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
The transition metal catalyzed trimethylenemethane [3+2] cycloaddition provides a direct route to functionalized heterocycles. Herein, we describe a catalytic, asymmetric protocol for the reaction between 3-acetoxy-2-trimethylsilylmethyl-1-propene and various imines. The corresponding pyrrolidines were obtained in excellent yields and enantioselectivities making use of the novel phosphoramidite L10.Pyrrolidines are ubiquitous structural units in the chemical literature, with numerous applications seen throughout the pharmaceutical industry as well as among natural products. 1 As such, much attention has been devoted towards their synthesis. While cycloaddition strategies to form pyrrolidines are well documented, they are largely based on the reaction of azomethine ylides with two carbon units. 2 Complementary strategies involving the addition of imines to suitable three carbon units have received less attention. The transition metalcatalyzed [3+2] trimethylenemethane (TMM) cycloaddition is a highly efficient process that provides a direct route to five, seven, and nine-membered ring systems. 3 Though this venerable reaction has been primarily studied in the construction of carbocycles, there have been few accounts detailing TMM cycloaddition reactions of imines to form pyrrolidines. 4 Further, asymmetric syntheses of this moiety are highly desirable. Our recent disclosure of an asymmetric variant of the TMM reaction between 3-acetoxy-2-trimethylsilylmethyl-1-propene and olefins 5 prompted us to investigate the enantioselective synthesis of pyrrolidines using this methodology.Initial studies focused on the reaction of benzylidene aniline under the previously developed conditions (5 mol% Pd(dba) 2 , 10 mol% ligand, 1.6 equiv TMS propenyl acetate) at 45°C (Scheme 1). Ligand L1 6 gave only 3% ee at 71% conversion. Based on a report detailing the beneficial effects that minor alterations of phosphoramidite ligands have on the selectivity of iridium-catalyzed AAA reactions, 7 we tested L2-L3. Unfortunately, enantiomeric excesses remained low, though increased conversion was observed. Further variations of this segment that may affect conformation such as inverting the stereochemistry of the methyl group (L4) increased the ee, but removal of a methyl group (L5) provided an inactive catalyst. The previously utilized asymmetric palladium catalyst for the TMM reaction of olefins (L6) 5,8 provided the desired product in only 35% ee and 73% conversion. Adjusting the nature of the chiral space by increasing the size of the aryl groups led initially to replacement of one phenyl group with a 2-naphthyl group (L7), which did increase the ee. Substitution with 4-biphenyl groups (L8) or even better, the bis-1-naphthyl ligand (L9) boosted the ee. Bis-2-naphthyl ligand L10 gave the best results with a 76% conversion and 84% ee. In order to examine the effects of ring size, we turned to azetidine ligand L11, which gave significantly lower ee.
Transition-metal-catalyzed trimethylenemethane (TMM) [3 + 2] cycloadditions provide direct routes to functionalized cyclopentanes. This reaction has been shown to be a highly chemo-, regio-, and diastereoselective process. We report a palladium-catalyzed asymmetric [3 + 2] trimethylenemethane (TMM) cycloaddition between 3-acetoxy-2-trimethylsilylmethyl-1-propene and various di- and trisubstituted olefins. Yields of exo-methylenecyclopentane products range from 59 to 99%, and enantiomeric excesses range from 58 to 92% ee.
A protocol for the enantioselective [3+2] cycloaddition of trimethylenemethane with electron-deficient olefins has been developed. The synthesis of novel phosphoramidite ligands was critical in this effort, and the preparation and reactivity of these ligands is detailed. The evolution of the ligand design, commencing with acyclic amine-derived phosphoramidites and leading to cyclic pyrrolidine and azetidine structures is discussed. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of alkene acceptors, providing the desired methylenecyclopentanes with high levels of enantioselectivity. The donor scope was also explored and substituted systems were tolerated, including one bearing a nitrile moiety. These donors were reactive with unsaturated acylpyrroles, giving the product cyclopentane rings bearing three stereocenters in high enantioselectivity and complete diastereoselectivity.
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