作者: Fang, Francis G. ; Yang, Jiong ; Schreiber, Stuart L. ; Gusovsky, Fabian ; Vaddi, Anand ; Balla, Venkata Sasidhar ; Sugandham, Srinivasa Rao ; Girish, Dixit ; Khile, Anil Shahaji ; Terli, Chiranjeevi ; Kalla, Vijay ; Gotoda, Masaharu ; Rayaprolu, Pavan Kumar ; Talabhakthula, Ravi Kumar ; Melillo, Bruno ; Bathula, Srikanth ; Vikram, Venugopalarao ; Mitasev, Branko
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 chromatog. separationsA 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.Multiple crystalline intermediates enabled the complete removal of chromatog. from the synthesis resulting in a substantially reduced cost and waste generation with enhanced throughput and quality control.
