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1.
J Org Chem ; 85(7): 4881-4895, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32154712

RESUMO

Herein, we report a simple, efficient, highly regioselective, and broad-scope hydration method that is facilitated by an unusual interception of an electrophilic intermediate by water generated via acetate group participation during [3,3]-acyloxy rearrangement. Various carboxylate-directing groups including acetate, acrylates, pivalates, benzoate or its derivatives, and those derived from bioactive natural products were successfully implemented to direct the regioselective hydration for various functionalized δ-acyloxy-ß-ketoester synthesis. The reaction pathway was further confirmed by 18O labeling experiments, and to the best of our knowledge, this is the first report of hydration through an electrophilic intermediate generated during [3,3]-acyloxy rearrangement. Synthetic application includes the synthesis of a modifiable C5-carbon chain, five-, six-, and seven-membered heterocycles, and natural product diversification.

2.
Org Biomol Chem ; 18(14): 2685-2695, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32202577

RESUMO

An efficient CuBr2-catalyzed diastereoselective allylation of a cyclic hemiacetal with allyltrimethylsilane as a nucleophile has been developed. The protocol offers a cost effective, protecting group tolerant, and operationally simple approach to 2,6-trans-disubstituted tetrahydropyran with excellent diastereoselectivity. Furthermore, the application of this methodology has been demonstrated in the total synthesis of decytospolides A and B and their C6-epimers.

3.
J Org Chem ; 85(6): 4122-4129, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32098474

RESUMO

A unified and concise first asymmetric total synthesis of (-)-citreoisocoumarin (2), (-)-citreoisocoumarinol (3), 12-epi-citreoisocoumarinol (4), and (-)-mucorisocoumarins A (5) and B (6) have been accomplished from the common intermediate (-)-6-O-methyl-citreoisocoumarin (1). Central to the synthetic approach is a regioselective gold(I)-catalyzed 6-endo-dig cyclization strategy for the construction of the isocoumarin skeleton. The other key steps in this approach included Sonogashira coupling, Tsuji-Wacker oxidation, Evans-Saksena's 1,3-anti-reduction, and Narasaka-Prasad's 1,3-syn-reduction. The synthetic results unambiguously confirmed the absolute configuration of the natural products mucorisocoumarins A and B as (-)-(10R,12S)-5 and (+)-(10S,12S)-6, respectively.

4.
Org Biomol Chem ; 17(41): 9169-9181, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31595914

RESUMO

An efficient synthesis protocol for the preparation of trans-2,6-disubstituted tetrahydropyrans by the reaction of 1-phenyl-1-triemthylsiloxyethylene with six membered cyclic hemiacetals in the presence of iodine is developed. This reaction proceeds smoothly under mild conditions employing a catalytic amount of molecular iodine. The feature of this novel conversion includes milder reaction conditions, broader substrate scope, functional group tolerance and good diastereoselectivity. The efficiency and practicality of the current method were successfully displayed in the total synthesis of diospongin A and B in good yields.

5.
Org Lett ; 21(15): 5952-5956, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31333026

RESUMO

The first asymmetric total synthesis of macrolactone monocillin VII and its C-10' epimer was achieved starting from a known chiral pure epoxide in 16 longest linear sequences. The present synthesis highlights the macrolactone formation involving an alkyne-dicobalt carbonyl complex under De Brabander's conditions followed by an unexpected regioselective hydration. The asymmetric total synthesis resulted in the revision of the configuration at C10' and reassignment of the absolute configuration of the natural product.

6.
Org Biomol Chem ; 17(22): 5601-5614, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31119247

RESUMO

The first asymmetric total synthesis and stereochemical assignments of 10-membered macrolactones relgro and 10'-oxorelgro are disclosed. To this end, palladium-catalyzed Stille coupling, the Mitsunobu reaction, ring-closing metathesis, EDCI promoted coupling and the Jacobsen hydrolytic kinetic resolution are used as key steps. The total synthesis followed by thorough evaluation of the optical rotation and CD spectral data led to the revision of the absolute configuration at C-6' for both relgro and 10'-oxorelgro. Moreover, the 1H as well as 13C NMR data are reported for the first time for relgro.

7.
Org Biomol Chem ; 17(2): 397, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30520924

RESUMO

Correction for 'A synthetic study toward the core structure of (-)-apicularen A' by Tapas R. Pradhan et al., Org. Biomol. Chem., 2018, 16, 8810-8818.

8.
Org Biomol Chem ; 16(45): 8810-8818, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30403225

RESUMO

A concise synthetic strategy towards the core structure of (-)-apicularen A has been described in an 11-step synthetic sequence from a known intermediate. The key steps include tandem isomerization followed by C-O and C-C bond-forming reactions and iodocyclization strategies for the synthesis of a bicyclic ether embedded in the macrolactone ring. The applied reagent-controlled Keck-Maruoka allylation, Lin Pu alkynylation and Ricket-Diels-Alder reactions were used to simplify the synthetic sequence of related natural products. An intramolecular Yamaguchi lactonization constructed the macrolactone core, while the attempt to install the C11 hydroxyl chiral centre either under catalytic hydrogenation conditions or oxidative conditions was not successful.

9.
Org Lett ; 20(21): 6910-6914, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30354147

RESUMO

A protocol for general diastereoselective tandem dihydroxylation followed by SN2 cyclization was developed for the convenient and efficient synthesis of cis- and trans-2,6-disubstituted tetrahydropyrans from ζ-mesyloxy α,ß-unsaturated esters. The application of this novel method was demonstrated through the concise formal synthesis of (+)-muconin, a nonclassical acetogenin, with sequential THP-THF ring formation.

10.
Org Lett ; 19(24): 6506-6509, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29189014

RESUMO

The first asymmetric convergent total synthesis of four isomers of proposed structures of cryptorigidifoliol K (1a, 1b, 1c, and 1d) has been achieved from commercially available starting materials. The key steps in this synthesis involve tandem isomerization followed by a C-O and C-C bond-forming reaction for the construction of trans-2,6-disubstituted dihydropyran, iodolactonization, isomerization of terminal alkene, and cross-metathesis reaction. The large discrepancies in the spectroscopic data (1H NMR) of synthetic cryptorigidifoliol K from the natural product suggest that the structure of the natural cryptorigidifoliol K requires revision.

11.
mSphere ; 2(4)2017.
Artigo em Inglês | MEDLINE | ID: mdl-28875178

RESUMO

Leishmania donovani is a protozoan parasite that causes visceral leishmaniasis. Increasing resistance and severe side effects of existing drugs have led to the need to identify new chemotherapeutic targets. Aminoacyl-tRNA synthetases (aaRSs) are ubiquitous and are required for protein synthesis. aaRSs are known drug targets for bacterial and fungal pathogens. Here, we have characterized and evaluated the essentiality of L. donovani lysyl-tRNA synthetase (LdLysRS). Two different coding sequences for lysyl-tRNA synthetases are annotated in the Leishmania genome database. LdLysRS-1 (LdBPK_150270.1), located on chromosome 15, is closer to apicomplexans and eukaryotes, whereas LdLysRS-2 (LdBPK_300130.1), present on chromosome 30, is closer to bacteria. In the present study, we have characterized LdLysRS-1. Recombinant LdLysRS-1 displayed aminoacylation activity, and the protein localized to the cytosol. The LdLysRS-1 heterozygous mutants had a restrictive growth phenotype and attenuated infectivity. LdLysRS-1 appears to be an essential gene, as a chromosomal knockout of LdLysRS-1 could be generated when the gene was provided on a rescuing plasmid. Cladosporin, a fungal secondary metabolite and a known inhibitor of LysRS, was more potent against promastigotes (50% inhibitory concentration [IC50], 4.19 µM) and intracellular amastigotes (IC50, 1.09 µM) than were isomers of cladosporin (3-epi-isocladosporin and isocladosporin). These compounds exhibited low toxicity to mammalian cells. The specificity of inhibition of parasite growth caused by these inhibitors was further assessed using LdLysRS-1 heterozygous mutant strains and rescue mutant promastigotes. These inhibitors inhibited the aminoacylation activity of recombinant LdLysRS. Our data provide a framework for the development of a new class of drugs against this parasite. IMPORTANCE Aminoacyl-tRNA synthetases are housekeeping enzymes essential for protein translation, providing charged tRNAs for the proper construction of peptide chains. These enzymes provide raw materials for protein translation and also ensure fidelity of translation. L. donovani is a protozoan parasite that causes visceral leishmaniasis. It is a continuously proliferating parasite that depends heavily on efficient protein translation. Lysyl-tRNA synthetase is one of the aaRSs which charges lysine to its cognate tRNA. Two different coding sequences for lysyl-tRNA synthetases (LdLysRS) are present in this parasite. LdLysRS-1 is closer to apicomplexans and eukaryotes, whereas LdLysRS-2 is closer to bacteria. Here, we have characterized LdLysRS-1 of L. donovani. LdLysRS-1 appears to be an essential gene, as the chromosomal null mutants did not survive. The heterozygous mutants showed slower growth kinetics and exhibited attenuated virulence. This study also provides a platform to explore LdLysRS-1 as a potential drug target.

12.
Org Lett ; 19(16): 4167-4170, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28762745

RESUMO

The first asymmetric total synthesis of two possible diastereomers (4S,5R)-4,8-dihydroxy-3,4-dihydrovernoniyne 5 and (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a is accomplished. Salient features of the synthesis involve Cadiot-Chodkiewicz coupling and Sonogashira cross-coupling of terminal acetylenes. Detailed comparison of the 1H and 13C NMR data and specific rotation with that of the natural product led to the revision of the absolute stereochemistry of the natural product as (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a.

13.
Org Lett ; 19(8): 2074-2077, 2017 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-28383900

RESUMO

A highly regioselective gold(I)-catalyzed 6-endo-dig cyclization of 2,2-dimethyl-5-(alkynyl)-4H-benzo[d][1,3]dioxin-4-ones for the synthesis of 8-hydroxy-3-substituted isocoumarins is described. Key features of the reaction include the broad substrate scope, scalability, and tolerance for protecting groups. The synthetic utility of this novel method is demonstrated by the first total synthesis of exserolide F, an isocoumarin-containing polyol natural product.

14.
J Org Chem ; 82(9): 4561-4568, 2017 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-28388091

RESUMO

The first asymmetric total synthesis of the putative structure of diplopyrone was achieved in 17 linear steps starting from cis-1,4-butene-diol. The synthetic route features iodine-catalyzed tandem isomerization followed by C-O and C-C bond formation reaction strategy developed by our own group to construct the trans-2,6-disubstituted dihydropyran ring, asymmetric α-aminoxylation reaction, and Still-Gennari (Z)-selective olefination reactions. Careful comparison of 1H and 13C NMR spectroscopic data as well as investigation of the UV and circular dichroism spectrum in trifluoroethanol for compound 2 suggest that the putative structure for diplopyrone {6-[(1S)-1-hydroxyethyl]-2,4a(S),6(R),8a(S)-tetrahydropyran[3,2-b]pyran-2-one} requires revision.

15.
Org Biomol Chem ; 15(8): 1863-1871, 2017 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-28165093

RESUMO

The first asymmetric total synthesis of a 16-membered macrolide, aspergillide D, is described. The chiral centers of the acid are derived from d-ribose and the alcohol subunit from 1,8-octane diol through Sharpless kinetic resolution, respectively. The other key reactions include Yamaguchi esterification, ring-closing metathesis reaction, and Shiina macrolactonization to construct the fully functionalized macrocycle.


Assuntos
Macrolídeos/síntese química , Cinética , Macrolídeos/química , Estrutura Molecular , Ribose/química
16.
J Org Chem ; 82(2): 1053-1063, 2017 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-27992722

RESUMO

The first total syntheses of two possible diastereomers of gliomasolide E, a 14-membered macrolides isolated from the marine sponge Phakellia fusca Thiele, which was collected from the South China Sea, is reported. Highlights of the synthesis include macrolactonization through intramolecular Horner-Wadsworth-Emmons olefination, Yamaguchi-Hirao alkynylation, and base-induced elimination reactions for propargyl alcohol synthesis as the key reactions. Detailed comparison of their 1H and 13C NMR (1D and 2D NMR data) and specific rotation with those of the natural product revealed that the absolute stereochemistry of gliomasolide E should be (2E,5R,7R,9R,13R).

17.
J Nat Prod ; 79(11): 2788-2796, 2016 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-27933895

RESUMO

A unified and efficient synthetic route for both tetraketide (1) and cryptorigidifoliol I (2) has been devised successfully from commercially available starting materials in 11 and 17 steps, with 16% and 11% overall yields, respectively. Highlights of the syntheses involved sequential Lewis acid-catalyzed highly regio- and diastereoselective allylations and intramolecular Mitsunobu lactonization.


Assuntos
Cicloexanonas/síntese química , Dissacarídeos/síntese química , Policetídeos/síntese química , Catálise , Cicloexanonas/química , Dissacarídeos/química , Magnoliopsida/química , Estrutura Molecular , Policetídeos/química , Estereoisomerismo
18.
Org Biomol Chem ; 14(26): 6212-24, 2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27193332

RESUMO

Total synthesis of herboxidiene/GEX1A/TAN-1609 has been accomplished in the 22 longest linear sequences starting from 2-butyne-1,4-diol following our recently developed gold-catalyzed Hosomi-Sakurai type of reaction on lactols with allyltrimethyl silane and Stille cross coupling to assemble the advanced fragment. The synthesis of the C10-C19 fragment was accomplished by means of Sharpless epoxidation and asymmetric alkylation reactions starting from (R)-methyl lactate.


Assuntos
Álcoois Graxos/síntese química , Ouro/química , Piranos/síntese química , Catálise , Álcoois Graxos/química , Estrutura Molecular , Piranos/química
19.
Int J Nanomedicine ; 10: 6411-23, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26491299

RESUMO

A number of diseases can result from abnormal gene expression. One of the approaches for treating such diseases is gene therapy to inhibit expression of a particular gene in a specific cell population by RNA interference. Use of efficient delivery vehicles increases the safety and success of gene therapy. Here we report the development of functionalized biocompatible fluorescent nanoparticles from para amino benzoic acid nanoparticles for efficient delivery of short interfering RNA (siRNA). These nanoparticles were non-toxic and did not interfere with progression of the cell cycle. The intrinsic fluorescent nature of these nanoparticles allows easy tracking and an opportunity for diagnostic applications. Human Bcl-2 siRNA was complexed with these nanoparticles to inhibit expression in cells at both the transcriptional and translational levels. Our findings indicated high gene transfection efficiency. These biocompatible nanoparticles allow targeted delivery of siRNA, providing an efficient vehicle for gene delivery.


Assuntos
Benzoatos/química , Materiais Biocompatíveis/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , Apoptose , Materiais Biocompatíveis/química , Western Blotting , Ciclo Celular , Proliferação de Células , Endocitose , Citometria de Fluxo , Inativação Gênica , Terapia Genética , Células HeLa , Humanos , Técnicas Imunoenzimáticas , Nanopartículas/química , Neoplasias/patologia , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
20.
J Org Chem ; 80(11): 5517-31, 2015 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-25941839

RESUMO

The Au(I)-catalyzed regioselective hydration of γ-acetoxy-α,ß-acetylinic ester by the assistance of a neighboring carbonyl group has been developed. Varieties of simple primary, secondary, and tertiary γ-acetoxy-α,ß-acetylinic esters, even those bearing sensitive functional group in the remote reaction sites, are selectively hydrated to the corresponding ß-keto esters. The reaction tolerates a wide variety of other carboxylates, such as benzoates, propionates, acrylates, and pivalates, including chiral carboxylates with retention of the configuration. The broad substrate scope, including the derivatization of complex natural products and neutral and open air conditions, makes this atom economical approach very practical. (18)O labeling experiments disclose that the oxygen transposition occurs from the carboxylate group to the triple bond, not from water.

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