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

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.

total synthesis - alkaloids - amination - cyclization - ­heterocycles

References and Notes

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Pumiliotoxin C has been synthesized numerous times using a variety of creative routes. However, to the best of our knowledge hydroamination routes have not been reported. For recent syntheses, see:

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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] .

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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).

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For pumilotoxin C, data obtained for the free base (ref. 6d, 19a) and the HCl salt (ref. 19b) was in good agreement with literature data:

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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.