RESUMO
Vanadium-dependent haloperoxidases (VHPOs) from Streptomyces bacteria differ from their counterparts in fungi, macroalgae, and other bacteria by catalyzing organohalogenating reactions with strict regiochemical and stereochemical control. While this group of enzymes collectively uses hydrogen peroxide to oxidize halides for incorporation into electron-rich organic molecules, the mechanism for the controlled transfer of highly reactive chloronium ions in the biosynthesis of napyradiomycin and merochlorin antibiotics sets the Streptomyces vanadium-dependent chloroperoxidases apart. Here we report high-resolution crystal structures of two homologous VHPO family members associated with napyradiomycin biosynthesis, NapH1 and NapH3, that catalyze distinctive chemical reactions in the construction of meroterpenoid natural products. The structures, combined with site-directed mutagenesis and intact protein mass spectrometry studies, afforded a mechanistic model for the asymmetric alkene and arene chlorination reactions catalyzed by NapH1 and the isomerase activity catalyzed by NapH3. A key lysine residue in NapH1 situated between the coordinated vanadate and the putative substrate binding pocket was shown to be essential for catalysis. This observation suggested the involvement of the ε-NH2, possibly through formation of a transient chloramine, as the chlorinating species much as proposed in structurally distinct flavin-dependent halogenases. Unexpectedly, NapH3 is modified post-translationally by phosphorylation of an active site His (τ-pHis) consistent with its repurposed halogenation-independent, α-hydroxyketone isomerase activity. These structural studies deepen our understanding of the mechanistic underpinnings of VHPO enzymes and their evolution as enantioselective biocatalysts.
Assuntos
Streptomyces , Vanádio , Antibacterianos/química , Catálise , Isomerases , Vanádio/químicaRESUMO
Inspired by a new biosynthetic hypothesis, we report a biomimetic total synthesis of atrachinenins A and B that explains their racemic nature. The synthesis exploits an intermolecular Diels-Alder reaction between a quinone meroterpenoid and E-ß-ocimene, followed by intramolecular (3 + 2) cycloaddition and a late-stage aerobic oxidation. Divergent transformations of a simple model system gave several complex polycyclic scaffolds, while also suggesting a structure revision for atrachinenin C.
Assuntos
Biomimética , Quinonas , Oxirredução , Ciclização , Reação de Cicloadição , EstereoisomerismoRESUMO
Natural products are biosynthesized from a limited pool of starting materials via pathways that obey the same chemical logic as textbook organic reactions. Given the structure of a natural product, it is therefore often possible to predict its likely biosynthesis. Although biosynthesis mainly occurs in the highly specific chemical environments of enzymes, the field of biomimetic total synthesis attempts to replicate predisposed pathways using chemical reagents.We have followed several guidelines in our biomimetic approach to total synthesis. The overarching aim is to construct the same skeletal C-C and C-heteroatom bonds and in the same order as our biosynthetic hypothesis. In order to explore the innate reactivity of (bio)synthetic intermediates, the use of protecting groups is avoided or at least minimized. The key step, which is usually a cascade reaction, should be predisposed to selectively generate molecular complexity under substrate control (e.g., cycloadditions, radical cyclizations, carbocation rearrangements). In general, simple reagents and mild conditions are used; many of the total syntheses presented in this Account could be achieved using pre-1980s methodology. We have focused almost exclusively on the synthesis of meroterpenoids, that is, natural products of mixed terpene and aromatic polyketide origin, using commercially available terpenes and electron-rich aromatic compounds as starting materials. Finally, all of the syntheses in this Account involve a dearomatization step as a means to trigger a cascade reaction or to construct stereochemical complexity from a planar, aromatic intermediate.A biomimetic strategy can offer several advantages to a total synthesis project. Most obviously, successful biomimetic syntheses are usually concise and efficient, naturally adhering to the atom, step, and redox economies of synthesis. For example, in this Account, we describe a four-step synthesis of garcibracteatone and a three-step synthesis of nyingchinoid A. It is difficult to imagine shorter, non-biomimetic syntheses of these intricate molecules. Furthermore, biomimetic synthesis gives insight into biosynthesis by revealing the chemical relationships between biosynthetic intermediates. Access to these natural substrates allows collaboration with biochemists to help uncover the function of newly discovered enzymes and elucidate biosynthetic pathways, as demonstrated in our work on the napyradiomycin family. Third, by making biosynthetic connections between natural products, we can sometimes highlight incorrect structural assignments, and herein we discuss structure revisions of siphonodictyal B, rasumatranin D, and furoerioaustralasine. Last, biomimetic synthesis motivates the prediction of "undiscovered natural products" (i.e., missing links in biosynthesis), which inspired the isolation of prenylbruceol A and isobruceol.
Assuntos
Produtos Biológicos/síntese química , Biomimética/métodos , Terpenos/síntese química , Benzopiranos/síntese química , Benzopiranos/química , Produtos Biológicos/química , Ciclização , Reação de Cicloadição , Oxirredução , Floroglucinol/síntese química , Floroglucinol/química , Compostos Policíclicos/síntese química , Compostos Policíclicos/química , Terpenos/químicaRESUMO
Oxidative degradation and rearrangement of polycyclic polyprenylated acylphloroglucinols (PPAPs) has created diverse families of unique natural products that are attractive targets for biomimetic synthesis. Herein, we report a racemic synthesis of hyperibrin A and its oxidative radical cyclization to give yezo'otogirin C, followed by epoxidation and House-Meinwald rearrangement to give hypermogin D. We also investigated the biomimetic synthesis of norascyronone A via a similar radical cyclization pathway, with unexpected results that give insight into its biosynthesis.
Assuntos
Produtos Biológicos , Materiais Biomiméticos , Floroglucinol , Terpenos , Produtos Biológicos/síntese química , Produtos Biológicos/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Estrutura Molecular , Floroglucinol/síntese química , Floroglucinol/química , Terpenos/síntese química , Terpenos/químicaRESUMO
Structurally unique natural products pose biosynthetic puzzles whose solution can inspire new chemical reactions. Herein, we propose a unified biosynthetic pathway towards some complex meroterpenoids-the hyperireflexolides, biyoulactones, hybeanones and hypermonones. This hypothesis led to the discovery of uncatalyzed, intramolecular carbonyl-ene reactions that are spontaneous at room temperature. We also developed an anionic cascade reaction featuring an α-hydroxy-ß-diketone rearrangement and an intramolecular aldol reaction to access four distinct natural product scaffolds from a common intermediate.
Assuntos
Produtos Biológicos , Cetonas , CiclizaçãoRESUMO
The field of biomimetic synthesis seeks to apply biosynthetic hypotheses to the efficient construction of complex natural products. This approach can also guide the revision of incorrectly assigned structures. Herein, we describe the evolution of a concise total synthesis and structural reassignment of hyperelodione D, a tetracyclic meroterpenoid derived from a Hypericum plant, alongside some biogenetically related natural products, erectones A and B. The key step in the synthesis of hyperelodione D forms six stereocentres and three rings in a bioinspired cascade reaction that features an intermolecular Diels-Alder reaction, an intramolecular Prins reaction and a terminating cycloetherification.
Assuntos
Produtos Biológicos , Hypericum , Produtos Biológicos/química , Biomimética , Reação de CicloadiçãoRESUMO
Covering: Up to January 2020Meroterpenoids derived from the polyketide 1,3,6,8-tetrahydroxynaphthalene (THN) are complex natural products produced exclusively by Streptomyces bacteria. These antibacterial compounds include the napyradiomycins, merochlorins, marinones, and furaquinocins and have inspired many attempts at their chemical synthesis. In this review, we highlight the role played by biosynthetic studies in the stimulation of biomimetic and, ultimately, chemoenzymatic total syntheses of these natural products. In particular, the application of genome mining techniques to marine Streptomyces bacteria led to the discovery of unique prenyltransferase and vanadium-dependent haloperoxidase enzymes that can be used as highly selective biocatalysts in fully enzymatic total syntheses, thus overcoming the limitations of purely chemical reagents.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Enzimas/química , Streptomyces/química , Terpenos/química , Antibacterianos/química , Antibacterianos/farmacologia , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/metabolismo , Enzimas/genética , Enzimas/metabolismo , Estrutura Molecular , Naftoquinonas/síntese química , Streptomyces/genética , Streptomyces/metabolismo , Terpenos/síntese química , Terpenos/metabolismoRESUMO
Singlet oxygen is a versatile reagent for the selective oxidation of organic compounds under mild reaction conditions. It is frequently invoked in biosynthetic pathways, so it is especially suitable for application in the biomimetic synthesis of natural products. Herein, we show that use of the singlet oxygen ene reaction, combined with [2 + 2] cycloadditions, leads to concise, divergent, and redox-economic total syntheses of several polycyclic members of the rhodonoid family of meroterpenoids.
Assuntos
Produtos Biológicos , Oxigênio Singlete , Biomimética , Reação de Cicloadição , OxirreduçãoRESUMO
A biomimetic approach to total synthesis can offer several benefits, including the development of cascade reactions for the rapid generation of molecular complexity, and guidance in the structure revision of old natural products and the anticipation of new ones. Herein, we describe how a biomimetic synthesis of bruceol, a pentacyclic meroterpenoid, led to the anticipation, isolation, and synthesis of isobruceol. The key step in the synthesis of both bruceol and isobruceol was an intramolecular hetero-Diels-Alder reaction of an o-quinone methide that was formed by dearomatization of an electron-rich chromene. The synthesis of an elusive biosynthetic intermediate also allowed a concise synthesis of eriobrucinol via a photochemical [2 + 2] cycloaddition. Furthermore, some speculation on the biosynthesis of prenylated bruceol derivatives inspired the development of a Claisen/Cope/Diels-Alder cascade reaction. We also report the generation of halogenated bruceol derivatives and the synthesis of several protobruceol natural products using singlet oxygen ene reactions.
Assuntos
Produtos Biológicos , Biomimética , Benzopiranos , Reação de Cicloadição , TerpenosRESUMO
Reinvestigation of the coumarin meroterpenoids of Philotheca myoporoides using pressurized hot water extraction (PHWE) procedures led to the isolation of prenylbruceol A, a proposed biosynthetic precursor of seven previously reported bruceol derivatives, prenylbruceols B-H. Protobruceol-I, ostruthin, dipetalactone, and a new dihydrocoumarin natural product were isolated alongside prenylbruceol A. A biomimetic singlet oxygen ene reaction of prenylbruceol A allowed the semisynthesis of prenylbruceols B, C, and D.
Assuntos
Produtos Biológicos/isolamento & purificação , Biomimética , Rutaceae/química , Estrutura Molecular , Oxirredução , Análise Espectral/métodosRESUMO
The marine sponge Aka coralliphaga is a rich source of biologically active and structurally interesting meroterpenoids. Inspired by these natural products, we have used biosynthetic speculation to devise biomimetic syntheses of siphonodictyal B, liphagal and corallidictyals A-D from sclareolide. This work resulted in the development of new cascade reactions in the synthesis of liphagal, the reassignment of the structure of siphonodictyal B, and the realisation that corallidictyals A and B are possibly isolation artefacts.
Assuntos
Produtos Biológicos/química , Hidroquinonas/síntese química , Poríferos/química , Sesquiterpenos/síntese química , Terpenos/síntese química , Animais , Produtos Biológicos/síntese química , Biomimética , Ciclização , Diterpenos/química , Hidroquinonas/química , Oxirredução , Poríferos/metabolismo , Sesquiterpenos/química , Terpenos/químicaRESUMO
The total synthesis of nyingchinoidsâ A and B has been achieved through successive rearrangements of a 1,2-dioxane intermediate that was assembled using a visible-light photoredox-catalysed aerobic [2+2+2] cycloaddition. Nyingchinoidâ D was synthesised with a competing [2+2] cycloaddition. Based on NMR data and biosynthetic speculation, we proposed a structure revision of the related natural product rasumatraninâ D, which was confirmed through total synthesis. Under photoredox conditions, we observed the conversion of a cyclobutane into a 1,2-dioxane through retro-[2+2] cycloaddition followed by aerobic [2+2+2] cycloaddition.
Assuntos
Materiais Biomiméticos/síntese química , Luz , Terpenos/síntese química , Materiais Biomiméticos/química , Catálise , Estrutura Molecular , Oxirredução , Processos Fotoquímicos , Estereoisomerismo , Terpenos/químicaRESUMO
The first total synthesis of bruceol has been achieved using a biomimetic cascade cyclization initiated by a stereoselective Jacobsen-Katsuki epoxidation (and kinetic resolution) of racemic protobruceol-I. A bacterial cytochrome P450 monooxygenase was also found to catalyze the conversion of protobruceol-I into bruceol. The first full analysis of the NMR data of natural bruceol suggested that "isobruceol" was a previously unrecognized natural product also isolated from Philotheca brucei. This was confirmed by the re-isolation, synthesis, and X-ray analysis of isobruceol. In total, eight stereoisomers and structural isomers of bruceol have been synthesized in a highly divergent approach.
Assuntos
Produtos Biológicos/metabolismo , Materiais Biomiméticos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Terpenos/metabolismo , Biocatálise , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Materiais Biomiméticos/química , Materiais Biomiméticos/isolamento & purificação , Cristalografia por Raios X , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação , Modelos Moleculares , Estrutura Molecular , Terpenos/química , Terpenos/isolamento & purificaçãoRESUMO
The biosynthetic route to the napyradiomycin family of bacterial meroterpenoids has been fully described 32 years following their original isolation and 11 years after their gene cluster discovery. The antimicrobial and cytotoxic natural products napyradiomycins A1 and B1 are produced using three organic substrates (1,3,6,8-tetrahydroxynaphthalene, dimethylallyl pyrophosphate, and geranyl pyrophosphate), and catalysis via five enzymes: two aromatic prenyltransferases (NapT8 and T9); and three vanadium dependent haloperoxidase (VHPO) homologues (NapH1, H3, and H4). Building upon the previous characterization of NapH1, H3, and T8, we herein describe the initial (NapT9, H1) and final (NapH4) steps required for napyradiomycin construction. This remarkably streamlined biosynthesis highlights the utility of VHPO enzymology in complex natural product generation, as NapH4 efficiently performs a unique chloronium-induced terpenoid cyclization to establish two stereocenters and a new carbon-carbon bond, and dual-acting NapH1 catalyzes chlorination and etherification reactions at two distinct stages of the pathway. Moreover, we employed recombinant napyradiomycin biosynthetic enzymes to chemoenzymatically synthesize milligram quantities in one pot in 1 day. This method represents a viable enantioselective approach to produce complex halogenated metabolites, like napyradiomycin B1, that have yet to be chemically synthesized.
Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias/química , Dimetilaliltranstransferase/química , Peroxidases/química , Proteínas de Bactérias/isolamento & purificação , Biocatálise , Dimetilaliltranstransferase/isolamento & purificação , Naftoquinonas/síntese química , Peroxidases/isolamento & purificação , Streptomyces/enzimologiaRESUMO
The naphterpins and marinones are naphthoquinone meroterpenoids with an unusual aromatic oxidation pattern that is biosynthesized from 1,3,6,8-tetrahydroxynaphthalene (THN). We propose that cryptic halogenation of THN derivatives by vanadium-dependent chloroperoxidase (VCPO) enzymes is key to this biosynthetic pathway, despite the absence of chlorine in these natural products. This speculation inspired a total synthesis to mimic the naphterpin/marinone biosynthetic pathway. In validation of this biogenetic hypothesis, two VCPOs were discovered that interconvert several of the proposed biosynthetic intermediates.
Assuntos
Produtos Biológicos/metabolismo , Naftoquinonas/metabolismo , Terpenos/metabolismo , Produtos Biológicos/química , Biomimética , Cloreto Peroxidase/metabolismo , Ciclização , Halogenação , Naftóis/química , Naftóis/metabolismo , Naftoquinonas/química , Oxirredução , Reprodutibilidade dos Testes , Terpenos/químicaRESUMO
The synthesis of verrubenzospirolactone from its proposed biosynthetic precursor, capillobenzopyranol, has been shown to be chemically feasible via a simple reaction sequence. The key steps are a chemoselective furan oxidation mediated by NaClO2, a stereoselective dehydration of a γ-methoxybutenolide, and an intramolecular Diels-Alder reaction.
RESUMO
A five-step total synthesis of (±)-verrubenzospirolactone has been achieved using a biomimetic, intramolecular Diels-Alder reaction of a 2H-chromene to form two rings and four stereocenters in the final step. This Diels-Alder reaction occurs spontaneously at 30 °C "on-water", and thus suggests that it is likely to be non-enzymatic in nature. The structure of (±)-verrubenzospirolactone was also used to inspire a quadruple cascade reaction to generate seven stereocenters, four rings, three C-C bonds, and two C-O bonds in one step.
RESUMO
The efficient conversion of siphonodictyal B into the spirocyclic natural products corallidictyals A-D has been achieved via oxidative and acid catalyzed cyclizations. The oxidative cyclization of siphonodictyal B occured spontaneously under aerobic oxidation conditions, which suggests that corallidictyals A and B are possibly artefacts of the isolation process. The mechanism of the oxidative cyclization of siphonodictyal B could be described as either an anionic 5-endo-trig cyclization (which is formally disfavoured by Baldwin's rules), or as an electrocyclic reaction, of an ortho-quinone intermediate.
Assuntos
Sesquiterpenos/química , Sesquiterpenos/metabolismo , Animais , Ciclização , Oxirredução , Poríferos/metabolismoRESUMO
Hyperjaponesâ A-E and hyperjaponolsâ A-C are complex natural products of mixed aromatic polyketide and terpene biosynthetic origin that have recently been isolated from Hypericum japonicum. We have synthesized hyperjaponesâ A-E using a biomimetic, oxidative hetero-Diels-Alder reaction to couple together dearomatized acylphloroglucinol and cyclic terpene natural products. Hyperjaponeâ A is proposed to be the biosynthetic precursor of hyperjaponolâ C through a sequence of: 1)â epoxidation; 2)â acid-catalyzed epoxide ring-opening; and 3)â a concerted, asynchronous alkene cyclization and 1,2-alkyl shift of a tertiary carbocation. Chemical mimicry of this proposed biosynthetic sequence allowed a concise total synthesis of hyperjaponolâ C to be completed in which six carbon-carbon bonds, six stereocenters, and three rings were constructed in just four steps.
Assuntos
Materiais Biomiméticos/síntese química , Hypericum/química , Policetídeos/síntese química , Terpenos/síntese química , Materiais Biomiméticos/química , Conformação Molecular , Policetídeos/química , Estereoisomerismo , Terpenos/químicaRESUMO
A full account of our oxidative radical cyclization approach to the synthesis of garcibracteatone and doitunggarcinone A is presented. This includes the first enantioselective synthesis of garcibracteatone, which allowed the absolute configuration of the natural compound to be determined. The first synthesis of doitunggarcinone A is also described, which confirms our reassignment of the relative configuration of this molecule. Novel syntheses of monoterpene fragments used to construct the target molecules are also reported.