Mitsuru Kitamura

Synthesis of (-)-sordarin.

The first total synthesis of (-)-sordarin (1) was accomplished exploiting the following key reactions: (i) Ag(I)-catalyzed oxidative radical cyclization of a cyclopropanol derivative leading to a bicyclo[5.3.0]decan-3-one skeleton; (ii) Pd(0)-catalyzed intramolecular allylation reaction resulting in the entire strained bicyclo[2.2.1]heptan-2-one framework of sordaricin (2); (iii) selective dihydroxylation of terminal alkenes by the combined use of OsO(4) and PhB(OH)(2); and (iv) beta(1,2-cis)-selective glycosidation via a 1,3-anchimeric assistance from a 4-methoxybenzoyl group.

Pd(OAc)2-Catalyzed Macrocyclization of 1,2-Diazonaphthoquinones with Cyclic Ethers

Pd(OAc)2 was found to be an efficient catalyst for the macrocyclization of 1,2-diazonaphthoquinones and cyclic ethers. This transformation serves as an efficient method for the synthesis of protected 1,2-naphthalenediols.

TOTALSYNTHESE VON PRADIMICINON, DEM GEMEINSAMEN AGLYCON DER PRADIMICIN/ BENANOMICIN-ANTIBIOTIKA

Eine Benzo[a]naphthacenchinoneinheit, eine Aminosaure und ein Disaccharid sind die Grundbausteine der Pradimicin/Benanomicin-Antibiotika 1 (R1 = Disaccharid), einer Naturstoffklasse mit betrachtlicher antimykotischer und Anti-HIV-Wirkung. Fur das gemeinsame Aglycon dieser Verbindungen, Pradimicinon (Benanomicinon) 1 (R1 = H), gelang jetzt die erste Totalsynthese, die auf der Chiralitatsubertragung bei der Pinakolcyclisierung von 2,2′-Biaryldicarbaldehyden beruht.

Identification of Compounds with Potential Antibacterial Activity against Mycobacterium through Structure-Based Drug Screening

To identify novel antibiotics against Mycobacterium tuberculosis, we performed a hierarchical structure-based drug screening (SBDS) targeting the enoyl-acyl carrier protein reductase (InhA) with a compound library of 154,118 chemicals. We then evaluated whether the candidate hit compounds exhibited inhibitory effects on the growth of two model mycobacterial strains: Mycobacterium smegmatis and Mycobacterium vanbaalenii. Two compounds (KE3 and KE4) showed potent inhibitory effects against both model mycobacterial strains. In addition, we rescreened KE4 analogs, which were identified from a compound library of 461,383 chemicals through fingerprint analysis and genetic algorithm-based docking simulations. All of the KE4 analogs (KES1-KES5) exhibited inhibitory effects on the growth of M. smegmatis and/or M. vanbaalenii. Based on the predicted binding modes, we probed the structure-activity relationships of KE4 and its analogs and found a correlative relationship between the IC50 values and the interaction residues/LogP values. The most potent inhibitor, compound KES4, strongly and stably inhibited the long-term growth of the model bacteria and showed higher inhibitory effects (IC50 = 4.8 μM) than isoniazid (IC50 = 5.4 μM), which is a first-line drug for tuberculosis therapy. Moreover, compound KES4 did not exhibit any toxic effects that impede cell growth in several mammalian cell lines and enterobacteria. The structural and experimental information of these novel chemical compounds will likely be useful for the development of new anti-TB drugs. Furthermore, the methodology that was used for the identification of the effective chemical compound is also likely to be effective in the SBDS of other candidate medicinal drugs.

Semi-pinacol strategy for constructing B-ring of pradimicin–benanomicin antibiotics

Abstract Semi-pinacol cyclization of compound 8 , having an acetal and an aldehyde substituent, was achieved by employing SmI2 and BF3·OEt2, leading to the highly stereoselective formation of cyclized product 9 . The vicinal diol in 9 is discriminated, so as to allow selective glycosylation for the synthesis of pradimicin–benanomicin antibiotics.

Discovery of InhA inhibitors with anti-mycobacterial activity through a matched molecular pair approach.

The Mycobacterium tuberculosis (M. tuberculosis) enoyl-acyl carrier protein reductase (mtInhA) is an attractive enzyme and a thoroughly studied target for tuberculosis therapy. In this study, to identify novel structure-activity relationships (SARs) of mtInhA inhibitors, a series of diphenyl ether derivatives were designed based on the matched molecular pair (MMP) method, and the binding energies of these compounds were subsequently estimated by in silico structure-based drug screening (SBDS) to provide more useful data. Consequently, the 10 unique candidate compounds (KEM1-KEM10) were identified and assessed for the inhibition of mtInhA enzymatic activity, in vitro antibiotic effects against model mycobacteria and toxicity level on both intestinal bacteria and mammalian cells. Among the compounds tested, phenyl group (KEM4) and 2-fluorobenzyl group (KEM7) substitutions produced preferable inhibitory effects on mtInhA enzymatic activity relative to those provided by a furyl group (KES4: base compound) at the terminal of the compound, and KEM7 inhibited the growth of the mycobacteria strain with a lower IC50 value. Moreover, most of the candidate compounds exhibited neither inhibition of the growth of enterobacteria nor toxic effects on mammalian cells, though KEM10 exhibited toxicity against cultured MDCK cells. The structural and experimental information concerning these mtInhA inhibitors identified through MMP-based in silico screening will likely contribute to the lead optimisation of novel antibiotics for M. tuberculosis.

Synthesis of 5-Phenyl 2-Functionalized Pyrroles by Amino Heck and Tandem Amino Heck Carbonylation Reactions

2-Methyl-, 2-(methoxycarbonyl)methyl-, and 2,2-[(ethoxycarbonyl)(methoxycarbonyl)]methyl-5-phenylpyrroles are prepared from the corresponding 3-butynyl and 4-(methoxycarbonyl)-3-butynyl phenyl ketone O-pentafluorobenzoyl oximes by amino Heck cyclization and tandem amino Heck carbonylation, respectively.

Intramolecular Substitution Reaction of Alkylidene-Lithium Carbenoids: Regioselective Synthesis of Indenes

Intramolecular substitution reaction of geminal dibromo alkenes proceeds to afford indenes, dihydronaphthalenes, dihydrofurans, and dihydropyran via in situ generated lithium alkylidene carbenoids, which have a carbon or oxygen nucleophilic moiety. This reaction provides a regioselective method for the preparation of polysubstituted indenes.

Divergent behavior of cobalt- complexed enynehaving a leaving group

Abstract Behavior of the compounds 2 with a Co-complexed enyne moiety was examined. When R in 2was a prim-alkyl group, the cyclization to give a cyclobutane proceeded in high yield, whereas, when R was bulkier, an interesting substitution involving a 1,2-shift was observed.

Rh-Catalyzed Cyclization of 3-Aryloxycarbonyldiazonaphthoquinones for the Synthesis of β-Phenylnaphthalene Lactones and Formal Synthesis of Pradimicinone.

In this study, we developed a novel method for the synthesis of β-phenylnaphthalene lactones. The diazo-transfer reactions of 2-azido-1,3-dimethylimidazolinium chlorides to 3-aryloxycarbonyl-1-naphthols proceeded smoothly to give corresponding 3-aryloxycarbonyldiazonaphthoquinones in high yields. These intermediates were further transformed to β-phenylnaphthalene lactones through a Rh-catalyzed intramolecular formal C-H insertion reaction. This method of lactone formation was efficiently applied to the formal total synthesis of pradimicinone.