DOI: 10.1002/chem.201501271
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Organic Chemistry
Asymmetric Isothiourea-Catalysed Formal [3+2] Cycloadditions of
Ammonium Enolates with Oxaziridines
Siobhan R. Smith, Charlene Fallan, James E. Taylor, Ross McLennan, David S. B. Daniels,
Louis C. Morrill, Alexandra M. Z. Slawin, and Andrew D. Smith*[a]
Abstract: A highly enantioselective Lewis base-catalysed
formal [3+2] cycloaddition of ammonium enolates and oxa-
ziridines to give stereodefined oxazolidin-4-ones in high
yield is described. Employing an enantioenriched oxaziridine
in this process leads to a matched/mis-matched effect with
the isothiourea catalyst and allowed the synthesis of either
syn- or anti-stereodefined oxazolidin-4-ones in high d.r.,
yield and ee. Additionally, the oxazolidin-4-one products
have been derivatised to afford functionalised enantioen-
riched building blocks.
Introduction
The ubiquitous use of heterocycles in the pharmaceutical,
agrochemical as well as in the dye and fine-chemical industries
has led to the establishment of numerous strategies for their
synthesis and functionalisation.[1] Stereodefined heterocycles
are also significant components of numerous biologically
active natural products.[2] As a result of the widespread preva-
lence of heterocyclic motifs in synthetic chemistry,[3] alongside
the continued drive for efficient, selective synthetic protocols
within the chemical community, there is an ongoing require-
ment for novel asymmetric syntheses of heterocyclic scaffolds.
Oxazolidin-4-ones represent a unique heterocyclic structural
motif found within natural products and bioactive molecules.
For example, the oxazolidin-4-one core is found in the natural
products synoxazolidinone A and B which were isolated from
S. pulmonaria and exhibit antibiotic and antifungal activity at
low concentrations (Figure 1).[4] In addition, oxazolidin-4-ones
are found in lipoxazolidinones A, B, and C isolated from
a marine actinomycete strain.[5] These naturally occurring oxa-
zolidin-4-ones also exhibit antibacterial activity comparable
with the commercial antibacterial agent Linezolid (Zyvox) that
contains a structurally related oxazolidin-2-one core.[6] There-
fore, the development of a synthetic strategy for the asymmet-
ric generation of heterocyclic scaffolds of this type is a worth-
while goal. In this manuscript, we describe an isothiourea-cata-
Figure 1. Biologically active natural products and medicinal agents based
upon the oxazolidinone core.
lysed formal [3+2] cycloaddition using both racemic and enan-
tioenriched oxaziridines[7] to form stereodefined oxazolidin-4-
ones.
Building on Birman and Okamoto’s introduction of isothiour-
ea catalysts for kinetic resolutions[8] we have recently estab-
lished, alongside Romo,[9] isothiourea Lewis base catalysis[10] for
the preparation of a range of synthetically relevant heterocyclic
scaffolds. Substituted THFs,[11] dihydrobenzofurans and pyrroli-
dines[12] have been accessed by an asymmetric intramolecular
Michael addition/lactonisation process. In addition, stereode-
fined anti-d-lactams[13] and dihydropyranones[14] were obtained
by related intermolecular Michael addition/cyclisation proto-
cols. This methodology was extended using a strategic PhSH
elimination as part of a cascade process for the synthesis of
substituted pyrones[15] and functionalised pyridines.[16] Addi-
tionally, asymmetric formal [2+2] cycloadditions employing N-
sulfonyl imines to form anti-b-lactams have been studied.[17]
However, to date, formal [3+2] cycloaddition processes cata-
lysed by isothioureas have not been developed.[18]
[a] S. R. Smith, Dr. C. Fallan, Dr. J. E. Taylor, R. McLennan, Dr. D. S. B. Daniels,
Dr. L. C. Morrill, Prof. A. M. Z. Slawin, Prof. A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews
North Haugh, St Andrews, KY16 9ST (UK)
Supporting information for this article is available on the WWW under
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons At-
tribution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.
Oxaziridines have previously been reported as electrophiles
for the synthesis of oxazolidin-4-ones by Ye and co-workers
Chem. Eur. J. 2015, 21, 10530 – 10536
10530 ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim