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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 ( IF 3.1 ) Pub Date : 2021-09-15 , DOI: 10.1021/acs.oprd.1c00225 Branko Mitasev 1 , Jiong Yang 1 , Fabian Gusovsky 1 , Dixit Girish 2 , Anil Shahaji Khile 2 , Venkata Sasidhar Balla 2 , Venugopalarao Vikram 2 , Anand Vaddi 2 , Srikanth Bathula 2 , Srinivasa Rao Sugandham 2 , Chiranjeevi Terli 2 , Vijay Kalla 2 , Pavan Kumar Rayaprolu 2 , Ravi Kumar Talabhakthula 2 , Masaharu Gotoda 3 , Bruno Melillo 4, 5 , Stuart L. Schreiber 4, 6 , Francis G. Fang 1
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2021-09-15 , DOI: 10.1021/acs.oprd.1c00225 Branko Mitasev 1 , Jiong Yang 1 , Fabian Gusovsky 1 , Dixit Girish 2 , Anil Shahaji Khile 2 , Venkata Sasidhar Balla 2 , Venugopalarao Vikram 2 , Anand Vaddi 2 , Srikanth Bathula 2 , Srinivasa Rao Sugandham 2 , Chiranjeevi Terli 2 , Vijay Kalla 2 , Pavan Kumar Rayaprolu 2 , Ravi Kumar Talabhakthula 2 , Masaharu Gotoda 3 , Bruno Melillo 4, 5 , Stuart L. Schreiber 4, 6 , Francis G. Fang 1
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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.
中文翻译：
抗疟剂 BRD5018 的基于结晶的合成途径：通过氮杂环丁烷-核糖模板上的施陶丁格-氮杂-维蒂希反应形成重氮环
描述了一种完全基于结晶的抗疟 BRD5018 合成路线的开发，该路线组装了一个结构复杂的双环氮杂环丁烷支架，装饰有五个立体中心，无需任何色谱分离。非对映选择性甘氨酸酯 Claisen 重排、非对映体盐拆分和非对映选择性碘内酯化用于提供对具有所需相对和绝对构型的无环模板上三个连续立体中心的有效访问。开发了衍生的 2-氨基-1,4-二醇模板上的串联氮丙啶开环/氮杂环丁烷环闭合，以有效地建立具有适当辅助功能的全顺式三取代氮杂环丁烷支架，用于终局操作。d -Ribose-2,3-acetonide 提供了一种方便区分的连位顺二醇，适用于计划的还原胺化/高碘酸盐裂解/施陶丁格-氮杂-维蒂希序列以形成八元重氮环。通过在电子匹配的 4-溴肉桂酸甲酯上的 Sonogashira 偶联，二芳基乙炔部分的早期定量安装规避了第一代合成中的低产率后期反应。多晶中间体能够从合成中完全去除色谱，从而显着降低成本和废物产生，同时提高通量和质量控制。
更新日期：2021-09-15
中文翻译：
抗疟剂 BRD5018 的基于结晶的合成途径：通过氮杂环丁烷-核糖模板上的施陶丁格-氮杂-维蒂希反应形成重氮环
描述了一种完全基于结晶的抗疟 BRD5018 合成路线的开发，该路线组装了一个结构复杂的双环氮杂环丁烷支架，装饰有五个立体中心，无需任何色谱分离。非对映选择性甘氨酸酯 Claisen 重排、非对映体盐拆分和非对映选择性碘内酯化用于提供对具有所需相对和绝对构型的无环模板上三个连续立体中心的有效访问。开发了衍生的 2-氨基-1,4-二醇模板上的串联氮丙啶开环/氮杂环丁烷环闭合，以有效地建立具有适当辅助功能的全顺式三取代氮杂环丁烷支架，用于终局操作。d -Ribose-2,3-acetonide 提供了一种方便区分的连位顺二醇，适用于计划的还原胺化/高碘酸盐裂解/施陶丁格-氮杂-维蒂希序列以形成八元重氮环。通过在电子匹配的 4-溴肉桂酸甲酯上的 Sonogashira 偶联，二芳基乙炔部分的早期定量安装规避了第一代合成中的低产率后期反应。多晶中间体能够从合成中完全去除色谱，从而显着降低成本和废物产生，同时提高通量和质量控制。
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