Crystallization-Based Synthetic Route to Antimalarial Agent BRD5018: Diazocene Ring Formation via a Staudinger-aza-Wittig Reaction on an Azetidine-Ribose Template
Organic Process Research & Development(2022)
摘要
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.
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关键词
malaria,bicyclic,azetidine,diazocane,Staudinger,aza-Wittig,Claisen rearrangement,Sonogashira coupling
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