Crystallization-Based Synthetic Route to Antimalarial Agent BRD5018: Diazocene Ring Formation via a Staudinger-aza-Wittig Reaction on an Azetidine-Ribose Template

• Published in: Organic process research & development 2022-03, Vol.26 (3), p.817-831
• Main Authors: Mitasev, Branko, Yang, Jiong, Gusovsky, Fabian, Girish, Dixit, Khile, Anil Shahaji, Balla, Venkata Sasidhar, Vikram, Venugopalarao, Vaddi, Anand, Bathula, Srikanth, Sugandham, Srinivasa Rao, Terli, Chiranjeevi, Kalla, Vijay, Rayaprolu, Pavan Kumar, Talabhakthula, Ravi Kumar, Gotoda, Masaharu, Melillo, Bruno, Schreiber, Stuart L, Fang, Francis G
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.1c00225

The development of an entirely crystallization-based synthetic route to the antimalarial BRD5018 is described, which assembles a structurally complex bicyclic azetidine scaffold adorned with five stereogenic centers without the need for any chromatographic separations. A diastereoselective glycine ester Claisen rearrangement, diastereomeric salt resolution, and diastereoselective iodo-lactonization are utilized to provide an efficient access to three contiguous stereogenic centers on an acyclic template with the desired relative and absolute configurations. A tandem aziridine ring-opening/azetidine ring-closure on the derived 2-amino-1,4-diol template was developed to efficiently establish the all-cis trisubstituted azetidine scaffold with the proper ancillary functionality for end-game maneuvers. d-Ribose-2,3-acetonide provided a conveniently differentiated vicinal syn-diol suitable for the planned reductive amination/periodate cleavage/Staudinger-aza-Wittig sequence to form the eight-membered diazocene ring. An early quantitative installation of the diaryl acetylene moiety via a Sonogashira coupling on an electronically matched methyl 4-bromocinnamate circumvented a low-yielding, late-stage reaction in the first-generation synthesis. Multiple crystalline intermediates enabled the complete removal of chromatography from the synthesis resulting in a substantially reduced cost and waste generation with enhanced throughput and quality control.