Synthesis, Enantiomer Separation, and Absolute Configuration of 2,6-Oxygenated 9-Azabicyclo[3.3.1]nonanes

Abstract

The synthesis of the enantiomerically pure N-Boc 9-azabicyclo[3.3.1]nonane-2,6-dione (4b), a potentially useful chiral building block, from N-Bn and N-Boc 9-azabicyclo[3.3.1]nonane-2,6-diols 2a and 2b was accomplished. The enantiomer resolution of diols 2a and 2b was achieved by crystallization of their diastereomeric esters or by kinetic resolution of the racemic diol 2a using lipase from Candida rugosa (CRL). Both enantiomers of N-Boc protected diol 2b were converted into the corresponding enantiomerically pure diones 4b, the absolute configuration of which was determined by comparison of the experimental and simulated circular dichroism (CD) spectra, obtained by ab initio time-dependent density functional theory (TDDFT) calculations. The (-)-(1R,5R)/(+)-(1S,5S) absolute configuration of 4b inferred from the TDDFT calculations was confirmed via analysis of the CD spectrum of endo,endo-dibenzoate (+)-7 derived from diol (+)-2b and application of the benzoate exciton chirality method. The assigned absolute configuration was further supported by the results of kinetic resolution of diol 2a using Candida rugosa lipase, which exhibited kinetic preference toward the (1R,2R,5R,6R)-enantiomer in agreement with the Kazlauskas' rule.