3-Substituted 6-Azabicyclo[3.1.1]heptanes: Nonclassical Piperidine Isosteres for Drug Discovery.

Advanced analogs of piperidine and smaller homologues of tropane─3-substituted 6-azabicyclo[3.1.1]heptanes─were synthesized on a large scale using readily available bulk reagents. The key step of the approach involved the double alkylation reaction of malonate with -2,4-bis(mesyloxymethyl)azetidine-1-carboxylate, in turn easily prepared on up to 1 kg scale. After hydrolysis, -Boc-6-azabicyclo[3.1.1]heptane-3,3-dicarboxylic acid was obtained (up to 400 g in a single run), which was used as a common intermediate for the preparation of all the title building blocks. In particular, Pb(OAc)-mediated oxidative decarboxylation of this intermediate gave 2,6-methanopiperidone derivative (up to 400 g scale), while monodecarboxylation gave -Boc-6-azabicyclo[3.1.1]heptane-3-carboxylic acids as an easily separatable mixture of and diastereomers (up to 100 g scale). Further functional group transformations gave diastereopure - and --Boc-monoprotected diamines and amino alcohols. Molecular structure analysis using exit vector parameters (EVP) revealed that isomers of 3-substituted 6-azabicyclo[3.1.1]heptanes are three-dimensional analogs of common 1,4-disubstituted piperidine conformer, whereas isomers can be considered as unusual "" piperidines.