Kinetically E-selective macrocyclic ring-closing metathesis

Macrocyclic organic molecules are central to discovery of new drugs but their preparation is often challenging because of the energy barrier required for bringing together and fusing the two ends of an acyclic precursor. Ring-closing metathesis (RCM) is a widely used catalytic process that has allowed access to countless biologically active macrocyclic organic molecules even on large scale (up to 200 kilograms). The potency of a macrocyclic compound can depend on the stereochemistry of its alkene, or one isomer might be needed for subsequent stereoselective modification (e.g., dihydroxylation). Professor Amir Hoveyda and his research group reported in a paper in Nature in 2011 the discovery of kinetically controlled Z-selective RCM. However, a generally applicable kinetically E-selective strategy has remained elusive until now. In a new paper just published by the journal Nature (doi:10.1038/nature 20800), the same research group at Boston College chemistry department show that dienes containing an E-alkenyl–B(pinacolato) group, widely used in catalytic cross-coupling, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E macrocyclic alkenes. The team, which includes postdoctoral fellows Dr. Xiao Shen (soon to join the faculty at Wuhan University in China) and Dr. Alex Speed (now a faculty member at Dalhousie University in Canada), graduate students Thach Nguyen and Ming-Joo Koh and undergraduate scholar Dongmin Xu, finds that reactions can be promoted by a molybdenum monoaryloxide pyrrolide complex and afford products in up to 73 percent yield and >98:2 E:Z ratio. Utility is highlighted by application to preparation of the eighteen-membered ring Janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor pacritinib the Z isomer of which has lower potency than the E. The eighteen-membered ring moiety of pacritinib, a potent in vivo anti-cancer agent in advanced clinical trials for treatment of lymphoma and myelofibrosis, was prepared by an RCM carried out at 20 times higher concentration than when a ruthenium carbene was employed. This study is part of a 20-year old collaboration between the Hoveyda group and the research team of Professor Richard Schrock at MIT.

See the recent publication by Richard Schrock and Amir Hoveyda: 
Kinetically E-selective macrocyclic ring-closing metathesis

(Xiao Shen, Thach T. Nguyen, Ming Joo Koh, Dongmin Xu, Alexander W. H. Speed, Richard R. Schrock & Amir H. Hoveyda, Nature, doi:10.1038/nature 20800)

30. January, 2017



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