First asymmetric synthesis of a C2-symmetric 2-endo,6-endo-disubstituted bispidine

The enantioselective synthesis of a C2-symmetric 2-endo,6-endo-disubstituted bispidine (3,7-diazabicyclo[3.3.1]nonane) has been accomplished for the first time. The key step was a Michael addition of the protected β-amino ester methyl (R)-3-{N-benzyl-N-[(S)-1-phenylethyl]amino}-3-phenylpropionate to its α-methylene derivative delivering an anti,anti-configured α,α′-methylene-bridged bis(β-amino ester) as the major diastereomer. Deprotection, reduction and cyclisation furnished (1R,2R,5R,6R)-2,6-diphenyl-3,7-bis((S)-1-phenylethyl)-3,7-diazabicyclo[3.3.1]nonane in six steps and 15% overall yield.

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Methyl 2-{(S)-[N-benzyl-N-((S)-1-phenylethyl)amino]phenylmethyl}acrylateC26H27NO2Ee >97%, de >95% (NMR)[α]D21=+88.7 (c 0.13, CHCl3)Source of chirality: asymmetric synthesis

Methyl (R)-3-[N-benzyl-N-((S)-1-phenylethyl)amino]-2-{[N-benzyl-N-((S)-1-phenylethyl)amino]methyl}-3-phenylpropionate [faster eluting diastereomer (silica gel, n-pentane–Et2O 10:1)]C41H44N2O2Ee >97%, de >95% (NMR)[α]D22=-102.2 (c 0.14, CHCl3)Source of chirality: asymmetric synthesis

Methyl (R)-3-[N-benzyl-N-((S)-1-phenylethyl)amino]-2-{[N-benzyl-N-((S)-1-phenylethyl)amino]methyl}-3-phenylpropionate [slower eluting diastereomer (silica gel, n-pentane–Et2O 10:1)]C41H44N2O2Ee >97%, de >95% (NMR)[α]D22=+25.9 (c 0.10, CHCl3)Source of chirality: asymmetric synthesis

(2S,4S)-2,4-Bis[(R)-phenyl-((S)-1-phenylethylamino)methyl]pentane-1,5-diolC35H42N2O2Ee >97%, de >95% (NMR)[α]D21=-125.5 (c 0.06, CHCl3)Source of chirality: asymmetric synthesis

(1S,4R,5S,8R)-4,8-Diphenyl-3,7-bis((S)-1-phenylethyl)-3,7-diazabicyclo[3.3.1]nonane-2,6-dioneC35H34N2O2Ee >97%, de >95% (NMR)[α]D21=+15.7 (c 0.10, CHCl3)Source of chirality: asymmetric synthesis

(1R,2R,5R,6R)-2,6-Diphenyl-3,7-bis((S)-1-phenylethyl)-3,7-diazabicyclo[3.3.1]nonaneC35H38N2Ee >97%, de >95% (NMR)[α]D21=-5.5 (c 0.10, CHCl3)Source of chirality: asymmetric synthesis

(2R,4R)-2,4-Dibenzyl-N,N′-bis((S)-1-phenylethyl)-pentane-1,5-diamineC35H42N2Ee >97%, de >95% (NMR)[α]D22=+26.9 (c 0.10, CHCl3)Source of chirality: asymmetric synthesis

Dimethyl (2S,4S)-2,4-bis{(R)-[N-benzyl-N-((S)-1-phenylethyl)amino]phenylmethyl}glutarateC51H54N2O4Ee >97%, de >95% (NMR)[α]D21=+9.8 (c 0.13, CHCl3)Source of chirality: asymmetric synthesis

Dimethyl (2S,4R)-2,4-bis{(R)-[N-benzyl-N-((S)-1-phenylethyl)amino]phenylmethyl}glutarateC51H54N2O4Ee >97%, de >95% (NMR)[α]D21=+29.9 (c 0.14, CHCl3)Source of chirality: asymmetric synthesis

Dimethyl (2S,4S)-2,4-bis[(R)-phenyl-((S)-1-phenylethylamino)methyl]glutarateC37H42N2O4Ee >97%, de >95% (NMR)[α]D19=-40.3 (c 0.18, CHCl3)Source of chirality: asymmetric synthesis