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Issue 22, 2003
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Synthesis of sparteine-like chiral diamines and evaluation in the enantioselective lithiation–substitution of N-(tert-butoxycarbonyl)pyrrolidine

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Abstract

Three chiral diamines were synthesised and evaluated as sparteine surrogates in the lithiation–substitution of N-(tert-butoxycarbonyl)pyrrolidine. The synthesis and attempted resolution of sparteine-like diamines {(1S*,2R*,8R*)-10-methyl-6,10-diazatricyclo[6.3.1.02,6]dodecane and (1S*,2R*,9R*)-11-methyl-7,11-diazatricyclo[7.3.1.02,7]tridecane} (via inclusion complex formation) are reported. Unfortunately, it was only possible to resolve the diazatricyclo[7.3.1.02,7]tridecane compound. An alternative route to (1R,2S,9S)-11-methyl-7,11-diazatricyclo[7.3.1.02,7]tridecane starting from the natural product, (−)-cytisine, is described. This simple three-step route furnished gram-quantities of a (+)-sparteine surrogate. X-Ray crystallography of an intermediate in the route, (1R,5S,12S)-3-methoxycarbonyldecahydro-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, enabled the stereochemistry of all of the tricyclic diamines described in this paper to be unequivocally established. Two other diamines, starting from (S)-proline and resolved 2-piperidine ethanol, were prepared using standard methods. These diamines lacked the bispidine framework of (−)-sparteine and were found to impart vastly inferior enantioselectivity. It was concluded that, for the asymmetric lithiation–substitution of N-Boc pyrrolidine, a rigid bispidine framework and only three of the four rings of (−)-sparteine are needed for high enantioselectivity. Furthermore, it is shown that diamine (1R,2S,9S)-11-methyl-7,11-diazatricyclo[7.3.1.02,7]tridecane is the first successful (+)-sparteine surrogate.

Graphical abstract: Synthesis of sparteine-like chiral diamines and evaluation in the enantioselective lithiation–substitution of N-(tert-butoxycarbonyl)pyrrolidine

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Supplementary files

Article information


Submitted
22 Jul 2003
Accepted
18 Sep 2003
First published
07 Oct 2003

Org. Biomol. Chem., 2003,1, 3977-3988
Article type
Paper

Synthesis of sparteine-like chiral diamines and evaluation in the enantioselective lithiation–substitution of N-(tert-butoxycarbonyl)pyrrolidine

J. R. Hermet, D. W. Porter, M. J. Dearden, J. R. Harrison, T. Koplin, P. O'Brien, J. Parmene, V. Tyurin, A. C. Whitwood, J. Gilday and N. M. Smith, Org. Biomol. Chem., 2003, 1, 3977
DOI: 10.1039/B308410H

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