An efficient regioconvergent synthesis of 3-aza-obeticholic acid

[Display omitted] •A mild and efficient synthesis of 3-aza-obeticholic acid starting from obeticholic acid (OCA).•Regiomeric amino-alcohols were prepared from a mixture of Baeyer-Villiger-reaction-derived lactones by ammonolysis and Hofmann degradation.•Annulation of N-Boc-protected amino-alcohols was accomplished via mesylation or a Dess-Martin oxidation/hydrogenation sequence.•Our synthesis is scalable and can be employed to access other 3-aza-bile acids. Bile acids (BAs) are steroidal molecules that play important roles in nutrient absorption, distribution, and excretion. They also act on specific receptors implicated in various metabolic and inflammatory diseases demonstrating their importance as potential drug candidates. Accordingly, there has been a concerted effort to develop new BA derivatives to probe structure–activity relationships with the goal of discovering BA analogues with enhanced pharmacological properties. Among the many steroidal derivatisations reported, the formation of endocyclic azasteroids appeals due to their potential to deliver altered biological responses with minimal change to the steroidal superstructure. Here, we report the synthesis of 3-aza-obeticholic acid (6) via a regioconvergent route. Ammoniolysis of lactones, formed from an m-CPBA-mediated Baeyer-Villiger reaction on a 3-keto-OCA derivative, furnished protected intermediate amido-alcohols which were separately elaborated to amino-alcohols via Hofmann degradation with BAIB. Upon individual N-Boc-protection, these underwent annulation to the 3-aza-A-ring when subjected to either mesylation or a Dess-Martin oxidation/hydrogenation sequence. Global deprotection of the 3-aza-intermediate delivered 3-aza-OCA in ten steps and an overall yield of up to 19%.