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Synlett 2009(7): 1087-1090  
DOI: 10.1055/s-0028-1088146
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 2-epi-Pumiliotoxin C via a Challenging Intramolecular Hydroamination Key Step

Marie-Eve Lebrun, Jennifer Y. Pfeiffer, André M. Beauchemin*
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie-Curie, Ottawa, ON K1N 6N5, Canada
Fax: +1(613)5625170; e-Mail: andre.beauchemin@uottawa.ca;
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Publication History

Received 29 January 2009
Publication Date:
20 March 2009 (online)

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Abstract

The synthesis of 2-epi-pumiliotoxin C was achieved in ten steps from cyclohexadiene oxide, using a challenging Cope-type hydroamination key step. This cyclization was performed on a mixture of two epimeric hydroxylamines, and a boat transition state is proposed to explain the kinetic preference observed for the cyclization of the epimer leading to N-hydroxy-epipumiliotoxin C.

Key words

total synthesis - alkaloids - amination - cyclization - ­heterocycles

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5

To the best of our knowledge, there are only few reported examples of a formation of six-membered piperidine ring via hydroamination onto an internal alkene: see ref. 4e,g,z for examples.

9

O’Neil has reported cyclizations of unsaturated N-methyl-hydroxylamines leading to various six-membered ring systems: see ref. 8h-m. The cyclization to form morpholine N-oxides is compatible with distal alkene substitution: see ref. 8k,l.

10

A first generation synthesis designed to provide access to various hydroamination precursors is shown in Scheme  [8] .

16

None of the hydroxylamine 1a could be recovered from the reaction mixture. ¹³C NMR analysis indicated that recovered hydroxylamine 1b was diastereomerically pure (within detection limits).

20

This rationale is consistent with results from DFT calculations in simpler systems: Dr. Serge I. Gorelsky, private communication.

21

Complete experimental procedures and characterization data for all new compounds can be obtained from the authors.