Streamlined Synthesis of a Bicyclic Amine Moiety Using an Enzymatic Amidation and Identification of a Novel Solid Form
journal contributionposted on 27.05.2021, 03:03 authored by Maria S. Brown, Michaella A. Caporello, Adam E. Goetz, Amber M. Johnson, Kris N. Jones, Kevin M. Knopf, Samir A. Kulkarni, Taegyo Lee, Bryan Li, Cuong V. Lu, Javier Magano, Angela L. A. Puchlopek-Dermenci, Giselle P. Reyes, Sally Gut Ruggeri, Lulin Wei, Gerald A. Weisenburger, Richard A. Wisdom, Mengtan Zhang
We describe a series of improvements to the synthesis of a 3,8-diazabicyclo[3.2.1]octane derivative that result in a reduced step count and higher overall efficiency compared to previously published syntheses. Our method includes optimization and mechanistic understanding of a key diastereoselective cyclization to achieve a >95:5 diastereomeric ratio, as well as demonstration of a unique enzyme-catalyzed amidation reaction using hexamethyldisilazane as both an ammonia source and scavenger. Finally, we identify a novel cocrystal solid form of the target compound that provides improved purity and material properties. Demonstration of the new chemistry to prepare >100 kg of the target compound serves to illustrate the robustness of the new process.
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diastereoselectiveseriesIdentificationscavengerhexamethyldisilazaneAmidationdiastereomerictarget compoundmaterialratiodemonstrationcyclizationBicyclic Amine MoietysourcediazabicyclomethodsynthesisEnzymaticpurityammoniaunderstandingefficiencysyntheseStreamlinedenzyme-catalyzed amidation reactioncountkgrobustnesscocrystaloptimizationSynthesiDemonstration