HETEROCYCLES

■ Contents

■ Synthesis of Pyrimidines and Condensed Pyrimidines through Reactions of Nitriles with o-Aminocarbonyl Substrates under Acidic Conditions

Chamanlal Shishoo, Subramaniam Ananthan, Vishweshwar Bhadti, Giliyar Ullas, Mahesh Chhabria, Jitender Bariwal, Laxmi Venkatesh Gurachar Nargund, and Kishor Jain*

*Department of Pharmaceutical Chemistry, Sinhgad College of Pharmacy, S No 44/1, Vadgaon (BK), Sinhgad Road, Pune, 411 041, India

Abstract

The single pot facile reaction of a host of nitriles with a variety of o-aminocarbonyl substrates of benzene, thiophene, benzothiophene, pyridothiophene, furan, pyrrole, pyridopyrazole, naphthopyran etc., to form corresponding condensed pyrimidines functionalized at 2- and 4-positions has been reviewed and investigation into the reaction mechanisms and isolation of intermediates have been discussed. A new modification of this reaction under microwave condition has also been discussed. Further, a few applications of this novel reaction for the synthesis of API’s are also presented.

■ Recent Advances in the Syntheses of Biologically Active Natural Products Using Biocatalyst

Hiroyuki Akita*

*School of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan

Abstract

This review summarizes the chemoenzymatic synthesis of biologically active natural products based on a combination of chemical diastereoselectivity and enzymatic enantioselectivity using lipase. Diastereoselective synthesis of (±)-(2,3)-syn-2-methyl-3-hydroxy ester I or (±)-(2,3)-syn-3-methyl-2-hydroxy ester III was achieved based on diastereoselective reduction of (±)-2-methyl-3-keto ester IV or the reaction of (±)-trans-epoxybutanoate V and carbon-nucleophile, respectively. These racemic alcohols were subjected to enzymatic resolution to afford the corresponding enantiomers. Each enantiomerically pure compound was converted to biologically active natural products such as oudemansins, chuangxinmycin, asperlin, indolmycin, cystothiazoles, melithiazols and myxothiazols possessing antifungal and cytotoxic activities, inhibition of NADH oxidation, etc.

■ Synthesis and Structure of New Methylene-Bridged Hexopyranosyl Nucleoside (BHNA)

Chuanzheng Zhou, Oleksandr Plashkevych, Yi Liu, Naresh Badgujar, and Jyoti Chattopadhyaya*

*Department of Bioorganic Chemistry, Biomedical Center, Uppsala University, Box 581, S-75123 Uppsala, Sweden

Abstract

A new member of hexopyranosyl nucleoside family, methylene-bridged hexopyranosyl nucleoside (BHNA), has been synthesized through generation of carbon radical at C6’ in [6’S-Me, 7’S-Me]-carba-LNA T nucleoside, followed by rearrangement to C4’ radical which was quenched by hydrogen atom to give BHNA. The stereoelectronic requirement for this unusual radical rearrangement has been elucidated by chemical model building and ab intio calculations to show that the coplanarity of the single electron occupied p-orbital at C6’ with σ*O4’-C4’ plays an important role for the rearrangement reaction to take place. The solution structure of BHNA has also been studied using NMR as well as by ab initio calculations. The new six-membered pyranosyl ring in BHNA, unlike other known hexopyranosyl nucleosides, adopts a twist conformation, with base moiety occupying the axial position while 3’-hydroxymethyl and 4’-hydroxyl occupying the equatorial position.

■ New Thiazolidinone and Triazinethione Conjugates Derived from Amino-β-lactams

Katarina Radolović, Ivan Habuš,* and Bogdan Kralj

*Ruđer Bošković Institute, Bijenička c. 54, P.O.B. 180, HR-10002 Zagreb, Croatia

Abstract

Thioureas 3a-s, generated from amino-β-lactams 1a-c, were used to achieve two different cyclizations: (i) condensation with ethyl bromoacetate which resulted in the formation of a variety of iminothiazolidinones 4a/a'-n, and (ii) condensation with aqueous formaldehyde and methylamine which resulted in the formation of triazinethiones 5a-g. The condensation of thioureas 3b-f, 3h and 3m-s (R1 = cyclohexyl, exo-norbornyl, aryl, R2 = β-lactam) with ethyl bromoacetate proceeded with high regioselectivity leading exclusively to the formation of a single regioisomer A of iminothiazolidinones 4b-n. However, the cyclization of thiourea 3a (R1 = n-hexyl, R2= β-lactam) with ethyl bromoacetate led to the formation of a mixture of two regioisomers A (minor) and B (major) of the iminothiazolidinones 4a/a' in the ratio 23:77. Furthermore, condensation of thioureas 3d, 3g, 3i-l and 3n with aqueous formaldehyde and methylamine, furnished triazinethiones 5a-g.

■ Synthesis and Heterocyclizations of 3,4-Dihydroquinazolin-2-yl Guanidine in the Search of New Anticancer Agents

Anton V. Dolzhenko, Mi Chelle Foo, Bee Jen Tan, Anna V. Dolzhenko, Gigi Ngar Chee Chiu, and Wai Keung Chui*

*Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore

Abstract

The cyclocondensations of 3,4-dihydroquinazolin-2-yl guanidine with a variety of electrophilic reagents viz. aldehydes, ketones, triethyl orthoformate, diethyl ethoxymethylenemalonate, carbon disulfide and trichloroacetonitrile were found to afford 1,3,5-triazino[2,1-b]quinazolines. However, some unexpected reactions were also observed. The structural properties such as tautomerism and hinderance to conformational rotation were also investigated. The results of biological testing suggested that the 1,3,5-triazino[2,1-b]quinazoline nucleus could be a new promising scaffold for the development of potential anticancer agents.

■ Reaction of 1-Azabicyclo[1.1.0]butane with Activated Amides

Kazuhiko Hayashi,* Eiko Kujime, Hajime Katayama, Shigeki Sano, and Yoshimitsu Nagao

*College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyama-ku, Nagoya 463-8521, Japan

Abstract

1-Azabicyclo[1.1.0]butane (ABB, 1) reacted with 3-acyl-1,3-thiazolidine-2-thiones (7,11a—m) in the presence of a catalytic amount of Mg(OTf)2 to give the corresponding 2-(1-acylazetidin-3-yl)thio-1,3-thiazolines (8,12a—m). It was hypothesized that this reaction is primarily influenced by a steric bulkiness of acyl groups in 3-acyl-1,3-thiazolidine-2-thiones. Resulting compounds (8, 12k) were readily converted to thiols (13,14), and azetidine-3-thiol hydrochloride (15), which is the key intermediate of 1-(1,3-thiazolin-2-yl)azetidine-3-thiol hydrochloride (4) useful for the preparation of a new oral 1β-methylcarbapenem antibiotic L-084, was obtained quantitatively by hydrolysis of 14.

■ Synthesis and Antimicrobial Evaluation of New Pyrazole, Thiophene, Thiazole and 1,3,4-Thiadiazole Derivatives Incorporating Pyrimidine Ring

Ahmad M. Farag,* Nabila A. Kheder, and Yahia N. Mabkhot

*Department of Chemistry, Faculty of Science, University of Cairo, Giza 12613, Egypt

Abstract

The utility of 3-oxo-N-(pyrimid-2-yl)butanamide (1) in the synthesis of some new pyrazole, thiophene, thiazole, and 1,3,4-thiadiazole derivatives is reported. Antimicrobial evaluation of some selected examples from the synthesized products was carried out and showed moderate activity.

■ Synthesis, Photophysical and Electrochemical Properties of a D-σ-A Ensemble Derived from Porphyrazine and Tetrathiafulvalene

Ruibin Hou, Han Qiu, Tie Chen, and Bingzhu Yin*

*Key Laboratory of Organism Functional Factor of Changbai Mountain, Ministry of Education, Yanbian University, 977, Park Road, Yanji City, Jilin Prov. 133002, China

Abstract

Cis/trans 1,2-dicyanoethylenes bearing tetrathiafulvalene units linked by ethylenedithio spacer were prepared. The cis isomer was converted to eight tetrathiafulvalene unit substituted magnesium porphyrazine upon a metal-templated cyclotetramerization with magnesium propoxide in propanol. The dicyanoethylenes and target compound were characterized by EA, NMR, and MALDI-TOF mass and photophysical and Electrochemical properties were discussed.

■ Chemical Constituents from the Fruiting Bodies of the Basidiomycete Albatrellus Sp.

An-Ling Zhang, Tian Xu, Jin-Ming Gao,* Ming-Sheng Bai, Gao Zhang, Han-Wei Liu, Shi-Qing Li, and Yasuo Konishi

*College of Science, Northwest A ＆ F University, Yangling, Shaanxi 712100, China

Abstract

A new prenylated orcinol derivative, namely albatrellutin [3'R-(7',11'-dimethylnona-6',10'-dienyl)-3',7-dimethyl-chroman-1-ol] (1), together with eight known compounds was isolated from ethyl acetate extract of the fruiting bodies of the basidiomycete Albatrellus sp. The structure of this new compound was completely elucidated using a combination of 2D NMR techniques (COSY, NOESY, HMQC and HMBC) and HR-EI-MS analyses. The known compounds were elucidated by comparison of their spectroscopic and physical data with those reported in the literatures.

■ Synthesis of Some Novel Bis(pyrazole), Bis(pyridine) and Bis(pyrazolo[5,1-c]-1,2,4-triazine Derivatives

Nabila A. Kheder*

*Department of Chemistry, Faculty of Science, University of Cairo, Giza 12613, Egypt

Abstract

Treatment of N,N'-(ethane-1,2-diyl)bis(cyanoacetamide) (1) with hydrazonoyl chlorides 2a,b afforded bis(aminopyrazoles) 5a,b. Heating of compound 1 with arylmethylenepropanedinitrile 9a-c afforded bis(pyridine) derivatives 13a-c. Also, compound 1 coupled smoothly with the arenediazonium salt generated from 3-chloroaniline or 5-amino-4-methyl-3-phenylpyrazole (16) to afford the corresponding hydrazones 15 or bis(pyrazolo[5,1-c]-1,2,4-triazine-3-carboxamide) 19. Refluxing of compound 1 with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in xylene afforded bis(2-cyano-3-(dimethylamino)acrylamide) (20) which reacted with hydrazine hydrate to afford the novel bis(cyanoopyrazole) 23.

■ Relative Stability of Cryptolepinone and Hydroxycryptolepine

Masahiro Kataoka* and Tsuguo Sato

*Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

The relative stability between cryptolepinone and 11-hydroxycryptolepine in solvents has been investigated by use of semiempirical molecular orbital and hybrid-density functional methods. The results have predicted that only cryptolepinone exists in all solvents examined (pyridine, acetone, MeOH, MeCN and DMSO), disagreeing with the experimental findings in which in MeOH and MeCN both cryptolepinone and 11-hydroxycryptolep are present. This disagreement suggests that MeOH and MeCN solutions include chemical species other than 11-hydroxycryptolepin.

■ Antimalarial Activity of Cassiarin A from the Leaves of Cassia siamea

Wiwied Ekasari,* Aty Widyawaruyanti, Noor Cholies Zaini, Din Syafruddin, Toshio Honda, and Hiroshi Morita

*Departement of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Airlangga University, Jl. Dharmawangsa Dalam Selatan, Surabaya 60286, Indonesia

Abstract

The extracts and cassiarin A from the leaves of Cassia siamea showed promising antimalarial activities. The ethanol and chloroform extracts, alkaloid fraction, cassiarin A, and chloroquine as a positive control exhibited the inhibition against Plasmodium falciparum (IC50: 7.06, 2.41, 0.24, 0.005, and 0.006 μg/mL, respectively). The in vivo antimalarial activity was assessed using the 4-day suppressive test procedure. The ethanol, chloroform extracts, and alkaloid fraction were found to give an ED50 34.7, 19.59, and 0.47 mg/kg, respectively (p.o.). The ED50 values of cassiarin A and chloroquine were 0.17 and 0.21 mg/kg, respectively (i.p.). The result showed that cassiarin A deserved further investigation toward development of a promising antimalarial drug.

■ Effective Procedure for the Oxidative Cleavage of Olefins by OsO4-NaIO4

Hong Woo Lee,* Sung Kwon Kang, Choong Leol Yoo, and Seung Uk Lee

*New Drug Development Laboratories, Chemical Research Group, Chong Kun Dang Research Institute, Chonan P.O. Box 74, Chonan, 330-831, Korea

Abstract

Oxidative cleavage of olefins by OsO4-NaIO4 sometimes suffers from low yields due to the formation of side products. It is reported that the addition of pyrimidine can suppress the side reactions and dramatically improve the yield of this classic reaction.