Synthesis of non-natural l-alanine derivatives using the aza-Cope–Mannich reaction

Non-natural l-alanine derived trans-octahydrocyclohepta[b]pyrroles were synthesized with high enantiomeric purity using the aza-Cope–Mannich reaction. The study showed that the conditions of the aza-Cope–Mannich reaction and metal catalysed cyclization are mild enough to be applied to the synthesis of molecules with stereocenters, which are prone to racemization. We believe that these compounds will be of interest to medicinal chemists.

Figure optionsDownload as PowerPoint slide

(S)-Ethyl 2-((1S,2R)-2-ethynyl-2-hydroxycyclohexylamino)propanoateC13H21NO3[α]D23=+37 (c 1, CHCl3)Source of chirality: Chiral pool, asymmetric synthesisAbsolute configuration: (S,1S,2R)

(R)-Ethyl 2-((1S,2R)-2-ethynyl-2-hydroxycyclohexylamino)propanoateC13H21NO3[α]D23=+41 (c 1, CHCl3)Source of chirality: Chiral pool, asymmetric synthesisAbsolute configuration: (R,1S,2R)

(S)-Ethyl 2-(4,5,6,7-tetrahydro-1H-indol-1-yl)propanoateC13H19NO2[α]D23=-26.8 (c 1, CHCl3)Source of chirality: Chiral poolAbsolute configuration: (S)

(S)-Ethyl 2-((1S,2R)-2-hydroxy-2-vinylcyclohexylamino)propanoateC13H23NO3[α]D23=+39.7 (c 0.5, CHCl3)Source of chirality: Chiral pool, asymmetric synthesisAbsolute configuration: (S,1S,2R)

(R)-Ethyl 2-((1S,2R)-2-hydroxy-2-vinylcyclohexylamino)propanoateC13H23NO3[α]D23=+27.6 (c 2, CHCl3).Source of chirality: Chiral pool, asymmetric synthesisAbsolute configuration: (R,1S,2R)

(S)-Ethyl 2-((3aR,8aS)-4-oxooctahydrocyclohepta[b]pyrrol-1(2H)-yl)propanoateC14H23NO3[α]D23=+2.8 (c 1, CHCl3).Source of chirality: Chiral pool, asymmetric synthesisAbsolute configuration: (S,3aR,8aS)

(R)-Ethyl 2-((3aR,8aS)-4-oxooctahydrocyclohepta[b]pyrrol-1(2H)-yl)propanoateC14H23NO3[α]D23=+18.2 (c 1, CHCl3)Source of chirality: Chiral pool, asymmetric synthesisAbsolute configuration: (R,3aR,8aS)