RESUMO
Two scalable and efficient synthetic routes for the synthesis of a T-type calcium channel antagonist MK-8998 were developed from a simple pyridine building block. The key step to set the stereochemistry relied on either chiral rhodium catalyst-mediated asymmetric hydrogenation of an enamide or transamination of an arylketone that provided the corresponding product in high enantioselectivity and high yield.
Assuntos
Bloqueadores dos Canais de Cálcio , Ródio , Aminação , Bloqueadores dos Canais de Cálcio/farmacologia , Catálise , Hidrogenação , EstereoisomerismoRESUMO
Reaction optimization is fundamental to synthetic chemistry, from optimizing the yield of industrial processes to selecting conditions for the preparation of medicinal candidates1. Likewise, parameter optimization is omnipresent in artificial intelligence, from tuning virtual personal assistants to training social media and product recommendation systems2. Owing to the high cost associated with carrying out experiments, scientists in both areas set numerous (hyper)parameter values by evaluating only a small subset of the possible configurations. Bayesian optimization, an iterative response surface-based global optimization algorithm, has demonstrated exceptional performance in the tuning of machine learning models3. Bayesian optimization has also been recently applied in chemistry4-9; however, its application and assessment for reaction optimization in synthetic chemistry has not been investigated. Here we report the development of a framework for Bayesian reaction optimization and an open-source software tool that allows chemists to easily integrate state-of-the-art optimization algorithms into their everyday laboratory practices. We collect a large benchmark dataset for a palladium-catalysed direct arylation reaction, perform a systematic study of Bayesian optimization compared to human decision-making in reaction optimization, and apply Bayesian optimization to two real-world optimization efforts (Mitsunobu and deoxyfluorination reactions). Benchmarking is accomplished via an online game that links the decisions made by expert chemists and engineers to real experiments run in the laboratory. Our findings demonstrate that Bayesian optimization outperforms human decisionmaking in both average optimization efficiency (number of experiments) and consistency (variance of outcome against initially available data). Overall, our studies suggest that adopting Bayesian optimization methods into everyday laboratory practices could facilitate more efficient synthesis of functional chemicals by enabling better-informed, data-driven decisions about which experiments to run.
Assuntos
Teorema de Bayes , Técnicas de Química Sintética/métodos , Algoritmos , Conjuntos de Dados como Assunto , Tomada de Decisões , Halogenação , Paládio/química , Reprodutibilidade dos TestesRESUMO
Over the past decade, chemists have embraced visible-light photoredox catalysis due to its remarkable ability to activate small molecules. Broadly, these methods employ metal complexes or organic dyes to convert visible light into chemical energy. Unfortunately, the excitation of widely utilized Ru and Ir chromophores is energetically wasteful as â¼25% of light energy is lost thermally before being quenched productively. Hence, photoredox methodologies require high-energy, intense light to accommodate said catalytic inefficiency. Herein, we report photocatalysts which cleanly convert near-infrared (NIR) and deep red (DR) light into chemical energy with minimal energetic waste. We leverage the strong spin-orbit coupling (SOC) of Os(II) photosensitizers to directly access the excited triplet state (T1) with NIR or DR irradiation from the ground state singlet (S0). Through strategic catalyst design, we access a wide range of photoredox, photopolymerization, and metallaphotoredox reactions which usually require 15-50% higher excitation energy. Finally, we demonstrate superior light penetration and scalability of NIR photoredox catalysis through a mole-scale arene trifluoromethylation in a batch reactor.
RESUMO
The identification of Yb(OTf)3 through a multivariable high-throughput experimentation strategy has enabled a unified protocol for the direct conversion of enantioenriched N-acyloxazolidinones to the corresponding chiral esters, amides, and carboxylic acids. This straightforward and catalytic method has shown remarkable chemoselectivity for substitution at the acyclic N-acyl carbonyl for a diverse array of N-acyloxazolidinone substrates. The ionic radius of the Lewis acid catalyst was demonstrated as a key driver of catalyst performance that led to the identification of a robust and scalable esterification of a pharmaceutical intermediate using catalytic Y(OTf)3.
RESUMO
Two efficient asymmetric routes to γ-secretase modulator BMS-932481, under investigation for Alzheimer's disease, have been developed. The key step for the first route involves a challenging enantioselective hydrogenation of an unfunctionalized trisubstituted alkene to establish the benzylic stereocenter, representing a very rare case of achieving high selectivity on a complex substrate. The second route demonstrates the first example of a vinylogous dynamic kinetic resolution (VDKR) ketone reduction, where the carbonyl and the racemizable stereocenter are not contiguous, but are conjugated through a pyrimidine ring. Not only did this transformation require both catalyst and substrate control to correctly establish the two stereocenters, but it also necessitated that the nonadjacent benzylic center of the ketone substrate be more acidic than that of the alcohol product to make the process dynamic. DFT computations aided the design of this novel VDKR pathway by reliably predicting the relative acidities of the intermediates involved.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Compostos de Anilina/química , Compostos de Anilina/síntese química , Pirimidinas/química , Pirimidinas/síntese química , Compostos de Anilina/farmacologia , Catálise , Técnicas de Química Sintética , Ciclização , Teoria da Densidade Funcional , Hidrogenação , Cetonas/química , Cinética , Oxirredução , Pirimidinas/farmacologia , EstereoisomerismoRESUMO
A strategy to prepare compounds with multiple chirality axes, which has led to a concise total synthesis of compound 1A with complete stereocontrol, is reported.
RESUMO
Described here is an efficient stereoselective synthesis of vibegron enabled by an enzymatic dynamic kinetic reduction that proceeds in a high-pH environment. To overcome enzyme performance limitations under these conditions, a ketoreductase was evolved by a computationally and structurally aided strategy to increase cofactor stability through tighter binding.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3/síntese química , Pirimidinonas/síntese química , Pirrolidinas/síntese química , Biocatálise , Concentração de Íons de Hidrogênio , Cinética , Modelos Moleculares , Oxirredução , Oxirredutases/química , EstereoisomerismoRESUMO
Zinc salts have been shown to promote the Buchwald-Hartwig coupling of azaindoles and azaindazoles with heteroaryl chlorides to provide the corresponding 1-aryl-1H-azaindoles and 1-aryl-1H-azaindazoles. The substrate scope and mechanistic aspects of this reaction were explored.
RESUMO
High-throughput (HT) techniques built upon laboratory automation technology and coupled to statistical experimental design and parallel experimentation have enabled the acceleration of chemical process development across multiple industries. HT technologies are often applied to interrogate wide, often multidimensional experimental spaces to inform the design and optimization of any number of unit operations that chemical engineers use in process development. In this review, we outline the evolution of HT technology and provide a comprehensive overview of how HT automation is used throughout different industries, with a particular focus on chemical and pharmaceutical process development. In addition, we highlight the common strategies of how HT automation is incorporated into routine development activities to maximize its impact in various academic and industrial settings.
Assuntos
Ensaios de Triagem em Larga Escala/métodos , Tecnologia Farmacêutica/métodos , Animais , Bioengenharia/instrumentação , Bioengenharia/métodos , Descoberta de Drogas/instrumentação , Descoberta de Drogas/métodos , Desenho de Equipamento , Ensaios de Triagem em Larga Escala/instrumentação , Humanos , Tecnologia Farmacêutica/instrumentaçãoRESUMO
The development of a diastereoselective nucleoside phosphorylation is described, which produces a single isomer of a complex nucleoside monophosphate pro-drug. A stable phosphoramidic acid derivative is coupled to the nucleoside, in a process mediated by HATU and quinine, to deliver the coupled product in high chemical yield and good diastereoselectivity. This unusual process was shown to proceed through a dynamic kinetic resolution of a 1:1 mixture of activated phosphonate ester diastereoisomers. The optimized conditions afforded the product with a combined [S,S(P)] and [S,R(P)] in-process yield of 89% and a â¼7:1 [S,S(P):S,R(P)] diastereomeric ratio. Isolation of the major isomer was facilitated by single crystallization from anisole, where the product was obtained in 57% isolated yield, excellent purity (>95%), and a high diastereomeric ratio (>50:1).
Assuntos
Amidas/química , Nucleosídeos/síntese química , Ácidos Fosfóricos/química , Pró-Fármacos/síntese química , Anisóis/química , Cristalização , Cinética , Estrutura Molecular , Nucleosídeos/química , Fosforilação , Pró-Fármacos/química , EstereoisomerismoRESUMO
A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the diene substrate at a concentration of 0.13 M.
Assuntos
Hepacivirus/efeitos dos fármacos , Indóis/síntese química , Inibidores de Proteases/síntese química , Rutênio/química , Catálise , Ciclização , Ciclopropanos , Indóis/química , Isoindóis , Lactamas Macrocíclicas , Leucina/análogos & derivados , Estrutura Molecular , Prolina/análogos & derivados , Inibidores de Proteases/química , SulfonamidasRESUMO
Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.
Assuntos
Aminas/síntese química , Evolução Molecular Direcionada , Hipoglicemiantes/síntese química , Cetonas/química , Engenharia de Proteínas , Pirazinas/síntese química , Transaminases/química , Triazóis/síntese química , Biocatálise , Domínio Catalítico , Hipoglicemiantes/metabolismo , Cetonas/metabolismo , Modelos Moleculares , Estrutura Molecular , Mutagênese , Conformação Proteica , Pirazinas/metabolismo , Fosfato de Sitagliptina , Solubilidade , Estereoisomerismo , Especificidade por Substrato , Transaminases/genética , Transaminases/metabolismo , Triazóis/metabolismoRESUMO
Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of vinyl hydroxy-acid 22 followed by a robust end-game featuring a through-process hydrazide acylation/1,3,4-oxadiazole ring closure/salt formation sequence to afford MK-0633 p-toluenesulfonate (1).
Assuntos
Benzenossulfonatos/síntese química , Benzopiranos/síntese química , Inibidores de Lipoxigenase , Inibidores de Lipoxigenase/síntese química , Oxidiazóis/síntese química , Araquidonato 5-Lipoxigenase/química , Benzenossulfonatos/química , Benzopiranos/química , Inibidores de Lipoxigenase/química , Estrutura Molecular , Oxidiazóis/química , EstereoisomerismoRESUMO
A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey-Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5.
Assuntos
Química Orgânica/métodos , Química Farmacêutica/métodos , Ciclopropanos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Receptores de Prostaglandina E/antagonistas & inibidores , Succinimidas/química , Ácidos Carboxílicos/química , Química Orgânica/instrumentação , Química Farmacêutica/instrumentação , Cristalização , Ciclopropanos/química , Desenho de Fármacos , Eletrônica , Compostos Heterocíclicos com 3 Anéis/química , Modelos Químicos , Estrutura Molecular , Receptores de Prostaglandina E Subtipo EP4 , Estereoisomerismo , Sulfonamidas/química , Tecnologia FarmacêuticaRESUMO
An expedient, five step synthesis of caprolactam 1 is reported starting from natural L-homoserine. The key step is a chemoselective reductive cyclization of alpha,beta-unsaturated nitrile 10 mediated by Raney-Co type metals. This hydrogenation is extensively investigated in order to account for the observed product distribution and yields.
Assuntos
Cobalto/química , Nitrilas/química , Aldeídos/síntese química , Aldeídos/química , Caprolactama/química , Ciclização , Homosserina/síntese química , Homosserina/química , Isomerismo , Metionina/química , Estrutura Molecular , Oxirredução , TemperaturaRESUMO
[reaction: see text] A highly stereoselective L-proline-catalyzed, asymmetric direct Mannich reaction between a glyoxalate-derived imine and phenyl acetaldehyde was employed for the formation of a syn substituted beta-phenyl homoserine. This Mannich adduct was then readily elaborated to a functionalized beta-phenyl aspartic acid derivative through a series of mild and efficient transformations.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Prolina/química , Inibidores de Proteases/síntese química , Aldeídos/química , Amino Álcoois/química , Catálise , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , EstereoisomerismoRESUMO
The direct introduction of either a nitrogen or oxygen atom adjacent to a carbonyl group in a catalytic, enantioselective manner using both chiral Lewis acid and Lewis base catalysis has been described recently. The enantiomerically enriched products of these reactions, such as alpha-amino acids, represent fundamental building blocks for the construction of complex natural products and other important bioactive molecules. This Minireview provides a synopsis of this ever-growing field and highlights some of the challenges that still remain.
Assuntos
Ácidos Carboxílicos/química , Cetonas/química , Oxigênio/química , Aminação , Catálise , Imidas/química , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
1-Amino-3-siloxy-1,3-butadienes represent a novel class of heteroatom-containing dienes with several useful properties. These dienes can be prepared efficiently by deprotonation of readily available vinylogous amides with potassium hexamethylsilazide, followed by silylation of the corresponding potassium enolates. This protocol has been found to be quite general for the preparation of various dienes containing different silyl and amino groups. Amino siloxy dienes readily undergo [4 + 2] cycloadditions with a wide range of electron-deficient dienophiles. The reactions generally occur under very mild conditions to afford the corresponding [4 + 2] adducts in high yields and with complete regioselectivity. High endo selectivity is observed in the case of N-phenylmaleimide and methacrolein. Other cycloadducts are usually obtained as mixtures of endo/exo diastereomers. The cycloadducts are versatile synthetic intermediates. They can be subjected to deprotonation, reduction, and Wittig olefination without any hydrolysis or elimination. In addition, the elimination of the amino group can be cleanly accomplished under acidic conditions leading to the formation of enones. A variety of substituted cyclohexenones can be prepared by this procedure.
RESUMO
Air-stable and recyclable, the CuII -(bis)oxazoline complex 1 efficiently catalyzes diastereo- and enantioselective hetero-Diels-Alder reactions between ß,γ-unsaturated α-keto acid derivatives 2 and vinyl ethers for the synthesis of substituted dihydropyrans 3 [Eq. (1)]. Results of the crystal structure analysis of 1 in combination with calculations on model compounds indicate the formation of a reactive intermediate through replacement of the two H2 O ligands with a chelating substrate. X=OEt, N(OMe)Me; R=alkyl, aryl, alkoxy, thiobenzyl.