RESUMO
E7130 is a novel drug candidate with an exceedingly complex chemical structure of the halichondrin class, discovered by a total synthesis approach through joint research between the Kishi group at Harvard University and Eisai. Only 18 months after completion of the initial milligram-scale synthesis, ten-gram-scale synthesis of E7130 was achieved, providing the first good manufacturing practice (GMP) batch to supply clinical trials. This paper highlights the challenges in developing ten-gram-scale synthesis from the milligram-scale synthesis.
Assuntos
Antineoplásicos , Humanos , Antineoplásicos/farmacologiaRESUMO
Guangnanmycin A is a recently discovered congener of the well-known antitumor drug lead leinamycin; its macrolactam ring, however, is even more strained than that of the parent compound. The first synthetic foray towards this challenging target is reported, which relies on molybdenum-catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed by ruthenium-catalyzed redox isomerization of the propargyl alcohol thus formed; the resulting enone enabled the introduction of the yet missing exo-methylene group by a modified Peterson olefination. The signature disulfide moiety of guangnanmycin A was installed by strain-driven thia-Michael addition followed by conversion of the thioether thus formed into an unsymmetric disulfide with the aid of (methylthio)dimethylsulfonium tetrafluoroborate and MeSSMe. While this sequence furnished racemic guangnanmycin A alcohol in good overall yield, the final oxidation to the corresponding acid failed, most likely because of the exceptional sensitivity of the strained scaffold.
RESUMO
After a recent total synthesis had resolved all issues surrounding the constitution and stereostructure of prorocentin, it was possible to devise a new approach aiming at an improved supply of this scarce marine natural product; this compound is a cometabolite of the prototypical phosphatase inhibitor okadaic acid but still awaits detailed biological profiling. The revised entry starts from 2-deoxy-d-glucose; keys to success were a telescoped hemiacetal reduction/acetal cleavage and an exquisitely selective gold/Brønsted acid-cocatalyzed spiroacetalization.
Assuntos
Inibidores Enzimáticos , Furanos , Ácido Okadáico/química , Ácido Okadáico/farmacologia , Inibidores Enzimáticos/química , Acetais/químicaRESUMO
The dinoflagellate-derived polyether prorocentin is a co-metabolite of the archetypical serine/threonine phosphatase inhibitor okadaic acid. Whereas a structural relationship cannot be missed and a biosynthetic link was proposed, it is currently unknown whether there is any parallel in the bioactivity profile of these natural products. However, it was insinuated in the past that the structure assigned to prorocentin might need to be revised. Indeed, re-examination of the published spectra cast doubts as to the constitution of the fused/spirotricyclic BCD-ring system in the core. To clarify this issue, a flexible synthesis blueprint was devised that allowed us to obtain the originally proposed structure as well as the most plausible amended structure. The key to success was late-stage gold-catalyzed spirocyclization reactions that furnished the isomeric central segments with excellent selectivity. The lexicon of catalytic transformations used to make the required cyclization precursors comprised a titanium-mediated ester methylenation/metathesis cascade, a rare example of a gold-catalyzed allylic substitution, and chain extensions via organocatalytic asymmetric aldehyde propargylation. A wing sector to be attached to the isomeric cores was obtained by Krische allylation, followed by a superbly selective cobalt-catalyzed oxidative cyclization of the resulting di-unsaturated alcohol with the formation of a 2,5-trans-disubstituted tetrahydrofuran; the remaining terminal alkene was elaborated into an appropriate handle for fragment coupling by platinum-catalyzed asymmetric diboration/oxidation. The assembly of the different building blocks to the envisaged isomeric target compounds proved that the structure of prorocentin needs to be revised as disclosed herein.
RESUMO
In recent years, London dispersion interactions, which are the attractive component of the van der Waals potential, have been found to play an important role in controlling the regio- and/or stereoselectivity of various reactions. Particularly, the dispersion interactions between substrates and catalysts (or ligands) are dominant in various selective catalyzes. In contrast, repulsive steric interactions, rather than the attractive dispersion interactions, between bulky substituents are predominant in most of the noncatalytic reactions. Herein, we demonstrate the first example of London dispersion-controlled noncatalytic (2 + 2) cyclodimerization of substituted benzynes to selectively afford proximal biphenylenes in high yields and regioselectivities, depending on the extent of dispersion interactions in the substituents. This method can be applied for the synthesis of novel helical biphenylenes, which would be fascinating for chemists as these compounds are potential skeletons for ligands, catalysts, and medicines.
RESUMO
Herein, we describe a novel synthetic method for 2,5-disubstituted tetrazoles from 5-substituted tetrazoles using cobalt-catalyzed intermolecular hydroamination reaction of nonactivated olefins. Owing to its mild conditions, the method enabled the use of substrates having acid-labile functional groups, such as silyloxy and methoxymethyloxy groups. By using optically active cobalt complexes, asymmetric intermolecular hydroamination of nonactivated olefins, a longstanding challenge in synthetic organic chemistry, was developed to produce optically active disubstituted tetrazoles.
Assuntos
Alcenos/química , Cobalto/química , Tetrazóis/química , Tetrazóis/síntese química , Aminação , Catálise , Estrutura MolecularRESUMO
Ketones are a fundamental functionality found throughout a range of natural and synthetic compounds, making their synthesis essential throughout the chemical disciplines. Herein, we describe a one-pot synthesis of ketones via decatungstate-mediated formal dehydrogenative coupling between aldehydes and non-activated hydrocarbons. A variety of substituted benzaldehydes and cycloalkanes could be used in the optimized reaction to produce the desired ketones in moderate yields. The decatungstate photocatalyst functions in two reactions in this synthesis, catalyzing both the coupling and oxidation steps of the process. Notably, the reaction displays both high atom economy and sustainability, as it uses light and oxygen as key energy sources.
Assuntos
Aldeídos/química , Hidrocarbonetos/química , Cetonas/síntese química , Cetonas/química , Estrutura MolecularRESUMO
Cobalt-catalyzed Markovnikov-selective hydroamination of nonactivated olefins was developed. Hydrogen atom transfer from a catalytically generated cobalt(III)-hydride complex to the olefins proceeded regioselectively, and the nucleophilic addition of benzotriazoles occurred selectively at their N2-positions. The synthetic utility of the obtained N2-alkylated benzotriazoles as stable amine protecting groups under various reaction conditions was demonstrated, and the products were also transformed into primary amines by zinc-mediated reduction.
RESUMO
Herein, we describe the generation of an organochromium-type carbanion species from a non-activated C-H bond and its nucleophilic addition to aldehydes. The catalytic carbanion generation occurred through formal deprotonation of a non-activated C-H bond under mild conditions and did not need the prefunctionalization or anion stabilizing group. Carbon radical intermediates generated by decatungstate photocatalyst-mediated hydrogen abstraction were captured by a chromium salt with the reductive radical-polar crossover reaction to produce organochromium carbanions.
RESUMO
Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Éteres Cíclicos/síntese química , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Macrolídeos/síntese química , Moduladores de Tubulina/síntese química , Actinas/genética , Actinas/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Cetuximab/farmacologia , Descoberta de Drogas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Éteres Cíclicos/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Macrolídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Análise de Sobrevida , Moduladores de Tubulina/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The right halves of halichondrins A-C were synthesized by coupling the common C20-C37 building block 9 with the C1-C19 building blocks 10a-c, respectively. Catalytic, asymmetric Ni/Cr-mediated coupling was used for three C-C bond formations. For all cases, the stereochemistry was controlled with the Cr catalyst prepared from the chiral sulfonamide identified via the toolbox approach. For (3 + 4)-, (6 + 7)-, and (9 + 10)-couplings, the stereoselectivity of 28:1, >40:1, and â¼20:1 was achieved by the Cr catalysts prepared from (S)-H, (S)-I, and (R)-L, respectively. Unlike the first and second couplings, the third coupling used the structurally complex nucleophile. It was demonstrated that the coupling efficiency was excellent even with the electrophile/nucleophile molar ratio = 1.0/1.1. In addition, the third coupling was achieved with the substrate bearing a free hydroxyl group. The products obtained in the Ni/Cr-mediated couplings were converted to the right halves of halichondrins A-C in excellent overall yields. The right halves of halichondrins A-C (1a-c) were synthesized in 28, 24, and 24 steps from commercial d-galactal in 13.4%, 21.1%, and 16.7% overall yield, respectively.
RESUMO
A stereocontrolled synthesis of the left halves of halichondrins was reported. An intramolecular oxy-Michael reaction under basic conditions was used to construct the [6,6]-spiroketal in a stereocontrolled manner. With this approach, the left halves of halichondrins, homohalichondrins, and norhalichondrins were synthesized.
RESUMO
A zirconium/nickel-mediated one-pot synthesis of ketones is reported. In the presence of Zn or Mn, Cp2 ZrCl2 was found to dramatically accelerate the coupling and suppress side product formation via an IâSPy displacement at the same time. Unlike Zn/Pd- and Fe/Cu-mediated one-pot ketone syntheses, the new method is effective for nucleophiles bearing OR or equivalent functional groups at the α-position. A mechanism comprising a nickel catalytic cycle, a zirconium catalytic cycle, and ZrâNi transmetalation is proposed, and Cp2 ZrCl2 and/or low-valent Zr species are suggested to play crucial dual roles.
RESUMO
Unified, efficient, and scalable syntheses of the halichondrin natural products are reported. A newly developed Zr/Ni-mediated one-pot ketone synthesis was used to couple the two halves of the final product at a late stage in the synthesis. With the use of a slight excess of the left halves, the desired ketones were isolated in yields of 80-90 %. The halichondrins were obtained from these ketones in two steps, namely desilylation and [5,5]-spiroketal formation. The new synthetic route was effective for the total synthesis of all members in the homohalichondrin subgroup. The scalability of this process was demonstrated with halichondrinâ B; 150â mg of halichondrinâ B (68 % overall yield) were obtained from 200â mg of the right-half precursor.
RESUMO
Highly discriminative transformation of α,ß-unsaturated esters in the presence of enones using two types of phosphonium salts, and their application to the synthesis of oxacyclic compounds in six steps in one pot have been achieved.
RESUMO
An Fe/Cu-mediated one-pot ketone synthesis was reported. Unlike Ni- and Pd-mediated one-pot ketone syntheses, the reported Fe/Cu-mediated method allowed selective activation and coupling of alkyl iodides over vinyl iodides. The newly developed one-pot ketone synthesis was applied to a synthesis of vinyl iodide/ketone 13, the left half of halichondrin B, as well as vinyl iodide/ketone 8a, the C20-C26 building block of halichondrins.
RESUMO
A concise and unified strategy for the synthesis of C1-C18 macrolactone fragments of FD-891 and FD-892 as well as their analogues is reported. The strategy includes a stereoselective vinylogous Mukaiyama aldol reaction (VMAR) using chiral silyl ketene N,O-acetal to construct C6-C7 stereocenters, an E-selective ring closing metathesis to construct a C12-C13 olefin, and stereodivergent construction of a C8-C9 epoxide.
Assuntos
Lactonas/síntese química , Macrolídeos/síntese química , Aldeídos/química , Lactonas/química , Macrolídeos/química , Estrutura Molecular , EstereoisomerismoRESUMO
Enones selectively react with a combination of PPh(3) and TMSOTf to produce phosphonium silyl enol ethers, which work as protective groups of enones during the reduction of other carbonyl functions and can be easily deprotected to regenerate parent enones at workup. Furthermore, the first ketone selective alkylations in the presence of enones were also accomplished. This in situ protection method was applied to concise asymmetric total syntheses of decytospolides A and B.
Assuntos
Cetonas/química , Cetonas/síntese química , Piranos/síntese química , Alquilação , Catálise , Técnicas de Química Combinatória , Éteres/química , Estrutura Molecular , Compostos de Organossilício/química , Piranos/química , EstereoisomerismoRESUMO
Recent progress in selective transformation of carbonyl groups using in situ protection methodology is described. These techniques which enable reversing reactivity of functional groups have potential usefulness because they can remove complicated protection-deprotection sequences. In this review, we discuss various in situ protection strategies and their synthetic applications.
Assuntos
Química OrgânicaRESUMO
A methodology for selective transformations of ketones, esters, Weinreb amides, and nitriles in the presence of aldehydes has been developed. The use of a combination of PPh(3)-trimethylsilyl trifluoromethanesulfonate (TMSOTf) promotes selective transformation of aldehydes to their corresponding, temporarily protected, O,P-acetal type phosphonium salts. Because, hydrolytic work-up following ensuing reactions of other carbonyl moieties in the substrates liberates the aldehyde moiety, a sequence involving aldehyde protection, transformation of other carbonyl groups, and deprotection can be accomplished in a one-pot manner. Furthermore, the use of PEt(3) instead of PPh(3) enables ketones to be converted in situ to their corresponding O,P-ketal type phosphonium salts and, consequently, selective transformations of esters, Weinreb amides, and nitriles in the presence of ketones can be performed. This methodology is applicable to various dicarbonyl compounds, including substrates that possess heteroaromatic skeletons and hydroxyl protecting groups.