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1.
Org Lett ; 23(1): 60-65, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33351641

RESUMO

The use of the unprecedented annulating reagents methyl N-(tert-butylsulfinyl)-4-chlorobutanimidate and methyl N-(tert-butylsulfinyl)-5-bromopentanimidate enables the diastereoselective preparation of 5- and 6-membered carbocycles bearing three contiguous stereocenters. These synthons undergo cycloaddition with a variety of Michael acceptors to form cyclopentane/cyclohexane rings with excellent stereochemical control, generating only one of the eight possible diastereomers. This novel methodology has enabled the highly enantioselective and high yielding synthesis of novel chemotypes of pharmacological relevance.

2.
Nature ; 573(7775): 563-567, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31554978

RESUMO

(+)-Perseanol is an isoryanodane diterpene that is isolated from the tropical shrub Persea indica1 and has potent antifeedant and insecticidal properties. It is structurally related to (+)-ryanodine, which is a high-affinity ligand for and modulator of ryanodine receptors-ligand-gated ion channels that are critical for intracellular Ca2+ signalling in most multicellular organisms2. Ryanodine itself modulates ryanodine-receptor-dependent Ca2+ release in many organisms, including mammals; however, preliminary data indicate that ryanodane and isoryanodane congeners that lack the pyrrole-2-carboxylate ester-such as perseanol-may have selective activity in insects3. Here we report a chemical synthesis of (+)-perseanol, which proceeds in 16 steps from commercially available (R)-pulegone. The synthesis involves a two-step annulation process that rapidly assembles the tetracyclic core from readily accessible cyclopentyl building blocks. This work demonstrates how convergent fragment coupling, when combined with strategic oxidation tactics, can enable the concise synthesis of complex and highly oxidized diterpene natural products.


Assuntos
Técnicas de Química Sintética , Diterpenos/síntese química , Produtos Biológicos/química , Monoterpenos Cicloexânicos/química , Persea/química
3.
Org Lett ; 20(13): 3793-3796, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29897247

RESUMO

An approach to synthesize the pentacyclic framework of the polyol diterpenoid ryanodol is reported. The ABC tricycle was constructed by a Co-mediated Pauson-Khand reaction, and both radical and anionic cyclization pathways were developed to form the E-ring. In addition, a reaction sequence involving SeO2-mediated enone oxidation and hydroxyl-directed oxy-Michael addition was developed to introduce the A-ring oxidation. The feasibility of forming the bridging D-ring by an oxidative dearomatization was established.

4.
ACS Cent Sci ; 3(4): 278-282, 2017 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-28470044

RESUMO

(+)-Ryanodine is a natural product modulator of ryanodine receptors, important intracellular calcium ion channels that play a critical role in signal transduction leading to muscle movement and synaptic transmission. Chemical derivatization of (+)-ryanodine has demonstrated that certain peripheral structural modifications can alter its pharmacology, and that the pyrrole-2-carboxylate ester is critical for high affinity binding to ryanodine receptors. However, the structural variation of available ryanodine analogues has been limited by the challenge of site-specific functionalization of semisynthetic intermediates, such as (+)-ryanodol. Here we report a synthetic strategy that provides access to (+)-ryanodine and the related natural product (+)-20-deoxyspiganthine in 18 and 19 steps, respectively. A key feature of this strategy is the reductive cyclization of an epoxide intermediate that possesses the critical pyrrole-2-carboxylate ester. This approach allows for the direct introduction of this ester in the final stage of the synthesis and provides a framework for the synthesis of previously inaccessible synthetic ryanoids.

5.
J Am Chem Soc ; 138(24): 7698-704, 2016 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-27167594

RESUMO

Under H2 pressure, Co(II)(dmgBF2)2L2 (L = H2O, THF) generates a low concentration of an H• donor. Transfer of the H• onto an olefin gives a radical that can either (1) transfer an H• back to the metal, generating an isomerized olefin, or (2) add intramolecularly to a double bond, generating a cyclized radical. Transfer of an H• back to the metal from the cyclized radical results in a cycloisomerization. Both outcomes are favored by the low concentration of the cobalt H• donor, whereas hydrogenation and cyclohydrogenation are more likely with other catalysts (when the concentration of the H• donor is high).

6.
J Am Chem Soc ; 137(3): 1036-9, 2015 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-25569214

RESUMO

Transition-metal hydrides generate α-alkoxy radicals by H• transfer to enol ethers. We have measured the rate constant for transfer from CpCr(CO)3H to n-butyl vinyl ether and have examined the chemistry of radicals generated by such transfers. Radicals from appropriate substrates undergo 5-exo cyclization, with higher diastereoselectivity than the analogous all-carbon radicals. From such radicals it is straightforward to make substituted tetrahydrofurans.

7.
J Org Chem ; 79(5): 1938-46, 2014 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-24502650

RESUMO

Rate constants have been calculated, and compared with experimental results, for the cyclizations of 1-carbomethoxy-1-methyl-5-hexenyl radicals (2) with various substituents on C6. The calculations have been done by DFT at the B3LYP/6-311++G** level of theory. They show considerable interaction between C5 and the radical centers even in the ground state of all of the radicals 2. Experimentally, the radicals have been generated by H(•) transfer to the corresponding acrylate esters 1 and the yields of cyclized products compared to the calculated rate constants. (The "cyclized products" include those from cyclohydrogenation, 4, and those from cycloisomerization, 9.) Two phenyl substituents on C6 (2i), or a phenyl and a methyl substituent (2g, 2h), increase the rate of cyclization, but a single phenyl substituent on C6 produces a greater increase. The calculations show that the two phenyl substituents are twisted in the transition state for cyclization, while a single phenyl substituent remains flat in that transition state. A methyl substituent on C6 along with a single phenyl causes the phenyl to twist in the transition state and decreases the rate constant for cyclization below that of the H/Ph-substituted 2e, 2f.

8.
J Am Chem Soc ; 134(36): 14662-5, 2012 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-22897586

RESUMO

Under H(2), the radical cyclization of appropriate dienes can be catalyzed by cobaloximes. H• can be abstracted from an intermediate (presumably a cobalt hydride) by trityl radicals (Ar(3)C•) or by TEMPO. The rate-determining step in these reactions is the uptake of H(2), which is second order in cobalt and first order in hydrogen; the third-order rate constant is 106(3) M(-2)·s(-1).


Assuntos
Cobalto/química , Hidrogênio/química , Compostos Organometálicos/química , Alcadienos/química , Ciclização , Radicais Livres/química
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