Synthesis of chloroquinocin, a pyranonaphthoquinone antibiotic against Gram-positive bacteria

Chloroquinocin 1 is an antimicrobial agent against Gram-positive bacteria, including MRSA (methicillin-resistant Staphylococcus aureus). A successful synthesis of 1 was attained through a unique chlorination of the corresponding naphthoquinone derivative 12 as a key step.     

Synthesis of triazole analogues of the nanaomycin antibiotics using ‘click chemistry’

A series of triazole analogues of the nanaomycin family of antibiotics have been prepared using a ‘click’ dipolar cycloaddition of a naphthalene azide to various alkynes, followed by oxidation to the desired pyranonaphthoquinones.     

Addition of 2-tert-butyldimethylsilyloxythiophene to activated quinones: an approach to thia analogues of kalafungin

The uncatalyzed reaction of 2-tert-butyldimethylsilyloxythiophene 2 with 1,4-quinones bearing either an electron withdrawing acetyl or a carbomethoxy group at C-2, was investigated. No reaction was observed using 1,4-quinones 8 and 9 bearing an ester group at C-2 whereas use of 1,4-quinones 10 and 11 bearing an acetyl group at C-2 only provided low yields of the silyloxythiophenes 15 and 16 resulting from electrophilic substitution of the silyloxythiophene by the 1,4-quinone. Use of the Lewis acids InCl₃, Cu(OTf)₂ and BF₃·Et₂O were investigated in an effort to improve the yield of the desired annulation reaction. BF₃·Et₂O proved to be the optimum catalyst for the synthesis of thiolactone naphthofuran adducts 14 and 18 from 1,4-naphthoquinones 9 and 11, respectively. Reaction of 2-tert-butyldimethylsilyloxythiophene 2 with 1,4-benzoquinones 8 and 10 bearing a carbomethoxy or an acetyl group at C-2, respectively, afforded thiolactone benzofuran adducts 13 and 17, respectively, catalyzed by either InCl₃ or Cu(OTf)₂. Addition of 2-tert-butyldimethylsilyloxythiophene 2 to 3-acetyl-5-methoxy-1,4-naphthoquinone 12 afforded adduct 19 that underwent oxidative rearrangement to thiolactone pyranonaphthoquinone 20 using ceric ammonium nitrate in acetonitrile, thus providing a novel approach for the synthesis of a thia analogue of the pyranonaphthoquinone antibiotic kalafungin.     

An approach to an enantioselective synthesis of crisamicin A via a novel double Hauser-Kraus annulation strategy

A double Hauser-Kraus annulation between biscyanophthalide 4 and the d-mannose derived enone 39 provides access to an advanced intermediate 54 that is an excellent scaffold to effect an enantioselective total synthesis of crisamicin A 1.     

First total synthesis of parvistone C and its C8-epimer

Diastereoselective first total synthesis of parvistone C 1 and C8-epimer 1a are described. The key features of our synthesis include Sharpless asymmetric dihydroxylation, stereoselective aryl Grignard reactions, Still–Gennari olefination, and intramolecular cyclization.     

Synthesis of (±)-pyranonaphthoquinone derivatives, a Cdc25A phosphatase inhibitor

The novel pyranonaphthoquinone 2, carrying Cdc25A phosphatase inhibitory activity, has been successfully synthesized through tricyclic compound 16, which was obtained from 15 by using the intramolecular Michael addition. The precursor 9 was derived from 5-bromoveratraldehyde.     

Synthesis and structure of 8-hydroxy-6-methoxy-3,7-dimethylisochromane and its analogues

The title compound 1 was obtained by the reaction of alcohol 18 and triethyl orthoformate catalyzed by aluminum chloride followed by catalytic hydrogenation in good yield. Similarly, compounds 1 and 3 were obtained by intramolecular cyclization of MOM ether 19 with titanium(IV) chloride in moderate yields and isochromanes 1, 3, 26 and 27 by intramolecular cyclization of ether 20 with titanium(IV) chloride in high yields. The structures of compounds 1-3 were elucidated by analysis of spectroscopic data and chemical reactions. The mechanisms on the formation of 1 and 3 are discussed.     

Synthesis of novel pyranoquinones using an acyl radical cyclization strategy

The thiol-catalysed cyclization of acyl radicals generated directly from benzaldehyde precursors has been investigated. Hindered β-benzyloxyacrylates cyclize efficiently providing a tin-free radical cyclization approach to the serine/threonine kinase AKT inhibitor frenolicin B, whilst γ-aryloxy crotonates give good yields of benzopyran-4-ones. This method is applied to the synthesis of a novel tetracyclic analogue of the pyranonaphthoquinone antibiotics.     

InBr3-catalyzed intramolecular cyclization of 2-alkynylanilines leading to polysubstituted indole and its application to one-pot synthesis of an amino acid precursor

We describe InBr₃-catalyzed cyclization of 2-alkynylaniline derivatives having a variety of functional groups producing polysubstituted indoles. This methodology could be applied to the one-pot synthesis of an amino acid precursor by the addition of a catalytic amount of the indium salt, an imine, and TMSCl.     

Synthesis of novel mercury heterocycles

Ortho-mercurated 4-aryloxymethylcoumarins and 1-azacoumarins have been found to undergo smooth intramolecular metalation in refluxing xylene in the presence of activated neutral alumina and anhydrous potassium carbonate. This is the first report on the synthesis of heterocycles not possessing a metal heteroatom linkage.     

Synthesis of tri- and tetrasubstituted imidazoles

A reliable sequence that allows for regiospecific incorporation of four alkyl substituents on an imidazole ring has been developed. This procedure involves the addition of a substituted amino alcohol to a thioamide and subsequent oxidation with PDC. Unlike many imidazole syntheses, acid-sensitive functionality is tolerated given the mild conditions.     

Traceless Approach for the Synthesis of 3,5-Disubstituted Thiohydantoins on Functionalized Ionic-Liquid Support

A traceless approach for the synthesis of 3,5-disubstituted thiohydantoins on a novel functionalized ionic-liquid support, 5, is described. Acylation of benzylamine functionalized ionic-liquid support with amino acids yielded ionic-liquid-supported amino acids, which reacted with isothiocyanates to afford ionic-liquid-supported thioureas. Following intramolecular cyclization cleavage from the ionic-liquid support by trifluoroacetic acid (TFA), the desired 3,5-disubstituted thiohydantoins were obtained in good yields and purities. The efficiency of this ionic-liquid-phase strategy facilitated isolation and analysis of intermediates and removal of excess reagents and by-products during the reaction process.     

Synthesis of N-benzothiazol-2-yl-amides by a copper-catalyzed intramolecular cyclization process

Employing N-(4,5-dihydrooxazol-2-yl)benzamide as novel and efficient ligand, the copper-catalyzed intramolecular cyclization of various substituted 1-acyl-3-(2-bromophenyl)thioureas could be successfully carried out under mild conditions. A variety of N-benzothiazol-2-yl-amides were synthesized in good to excellent yields.     

Synthesis of mono N-trifluoroethylated cyclic dipeptides

Trifluoroethylated N-termini in linear dipeptides l-TyrXOR [X = Gly, d-Ala, l-Leu, l-Phe, and l-Glu; R = H, Me, Et] exhibit sufficient nucleophilicity to give piperazine-2,5-dione ring formation through intramolecular cyclization reaction in acidic aqueous solutions. The reactions occur in high yield and with absolute configuration retention.     

Synthesis of cis-2-aryl-3-pyrrolidine carboxylic esters via diastereoselective cyclization of γ-imino esters using a TiCl4/Et3N reagent system

Facile synthesis of cis-2-aryl-3-pyrrolidine carboxylates from readily accessible γ-imino esters by intramolecular cyclization mediated by a TiCl₄/Et₃N reagent system is described.     

A Journey to the Total Synthesis of Daptomycin

Daptomycin, the first antibiotic of its class, provides a new structural motif for the development of new antibiotics. Recently, we have completed the total synthesis of daptomycin. The development of the successful synthetic strategy is described here, including the application of serine/threonine ligation mediated peptide cyclization to the daptomycin macrocyclization.     

Synthesis of Highly Substituted N-Hydroxy Piperidine via Intramolecular Reductive Cyclization of 1-Keto-5-ketoxime

Abstract

Diasteroselective synthesis of highly substituted N-hydroxypiperidine was achieved by an intramolecular reductive cyclization of monoxime (2) of the 1,5-diketone (1), generated from 2-(cyclohexylthio)-1-phenylethanone and arylaldehyde, using NaBH₃CN. The major product N-hydroxypiperidine (3) has been found to be racemate of a single diastereomer.     

Synthesis of latonduine derivatives via intramolecular Heck reaction

The synthesis of indole ring-fused benzazepinone series as latonduine derivatives has been developed via an intramolecular Heck reaction. The scope has been enlarged not only to indole moiety but also to pyrrolo and benzo[b]thiophene nuclei. Several derivatives prepared have been evaluated in vitro for their antiproliferative activities on breast cancer cell lines. Some of them showed promising cytotoxic activities.     

新型多取代2,7-萘二甲酸二乙酯的合成

以4,6-二甲基-2-甲氧基-1,3-苯二甲酸二乙酯为原料,经Micheal加成、环化、溴化、消除等5步反应,合成新型的多取代2,7-萘二甲酸二乙酯.该合成路线步骤少,收率高,反应条件温和.产物中的4个新化合物的结构均经元素分析、核磁共振、红外光谱和质谱确证.     

Synthesis of cyclic dimeric methyl morpholinoside—a common synthetic precursor to cyclic dinucleotide analogs

An eight-step synthesis of cyclic dimeric methyl morpholinoside (c-di-MM), a common synthetic precursor to a number of cyclic dinucleotide analogs is reported. The synthesis of c-di-MM proceeds through a morpholine monomer prepared from readily available inexpensive starting materials and culminates with a key macrolactamization reaction to provide the macrocycle in 15% overall yield.