RESUMEN
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.
Asunto(s)
Productos Biológicos , Productos Biológicos/química , CatálisisRESUMEN
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.
Asunto(s)
NucleósidosRESUMEN
α- and ß-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure α-methyl-ß-cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to this valuable framework. We used high throughput experimentation to define stereoconvergent Suzuki-Miyaura cross-coupling conditions affording (Z)-α-methyl-ß-cyclopropylcinnamates and subsequent ruthenium-catalyzed asymmetric hydrogenation conditions affording the desired products in excellent enantio- and diastereoselectivities. These conditions were executed on multigram to kilogram scale to provide three key enantiopure α-methyl-ß-cyclopropyldihydrocinnamates with high selectivity.
RESUMEN
Ir catalysts supported by bidentate silyl ligands that contain P- or N-donors are shown to effect ortho borylations for a range of substituted aromatics. The substrate scope is broad, and the modular ligand synthesis allows for flexible catalyst design.
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Compuestos de Boro/síntesis química , Quelantes/síntesis química , Complejos de Coordinación/química , Nitrógeno/química , Compuestos Organofosforados/síntesis química , Compuestos de Organosilicio/síntesis química , Compuestos de Boro/química , Catálisis , Quelantes/química , Iridio/química , Estructura Molecular , Compuestos Organofosforados/química , Compuestos de Organosilicio/químicaRESUMEN
A general and efficient asymmetric synthesis of cyclic indoline aminals was developed with a high level of 1,3-stereoinduction through a dynamic crystallization-driven condensation. Dehydrogenation of the indoline aminals with potassium permanganate produced the corresponding cyclic indole aminals in high yields and excellent enantioselectivities. This general methodology was successfully applied to the synthesis of a wide variety of chiral cyclic indoline aminals and indole aminals with aromatic and aliphatic functional groups.
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Indoles/síntesis química , Catálisis , Indoles/química , Estructura Molecular , EstereoisomerismoRESUMEN
With the aid of high-throughput screening, the efficiency of Ir-catalyzed C-H borylations has been assessed as functions of precatalyst, boron reagent, ligand, order of addition, temperature, solvent, and substrate. This study not only validated some accepted practices but also uncovered unconventional conditions that were key to substrate performance. We anticipate that insights drawn from these findings will be used to design reaction conditions for substrates whose borylations are difficult to impossible using standard catalytic conditions.
Asunto(s)
Compuestos de Boro/síntesis química , Ensayos Analíticos de Alto Rendimiento , Iridio/química , Compuestos Organometálicos/química , Compuestos de Boro/química , Catálisis , Estructura MolecularRESUMEN
Not a trace: Borylation of the nitrogen in nitrogen heterocycles or anilines provides a traceless directing group for subsequent catalytic C-H borylation. Selectivities that previously required Boc protection can be achieved; furthermore, the NBpin directing group can be installed and removed in-situ, and product yields are substantially higher. Boc=tert-butoxycarbonyl, pin=pinacolato.
Asunto(s)
Compuestos de Anilina/química , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Catálisis , Indoles/química , Pirroles/químicaRESUMEN
A stable adduct of CuI with Bu(4)NI, soluble in organic solvents, has been identified as an effective catalyst for copper-catalyzed C-N and C-O couplings. In addition, stable nonhygroscopic salts of some high performance ligands (diamine MsOH salts/CuX and copper(II) diketonates) were shown to be of similar and sometimes greater reactivity compared to the literature reagents for these couplings. Furthermore, these more robust conditions result in more reproducible results.
Asunto(s)
Cobre/química , Compuestos Organometálicos/química , Compuestos Orgánicos Volátiles/química , Catálisis , Ligandos , Estructura Molecular , Sales (Química)/química , SolubilidadRESUMEN
A robust and general catalyst system facilitates the alkoxylation of activated heteroaryl halides with primary, secondary, and select tertiary alcohols without the need for an excess of either coupling partner. This catalyst system displays broad functional-group tolerance and excellent regioselectivity, and is insensitive to the order of reagent addition.
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Alcoholes/química , Halógenos/química , Compuestos Heterocíclicos/química , Carbono/química , Catálisis , Cobre/química , Oxígeno/química , Paladio/química , EstereoisomerismoRESUMEN
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.
RESUMEN
An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.
RESUMEN
Bismuth(III) acetate is a safe, inexpensive, and selective facilitator of sequential protodeboronations, which when used in conjunction with Ir-catalyzed borylations allows access to a diversity of borylated indoles. The versatility of combining Ir-catalyzed borylations with Bi(III)-catalyzed protodeboronation is demonstrated by selectively converting 6-fluoroindole into products with Bpin groups at the 4-, 5-, 7-, 2,7-, 4,7-, 3,5-, and 2,4,7-positions and the late-stage functionalization of sumatriptan.
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Acetatos/química , Bismuto/química , Compuestos de Boro/química , Indoles/química , Catálisis , Estructura MolecularRESUMEN
The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Descubrimiento de Drogas , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Macrocíclicos/química , Estructura Molecular , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
[reaction: see text] A facile preparation of chiral alpha-aryloxy carboxylic acids via asymmetric hydrogenation of the corresponding unsaturated acids has been discovered. A number of catalysts have been identified that give high product enantioselectivity, and the scope of the reaction has been examined with respect to substitution on the aromatic ring and olefin.
RESUMEN
The synthesis of a spirobicyclic NK-1 receptor (Substance-P) antagonist 1 antipode is described. Retrosynthetic analysis reveals an allylic halide A bearing the cyclopropoxy-substituted aryl group and a 2-phenyl-3-piperidone B. The stereochemistry in the spirobicyclic system bearing three chiral centers is initially set via a highly diastereoselective zinc-mediated coupling of the allylic bromide 23 to the optically active ketopiperidine 3. The remaining benzylic asymmetric center is set by a diastereoselective hydroboration followed by cyclization to the spirobicyclic system.