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1.
Chem Sci ; 15(15): 5627-5632, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38638214

RESUMO

Highly substituted trans-hydrindanes were synthesized by the three-component coupling reactions of 1,3-diethyl 2-(2-oxopropylidene)propanedioate and two different α,ß-unsaturated aldehydes catalyzed by diphenylprolinol silyl ether. The reaction proceeds via two successive independent catalytic domino reactions in a one-pot reaction by a single chiral catalyst. Domino reactions involve Michael/Michael and Michael/aldol reactions to afford trans-hydrindanes with excellent diastereoselectivity and nearly optically pure form.

2.
Commun Biol ; 6(1): 956, 2023 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-37726448

RESUMO

Existing drugs often suffer in their effectiveness due to detrimental side effects, low binding affinity or pharmacokinetic problems. This may be overcome by the development of distinct compounds. Here, we exploit the rich structural basis of drug-bound gastric proton pump to develop compounds with strong inhibitory potency, employing a combinatorial approach utilizing deep generative models for de novo drug design with organic synthesis and cryo-EM structural analysis. Candidate compounds that satisfy pharmacophores defined in the drug-bound proton pump structures, were designed in silico utilizing our deep generative models, a workflow termed Deep Quartet. Several candidates were synthesized and screened according to their inhibition potencies in vitro, and their binding poses were in turn identified by cryo-EM. Structures reaching up to 2.10 Å resolution allowed us to evaluate and re-design compound structures, heralding the most potent compound in this study, DQ-18 (N-methyl-4-((2-(benzyloxy)-5-chlorobenzyl)oxy)benzylamine), which shows a Ki value of 47.6 nM. Further high-resolution cryo-EM analysis at 2.08 Å resolution unambiguously determined the DQ-18 binding pose. Our integrated approach offers a framework for structure-based de novo drug development based on the desired pharmacophores within the protein structure.


Assuntos
Aprendizado Profundo , Desenho de Fármacos , Estômago , Desenvolvimento de Medicamentos , Farmacóforo
3.
Org Biomol Chem ; 21(31): 6289-6292, 2023 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-37505101

RESUMO

Total syntheses of fawcettimine-class Lycopodium alkaloids having an imino bridge between C5 and C13 were accomplished. Fawcettimine was first prepared in 10 steps from a known compound, and the characteristic structures, including the imino bridge, were constructed via the formation of a bridgehead imine.

4.
Org Lett ; 25(24): 4530-4533, 2023 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-37310878

RESUMO

The total syntheses of tropolone-containing natural products malettinins C and E were accomplished. A nitro compound and a chiral enone were prepared by using palladium-mediated nitromethylation and an organocatalyst-mediated asymmetric aldol reaction, respectively, and were connected via a Michael reaction. Oxidative dearomatization of a phenol having a cyclic acetal moiety produced a spirocyclic dienone, which could be converted into a tropolone via a base-mediated ring-expansion reaction, with elimination of the nitro group, providing entry to malettinins C and E.


Assuntos
Produtos Biológicos , Tropolona , Fenóis , Estereoisomerismo
5.
Org Lett ; 25(15): 2718-2721, 2023 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-37036762

RESUMO

A total synthesis of kopsone was achieved, featuring stereoselective preparation of an acyclic aldehyde having a protected hydroxylamine moiety via Ireland-Claisen rearrangement and intramolecular cycloaddition of an eight-membered cyclic nitrone to form the 2-azabicyclo[3.3.1]nonane skeleton.

6.
ACS Org Inorg Au ; 2(3): 245-251, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-36855469

RESUMO

The asymmetric Michael reaction of methyl alkynyl ketone and α,ß-unsaturated aldehyde catalyzed by diphenylprolinol silyl ether was developed. Although methyl alkynyl ketone is a good Michael acceptor, it also acts as a Michael donor to afford the synthetically important δ-oxo aldehydes with excellent enantioselectivity. The products possessing several functional groups, such as alkyne, ketone, and aldehyde moieties, are useful chiral building blocks for further synthesis. Using this reaction as a key step, a side chain of atorvastatin (Lipitor), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was synthesized in a two-pot sequence with excellent diastereo- and enantioselectivities.

7.
Org Lett ; 22(23): 9365-9370, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33231082

RESUMO

The pot-economical synthesis of clinprost is reported, in which the core bicyclo[3.3.0]octenone structure was synthesized by two key steps: an asymmetric domino Michael/Michael reaction catalyzed by diphenylprolinol silyl ether and an intramolecular Horner-Wadsworth-Emmons reaction. The trisubstituted endocyclic alkene was selectively introduced by 1,4-reduction followed by trapping of the generated enolate with Tf2NPh and subsequent utilization of the Suzuki-Miyaura coupling reaction. Chiral, nonracemic clinprost was synthesized in seven pots with a 17% total yield and excellent enantioselectivity.

8.
Org Lett ; 22(21): 8603-8607, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33074004

RESUMO

An asymmetric domino reaction combining vinylogous Michael reaction, hydration of aldehyde, and oxy-Michael reaction proceeds with α,ß-unsaturated aldehydes and α-acyl α,ß-unsaturated cyclic ketones in the presence of diphenylprolinol silyl ether to afford tetrahydrochromane derivatives with excellent enantioselectivity. After the domino reaction, addition of Wittig reagent and acid in the same reaction vessel promoted a second domino reaction incorporating retro oxy-Michael reaction, isomerization, and Wittig reaction to afford chiral functionalized cyclic 1,3-diene derivatives with excellent enantioselectivity. Overall, six reaction steps proceed in a one-pot procedure.

9.
Chem Sci ; 11(41): 11293-11297, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34094371

RESUMO

The key nucleophile was found to be neither an enamine nor an enol, but an enolate in the direct Michael reaction of α,ß-unsaturated aldehydes and non-activated ketones catalyzed by two amine catalysts namely diphenylprolinol silyl ether and pyrrolidine. This is a rare example of an enolate from a ketone serving as a key intermediate in the asymmetric organocatalytic reaction involving secondary amine catalysts because the ketone enolates are generally generated using a strong base, and the enamine is a common nucleophile in this type of reaction.

10.
Chem Sci ; 11(5): 1205-1209, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34123244

RESUMO

The Corey lactone is a highly versatile intermediate for the synthesis of a variety of prostaglandin hormones that natively control a multitude of important physiological processes. Starting from commercially available compounds, we herein disclose a time-economical, one-pot enantioselective preparation of the Corey lactone by virtue of a new diphenylprolinol silyl ether-mediated domino Michael/Michael reaction to afford the substituted cyclopentanone core in a formal (3 + 2) cycloadditive fashion. More broadly, this work advances the on-demand, gram-scale synthesis of high-value targets involving chemically orthogonal transformations, whereby distinct reactions of acids, bases, organometalics, reductants and oxidants can be carried out in a single reaction vessel in a sequential fashion.

11.
Angew Chem Int Ed Engl ; 57(7): 1958-1962, 2018 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-29235717

RESUMO

A direct asymmetric Michael reaction of α,ß-unsaturated aldehydes and ketones proceeded in the presence of two pyrrolidine-type catalysts, a diphenylprolinol silyl ether and hydroxyproline, to afford synthetically useful δ-keto aldehydes with excellent diastereo- and enantioselectivity. Although there are several iminium ions and enamines in the reaction mixture, the iminium ion generated by the former catalyst reacts preferentially with the enamine generated by the latter catalyst.

12.
Org Lett ; 19(16): 4155-4158, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28783367

RESUMO

Potassium and tetrabutylammonium prolinate salts are efficient catalysts in the α-aminoxylation reaction of aldehydes and nitrosobenzene, to afford synthetically useful chiral α-aminoxylated aldehydes in nearly enantiomerically pure form. This is the first reaction in which prolinate is more reactive and enantioselective than proline. Because of its higher reactivity, the catalyst loading can be reduced. A reaction mechanism involving the activation of nitrosobenzene through N-protonation of a hydrogen-bonded water molecule is proposed.

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