Ni-Catalyzed Cross-Electrophile Coupling for the Synthesis of Skipped Polyenes

Skipped polyenes featuring high (E)-selectivity and varying methyl substitution patterns are synthesized using a nickel-catalyzed cross-coupling reaction between allyl trifluoroacetates and vinyl bromides. The utility of this cross-electrophile coupling is showcased in part by the synthesis of the RST fragment of the marine ladder polyether, maitotoxin. Construction of this fragment is particularly challenging due to the alternating methyl substitution pattern. ©2019 American Chemical Society.NIGMS (GM72566)NIGMS (GM117710

Progress Towards a Large-Scale Synthesis of Molnupiravir (MK-4482, EIDD-2801) from Cytidine

Molnupiravir (MK-4482, EIDD-2801) is a promising orally bioavailable drug candidate for treatment of COVID-19. Herein we describe a supply-centered and chromatography-free synthesis of molnupiravir from cytidine, consisting of two steps: a selective enzymatic acylation followed by transamination to yield the final drug product. Both steps have been successfully performed on decagram scale: the first step at 200 g, and the second step at 80 g. Overall, molnupiravir has been obtained in a 41% overall isolated yield compared to a maximum 17% isolated yield in the patented route. This route provides many advantages to the initial route described in the patent literature and would decrease the cost of this pharmaceutical should it prove safe and efficacious in ongoing clinical trials. </div

Progress Toward a Large-Scale Synthesis of Molnupiravir (MK-4482, EIDD-2801) from Cytidine

Molnupiravir (MK-4482, EIDD-2801) is a promising orally bioavailable drug candidate for the treatment of COVID-19. Herein, we describe a supply-centered and chromatography-free synthesis of molnupiravir from cytidine, consisting of two steps: a selective enzymatic acylation followed by transamination to yield the final drug product. Both steps have been successfully performed on a decagram scale: the first step at 200 g and the second step at 80 g. Overall, molnupiravir has been obtained in a 41% overall isolated yield compared to a maximum 17% isolated yield in the patented route. This route provides many advantages to the initial route described in the patent literature and would decrease the cost of this pharmaceutical should it prove safe and efficacious in ongoing clinical trials.National Science Foundation (Grant 1745302

A Concise Route to MK-4482 (EIDD-2801)

A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The reactions can be conducted in either order with overall yields of 67% (first step—esterification) and 37% (first step—hydroxamination). Selective esterification of the nucleoside’s primary alcohol by enzymatic means eliminated the need for diol protection/deprotection, and direct transamination with hydroxylamine precluded the necessity of activating the nucleobase for amine coupling. This results in a significant advancement over the reported synthesis which is formed in at best 17% yield. The step count is reduced from five transformation to two, and the more expensive uridine is replaced with the more available cytidine

A concise route to MK-4482 (EIDD-2801) from cytidine

© The Royal Society of Chemistry. A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The selective acylation and direct amination eliminate the need for protecting and activating groups and proceed in overall yield of 75%, a significant advancement over the reported yield of 17%. The step count is reduced from five transformations to two, and expensive uridine is replaced with the more available cytidine. This journal i