Chemoenzymatic synthesis of enantiopure geminally dimethylated cyclopropane-based C2- and pseudo-C2-symmetric diamines

Enantiopure (−)-(1S,3S)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxamide 2 and (+)-(1R,3R)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxylic acid 3 were easily obtained from a multigram scale biotransformation of racemic amide or nitrile in the presence of Rhodococcus erythropolis AJ270 whole cell catalyst under very mild conditions. Coupled with efficient and convenient chemical manipulations, comprising mainly of the Curtius rearrangement, oxidation, and reduction reactions, chiral C₂-symmetric (1S,2S)-3,3-dimethylcyclopropane-1,2-diamine 6 and ((1R,3R)-3-(aminomethyl)-2,2-dimethylcyclopropyl)methanamine 8 and pseudo-C₂-symmetric (1S,3S)-3-(aminomethyl)-2,2-dimethylcyclopropanamine 11 were prepared. These were also transformed into the corresponding chiral salen derivatives 12, 13, and 14, respectively, in almost quantitative yields.     

Synthesis and cytotoxic activity of benzo[a]pyrano[3,2-h] and [2,3-i]xanthone analogues of psorospermine, acronycine, and benzo[a]acronycine

Condensation of 2-hydroxy-1-naphthalenecarboxylic acid with phloroglucinol afforded 9,11-dihydroxy-12H-benzo[a]xanthen-12-one (6). Construction of an additional dimethylpyran ring onto this skeleton, by alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement, gave access to 6-hydroxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (12) and 5-hydroxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (13), which were methylated into 6-methoxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (14) and 5-methoxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (15), respectively. Osmium tetroxide oxidation of 14 and 15 gave the corresponding (+/-)-cis-diols 16 and 17, which afforded the corresponding esters 18-21 upon acylation. Similarly, condensation of 2-hydroxy-1-naphthalenecarboxylic acid with 3,5-dimethoxyaniline gave 11-amino-9-methoxy-12H-benzo[a]xanthen-12-one (23) which was converted into 11-amino-9-hydroxy-12H-benzo[a]xanthen-12-one (24) upon treatment with hydrogen bromide in acetic acid. Alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement afforded 6-amino-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (25) and 5-amino-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (26). The new benzopyranoxanthone derivatives only displayed marginal antiproliferative activity when tested against L1210 and KB-3-1 cell lines. The only compounds found significantly active against L1210 cell line, 16 and 20, belong to the benzo[a]pyrano[3,2-h]xanthen-7-one series, which possess a pyran ring fused angularly onto the xanthone basic core.     

Antiallergic agents from natural sources 9. Inhibition of nitric oxide production by novel chalcone derivatives from Mallotus philippinensis (Euphorbiaceae)

Three novel chalcone derivatives, mallotophilippens C (1), D (2) and E (3) were isolated from the fruits of Mallotus philippinensis MUELL. ARG. These compounds were identified, using chemical and spectral data, as 1-[6-(3,7-dimethyl-octa-2,6-dienyl)-5,7-dihydroxy-2,2-dimethyl-2H-chromen-8-yl]-3-(4-hydroxy-phenyl)-propenone, 3-(3,4-dihydroxy-phenyl)-1-[6-(3,7-dimethyl-octa-2,6-dienyl)-5,7-dihydroxy-2,2-dimethyl-2H-chromen-8-yl]-propenone and 1-[5,7-dihydroxy-2-methyl-6-(3-methyl-but-2-enyl)-2-(4-methyl-pent-3-enyl)-2H-chromen-8-yl]-3-(3,4-dihydroxy-phenyl)-propenone, respectively. They inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) gene expression by a murine macrophage-like cell line (RAW 264.7), which was activated by lipopolysaccharide (LPS) and recombinant mouse interferon-gamma (IFN-gamma). Furthermore, they downregulated cyclooxygenase-2 (COX-2) gene, interleukin-6 (IL-6) gene and interleukin-1beta (IL-1beta) gene expression. These results suggest that they have anti-inflammatory and immunoregulatory effects.     

Two new xanthones from the pericarp of Garcinia mangostana

Two new xanthones, designated garcimangosxanthone F (1) and garcimangosxanthone G (2), were isolated from the EtOAc-soluble fraction of ethanolic extract from the pericarp of Garcinia mangostana. Their structures were established as 1,6,7-trihydroxy-5-(3-methylbut-2-enyl)-8-(3-hydroxy-3-methylbutyl)-6′,6′-dimethylpyrano[2′,3′:3,2]xanthone and 1,6,7-trihydroxy-5-(3-methylbut-2-enyl)-8-(3-hydroxy-3-methylbutyl)-6′,6′-dimethyl-4′,5′-dihydropyrano[2′,3′:3,2]xanthone, respectively, on the basis of their 1D, 2D NMR and MS data interpretation.     

Investigation of reactions of the organozinc reagents prepared from zinc and dialkyl dibromomalonates with the derivatives of 2-arylmethyleneindan-1,3-dione and 5-arylmethylene-2,2-dimethyl-1,3-dioxane-4,6-dione

Organozinc compounds prepared from dialkyl dibromomalonates and zinc react with 2-arylmethyl-eneindan-4,6-diones, 5-arylmethylene-2,2-dimethyl-1,3-dioxane-4,6-diones, as well as with 2-[4-(1,3-dioxoindan-2-ylidenemethyl)phenyl]methyleneindan-1,3-dione and 5-[4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-2-ylidenemethyl)phenyl]methylene-2,2-dimethyl-1,3-dioxane-4,6-diones to form dialkyl 3-aryl-1′3′-dioxaspiro(cyclopropane-2,2′-indan)-1,1-dicarboxylates, dimethyl 3-aryl-6,6-dimethyl-5,7-dioxa-4,8-dioxaspiro[2,5]octan-2,2-dicarboxylates, dialkyl 2-{4-[3,3-bis (alkoxycarbonyl)-1′,3′-dioxaspiro(cyclopropane-2,2′-indan)-1-yl]phenyl}-1′,3′-dioxaspiro[cyclopropane-2,2′-indan]-1,1-dicarboxylates, and dialkyl 2-{4-[2,2-bis(alkoxycarbonyl)-6,6′-dimethyl-4,8-dioxo-5,7-dioxaspiro[2,5]oct-1-yl]phenyl}-6,6-dimethyl-4,8-dioxo-5,7-dioxaspiro[2,5]octan-1,1-dicarboxylate respectively.     

Synthesis of 2-hydroxy-3-methylbut-3-enyl substituted coumarins and xanthones as natural products. Application of the Schenck ene reaction of singlet oxygen with ortho-prenylphenol precursors

Application of our original photooxidation-reduction methodology to prenylated dihydroxycoumarin and trihydroxyxanthone compounds led to the corresponding ortho-(2-hydroxy-3-methylbut-3-enyl)phenol derivatives with yields ranging from 8 to 65%. In most of the reported experiments, the oxidation products distribution, after the photooxygenation step, was controlled by the competition between the large group effect and the stabilising phenolic assistance effect. We also showed that ortho-(3-hydroxy-3-methylbut-1-enyl)phenol derivatives could be considered as biogenetic precursors of 2,2-dimethylbenzopyranic structures.     

Gomadalactones A, B, and C: novel 3-oxabicyclo[3.3.0]octane compounds in the contact sex pheromone of the white-spotted longicorn beetle, Anoplophora malasiaca

The ether extract of the females of white-spotted longicorn beetle Anoplophora malasiaca showed activity as contact sex pheromone to males. The extract was fractionated, and a pheromonal activity was revealed only when three fractions; n-hexane, n-hexane/EtOAc 9:1, and EtOAc were blended. The relative structures of gomadalactone A, B, and C, three active components isolated from the EtOAc fraction, were determined by spectroscopic studies to be (1S^∗,4R^∗,5S^∗)-5-hydroxy-4-[(E)-7-hydroxy-4-methylhept-3-enyl]-4,8-dimethyl-3-oxabicyclo[3.3.0]octan-7-en-2,6-dione, (1R^∗,4R^∗,5R^∗)-5-hydroxy-4-[(E)-7-hydroxy-4-methylhept-3-enyl]-4,8-dimethyl-3-oxabicyclo[3.3.0]octan-7-en-2,6-dione, and (1S^∗,4R^∗,5S^∗,8S^∗)-5-hydroxy-4-[(E)-7-hydroxy-4-methylhept-3-enyl]-4,8-dimethyl-3-oxabicyclo[3.3.0]octan-2,6-dione, respectively.     

Reactions of Methyl Esters of 1-(α-Bromoisobutyryl)cyclohexanecarboxylic or 3-(1-Bromocyclohexyl)-2,2-dimethyl-3-oxopropanoic Acids with Zinc and Arylglyoxal

Methyl esters of 1-(-bromoisobutyryl)cyclohexanecarboxylic or 3-(1-bromocyclohexyl)-2,2-dimethyl-3-oxopropanoic acids react with zinc and arylglyoxals to form 3-aroyl-4,4-dimethyl-2-oxaspiro[5.5]undecane-1,5-diones or 1-aroyl-4,4-dimethyl-2-oxaspiro[5.5]undecane-3,5-diones, respectively. The former products react with phenylhydrazine, yielding 3-[aryl(2-phenylhydrazono)methyl]-4,4-dimethyl-2-oxaspiro[5.5]undecane-1,5-diones.     

Synthesis of 6-aryltetrahydropyran-2,4-diones containing a hexamethylene substituent in positions 3 or 5 of heterocycle

Methyl 3-(1-bromocycloheptyl)-2,2-dimethyl-3-oxopropanoate and methyl 1-(2-bromo-2-methylpropanoyl)cycloheptanecarboxylates react with zinc and arylcarbaldehydes yielding 5-aryl-2,2-dimethyl-4-oxaspiro[5.6]dodecan-1.3-diones and 3-aryl-4,4-dimethyl-2-oxaspiro[5.6]dodecan-1.5-diones respectively.     

Effect of the β-substituent with respect to the azido group on the reactivity of methyl (2E)-3-[5-(azidomethyl)-2,2-diethyl-1,3-dioxolan-4-yl]-2-methylprop-2-enoate

Unlike methyl (2E)-3-[5-(azidomethyl)-2,2-diethyl-1,3-dioxolan-4-yl]-2—methylprop-2-enoate which is stable on storage, its acyclic derivative, methyl (2E,4S,5S)-6-azido-5-hydroxy-2-methyl-4-(pent-3-yloxy) hex-2-enoate at 20°C undergoes unusual decomposition with formation of exo-methylidenepyrrolidine. Analogous transformation was also observed in the epoxide ring opening in methyl (2E)-2-methyl-4-[(S)-oxiran-2-yl]-4-(pent-3-yloxy)but-2-enoate and in the substitution reaction of ethyl 5,6-bis(methanesulfonyloxy)-2-methyl-4-(pent-3-yloxy)hex-2-enoate with azide ion. Opening of the oxirane ring in the former by the action of azide ion was accompanied by formation of oxazetidine derivative as a minor product. The major intramolecular cyclization products, 4-hydroxy- and 4-mehtanesulfonyloxypyrrolidines were converted into stable pyrrole derivatives via elimination of the leaving groups. The hydrogenation of methyl and ethyl (2E)-3-[5-(azidomethyl)-2,2-diethyl-1,3-dioxolan-4-yl]-2-methylprop-2-enoates over palladium catalyst afforded the expected reduction products.     

Di-4(3H)-quinazolinon-2-yl Derivatives from the Diacid Chlorides of Pinic and sym-Homopinic Acids

The corresponding diamides have been synthesized by the interaction of the diacid chlorides of cis-2,2-dimethyl-3-carboxycyclobutaneacetic acid (pinic acid) and cis-2,2-dimethylcyclobutane-1,3-diacetic acid (sym-homopinic acid) with two equivalents of anthranilic acid. Treatment of the diamides with formamide gave 2,2-dimethyl-1-[4(3H)-quinazolinon-2-yl]methyl-3-[4(3H)-quinazolinon-2-yl]cyclobutane and 2,2-dimethyl-1,3-di[4(3H)-quinazolinon-2-ylmethyl]cyclobutane respectively.     

Thermal rearrangement of {[2-(Arylmethylene)cyclopropyl]methyl}(phenyl)sulfanes and selanes

{[2-(Arylmethylene)cyclopropyl]methyl}(phenyl)sulfanes and {[2-(arylmethylene)cyclopropyl]methyl}(phenyl)selanes, generated in situ from 2-(arylmethylene)cyclopropylcarbinols with sodium benzenethiolate and sodium benzeneselenolate, could undergo rearrangement upon heating to afford (2-arylmethylidenebut-3-enyl)(phenyl)sulfanes and (2-arylmethylidenebut-3-enyl)(phenyl)selanes, in good to excellent yields as mixtures of E- and Z-isomers, respectively. A radical rearrangement was proposed on the basis of control experiments for this process.     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

Synthesis of a 6-aryloxymethyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one: a muscarinic (M3) antagonist

A synthesis of the racemic 6-aryloxymethyl-5-hydroxy-2,3,4,5-[1H]-2-tetrahydrobenzazepin-4-one , for evaluation as a muscarinic (M(3)) antagonist, is described. 2-[2-tert-Butyldimethylsilyloxymethyl-6-(2,6-dimethoxyphenoxymethyl)phenyl]propan-2-ol was prepared from 2,6-dimethyl-1-bromobenzene and taken through to N-[3-(2,6-dimethoxyphenoxymethyl)-2-(propen-2-yl)phenyl]methyl-N-prop-2-enyl 2-nitrobenzene sulfonamide . However, attempts to cyclise this diene by alkene metathesis were unsuccessful, the open-chain alkene being the only product isolated in yields of up to 70%. In a second approach to the 6-aryloxymethyl-5-hydroxytetrahydrobenzazepin-4-one, methyl (Z)-3-[2-(1-tert-butyldimethylsilyloxymethyl)-6-(1,6-dimethoxyphenoxymethyl)phenyl]but-2-enoate was converted into (Z)-3-[2-hydroxymethyl-6-(2,6-dimethoxyphenoxymethyl)phenyl]but-2-enyl 2-nitrobenzene sulfonamide which was cyclised under Mitsunobu conditions to the corresponding 2,3-dihydro-[1H]-2-benzazepine . The structure of this was confirmed by an X-ray crystal structure of its 2-(4-bromophenylsulfonyl) analogue , and functional group modification including hydroxylation, attachment of the requisite side-chain at C(2) and further oxidation gave the target compound which was assayed for muscarinic (M(3)) activity.     

水介质中9,10-二芳基吖啶的洁净合成

水介质中在十二烷基磺酸钠(SDS)催化下, 席夫碱与双甲酮反应合成了一系列9,10-二芳基吖啶衍生物, 同时分离得到一种中间产物. 所有产物的结构通过红外光谱和1H NMR光谱确定, 产物10-(4-氯苯基)-9-(4-甲氧基苯基)-3,3,6,6-四甲基-3,4,6,7,9,10-六氢化吖啶-1,8(2H,5H)-二酮(3i)和中间产物2-{4-氯苯基-[2-(4-甲氧基苯基氨基)-4,4-二甲基-6-氧代环已-1-烯基]甲基}-3-羟基-5,5-二甲基环已-2-烯酮(4h)的结构还通过单晶X射线衍射分析确证.     

Heterocyclization of 1,1-dicyano-2-(trifluoromethyl)ethylenes with 1,3,3-trimethyl-3,4-dihydroisoquinoline and its derivatives

1,3,3-Trimethyl-3,4-dihydroisoquinolines react with 1,1-dicyano-2,2-bis(trifluoromethyl)ethylene to give 4-amino-6,6-dimethyl-2,2-bis(trifluoromethyl)-3-cyano-6,7-dihydro-2H-benzo[a]quinolizines. The reaction of 3,3-dimethyl-1-cyanomethylidene-1,2,3,4-tetrahydroisoquinoline and the methyl ester of 3,3-dicyano-2-(trifluoromethyl)acrylic acid leads to 5,5-dimethyl-3-oxo-2-(trifluoromethyl)-2-(dicyanomethyl)-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline.A. N. Nesmeyanov Institute of Heteroorganic Compounds, Russian Academy of Sciences, 117813 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 8, pp. 1888–1892, August, 1992.     

Features of the reaction of 3,4-dihydroxy-6-oxo-2,4-alkadienoic acid esters with acetone and <Emphasis Type="Italic">p</Emphasis>-toluidine

Three-component reactions of 3,4-dihydroxy-6-oxo-2,4-alkadienoic acids with acetone and p-toluidine were studied; their specific feature was the formation of the regioisomeric esters of 4-hydroxy-2,2-dimethyl-1-(4-methylphenyl)-5-(2-oxoalkyliden)-2,5-dihydro-1H-pyrrole-3-carboxylic acids and [4-alkanoyl-3-hydroxy-5,5-dimethyl-1-(4-methylphenyl)-1,5-dihydro-2H-pyrrol-2-ylidene]acetic acid. Structure of the synthesized compounds was discussed based on the data of IR and ¹H NMR spectroscopy and X-ray diffraction analysis.     

Two new xanthones from the pericarp of Garcinia mangostana

Two new xanthones, 3-hydroxy-6-methoxy-5'-isopropyl-4',5'-dihydrofuro[2',3'?:?7, 8]-6″,6″-dimethyl-4″,5″-dihydropyrano[2″,3″?:?1,2]xanthone (1) and 1,6-dihydroxy-7-methoxy-8-(3-methylbut-3-enyl)-6',6'-dimethyl-4',5'-dihydropyrano[2'3'?:?3,2]xanthone (2), were isolated from the pericarp of Garcinia mangostana. Their structures were elucidated by spectral means (1-D and 2-D NMR, MS).     

Xanthones from Garcinia mangostana (Guttiferae)

Studies on the stem of Garcinia mangostana have led to the isolation of one new xanthone mangosharin (1) (2,6-dihydroxy-8-methoxy-5-(3-methylbut-2-enyl)-xanthone) and six other prenylated xanthones, alpha-mangostin (2), beta-mangostin (3), garcinone D (4), 1,6-dihydroxy-3,7-dimethoxy-2-(3-methylbut-2-enyl)-xanthone (5), mangostanol (6) and 5,9-dihydroxy-8- methoxy-2,2-dimethyl-7-(3-methylbut-2-enyl)-2H,6H-pyrano-[3,2-b]-xanthene-6-one (7). The structures of these compounds were determined by spectroscopic methods such as 1H NMR, 13C NMR, mass spectrometry (MS) and by comparison with previous studies. All the crude extracts when screened for their larvicidal activities indicated very good toxicity against the larvae of Aedes aegypti. This article reports the isolation and identification of the above compounds as well as bioassay data for the crude extracts. These bioassay data have not been reported before.     

The synthesis of ventiloquinone L, the monomer of cardinalin 3

Readily available ethyl-4-acetoxy-6,8-dimethoxynaphthalene-2-carboxylate was converted into 1-[3-allyl-4-(benzyloxy)-6,8-dimethoxy-2-naphthyl)-1-ethanol in seven steps. Subjection of this compound to Wacker oxidation conditions provided 5-benzyloxy-7,9-dimethoxy-1,3-dimethyl-1H-benzo[g]isochromene in good yield. Hydrogenation of the isochromene afforded (+/-)-cis-7,9-dimethoxy-1,3-dimethyl-1H-benzo[g]isochroman-5-ol as the major product, which was readily converted into ventiloquinone L.