Highly diastereoselective Staudinger reaction on 5,6-dihydropyrazin-2-(1H)-ones. Synthesis of enantiopure fused oxopiperazino-β-lactams

The highly diastereoselective synthesis of fused oxopiperazino-β-lactams 2 by Staudinger reaction between functionalized ketenes and 5,6-dihydropyrazin-2(1H)-ones 1 has been carried out. Further cleavage of the β-lactam ring produced 2-oxopiperazine-3-acetic acid derivatives 7 with no epimerization and in good yields.     

A substituent directed regioselective synthesis of aryl/pyronyl pendant unusual adipate and tetrahydronaphthalene

An efficient regioselective synthesis of pyronyl pendant ethyl methylthiocarbonylalkanoates 5 has been delineated from the base catalyzed reaction of suitably functionalized 2-pyranone 1 and 2-carbethoxycycloalkanones 2, 6 through successive substitution and regioselective ring opening by in situ generated mercaptide ion. To assess the effect of C-4 substituent on regioselectivity, reactions of 6-aryl-3-cyano-4-(piperidin-1-yl)-2-oxopyran 8 with 2-carbethoxycyclohexanone 6a and 2-carbethoxy-2-methylcyclohexanone 6b were carried out separately under analogous reaction conditions but the compounds isolated were identical and characterized as 4-aryl-8-methyl-2-piperidin-1-yl-5,6,7,8-tetrahydronaphthalene-1-carbonitriles 9. Ethyl 2-(5-amino-4′-bromo-4,6-dicyanobiphenyl-3-yl)-5-methylsulfanylcarbonylpentanoate 10 has also been prepared through base catalyzed ring transformation of ethyl 2-[6-(4-bromophenyl)-3-cyano-2-oxo-2H-pyran-4-yl]-5-methylsulfanylcarbonylpentanoate 5d by malononitrile in DMF.     

An unexpected oxidative decarboxylation reaction of 2,3-dihydroxybenzoic acid in the synthesis of new dibenzyltetrahydroquinoxalinediones

Chemical and electrochemical oxidation of different catechols were carried out in the presence of N,N′-dibenzylethylenediamine (DBEDA) in a phosphate buffer/acetonitrile solution for the synthesis of different new dibenzyltetrahydroquinoxalinedione derivatives. The oxidation of catechol (1a), 2,3-dihydroxybenzoic acid (1e), and 3,4-dihydroxybenzoic acid (1d) led to the same product, probably due to the decarboxylation reaction of intermediates. An oxidative decarboxylation reaction of 3,4-dihydroxybenzoic acid (1d) has been reported before, while an unexpected oxidative decarboxylation reaction of 2,3-dihydroxybenzoic acid (1e) in the presence of DBEDA is reported for the first time.     

Efficient dual catalytic enantioselective diethylzinc addition to the exocyclic CN double bond of some 1,2,4-N-triazinylarylimines using polymer-supported chiral β-amino alcohols derived from norephedrine

Chiral N,N-dialkylnorephedrines and their corresponding copolymers were evaluated as chiral ligands for the enantioselective diethylzinc addition to the exocyclic CN double bond of some 4-arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 2a-f. The use of a dual catalytic system (amino alcohol/halosilane) in the titled asymmetric reaction was examined. The enantioselective ethylation reaction has been successfully carried out in the heterogeneous system even at low temperature. The corresponding 4-(1-arylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 4a-f were obtained in high yields with high enantioselectivities using chiral polymers (up to 91% ee), which are almost the same as those obtained from homogeneous analogues (up to 92% ee). The diethylzinc reagent neither opened the 1,2,4-triazinyl heterocyclic ring nor attacked the carbonyl or the thione groups of the 1,2,4-triazinyl heterocyclic ring and the addition reaction took place exclusively at the exocyclic electrophilic carbon atom yielding the C-ethylated products 4a-f. Reductive cleavage of the 1,2,4-triazinyl heterocyclic ring led smoothly to the corresponding primary aromatic amines 11a-f without significant loss of enantiomeric purity. A suggestion about the possible transition state for the addition reaction is also presented.     

From lithium ketazides to isomeric silylketazine-rings - imine-enamine tautomerism

Di(tert-butylmethyl)ketazine (I) reacts with n-BuLi in a 1:1 molar ratio to give a monolithium salt (II). The reaction of II with ^tBu₂SiF₂ in n-hexane leads, even in a 1:1 molar ratio, to the formation of the isomeric five- and four-membered ring compounds 1 and 2. Compound 1 has an endocyclic imine and an exocyclic enamine unit. The opposite is found for 2. The acyclic monosubstitution product, ^tBu₂SiFCH₂-C^tBuN-NC^tBuCH₃ (III) could not be isolated. It reacts with the lithium ketazide to give 1 or 2. I is reformed. The reaction in THF yields only the four-membered ring 2. In a comparable reaction of the lithium ketazide and (H₃C)₂SiF₂, the substitution product 3 could be isolated. A possible formation mechanism for 2 includes an intermediate silene IV. Both compounds 1 and 2 react with H₃C-OH under cleavage of the endocyclic Si-N-bond to give the addition product 5. The reaction mechanism includes a hydrogen shift from a nitrogen atom to a carbon atom via an imine-enamine tautomerism. In a 2:1 molar ratio, n-BuLi and the di(tert-butylmethyl)-ketazine (I) form the dilithium salt, 6. Compound 6 crystallizes from THF as trimer with four imine and two enamine units. A seven-membered ring (7) isomeric to 1 and 2 is the result of the reaction of 6 with ^tBu₂SiF₂. Compound 7 contains one imine and one enamine unit in the ring skeleton.The comparable reaction of the (CH₃)₃Si-substituted dilithium-di(tert-butylmethyl)ketazide and ^tBu₂SiF₂ yields the five-membered ring compound 8 with one endocyclic imine and one exocyclic enamine unit.Quantum chemical calculations of 1, 2, 7 and the intermediate silene IV have been carried out and show a low energy difference between the cyclic silyl-ketazine isomers.     

One-pot reductive-cyclization as key step for the synthesis of rutaecarpine alkaloids

The quinazolinocarboline alkaloids including rutaecarpine (1a), euxylophoricine A (1b), and euxylophoricine C (1c) have been synthesized efficiently from the ring opened β-carboline derivative as key intermediate by a one-pot reductive-cyclization reaction. The key intermediate was prepared from tryptamine (6) following Bischler-Napieralski cyclization, benzoylation, and oxidative cleavage of the exocyclic double bond.     

Reaction behavior of cyclopropylmethyl cations derived 1-phenylselenocyclopropylmethanols with acids

The 1-phenylselenocyclopropylmethyl cations are generated by the reaction of the corresponding cyclopropylmethanols 1 with TsOH. The reaction in methanol proceeds to afford the homoallylic ethers 2, ring-enlargement products 3, 4, and ring opening products 5 depending upon the kind of substituent on the cyclopropane ring or the α-carbon. On the other hand, in the case of the absence of methanol as nucleophile, 4H-selenochromene derivative 7 is obtained exclusively. The oxidative elimination of the phenylselenyl group in the resulting phenylselenohomoallylic compounds 2 furnishes functionalized allene derivatives and alkyne derivatives.     

Synthesis of C1- and C8a-epimers of (+)-castanospermine from d-glucose derived γ,δ-epoxyazide: intramolecular 5-endo epoxide opening approach

A concise synthesis of two diastereomers of (+)-castanospermine namely 1- and 8a-epi-castanospermine 1b and 1c, respectively, is reported from d-glucose. The methodology involves stereoselective cross metathesis of d-glucose derived alkene 2 with 4-bromo-1-butene followed by azide displacement and m-CPBA oxidation to afford diastereomeric γ,δ-epoxyazides 5a/5b. The Staudinger reaction of epoxyazide 5a followed by reaction with benzylchloroformate (CbzCl) unexpectedly furnished 1,3-oxazinan-2-one derivative 7 whose stereochemistry was establish by single crystal X-ray. This helps to assign the stereochemistry in the epoxidation reaction. The reduction of 5a/5b was then carried out by transfer hydrogenation to provide γ,δ-epoxyamine that concomitantly undergoes intramolecular 5-endo-tet cyclization to afford hydroxypyrrolidine ring skeleton with sugar framework-a precursor to castanospermine analogues 1b/1c.     

Regioselective synthesis of 4- and 5-oxazole-phosphine oxides and -phosphonates from 2H-azirines and acyl chlorides

A simple and efficient regioselective synthesis of 4-oxazole-phosphine oxides 11 and -phosphonates 12 from 2H-azirine-phosphine oxides 1 and -phosphonates 6 is described. The key step for the synthesis of oxazoles 11 is a base-mediated ring closure of vinylogous α-aminophosphorus compounds derived from phosphine oxides 4 and from phosphonates 8. These derivatives 4 and 8 are obtained by reaction of functionalized azirines 1 and 6 with acyl chlorides 2 and subsequent acid-catalyzed ring opening of N-acylaziridine-phosphine oxides 3 and -phosphonates 7. Regioselective thermal ring cleavage of N-acylaziridine-phosphine oxides 3 leads α-chloro-β-(N-acylamido)-phosphine oxides 13 and their treatment with bases gives 5-oxazole-phosphine oxides 16.     

1,3-Dipolar cycloaddition of exo-methylenesugars with nitrone: approach to new amino-C-ketosyl disaccharides

Stereoselective 1,3-dipolar cycloadditions of exo-methylenesugars 1a-c to a sugar nitrone 2 were carried out with refluxing a toluene solution and afforded the corresponding cycloadducts, ketosyl spiro-isoxazolidine disaccharides 3a and 4a-c. Followed by reductive cleavage of the N-O bond of the isoxazolidine ring with the treatment of Zn-AcOH-Ac₂O or with catalytic hydrogenation (Pd(OH)₂/C), the cycloadduct 3a could be readily converted into a novel amino-C-disaccharide possessing a ketose form, providing an access to a novel amino-C-ketosyl disaccharides.     

Asymmetric synthesis of α,β-substituted β-aminoalkanamides and stereochemical determination

Highly enantiomerically enriched β-aminoalkanamides 12 and β-phenylaminoalkanamides 13 have been prepared by the addition reaction of α-lithiated 2-alkyl-2-oxazolines 9-Li, derived from optically active oxazolines 9, to N-cumyl nitrones 2. The relative stereochemistry of alkanamides 5 and 6 has been established by 1D-NOESY experiments carried out on the related pyrimidinones 7, whereas the absolute configuration of alkanamides 12 and 13 has been confirmed by an X-ray analysis.     

Alternative synthesis and novel oxidizing ability of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-dione derivatives

Synthesis of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-diones 7a-g was accomplished by ring opening and ring closure sequences of 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8,10(9H)-dione derivatives induced by several amines. Furthermore, alternative synthetic methodology for compounds 7a-e was also accomplished by single-step reaction of 2-chlorotropone with 6-aminouracil derivatives under mild conditions. X-ray crystal analysis of 7a was carried out to clarify the structural characteristics. The properties of 7a-e were studied by the UV-vis spectra and reduction potentials (−1.24 to −1.39 V vs Ag/AgNO₃). Novel photo-induced oxidation reaction of 7a-d toward some amines under aerobic conditions was carried out to give the corresponding imines in more than 100% yield [based on compounds 7a-d], suggesting the oxidation reaction occurs in an autorecycling process.     

Formation of new 4-isocyanobut-2-enenitriles by thermal ring cleavage of 3-pyridyl azides

A new thermal ring cleavage of 3-pyridyl nitrenes for the formation of 4-isocyanobut-2-enenitrile products is reported. Thermolysis of 4-(thien-3-yl)-3-pyridyl azide 1 and 3-azido-4-(1-TIPS-1H-pyrrol-3-yl)pyridine 5 afforded two new isonitrile-nitrile products by ring cleavage; 4-isocyano-2-(thiophen-3-yl)but-2-enenitrile (3, 27%) and 4-isocyano-2-(1-TIPS-1H-pyrrol-3-yl)but-2-enenitrile (7, 20%), in addition to our previously reported pyrido[3,4-b]thienopyrrole (2, 29%) and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (6, 71%) products. Minor amounts of 2-(thien-3-yl)-1H-pyrrole-3-carbonitrile (4, 6%), formed by ring contraction, were also isolated after thermolysis of azide 1. Isonitriles 3 and 7 underwent degradation into amine 3b and formamide 7a by acidic hydrolysis. The nature and chemistry of compounds 3, 4 and 7 were investigated.     

Synthesis of five and six membered aminocyclitols: stereoselective Michael and Henry reaction approach with d-glucose derived α,β-unsaturated ester

The stereoselective intermolecular Michael addition of nitromethane to d-glucose derived α,β-unsaturated ester 7 afforded l-ido-configurated nitroester 8 as the only product that on reduction of the ester functionality, cleavage of 1,2-acetonide and the intramolecular Henry reaction afforded exclusively muco-nitroinositol 9. While reduction of the ester functionality in 8, deprotection of 1,2-acetonide, oxidative cleavage with NaIO₄ and the intramolecular Henry reaction afforded nitrocyclopentitol 13. Nitrocyclitols 9 and 13 were converted to the hydroxyethyl substituted aminocyclohexitol 5 and aminocyclopentitol 6, respectively.     

A novel synthesis of aryl tethered imidazo[4,5-b]pyrazin-2-ones through in situ ring construction and contraction

An innovative synthesis of aryl tethered 1,3-dimethylimidazo[4,5-b]pyrazin-2-ones 4 and 6 has been delineated through base catalyzed ring transformation of 6-aryl-4-(piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1 and methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates 5 with 7-acetyl-1,3-dimethyllumazine 2 with subsequent ring contraction of the fused pyrimidine to an imidazole ring. An additional product, methyl [6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-4-thiophen-2-ylpyran-2-ylidene]acetate 8b, was also isolated from the reaction of 5 and 2, as a minor constituent.     

Ruthenium-catalyzed cycloisomerization of 1,1,2,2-tetramethyl-1,2-divinyldisilane: Selective formation of a five-membered silacycle

The cycloisomerization of 1,1,2,2-tetramethyl-1,2-divinyldisilane (1) in the presence of ruthenium-diphosphine complexes has been examined. A ruthenium-dppe (8) or a ruthenium-dppv (12) complex selectively catalyzed the reaction and 1,1,2,3,3-pentamethyl-1,3-disilycyclopent-4-ene (3) was isolated as the major product. The reaction was also carried out in the presence of a deuterated ruthenium-PⁱPr₃ complex and the incorporation of deuterium to 1,1,4,4-tetramethyl-1,4-disilacyclohex-2-ene (2) was observed. The mechanism of this reaction has been proposed.     

Coelodiol and coeloic acid, ent-isocopalane diterpenes from the Indonesian sponge Coelocarteria cfr. singaporensis

Two novel ent-isocopalane diterpenes, coelodiol (1) and coeloic acid (2), the latter characterized by an unique oxidative degradation of ring A, have been isolated from the Indonesian sponge Coelocarteria cfr. singaporensis. The stereostructure of these metabolites has been established through interpretation of NMR data and application of the exciton chirality CD method. Coelodiol (1) and coeloic acids (2) were found to inhibit the growth of MKN-45 cell line (human gastric adenocarcinoma).     

Chemoenzymatic total syntheses of the linear triquinane-type natural products (+)-hirsutic acid and (−)-complicatic acid from toluene

Total syntheses of title natural products, 1 and 2, have been achieved using the cis-1,2-dihydrocatechol 7 as starting material. Compound 7 is readily obtained in large quantity and enantiomerically pure form through the whole-cell biotransformation of toluene using the genetically engineered micro-organism Escherichia coli JM109 (pDTG601) that over-expresses the enzyme toluene dioxygenase (TDO). Three key chemical steps were employed in these syntheses, the first of which was a high-pressure-promoted Diels-Alder cycloaddition reaction between diene 8 and cyclopentenone to give adduct 9. The second key step was the photochemically promoted oxa-di-π-methane rearrangement of the bicyclo[2.2.2]octenone derivative, 18, of 9 to give 20 while the third key step was the reductive cleavage of the last compound so as to afford the linear triquinane 22. Elaboration of compound 22 to targets 1 and 2 followed conventional and/or established procedures. Single-crystal X-ray analyses were carried out on compounds 10-13, 15, 18, 24, and 34.     

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

Novel synthetic strategy toward abietane and podocarpane-type diterpenes from (−)-sclareol: synthesis of the antitumor (+)-7-deoxynimbidiol

A new route to abietane and podocarpane-type terpenoids from labdane diterpenes is reported. The key step is the transformation of β-ketoester 9 into the corresponding O-acetylsalicylate ester 18, via a manganese(III)-based oxidative free-radical cyclization carried out in Ac₂O. Utilizing this, the synthesis of the antitumor (+)-7-deoxynimbidiol (5) from (−)-sclareol (11) has been achieved. (+)-Nimbidiol (6) and the natural terpenoid 20 have also been synthesized.