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A four chemical step route to 2′-deoxy-2′-fluoro-N6,3′-dipivaloylarabinoadenosine and 2′-deoxy-2′-fluoro-N6-pivaloylarabinoadenosine from adenosine was developed for the preparation of ulevostinag in our STING (Stimulator of Interferon Genes) program. This 4-step route is based on the selective protection of adenosine with a dynamic kinetic crystallization of the desired N6,3′,5′-tripivaloyladenosine. This is followed by activation of the 2′-alcohol as its triflate without pivalate migration. Subsequently, the triflate is displaced with fluoride under mild conditions. Selective deprotection of the esters can give a variety of mono- and diacylated products including the 3′- or 5′-protected 2′-fluoroarabinonucleoside in the presence of the N6-pivalamide.

A simple and efficient process to prepare Uprifosbuvir intermediate, 2′-deoxy-α-2′-chloro-β-2′-methyluridine (1), from bis-pivaloyl tertiary alcohol 5ais described. The key discoveries are a novel BSA-promoted anhydrouridine formation catalyzed by HCl as an additive and a milder safe Me2SiCl2-promoted chlorination of anhydrouridine. These discoveries collectively enabled the establishment of a robust process toward compound 1, which was demonstrated successfully at the plant scale.

Our work required a reliable efficient preparation of 2-trimethylsilyloxymethyl((2R,3S)-3-(trimethylsilyloxy)-2,3-dihydrofuran (glycal 1). The best literature protocol for the preparation of this dihydrofuran glycal is the treatment of thymidine with 20 mol % (NH4)2SO4in (TMS)2NH (HMDS) at reflux. Unfortunately, this procedure was found to be extremely unreliable and messy on scale-up. The need for removal of ammonia formed during reactions using HMDS was identified as critical to the success of these reactions. A high throughput screening prototype setup enabling release of the gaseous ammonia byproduct was developed, allowing rapid screening of reaction conditions. Extensive high throughput screening initially identified 1 mol % (PhSO2)2NH (DBSI) in heptane at reflux gave more reliable and improved results. Despite this, this improvement still suffered from disadvantages such as the formation of a bisglycosylated byproduct, the need for a wiped film distillation to isolate the glycal, and the need to expel the formed NH3gas from the reaction mixture. Further screening revealed an unprecedented catalyst 1 mol % (Ph2PS)2NH (PTPI) with bistrimethylsilylacetamide (BSA) in heptane–toluene at 100 °C gave rapid and virtually quantitative conversion to the glycal. Throughout, process analytical technology (PAT) was extensively employed to improve process understanding and inform development from bench scale through over 3 orders of magnitude scale-up.

A class of organocatalysts that are highly active for the conversion of 2′-deoxynucleosides to furanoid glycals have been discovered. These phosphorimides, (Ph2PS)2NH and (Ph2PSe)2NH, were shown to effectively mediate persilylation of 2′-deoxynucleosides allowing the elimination of the nucleobase giving the corresponding glycal. These mild conditions were demonstrated in the syntheses of glycals with various substitution patterns while minimizing the formation of undesired byproducts and expanding the scope of this methodology.

The synthesis of rasfarnesylprotein transferase inhibitor 1is described on a multikilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2and a piperazinone 3as viable precursors. The 1,5disubstituted imidazole system was regioselectively assembled viaan improved Marckwald imidazole synthesis. A new imidazole dethionation procedure has been developed to convert the Marckwald mercaptoimidazole product to the desired imidazole. This methodology was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prepare the arylpiperazinone fragment 3.

As practitioners of organic chemistry strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation. These benefits are amplified when enzymatic processes are conducted in a cascade in combination with novel bond-forming strategies. In this article, we report a highly diastereoselective synthesis of MK-1454, a potent agonist of the stimulator of interferon gene (STING) signaling pathway. The synthesis begins with the asymmetric construction of two fluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thorough understanding of the role transition metals play in bond formation.

Nosylaziridines are highly reactive electrophiles towards a variety of nucleophiles yielding the corresponding S n2 adducts without competing attack on the nosyl functionality (S nAr). The resulting primary nosylamide adducts can be readily cleaved under mild conditions to provide the primary amines.

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.

A dependable high yielding palladium catalyzed aryl bromide cyanation procedure has been developed. The optimized cyanation features extremely low levels of palladium and DPPF ligand.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.