Synthesis of multisulfur-containing substituted dibenzothiophenes

New substituted dibenzothiophenes have been prepared and characterized. Selective functionalizations utilized substitutions of lithiodibenzothiophenes available from established methodology. New dibenzothiophenes prepared include 2-(bromomethyl)dibenzothiophene (5) , 2-(thiomethyl)dibenzothiophene (6) , 2-S-phenylthiomethyldibenzothiophene (24) , 2-S-(2′-dibenzothiophenylmethyl)thiomethyldibenzothiophene (25) , 2-S-methyldibenzothiophene (30) , 2-S-(p-bromophenyl)dibenzothiophene (31) , and 2-S-benzyldibenzothiophene (33). Dibenzothiophenes prepared from 4-lithiodibenzothiophene include 4-(bromomethyl)dibenzothiophene (13) , 4-(thiomethyl)dibenzothiophene (14) , 4-S-(4′-dibenzothiophenylmethyl)thiomethyldibenzothiophene (26) , 4-S-(p-tolyl)dibenzothiophene (34) , 4-S-methyldibenzothiophene (35) , 4-S-benzyldibenzothiophene (37) , and 4-S-(p-bromophenyl)dibenzothiophene (36). Similarly new 2,8-disubstituted dibenzothiophenes prepared include 2,8-bis(thiomethyl)dibenzothiophene (19) , 2,8-bis(S-benzyl)dibenzothiophene (27) , 2,8-bis(S-p-tolyl)dibenzothiophene (28) and 2,8-bis(S-methyl)dibenzothiophene (29). The cmr chemical shift data for these dibenzothiophenes are also included.     

Glyconothio-O-lactones. Part I. Preparation and reactions with nucleophiles

Furanoid and pyranoid glyconothio-O-lactones were prepared by photolysis of S-phenacyl thioglycosides or by thermolysis of S-glycosyl thiosulfinates, which gave better results than the thionation of glyconolactones with Lawesson's reagent. Thermolysis of the thiosulfinates obtained from the dimannofuranosyl disulfide 7 or the manofuranosyl methly disulfide 8 (Scheme 2) gave low yields of the thio-O-lactone 2 . However, photolysis of the S-phenacyl thioglycoside 6 obtained by in situ alkylation of the thiolato anion derived from 5 led in 78–89% to 2 . Similarly, the dithiocarbonate 10 was transformed, via 11a , into the ribo-thio-O-lactone 12 (79%). Thermolysis of the peracetylated thiosulfinates 14 (Scheme 3) led to the intermediate thio-O-lactone 15 , which underwent facile β-elimination of AcOH (→ 16 , 75%) during chromatography. The perbenzylated S-glucopyranosyl dithiocarbonate 18 (Scheme 4) was transformed either into the S-phenacyl thioglucoside 19 or into a mixture of the anomeric methyl disulfides 21a/b . Whereas the photolysis of 19 led in moderate yield to 2-deoxy-thio-O-lactone 20 , oxidation of 21b and thermolysis of resulting thiosulfinates gave the thio-O-lactone 4 (79%), which was transformed into 20 (36%) upon photolysis. The pyranoid manno-thio-O-lactone 26 was prepared in the same way and in good yields from 22 via the dithiocarbonate 24b and the disulfide 25 . The ring conformations of the δ-thio-O-lactones, flattened ⁴C₁ for 15 and 4 and B_2,5 for 26 , are similar to the ones of the O-analogous oxo-glyconolactones. The reaction of 2 (Scheme 5) with MeLi and then with MeI gave the thioglycoside 27 (29%) and the dimeric thio-O-lactone 29 (47%). The analogous treatment of 2 with lithium dimethylcuprate (LiCuMe₂) and MeI led to a 4:1 mixture (47%) of 31 and 27 . The structure of 2 was proven by an X-ray analysis, and the configuration at C(6) and C(5) of 29 was deduced from NOE experiments. Substitution of MeI by CD₃I led to the CD₃S analogues of 27 , 29 , and 31 , i.e. 28 , 30 , and 32 , respectively, evidencing carbophilic addition and ‘exo’-attack on 2 by MeLi and the enethiolato anion derived from 2 . The preferred ‘endo’-attack of LiCuMe₂ is rationalized by postulating a single-electron transfer and a diastereoselective pyramidalization of the intermediate radical anion.     

Synthesis of 5-Alkyl(aryl)-2-alkylsulfanyl(alkoxy)-4-hydroxy-6H-1,3-oxazin-6-ones

Alkyl carbamates and S-alkyl thiocarbamates react with substituted malonyl dichlorides in boiling benzene to give the corresponding 2,5-substituted 4-hydroxy-6H-1,3-oxazin-6-ones. The reaction of S-methyl thiocarbamate with unsubstituted malonyl dichloride in boiling diethyl ether or benzene leads to formation of S-methyl (3-methylsulfanylaminocarbonyl-3-oxopropionyl)thiocarbamate and is not accompanied by cyclization, whereas in boiling toluene 4-hydroxy-2-methylsulfanyl-6H-1,3-oxazin-6-one is obtained.__________Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 3, 2005, pp. 468–472.Original Russian Text Copyright © 2005 by Lalaev, Yakovlev, Zakhs.     

Asymmetric synthesis and molecular docking study of enantiomerically pure pyrrolidine derivatives with potential antithrombin activity

The (2R,4R,5S)- and (2S,4S,5R)-enantiomers of 4-(tert-butyl) 2-methyl 5-(4-bromophenyl)-pyrrolidine-2,4-dicarboxylate 3 were synthesized efficiently with an ee of >90% on a gram scale using a FAM-catalytic methodology. Subsequent modification afforded enantiopure N-((4-chlorophenyl)thio)acetyl pyrrolidine derivatives 4, which are potential thrombin inhibitors according to comprehensive molecular docking studies.     

An Efficient Stereoselective Synthesis of (±)-Sweroside and (±)-secologanin aglucone O-methyl ethers. Preliminary communication

A seven-step stereoselective synthesis of (±)-sweroside aglucone O-methyl ether ( 16a ) was achieved in 27% overall yield from 1, 4-cyclohexadiene ( 4 ) and methyl diformylacetate ( 5 ). Secologanin aglucone O-methyl ether ( 18a ) was then formed from 16a in 90% overall yield by a straightforward process. The key step in the synthesis was a [2+2]-enone-photoannelation of 4 and 5 to form the key intermediate 6 which possessed the desired cis-fused ring configuration, and all the caron atoms needed to complete the synthesis of 16a and 18a .     

Bioactive compounds from the endophytic fungus Fusarium proliferatum

The crude extract of an endophytic fungus isolated from Syzygium cordatum and identified as Fusarium proliferatum showed 100% cytotoxicity against the brine shrimp Artemia salina at 100 μg/mL. Seven coloured, biologically active metabolites – including ergosta-5,7,22-trien-3β-ol, nectriafurone-8-methyl ether, 9-O-methyl fusarubin, bostrycoidin, bostrycoidin-9-methyl ether and 8-hydroxy-5,6-dimethoxy-2-methyl-3-(2-oxo-propyl)-1,4-naphthoquinone– were isolated from the extract.     

Furopyridines. III. A new synthesis of furo[3,2-b]pyridine

A convenient synthesis of furo[3,2-b]pyridine and its 2- and 3-methyl derivatives from ethyl 3-hydroxypiconate ( 1 ) is described. The hydroxy ester 1 was O-alkylated with ethyl bromoacetate or ethyl 2-bromopropionate to give the diester 2a or 2b . Cyclization of compound 2a afforded ethyl 3-hydroxyfuro[3,2-b]pyridine-2-carboxylate ( 3 ) which in turn was hydrolyzed and decarboxylated to give furo[3,2-b]pyridin-3-(2H)-one ( 4a ). Cyclization of 2b gave the 2-methyl derivative 4b . Reduction of 4a and 4b with sodium borohydride yielded the corresponding hydroxy derivative 5a and 5b respectively, which were dehydrated with phosphoric acid to give furo[3,2-b]pyridine ( 6a ) and its 2-methyl derivative ( 6b ). 2-Acetylpyridin-3-ol ( 8 ) was converted to the ethoxycarbonylmethyl ether ( 9 ) by O-alkylation with ethyl bromoacetate, which was cyclized to give 3-methylfuro[3,2-b]pyridine-2-carboxylic acid ( 10 ). Decarboxylation of 10 afforded 3-methylfuro[3,2-b]pyridine ( 11 ).     

Total synthesis of 2-(β-D-ribofuranosyl)thiazole-4-carboxamide (Tiazofurin) and of precursors of ribo-C-nucleosides

(1R,2S,4R)-2-Cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl (1S′)-camphanate ( 5 ) was transformed into (?)-methyl 2,5-anhydro-3,4,6-O-tris[(tert-butyl)dimethylsilyl]-D -allonate ( 2 ), (+)-1,3-diphenyl-2-{2′,3′,5′-O-tris[(tert-butyl)dimethylsilyl]-β-D -ribofuranosyl}imidazolidine ( 3 ), and the benzamide 20 of 1-amino-2,5-anhydro-1-deoxy-3,4,6-O-tris-[((tert-butyl)dimethylsily)]-D -allitol. Compound 2 was converted efficiently into optically active tiazofurin ( 1 ).     

Syntheses of (+)- and (–)-Methyl 8-Epinonactate and (+)- and (–)-Methyl Nonactate

In four synthetic steps, (+)- and (–)-methyl 8-epinonactate ((+)- and (–)? 4 ) have been derived from (+)- and (–)-7-oxabicyclo[2.2.1]heptan-2-one ((+)- and (–)? 9 ), respectively. The (+)- and (–)-methyl nonactate ((+)- and (–)? 3 ) were obtained from (+)- and (–)? 4 , respectively, by Mitsunobu displacement reactions. Optical resolution of (±)? 9 via chromatographic separation of the corresponding N-methyl-S-alkyl-S-phenylsulfoximides 24 and 25 yielded the starting materials (+)- and (–)? 9 , respectively.     

Synthesis of aldehyde and carboxylic acid derivatives from 2-hydroxymethyl-3-hydroxy-4H-pyran-4-one (α-hydroxymaltol)

α-Hydroxymaltol (2-hydroxymethyl-3-hydroxy-4H-pyran-4-one) ( 1 ) has been converted to the 3-O-methyl ether 2 and 3-O-p-nitrobenzyl ether 4 by standard methods. The ethers 2 and 4 have been oxidized by barium manganate to the corresponding aldehydes, 3 and 5 , in 91 and 77% yields respectively. Long-term reaction of 5 with hydrogen bromide in acetic acid gives 3-hydroxy-4H-pyran-4-one-2-carboxaldehyde ( 6 ). The aldehyde 3 is readily oxidized by short-term reaction with silver oxide to the corresponding acid 7 .     

Three-component condensation in the synthesis of substituted tetrahydropyridinethiolates

Multicomponent cyclocondensation of Meldrum's acid, 2-chlorobenzaldehyde, and N-(4-bromophenyl)-3-amino-3-thioxopropanamide in the presence of N-methylmorpholine afforded N-methylmorpholinium 3-[N-(4-bromophenyl)carbamoyl]-4-(2-chlorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolate in 65% yield. When treated with dilute HCl, the thiolate easily transformed into N-(4-bromophenyl)-4-(2-chlorophenyl)-2-oxo-6-thioxopiperidine-5-carboxamide, which reacted with alkyl halides to give products of regioselective S-alkylation in high yields. Dedicated to Academician N. K. Kochetkov on the occasion of his 90th birthday. __________ Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1297–1298, May, 2005.     

Glyconothio-O-lactones. Part III. Thermolysis of a 4,5-Dihydro-1,2,3- and a 2,5-Dihydro-1,3,4-thiadiazole

Addition of CH₂N₂ to 2,3:5,6-di-O-isopropylidene-1-thio-mannono-1,4-lactone ( 1 ) gave the 2,5-dihydro-1,3,4-thiadiazole 2 and the 4,5-dihydro-1,2,3-thiadiazole 3 . First-order kinetics were observed for the thermolysis of 3 (Scheme 3) at 80–110° in C₆D₅Cl solution and of 2 (Scheme 3) at 20–35° in CDC1₃, respectively. The 1,2,3-thiadiazole 3 led to mixtures of the thiirane 9 , the starting thionolactone 1 , the thiono-1,5-lactone 8 , and the enol ether 7 , while the isomeric 1,3,4-thiadiazole 2 led to mixtures of the anomeric thiiranes 9 and 12 , the O-hydrogen S,O,O-ortholactone α-D - 14 , the S-methyl thioester 15 , the S,S,O-ortholactone 13 , and the 2,3:5,6-di-Oisopropylidene-mannono-1,4-iactone ( 16 ). Pure products of the thermolysis were isolated by semipreparative supercritical fluid chromatography (SFC), whereas preparative HPLC led to partial or complete decomposition. Thus, the β-D -mannofuranosyl β-D -mannofuranoside 10 , contaminated by an unknown S species, was isolated by preparative HPLC of the crude product of thermolysis of 3 at 115–120° and partially transformed in CD₃OD solution into the symmetric di(α-D -mannofuranosyl) tetrasulfide 11 . Its structure was evidenced by X-ray analysis. Similarly, HPLC of the thermolysis product of 2 gave the enethiol 17 , the sulfide 19 , and the mercapto alcohol 18 as secondary products. Thermolysis of the thiirane 9 at 110–120° (Scheme 4) led to the anomeric thiirane 12 which was transformed into mixtures of the enethiol 17 and the enol ether 7. Addition of H₂O to 17 and 7 gave the corresponding hemiacetals 18 and 20. The mechanism of the thermolysis of the dihydrothiadiazoles 2 and 3 , and the thiiranes 9 and 12 is discussed.     

Fast and reversible migrations of N,S-centered groups around the perimeter of cyclopropene and cycloheptatriene rings

The kinetics and mechanism of circumambulatory rearrangements of N-centered (NCS) and S-centered (SPh, SC₃Ph₃, SC(OEt)=S) groups in corresponding derivatives of 1,2,3-triphenylcyclopropene and cycloheptatriene were studied by dynamic¹H and¹³C NMR spectroscopy. Migrations of the isothiocyanate group occur by the dissociation-recombination mechanism with intermediate formation of a tight ionic pair. Migrations of the phenylthio group around the perimeter of cyclopropene and cycloheptatriene rings occur by the 1,2-shift mechanism. It was found that rearrangements of theO-ethyl dithiocarbonate group inS-(1,2,3-triphenylcyclopropen-3-yl)-O-ethyl dithiocarbonate occur by the 3,3-sigmatropic shift mechanism. The molecular and crystal structure ofO-ethylS-(1,2,3-triphenylcyclopropen-3-yl) dithiocarbonate was studied by X-ray analysis.     

Alkylation of cyclic mannich bases,derivatives of thiourea and simple amino acids

Aminomethylation of thiourea with aqueous formaldehyde and simple amino acids (glycine, β-alanine, γ-aminobutyric acid) have resulted in the formation of (4-thioxo-1,3,5-triazinan-1-yl)-substituted acetic, propionic, and butyric acids, respectively. By alkylation of these compounds corresponding S-methyl and S-ethyl iodides were obtained, and by the action of tert-butylamine, the corresponding salts. The same salts were obtained by the reaction of amine exchange between 5-tert-butyl-1,3,5-triazinan-2-thione and these amino acids in water. As a result of neutralization of S-methyl iodides with tert-butylamine in 2-propanol or aqueous 2-propanol zwitterionic [4-(methyl-sulfanyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl] derivatives of these acids were isolated. From aqueous solutions of S-methyl iodides and tert-butylamine ion associates of the corresponding zwitter-ions and tert-butylammonium iodide have crystallized. The same associates have formed at treating S-methyl iodides with tert-butylamine or diethylamine in the absence of a solvent.     

Synthesis of (5R)- and (5S)-5-Methyl-5, 6-dihydrouridine Derivatives

The hydrogenation of 2′, 3′-O-isopropylidene-5-methyluridine (1) in water over 5% Rh/Al₂O₃ gave (5 R)- and (5 S)-5-methyl-5, 6-dihydrouridine (2) , separated as 5′-O-(p-tolylsulfonyl)- (3) and 5′-O-benzoyl- (5) derivatives by preparative TLC. on silica gel and ether/hexane developments. The diastereoisomeric differentiation at the C(5) chiral centre depends upon the reaction media and the nature of the protecting group attached to the ribosyl moiety. The synthesis of iodo derivatives (5 R)- and (5 S)- 4 is also described. The diastereoisomers 4 were converted into (5 R)- and (5 S)-2′, 3′,-O-isopropylidene-5-methyl-2, 5′-anhydro-5, 6-dihydrouridine (7) .     

Mammalian Alkaloids: Configurations of Optically Active Salsoline- and 3′,4′-Dideoxynorlaudanosoline-1-carboxylic Acids

Synthesis of the optical isomers of (±)-methyl 6,7-dimethyl-3′,4′-dideoxynorlaudanosoline-1-carboxylate ((±)- 2 ) was accomplished by reaction of (±)- 2 with (+)-(R)-1-phenylethyl isocyanate, separation of the urea diastereoisomers (?)- 4A and (+)- 4B , and alcoholysis of the ureas in refluxing BuOH. Optically active isoquinoline-carboxylates 2A , B and hydantoins 8A , B isolated were characterized. The absolute configuration of the reaction products was established by X-ray analysis of the optically active hydantoin (+)- 8A . Hydrolysis of the methyl isoquinolinecarboxylates 2A , B with 48% HBr soln. at reflux afforded the desired optically active 3′,4′-dideoxynorlaudanosoline-1-carboxylic acids 1A , B required for enzyme-inhibition studies. Details of the X-ray diffraction analysis of (+)-methyl salsoline-1-carboxylate hydrobromide ((+)- 11A ·HBr) prepared earlier are included. CD spectra of (+)-(S)-methyl 6,7-dimethyl-3′,4′-dideoxynorlaudanosoline-1-carboxylate hydrobromide ((+)- 2A . HBr) and (?)-(R)-methyl salsoline-1-carboxylate hydrochloride ((?)- 11B ·HCl) confirmed the assignment of their (S)- and (R)-configurations, respectively.     

Preparation of 3-Amino-3-Deoxy-2,4,5,6-Tetra-O-Methyl-D-Altronic Acid Hydrochloride,a Precursor in the Preparation of a Chiral β-Polyamide (Nylon 3 Analog)

ABSTRACT

3-Amino-3-deoxy-2,4,5,6-tetra-O-methyl-D-altronic acid hydrochloride was prepared from methyl 3-azido-3-deoxy-4,6-O-benzylidene-α-D-altropyranoside in seven steps. The key intermediate in this synthesis was the 3-acetamido-3-deoxy-2,4,6-tri-O-methyl-D-altrono-1,5-lactone which could be transformed, in one step, into methyl 3-acetamido-3-deoxy-2,4,5,6-tetra-O-methyl-D-altronate. However, attempts to open the 3-azido-3-deoxy-tri-O-methyl (or O-benzyl)-D-altrono-1,5-lactone intermediates gave a mixture of products, mostly, α,β-unsaturated carbonyl compounds. The 3-amino-3-deoxy-2,4,5,6-tetra-O-methyl-D-altronic acid could be transformed into the corresponding β-lactam, (3S,4R)-3-methoxy-4-(D-erythro-trimethoxypropyl) azetidine-2-one, which was further polymerized by anionic ring-opening polymerization giving poly[(2S,3R)-2-methoxy-3-(D-erythro-trimethoxypropyl) propanamide], a chiral nylon 3 analog.     

Studies on ketene and its derivatives. CXI . Photoreaction of diketene with 2(1H)-quinolone derivatives

Photoreaction of diketene with 4-methyl-2(1H)-quinolone and 1,4-dimethyl-2(1H)-quinolone gave 2R*,2aR*,SbR*- and 2R*,2aS*8bS*-8b-methyl-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]quinoline-2-spiro-2′-(oxetan)-4′-one ( 6a and 6b ), and their 4-methyl derivatives 7a and 7b , respectively. Thermolysis of compounds 6 and 7 afforded 2aR*,8bS*-8b-methyl-2-methylene-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]quinoline ( 8 ) and its 4-methyl derivatives 9 , respectively. Similarly, photolysis of diketene and 4-acetoxy-2(1H)-quinolone gave 1R*,2aS*,8bS*- and 1R*,2aR*,8bR*-8b-acetoxy-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]-quinoline ( 11a and 11b ). Alcoholysis of compounds 11a and 11b with hydrogen chloride in methanol gave 1-hydroxy-1-(methoxycarbonyl)methylcyclobuta[c]quinoline derivative 12 and 13 which were transformed to 4-acetyl-3-methyl-2(1H)-quinolone ( 15 ) by further alcoholysis. Photoreaction of diketene with 2(1H)-quinolone derivatives gave the corresponding cyclobuta[c]quinoline spirooxetanone derivatives 18 and 23 , which, by thermolysis, were transformed to 2-methylenecyclobuta[c]quinoline 23 and 25 , respectively.     

Syntheses of substituted-1,2,4-triazoles

Starting from the readily available 3-phenylpropionitrile, 3-(or 5-)(2-phenethyl)-1,2,4-triazole 3 was prepared. Reaction of compounds 3 with diazomethane afforded 1-methyl-3-(2-phenethyl)-1,2,4-triazole (4) and 1-methyl-5-(2-phenethyl)-1,2,4-triazole (5) . Reaction of compound 3 with methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride afforded only one of the expected isomer; namely compounds 6 , 7 and 8 respectively.     

9-Hydroxy-2-methyl-4H-pyrido[1,2-α] pyrimidin-4-one and its derivatives

2-Amino-3-(o-bromobenzyloxy)pyridine ( 1 ) and ethyl acetoacetate gave 9-(o-bromobenzyl-oxy)-2-methyl-4H-pyrido[1,2-α]pyrimidin-4-one ( 2 ) in 2% yield. When 1 and methyl β-amino-crotonate ( 3 ) were reacted, benzyl ether cleavage occurred and the products were 9-hydroxy-2-methyl-4H-pyrido[1,2-α]pyrimidin-4-one ( 4 ) and its ammonium salt ( 5 ). These observations led to an alternative synthesis in which 2-amino-3-pyridinol ( 6 ) and either 3 or methyl acetoacetate, ( 8 ) in diethylbenzene at 185° gave 4 in 86 and 87% yields, respectively, and the anion of 4 and o-bromobenzyl bromide gave 2 in 61% yield. Even in diethylbenzene at 185°, 1 and 8 gave only trace amounts of 2 . Thus, o-bromobenzylation of the 3-hydroxyl group in 6 markedly decreased the reactivity of the amino group in 6 toward reactions with acetoacetic esters.