Molnupiravir (MK-4482)
is an investigational antiviral agent that
is under development for the treatment of COVID-19. Given the potential
high demand and urgency for this compound, it was critical to develop
a short and sustainable synthesis from simple raw materials that would
minimize the time needed to manufacture and supply molnupiravir. The
route reported here is enabled through the invention of a novel biocatalytic
cascade featuring an engineered ribosyl-1-kinase and uridine phosphorylase.
These engineered enzymes were deployed with a pyruvate-oxidase-enabled
phosphate recycling strategy. Compared to the initial route, this
synthesis of molnupiravir is 70% shorter and approximately 7-fold
higher yielding. Looking forward, the biocatalytic approach to molnupiravir
outlined here is anticipated to have broad applications for streamlining
the synthesis of nucleosides in general.
The intramolecular α-arylation of aldehydes has been accomplished using singly occupied molecular orbital (SOMO) catalysis. Selective oxidation of chiral enamines (formed by the condensation of an aldehyde and a secondary amine catalyst) leads to the formation of a 3π-electron radical species. These chiral SOMO-activated radical cations undergo enantioselective reaction with an array of pendent electron-rich aromatics and heterocycles thus efficiently providing cyclic α-aryl aldehyde products (10 examples: ≥70% yield and ≥90% ee). In accordance with our radical mechanism, when there is a choice between arylation at the ortho or para position of anisole substrates, we find that arylation proceeds selectively at the ortho position.
A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the diene substrate at a concentration of 0.13 M.
Exposure of Morita-Baylis-Hillman (MBH) acetates to tertiary phosphine catalysts in the presence of 4,5-dichlorophthalimide enables regiospecific allylic substitution through a tandem S(N)2'-S(N)2' mechanism. Through the use of the chiral phosphine catalyst (R)-Cl-MeO-BIPHEP, chiral racemic MBH acetate 4 is converted to the corresponding allylic amination product in 80% yield and 56% enantiomeric excess, thus establishing the feasibility of dynamic kinetic resolution. [reaction: see text]
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