epoxidation was then employed as a key synthetic step to facilitate the asymmetric syntheses of enantiopure dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3 (>98% ee in each case) from 1,3-cyclohexadiene.

Key words

amino alcohols - asymmetric synthesis - chemoselectivity - diastereoselectivity - epoxidation - regioselectivity - ring-opening - stereoselective synthesis

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References

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