The global AIDS epidemic has claimed the lives of more than 20 million people since 1981. Another 10 million are now living with HIV and most of these are likely to develop AIDS over the course of the next decade. In spite of the various treatment protocols available, including the mainstream

The transition metal-catalyzed [3+2] trimethylenemethane (TMM) cycloaddition is a powerful and versatile method for the construction of cyclopentanes. 1 Pd-TMM complexes generated from 3-acetoxy-2-trimethylsilylmethyl-1-propene and catalytic amounts of palladium react with electron deficient olefins to produce exo-methylenecyclopentanes in a highly chemo-, regio-, and diastereoselective manner. 2 The ubiquity of cyclopentane containing natural products makes the development of an efficient asymmetric process highly desirable. However, applications of this methodology in asymmetric catalysis are very rare. 3 Our ongoing efforts towards the synthesis of complex oxindole alkaloids prompted us to investigate the reactivity of 3-alkylidene-oxindoline-2-ones 1 towards Pd-TMM complexes. 4 We chose the cyanosubstituted TMM-precursor 2 ,5 reasoning it could enhance the asymmetric induction. Furthermore, this provides an increase in molecular complexity by the creation of an additional stereogenic center as well as installation of a synthetically valuable and versatile functionality.

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.

Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of d- or l-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2′- and C4′-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.

The global AIDS epidemic has claimed the lives of more than 20 million people since 1981. Another 10 million are now living with HIV and most of these are likely to develop AIDS over the course of the next decade. In spite of the various treatment protocols available, including the mainstream