ABSTRACT
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.
Subject(s)
Biological Products , Biological Products/chemistry , CatalysisABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
NucleosidesABSTRACT
The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.
Subject(s)
Amides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , Phosphoric Acids/chemical synthesis , Prodrugs/chemical synthesis , Catalysis , Computer Simulation , StereoisomerismABSTRACT
A gasometric titration method was developed to quantitate active alkylaluminum content in dimethylaluminum chloride solution to perform the stoichiometry calculation for the reaction charge. The procedure was reproducible with good precision, and the results showed good correlation with ICP-MS method. The gasometric titration is a simple, inexpensive alternative to analysis via ICP-MS which provides more selective analysis of methylaluminum species without the need for inertion.
Subject(s)
Organometallic Compounds/analysis , Spectrum Analysis/methods , Reproducibility of ResultsABSTRACT
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.
Subject(s)
Acetates/chemistry , Bismuth/chemistry , Boron Compounds/chemistry , Indoles/chemistry , Catalysis , Molecular StructureABSTRACT
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.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Drug Discovery , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Macrocyclic Compounds/chemistry , Molecular Structure , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
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.
ABSTRACT
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.
Subject(s)
Boron Compounds/chemical synthesis , Chelating Agents/chemical synthesis , Coordination Complexes/chemistry , Nitrogen/chemistry , Organophosphorus Compounds/chemical synthesis , Organosilicon Compounds/chemical synthesis , Boron Compounds/chemistry , Catalysis , Chelating Agents/chemistry , Iridium/chemistry , Molecular Structure , Organophosphorus Compounds/chemistry , Organosilicon Compounds/chemistryABSTRACT
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.
Subject(s)
Indoles/chemical synthesis , Catalysis , Indoles/chemistry , Molecular Structure , StereoisomerismABSTRACT
A concise, enantioselective synthesis of the HCV NS5a inhibitor MK-8742 (1) is reported. The features of the synthesis include a highly enantioselective transfer hydrogenation of an NH imine and a dynamic diastereoselective transformation. The synthesis of this complex target requires simple starting materials and nine linear steps for completion.
Subject(s)
Benzofurans/chemical synthesis , Imidazoles/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Benzofurans/chemistry , Hydrogenation , Imidazoles/chemistry , Imines/chemistry , Molecular Structure , StereoisomerismABSTRACT
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.
Subject(s)
Aniline Compounds/chemistry , Boron Compounds/chemical synthesis , Boron Compounds/chemistry , Catalysis , Indoles/chemistry , Pyrroles/chemistryABSTRACT
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.
Subject(s)
Boron Compounds/chemical synthesis , High-Throughput Screening Assays , Iridium/chemistry , Organometallic Compounds/chemistry , Boron Compounds/chemistry , Catalysis , Molecular StructureABSTRACT
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.
Subject(s)
Alcohols/chemistry , Halogens/chemistry , Heterocyclic Compounds/chemistry , Carbon/chemistry , Catalysis , Copper/chemistry , Oxygen/chemistry , Palladium/chemistry , StereoisomerismABSTRACT
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.
Subject(s)
Copper/chemistry , Organometallic Compounds/chemistry , Volatile Organic Compounds/chemistry , Catalysis , Ligands , Molecular Structure , Salts/chemistry , SolubilityABSTRACT
A stereoselective synthesis of (R)-beta-amino acid 1 via a beta-lactam intermediate is discussed.
Subject(s)
Amino Acids/chemical synthesis , beta-Lactams/chemistry , Acylation , Drug Design , Molecular Conformation , Stereoisomerism , Structure-Activity Relationship , beta-Lactams/chemical synthesisABSTRACT
[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.
ABSTRACT
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.