RESUMO
We disclose our studies on a copper-mediated reaction of alkynes with trimethylsilyl azide to afford nitriles, and proposed a reaction mechanism, which involves an iodoalkyne and an iodotriazole as intermediates.
Assuntos
Alcinos/química , Cobre/química , Nitrilas/química , Triazóis/química , Azidas/química , Azidas/metabolismo , Catálise , Reação de Cicloadição , Silanos/metabolismo , Solventes/químicaRESUMO
The total synthesis of halicloninâ A was accomplished. Starting from 3,5-dimethoxybenzoic acid, a functionalized cyclohexanone fused to a 17-membered ring was prepared through a Birch reduction/alkylation sequence, ring-closing metathesis, intramolecular cyclopropanation, and stereoselective 1,4-addition of an organocopper reagent to an enone moiety. Reductive C-N bond formation via an N,O-acetal forged the 3-azabicyclo[3.3.1]nonane core. The allyl alcohol moiety was constructed by a sequence involving stereoselective α-selenylation of an aldehyde via an enamine, syn-elimination of a selenoxide, and allylation of the aldehyde with an allylboronate. Formation of the 15-membered ring containing a skipped diene was achieved by ring-closing metathesis, and final transformations led to the synthesis of halicloninâ A.
RESUMO
A total synthesis of tetrodotoxin was accomplished. A Diels-Alder reaction between a known enone and a siloxy diene gave a tricyclic product, the steric bias of which was used to construct the remaining stereogenic centers. A nitrogen atom was introduced either by a four-step sequence involving a Curtius rearrangement, or a three-step sequence featuring a newly developed transformation of a terminal alkyne into a nitrile. Introduction of the guanidine moiety followed by the formation of the heterocyclic system by cascade reactions led to tetrodotoxin.
Assuntos
Tetrodotoxina/síntese química , Alcinos/química , Técnicas de Química Sintética , Guanidina/química , Nitrilas/química , Nitrogênio/química , Tetrodotoxina/químicaRESUMO
The enantioselective total synthesis of (-)-tetrodotoxin [(-)-TTX] and 4,9-anhydrotetrodotoxin, which are selective blockers of voltage-gated sodium channels, was accomplished from the commercially available p-benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3]-sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3-dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11-norTTX-6(R)-ol and 4,9-anhydro-11-norTTX-6(R)-ol through late-stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11-norTTX-6(R)-ol without competing dehydration to their 4,9-anhydro forms.
Assuntos
Bloqueadores dos Canais de Sódio/síntese química , Tetrodotoxina/análogos & derivados , Tetrodotoxina/síntese química , Benzoquinonas/síntese química , Benzoquinonas/química , Técnicas de Química Sintética , Bloqueadores dos Canais de Sódio/química , Estereoisomerismo , Tetrodotoxina/químicaRESUMO
The poison dart toxin batrachotoxin is exceptional for its high potency and toxicity, and for its multifaceted modification of the function of voltage-gated sodium channels. By using cryogenic electron microscopy, we identify two homologous, but nonidentical receptor sites that simultaneously bind two molecules of toxin, one at the interface between Domains I and IV, and the other at the interface between Domains III and IV of the cardiac sodium channel. Together, these two bound toxin molecules stabilize α/π helical conformation in the S6 segments that gate the pore, and one of the bound BTX-B molecules interacts with the crucial Lys1421 residue that is essential for sodium conductance and selectivity via an apparent water-bridged hydrogen bond. Overall, our structure provides insight into batrachotoxin's potency, efficacy, and multifaceted functional effects on voltage-gated sodium channels via a dual receptor site mechanism.
Assuntos
Venenos , Canais de Sódio Disparados por Voltagem , Batraquiotoxinas/metabolismo , Sítios de Ligação , Conformação Molecular , Canais de Sódio Disparados por Voltagem/metabolismoRESUMO
A straightforward synthesis of ecteinascidin 743 was accomplished from readily available l-glutamic acid as a single chiral source. Our novel synthesis features a concise and convergent approach for construction of the B-ring, consisting of a sequence involving a stereoselective Heck reaction between a diazonium salt and an enamide, oxidative cleavage of the resulting alkene, and intramolecular ortho substitution of the phenol by an aldehyde.
Assuntos
Antineoplásicos/síntese química , Dioxóis/síntese química , Descoberta de Drogas , Tetra-Hidroisoquinolinas/síntese química , Antineoplásicos/química , Dioxóis/química , Estrutura Molecular , Tetra-Hidroisoquinolinas/química , TrabectedinaRESUMO
A synthetic route to ecteinascidin 743 has been established via an intramolecular cascade Heck reaction to construct the diazabicyclo[3.3.1]nonane skeleton while controlling the two contiguous stereogenic centers. The strategically formed five-membered ring was oxidatively cleaved to generate a dialdehyde intermediate, from which the B ring of ecteinascidin 743 was constructed.
Assuntos
Alcanos , Ciclização , Estereoisomerismo , TrabectedinaRESUMO
A novel synthetic route to (+)-manzamine A was developed. It highlights an amazingly efficient construction of a highly strained 15-membered ring across a cyclohexenone ring with the aim of installing the requisite functionalities in a completely stereocontrolled manner. Other key features include a stereoselective Diels-Alder reaction of an optically active butenolide, construction of the 15-membered ring by intramolecular Mitsunobu reaction of a nosyl amide, [3,3]-sigmatropic rearrangement of allyl cyanate for stereoselective introduction of nitrogen functionality at a sterically congested position, and a ring-closing metathesis in the presence of labile functional groups.
Assuntos
Carbazóis/síntese química , Carbazóis/química , Ciclização , EstereoisomerismoRESUMO
A variety of oximes were synthesized from the corresponding alcohols, alkyl halides, or alkyl sulfonates without using external oxidants. With this simple two-step procedure involving substitution with readily available TsNHOTBS and subsequent treatment with CsF, a range of oximes were prepared including the ones hardly preparable with conventional procedures.
Assuntos
Álcoois/química , Oximas/química , Compostos de Tosil/química , Césio/química , Fluoretos/química , Indicadores e ReagentesRESUMO
The stereoselective synthesis of the tetracyclic intermediate 3 for (+)-manzamine A (1) has been achieved. The key features of this stereoselective synthesis of 3 are the Rh-catalyzed asymmetric hydrogenation and a diastereoselective intermolecular Diels-Alder reaction. The 8-membered ring is efficiently constructed utilizing our Ns-strategy.
Assuntos
Carbazóis/síntese química , Compostos Policíclicos/síntese química , EstereoisomerismoRESUMO
A novel entry to the synthesis of diazoacetates is disclosed. A variety of diazoacetates were synthesized from the corresponding bromoacetates by treatment with N,N'-ditosylhydrazine in moderate to high yields. Ease of operation with the stable crystalline reagent as well as a short reaction time offer a useful alternative to the conventional methods.
Assuntos
Acetatos/síntese química , Compostos de Diazônio/síntese química , Hidrazinas/química , Compostos de Tosil/química , Catálise , Técnicas de Química Combinatória , Indicadores e Reagentes , Estrutura MolecularRESUMO
The steroidal neurotoxin (-)-batrachotoxin functions as a potent agonist of voltage-gated sodium ion channels (NaVs). Here we report concise asymmetric syntheses of the natural (-) and non-natural (+) antipodes of batrachotoxin, as well both enantiomers of a C-20 benzoate-modified derivative. Electrophysiological characterization of these molecules against NaV subtypes establishes the non-natural toxin enantiomer as a reversible antagonist of channel function, markedly different in activity from (-)-batrachotoxin. Protein mutagenesis experiments implicate a shared binding side for the enantiomers in the inner pore cavity of NaV These findings motivate and enable subsequent studies aimed at revealing how small molecules that target the channel inner pore modulate NaV dynamics.
Assuntos
Batraquiotoxinas/síntese química , Batraquiotoxinas/farmacologia , Proteínas Musculares/antagonistas & inibidores , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Sítios de Ligação , Proteínas Musculares/química , Proteínas Musculares/genética , Mutação Puntual , Estrutura Secundária de Proteína , Ratos , Canais de Sódio/química , Canais de Sódio/genética , Bloqueadores do Canal de Sódio Disparado por Voltagem/químicaRESUMO
A novel family of small molecule inhibitors of voltage-gated sodium channels (NaVs) based on the structure of batrachotoxin (BTX), a well-known channel agonist, is described. Protein mutagenesis and electrophysiology experiments reveal the binding site as the inner pore region of the channel, analogous to BTX, alkaloid toxins, and local anesthetics. Homology modeling of the eukaryotic channel based on recent crystallographic analyses of bacterial NaVs suggests a mechanism of action for ion conduction block.