RESUMO
Natural products have played significant roles as medicine and food throughout human history. Here, we first provide a brief historical overview of natural products, their classification and biosynthetic origins, and the microbiological and genetic methods used for their discovery. We also describe and discuss the technologies that revolutionized the field, which transitioned from classic genetics to genome-centric discovery approximately two decades ago. We then highlight the most recent advancements and approaches in the current postgenomic era, in which genome mining is a standard operation and high-throughput analytical methods allow parallel discovery of genes and molecules at an unprecedented pace. Finally, we discuss the new challenges faced by the field of natural products and the future of systematic heterologous expression and strain-independent discovery, which promises to deliver more molecules in vials than ever before.
Assuntos
Produtos Biológicos , Genômica , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/história , Genômica/métodos , Humanos , Descoberta de Drogas/métodos , Descoberta de Drogas/história , História do Século XX , História do Século XXIRESUMO
Microbial natural products have provided an important source of therapeutic leads and motivated research and innovation in diverse scientific disciplines. In recent years, it has become evident that bacteria harbor a large, hidden reservoir of potential natural products in the form of silent or cryptic biosynthetic gene clusters (BGCs). These can be readily identified in microbial genome sequences but do not give rise to detectable levels of a natural product. Herein, we provide a useful organizational framework for the various methods that have been implemented for interrogating silent BGCs. We divide all available approaches into four categories. The first three are endogenous strategies that utilize the native host in conjunction with classical genetics, chemical genetics, or different culture modalities. The last category comprises expression of the entire BGC in a heterologous host. For each category, we describe the rationale, recent applications, and associated advantages and limitations.
Assuntos
Produtos Biológicos/química , Vias Biossintéticas/genética , Técnicas de Cultura/métodos , Família Multigênica , Genética Reversa/métodos , Bactérias/genética , Bactérias/metabolismo , Produtos Biológicos/metabolismo , Regulação da Expressão GênicaRESUMO
2021 marks the 30th anniversary of the revelation that cyclosporin A and FK506 act in a way previously not seen-as "molecular glues" that induce neo-protein-protein associations. As a torrent of new molecular-glue probes and medicines are fueling interest in this field, I explore the arc of this story.
Assuntos
Produtos Biológicos/farmacologia , Produtos Biológicos/química , Ciclosporina/farmacologia , Imunossupressores/farmacologia , Tacrolimo/química , Tacrolimo/farmacologiaRESUMO
Polyketides are a large family of structurally complex natural products including compounds with important bioactivities. Polyketides are biosynthesized by polyketide synthases (PKSs), multienzyme complexes derived evolutionarily from fatty acid synthases (FASs). The focus of this review is to critically compare the properties of FASs with iterative aromatic PKSs, including type II PKSs and fungal type I nonreducing PKSs whose chemical logic is distinct from that of modular PKSs. This review focuses on structural and enzymological studies that reveal both similarities and striking differences between FASs and aromatic PKSs. The potential application of FAS and aromatic PKS structures for bioengineering future drugs and biofuels is highlighted.
Assuntos
Ácido Graxo Sintases/química , Ácido Graxo Sintases/metabolismo , Policetídeo Sintases/química , Policetídeo Sintases/metabolismo , Animais , Biocatálise , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Ácido Graxo Sintases/classificação , Humanos , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Policetídeo Sintases/classificação , Policetídeos/química , Policetídeos/metabolismo , Domínios Proteicos , Homologia Estrutural de Proteína , Especificidade por SubstratoRESUMO
After an undergraduate degree in biology at Harvard, I started graduate school at The Rockefeller Institute for Medical Research in New York City in July 1965. I was attracted to the chemical side of biochemistry and joined Fritz Lipmann's large, hierarchical laboratory to study enzyme mechanisms. That work led to postdoctoral research with Robert Abeles at Brandeis, then a center of what, 30 years later, would be called chemical biology. I spent 15 years on the Massachusetts Institute of Technology faculty, in both the Chemistry and Biology Departments, and then 26 years on the Harvard Medical School Faculty. My research interests have been at the intersection of chemistry, biology, and medicine. One unanticipated major focus has been investigating the chemical logic and enzymatic machinery of natural product biosynthesis, including antibiotics and antitumor agents. In this postgenomic era it is now recognized that there may be from 105 to 106 biosynthetic gene clusters as yet uncharacterized for potential new therapeutic agents.
Assuntos
Antibacterianos/metabolismo , Antineoplásicos/metabolismo , Bioquímica/história , Produtos Biológicos/metabolismo , Pesquisa Biomédica/história , Indústria Farmacêutica/história , Antibacterianos/química , Antineoplásicos/química , Bioquímica/tendências , Produtos Biológicos/química , Pesquisa Biomédica/tendências , Indústria Farmacêutica/tendências , Regulação da Expressão Gênica , História do Século XX , História do Século XXI , Humanos , Ligases/genética , Ligases/metabolismo , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Resistência a Vancomicina/genética , Recursos HumanosRESUMO
Recent years have seen revived interest in computer-assisted organic synthesis1,2. The use of reaction- and neural-network algorithms that can plan multistep synthetic pathways have revolutionized this field1,3-7, including examples leading to advanced natural products6,7. Such methods typically operate on full, literature-derived 'substrate(s)-to-product' reaction rules and cannot be easily extended to the analysis of reaction mechanisms. Here we show that computers equipped with a comprehensive knowledge-base of mechanistic steps augmented by physical-organic chemistry rules, as well as quantum mechanical and kinetic calculations, can use a reaction-network approach to analyse the mechanisms of some of the most complex organic transformations: namely, cationic rearrangements. Such rearrangements are a cornerstone of organic chemistry textbooks and entail notable changes in the molecule's carbon skeleton8-12. The algorithm we describe and deploy at https://HopCat.allchemy.net/ generates, within minutes, networks of possible mechanistic steps, traces plausible step sequences and calculates expected product distributions. We validate this algorithm by three sets of experiments whose analysis would probably prove challenging even to highly trained chemists: (1) predicting the outcomes of tail-to-head terpene (THT) cyclizations in which substantially different outcomes are encoded in modular precursors differing in minute structural details; (2) comparing the outcome of THT cyclizations in solution or in a supramolecular capsule; and (3) analysing complex reaction mixtures. Our results support a vision in which computers no longer just manipulate known reaction types1-7 but will help rationalize and discover new, mechanistically complex transformations.
Assuntos
Algoritmos , Técnicas de Química Sintética , Ciclização , Redes Neurais de Computação , Terpenos , Cátions/química , Bases de Conhecimento , Terpenos/química , Técnicas de Química Sintética/métodos , Produtos Biológicos/síntese química , Produtos Biológicos/química , Reprodutibilidade dos Testes , SoluçõesRESUMO
The carbon skeleton of any organic molecule serves as the foundation for its three-dimensional structure, playing a pivotal role in determining its physical and biological properties1. As such, taxane diterpenes are one of the most well-known natural product families, primarily owing to the success of their most prominent compound, paclitaxel, an effective anticancer therapeutic for more than 25 years2-6. In contrast to classical taxanes, the bioactivity of cyclotaxanes (also referred to as complex taxanes) remains significantly underexplored. The carbon skeletons of these two groups of taxanes differ significantly, and so would typically their own distinct synthetic approaches. Here we report a versatile synthetic strategy based on the interconversion of complex molecular frameworks, providing general access to the wider taxane diterpene family. A range of classical and cyclotaxane frameworks was prepared including, among others, the total syntheses of taxinine K (2), canataxapropellane (5) and dipropellane C from a single advanced intermediate. The synthetic approach deliberately eschews biomimicry, emphasizing instead the power of stereoelectronic control in orchestrating the interconversion of polycyclic frameworks.
Assuntos
Hidrocarbonetos Aromáticos com Pontes , Técnicas de Química Sintética , Diterpenos , Taxoides , Produtos Biológicos/síntese química , Produtos Biológicos/química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Diterpenos/síntese química , Diterpenos/química , Estereoisomerismo , Taxoides/química , Taxoides/síntese química , Carbono/químicaRESUMO
In this Review, we explore natural product antibiotics that do more than simply inhibit an active site of an essential enzyme. We review these compounds to provide inspiration for the design of much-needed new antibacterial agents, and examine the complex mechanisms that have evolved to effectively target bacteria, including covalent binders, inhibitors of resistance, compounds that utilize self-promoted entry, those that evade resistance, prodrugs, target corrupters, inhibitors of 'undruggable' targets, compounds that form supramolecular complexes, and selective membrane-acting agents. These are exemplified by ß-lactams that bind covalently to inhibit transpeptidases and ß-lactamases, siderophore chimeras that hijack import mechanisms to smuggle antibiotics into the cell, compounds that are activated by bacterial enzymes to produce reactive molecules, and antibiotics such as aminoglycosides that corrupt, rather than merely inhibit, their targets. Some of these mechanisms are highly sophisticated, such as the preformed ß-strands of darobactins that target the undruggable ß-barrel chaperone BamA, or teixobactin, which binds to a precursor of peptidoglycan and then forms a supramolecular structure that damages the membrane, impeding the emergence of resistance. Many of the compounds exhibit more than one notable feature, such as resistance evasion and target corruption. Understanding the surprising complexity of the best antimicrobial compounds provides a roadmap for developing novel compounds to address the antimicrobial resistance crisis by mining for new natural products and inspiring us to design similarly sophisticated antibiotics.
Assuntos
Antibacterianos , Bactérias , Produtos Biológicos , Animais , Humanos , Aminoglicosídeos/farmacologia , Aminoglicosídeos/química , Aminoglicosídeos/metabolismo , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/metabolismo , Bactérias/efeitos dos fármacos , Bactérias/enzimologia , Bactérias/metabolismo , Antibióticos beta Lactam/química , Antibióticos beta Lactam/farmacologia , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/metabolismo , Desenho de Fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Peptidil Transferases/antagonistas & inibidores , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Sideróforos/metabolismo , Sideróforos/química , Sideróforos/farmacologiaRESUMO
Biosynthesis is an environmentally benign and renewable approach that can be used to produce a broad range of natural and, in some cases, new-to-nature products. However, biology lacks many of the reactions that are available to synthetic chemists, resulting in a narrower scope of accessible products when using biosynthesis rather than synthetic chemistry. A prime example of such chemistry is carbene-transfer reactions1. Although it was recently shown that carbene-transfer reactions can be performed in a cell and used for biosynthesis2,3, carbene donors and unnatural cofactors needed to be added exogenously and transported into cells to effect the desired reactions, precluding cost-effective scale-up of the biosynthesis process with these reactions. Here we report the access to a diazo ester carbene precursor by cellular metabolism and a microbial platform for introducing unnatural carbene-transfer reactions into biosynthesis. The α-diazoester azaserine was produced by expressing a biosynthetic gene cluster in Streptomyces albus. The intracellularly produced azaserine was used as a carbene donor to cyclopropanate another intracellularly produced molecule-styrene. The reaction was catalysed by engineered P450 mutants containing a native cofactor with excellent diastereoselectivity and a moderate yield. Our study establishes a scalable, microbial platform for conducting intracellular abiological carbene-transfer reactions to functionalize a range of natural and new-to-nature products and expands the scope of organic products that can be produced by cellular metabolism.
Assuntos
Azasserina , Azasserina/biossíntese , Azasserina/química , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Família Multigênica/genética , Estireno/química , Ciclopropanos/química , Coenzimas/química , Coenzimas/metabolismo , Biocatálise , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismoRESUMO
Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes1. This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges2-4. Although this approach forms the basis of undergraduate curriculum in organic chemistry5 and strategic applications of most synthetic methods6, the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography3,4,7. Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed.
Assuntos
Produtos Biológicos , Técnicas de Química Sintética , Descarboxilação , Eletroquímica , Eletrodos , Preparações Farmacêuticas , Ácidos Carboxílicos/química , Nanopartículas Metálicas/química , Oxirredução , Prata/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Níquel/química , Ligantes , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química , Eletroquímica/métodos , Técnicas de Química Sintética/métodosRESUMO
Cyclic organic molecules are common among natural products and pharmaceuticals1,2. In fact, the overwhelming majority of small-molecule pharmaceuticals contain at least one ring system, as they provide control over molecular shape, often increasing oral bioavailability while providing enhanced control over the activity, specificity and physical properties of drug candidates3-5. Consequently, new methods for the direct site and diastereoselective synthesis of functionalized carbocycles are highly desirable. In principle, molecular editing by C-H activation offers an ideal route to these compounds. However, the site-selective C-H functionalization of cycloalkanes remains challenging because of the strain encountered in transannular C-H palladation. Here we report that two classes of ligands-quinuclidine-pyridones (L1, L2) and sulfonamide-pyridones (L3)-enable transannular γ-methylene C-H arylation of small- to medium-sized cycloalkane carboxylic acids, with ring sizes ranging from cyclobutane to cyclooctane. Excellent γ-regioselectivity was observed in the presence of multiple ß-C-H bonds. This advance marks a major step towards achieving molecular editing of saturated carbocycles: a class of scaffolds that are important in synthetic and medicinal chemistry3-5. The utility of this protocol is demonstrated by two-step formal syntheses of a series of patented biologically active small molecules, prior syntheses of which required up to 11 steps6.
Assuntos
Produtos Biológicos , Carbono , Ácidos Carboxílicos , Cicloparafinas , Hidrogênio , Produtos Biológicos/química , Ácidos Carboxílicos/química , Cicloparafinas/química , Preparações Farmacêuticas/química , Piridonas/química , Carbono/química , Hidrogênio/química , Sulfonamidas/química , Ligantes , Química Farmacêutica , Quinuclidinas/química , Ciclobutanos/químicaRESUMO
Selenium is an essential micronutrient in diverse organisms. Two routes are known for its insertion into proteins and nucleic acids, via selenocysteine and 2-selenouridine, respectively1. However, despite its importance, pathways for specific incorporation of selenium into small molecules have remained elusive. Here we use a genome-mining strategy in various microorganisms to uncover a widespread three-gene cluster that encodes a dedicated pathway for producing selenoneine, the selenium analogue of the multifunctional molecule ergothioneine2,3. We elucidate the reactions of all three proteins and uncover two novel selenium-carbon bond-forming enzymes and the biosynthetic pathway for production of a selenosugar, which is an unexpected intermediate en route to the final product. Our findings expand the scope of biological selenium utilization, suggest that the selenometabolome is more diverse than previously thought, and set the stage for the discovery of other selenium-containing natural products.
Assuntos
Vias Biossintéticas , Genes Microbianos , Histidina/análogos & derivados , Compostos Organosselênicos , Selênio , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Vias Biossintéticas/genética , Carbono/metabolismo , Enzimas , Ergotioneína , Genes Microbianos/genética , Histidina/biossíntese , Metaboloma/genética , Micronutrientes/biossíntese , Família Multigênica/genética , Proteínas , Selênio/metabolismoRESUMO
Research in the field of asymmetric catalysis over the past half century has resulted in landmark advances, enabling the efficient synthesis of chiral building blocks, pharmaceuticals and natural products1-3. A small number of asymmetric catalytic reactions have been identified that display high selectivity across a broad scope of substrates; not coincidentally, these are the reactions that have the greatest impact on how enantioenriched compounds are synthesized4-8. We postulate that substrate generality in asymmetric catalysis is rare not simply because it is intrinsically difficult to achieve, but also because of the way chiral catalysts are identified and optimized9. Typical discovery campaigns rely on a single model substrate, and thus select for high performance in a narrow region of chemical space. Here we put forth a practical approach for using multiple model substrates to select simultaneously for both enantioselectivity and generality in asymmetric catalytic reactions from the outset10,11. Multisubstrate screening is achieved by conducting high-throughput chiral analyses by supercritical fluid chromatography-mass spectrometry with pooled samples. When applied to Pictet-Spengler reactions, the multisubstrate screening approach revealed a promising and unexpected lead for the general enantioselective catalysis of this important transformation, which even displayed high enantioselectivity for substrate combinations outside of the screening set.
Assuntos
Produtos Biológicos , Técnicas de Química Sintética , Preparações Farmacêuticas , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química , Estereoisomerismo , Especificidade por Substrato , Cromatografia com Fluido Supercrítico , Espectrometria de Massas , Técnicas de Química Sintética/métodosRESUMO
All organisms produce specialized organic molecules, ranging from small volatile chemicals to large gene-encoded peptides, that have evolved to provide them with diverse cellular and ecological functions. As natural products, they are broadly applied in medicine, agriculture and nutrition. The rapid accumulation of genomic information has revealed that the metabolic capacity of virtually all organisms is vastly underappreciated. Pioneered mainly in bacteria and fungi, genome mining technologies are accelerating metabolite discovery. Recent efforts are now being expanded to all life forms, including protists, plants and animals, and new integrative omics technologies are enabling the increasingly effective mining of this molecular diversity.
Assuntos
Bactérias/genética , Produtos Biológicos/química , Descoberta de Drogas/métodos , Fungos/genética , Genoma , Genômica/métodos , Plantas/genética , Animais , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Biologia Computacional/métodos , HumanosRESUMO
Synthetic chemistry aims to build up molecular complexity from simple feedstocks1. However, the ability to exert precise changes that manipulate the connectivity of the molecular skeleton itself remains limited, despite possessing substantial potential to expand the accessible chemical space2,3. Here we report a reaction that 'deletes' nitrogen from organic molecules. We show that N-pivaloyloxy-N-alkoxyamides, a subclass of anomeric amides, promote the intermolecular activation of secondary aliphatic amines to yield intramolecular carbon-carbon coupling products. Mechanistic experiments indicate that the reactions proceed via isodiazene intermediates that extrude the nitrogen atom as dinitrogen, producing short-lived diradicals that rapidly couple to form the new carbon-carbon bond. The reaction shows broad functional-group tolerance, which enables the translation of routine amine synthesis protocols into a strategy for carbon-carbon bond constructions and ring syntheses. This is highlighted by the use of this reaction in the syntheses and skeletal editing of bioactive compounds.
Assuntos
Aminas/química , Técnicas de Química Sintética , Nitrogênio/química , Amidas/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Carbono/química , Indicadores e Reagentes/químicaRESUMO
An ongoing challenge in chemical research is to design catalysts that select the outcomes of the reactions of complex molecules. Chemists rely on organocatalysts or transition metal catalysts to control stereoselectivity, regioselectivity and periselectivity (selectivity among possible pericyclic reactions). Nature achieves these types of selectivity with a variety of enzymes such as the recently discovered pericyclases-a family of enzymes that catalyse pericyclic reactions1. Most characterized enzymatic pericyclic reactions have been cycloadditions, and it has been difficult to rationalize how the observed selectivities are achieved2-13. Here we report the discovery of two homologous groups of pericyclases that catalyse distinct reactions: one group catalyses an Alder-ene reaction that was, to our knowledge, previously unknown in biology; the second catalyses a stereoselective hetero-Diels-Alder reaction. Guided by computational studies, we have rationalized the observed differences in reactivities and designed mutant enzymes that reverse periselectivities from Alder-ene to hetero-Diels-Alder and vice versa. A combination of in vitro biochemical characterizations, computational studies, enzyme co-crystal structures, and mutational studies illustrate how high regioselectivity and periselectivity are achieved in nearly identical active sites.
Assuntos
Biocatálise , Reação de Cicloadição , Enzimas/metabolismo , Aspergillus/enzimologia , Aspergillus/genética , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Domínio Catalítico , Enzimas/genética , Modelos MolecularesRESUMO
The modern biopharmaceutical industry traces its roots to the dawn of the twentieth century, coincident with marketing of aspirin-a signature event in the history of modern drug development. Although the archetypal discovery process did not change markedly in the first seven decades of the industry, the past fifty years have seen two successive waves of transformative innovation in the development of drug molecules: the rise of 'rational drug discovery' methodology in the 1970s, followed by the invention of recombinant protein-based therapeutic agents in the 1980s. An incipient fourth wave is the advent of multispecific drugs. The successful development of prospectively designed multispecific drugs has the potential to reconfigure our ideas of how target-based therapeutic molecules can work, and what it is possible to achieve with them. Here I review the two major classes of multispecific drugs: those that enrich a therapeutic agent at a particular site of action and those that link a therapeutic target to a biological effector. The latter class-being freed from the constraint of having to directly modulate the target upon binding-may enable access to components of the proteome that currently cannot be targeted by drugs.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Descoberta de Drogas , Animais , Produtos Biológicos/metabolismo , Indústria Farmacêutica , Humanos , Ligação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3-6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C-H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon-nitrogen (C-N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C-N coupling protocol by preparing commercial medicines and by the late-stage amination-aromatization of natural products, steroids and terpene feedstocks.
Assuntos
Compostos de Anilina/síntese química , Hidrogênio/química , Processos Fotoquímicos , Aminação , Aminas/química , Compostos de Anilina/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise/efeitos da radiação , Cicloexanonas/química , Oxirredução/efeitos da radiação , Processos Fotoquímicos/efeitos da radiação , Esteroides/síntese química , Esteroides/química , Terpenos/síntese química , Terpenos/químicaRESUMO
Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences1. Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements2. These structures are often generated from [1.1.1]propellane via opening of the internal C-C bond through the addition of either radicals or metal-based nucleophiles3-13. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, α-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.
Assuntos
Técnicas de Química Sintética , Cobre/química , Pentanos/química , Pentanos/síntese química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Ciclização , Preparações Farmacêuticas/metabolismoRESUMO
Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules1-3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.