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

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[6.3.1.0(2,6)]dodecane and (1S*, 2R*, 9R*)-11-methyl-7,11-diazatricyclo[7.3.1.0(2,7)]tridecane} ( via inclusion complex formation) are reported. Unfortunately, it was only possible to resolve the diazatricyclo[7.3.1.0(2,7)] tridecane compound. An alternative route to (1R, 2S, 9S)-11-methyl-7,11-diazatricyclo[ 7.3.1.0(2,7)]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-methoxycarbonyl-decahydro-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[7.3.1.0(2,7)]tridecane is the first successful (+)-sparteine surrogate.