Unprecedented single-pot protocol for the synthesis of N1, C6-linked bicyclic 3,4-dihydropyrimidinones via lithiation of Biginelli compounds

4-Aryl/alkyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one ester derivatives readily undergo metalation at the C6 methyl (vinylogous ester) position along with two acidic NHs upon treatment with n-butyllithium at −10 °C. The trianion of DHPMs thus obtained react smoothly with various terminal dibromoalkanes to afford N1, C6-linked bicyclic DHPM derivatives, which represent key structural features of the medicinally potent marine alkaloids such as batzelladine A and crambescin A.     

Regioselective addition reactions at C-2 of 3,4-dihydropyrimidinones. Synthesis and evaluation of multifunctionalized tetrahydropyrimidines

Multifunctionalized tetrahydropyrimidines derivatives have been synthesized from Biginelli 3,4-dihydropyrimidin-2-(1H)-thiones (DHPMs) efficiently. The transformation includes desulfurization of DHPMs with Raney-Ni and subsequent regioselective C-2 functionalization using a variety of C-nucleophiles with simultaneous activation with ethyl chloroformate. Functionalized pyrimidine derivatives containing bulky substituents at C-2 of the pyrimidine ring are cytostatic.     

Preparation of vinylogous 2-sulfonylindolines by the palladium-catalyzed heteroannulation of o-iodoanilines with dienyl sulfones and their further transformation to indoles and carbazoles.

The palladium-catalyzed heteroannulation of o-iodoanilines with dienyl sulfones provides a convenient route to vinylogous 2-sulfonylindolines 3. The reaction proceeds in DMF/water in the presence of potassium carbonate and catalytic palladium(II) acetate and is compatible with both electron-donating and -withdrawing substituents in the para position of the aniline, and with an alkyl substituent at C-2 of the dienyl sulfone. The indolines underwent oxidation with DDQ to afford the corresponding indoles 4. The latter were then employed as dienes in Diels-Alder reactions with dimethyl acetylenedicarboxylate (DMAD), methyl propiolate, or methyl acrylate. In the case of the latter two dienophiles, the cycloadditions were highly regioselective, affording the corresponding 1,3-products (with respect to the relative positions of the sulfone and ester groups), exclusively. The cycloadducts from acetylenic dienophiles were converted to the corresponding carbazoles by elimination of the sulfone moiety with DBU, and that from methyl acrylate was subjected to reductive desulfonylation and oxidation to the corresponding carbazole with DDQ. The method thus provides access to carbazoles with various substituents at the 3-, 4-, and 6-positions.     

Acid-catalysed rearrangements of steroid alkenes-III1. backbone rearrangement of de-a-steroid alkenes and preparation of an aromatic de-a-steroid.

Backbone rearrangement of 10a(methyl)-de-A-cholest-5-ene (3c), 6-ene (3d), 9-ene (3s) and 5(10)-ene (3b) affords products isomeric at C-20 and with the C-10 methyl group in the more stable equatorial position (6a. and 6b). 5-Methylene-10a(methyl)-de-A-cholestane (5) affords similar C-20 isomeric products with both the C-5 and C-10 methyls in the more stable equatorial positions (9a and 9b). The de-A-alkenes (3) provided a convenient starting point for preparation of de-A- cholesta-5,7,9-triene (7). Components (6a, 6b, 7, 9a and 9b) have been used to confirm the widespread occurrence of homologous series of de-A-steroids in marine shales with a mild thermal history.     

Versatile routes to C-2- and C-6-functionalized glucose derivatives of iminodiacetic acid

A series of novel d-glucose derivatives, functionalized at the C-2 or the C-6 position with an iminodiacetic acid moiety for transition-metal complexation, has been prepared. The sugar and the metal-chelating parts are separated by either propyl or octyl chains and were introduced by the reaction of bromoalkylamine. Either N-1-Boc-3-bromopropylamine (17) or N-(8-bromooctyl)phthalimide (19) reacted with methyl 3,5,6-tri-O-benzyl-alpha-beta-d-glucofuranoside (4) (C-2 position) and 1,2:3,5-(O-methylene)-alpha-d-glucose (11) (C-6 position), respectively, in the presence of sodium hydride in DMF at room temperature, affording the desired intermediates. For aminopropyl derivatives, yields varied between 57% and 65%, and for aminooctyl derivatives, yields varied between 40% and 71%. After deprotection of the amine functionality, the metal chelate was built up by dialkylation (6a-c and 13a,b) with methyl bromoacetate in the presence of triethylamine under reflux in THF. Yields varied between 56% and 69% for the glucose modified at the C-2 position and between 58% and 62% for the one modified at the C-6 position. All compounds were characterized by 1H or 13C NMR or both, IR, and mass spectroscopy. Final products were isolated as a mixture of alpha and beta anomers.     

An entry to the azocino[4,3-b]indole framework through a dehydrogenative activation of 1,2,3,4-tetrahydrocarbazoles mediated by DDQ: formal synthesis of (±)-uleine

It is presented that hexahydro-1,5-methano[4,3-b]indoles were efficiently synthesized in high yields (up to 89% yield) through the cyclization reaction of starting tetrahydrocarbazoles bearing a monoalkylaminocarbonylmethyl moiety at the C-2 position mediated by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). A mechanistic proposal is also given that mainly includes two cascade reactions: (i) formation of a vinylogous iminium cation via DDQ-mediated dehydrogenation of tetrahydrocarbazole functionality and (ii) intra-molecular and syn-selective addition of the amide functionality as the nucleophile to the vinylogous iminium cation. Furthermore, this cyclization reaction was successfully utilized in the formal total synthesis of (±)-uleine, an Aspidospermatan skeletal type alkaloid.     

Total synthesis and biological evaluation of the nakijiquinones.

The Her-2/Neu receptor tyrosine kinase is vastly overexpressed in about 30% of primary breast, ovary, and gastric carcinomas. The nakijiquinones are the only naturally occurring inhibitors of this important oncogene, and structural analogues of the nakijiquinones may display inhibitory properties toward other receptor tyrosine kinases involved in cell signaling and proliferation. Here, we describe the first enantioselective synthesis of the nakijiquinones. Key elements of the synthesis are (i) the reductive alkylation of a Wieland-Miescher-type enone with a tetramethoxyaryl bromide, (ii) the oxidative conversion of the aryl ring into a p-quinoid system, (iii) the regioselective saponification of one of the two vinylogous esters incorporated therein, and (iv) the selective introduction of different amino acids via nucleophilic conversion of the remaining vinylogous ester into the corresponding vinylogous amide. The correct stereochemistry and substitution patterns are completed by conversion of two keto groups into a methyl group and an endocyclic olefin via olefination/reduction and olefination/isomerization sequences, respectively. This synthesis route also gave access to analogues of nakijiquinone C with inverted configuration at C-2 or with an exocyclic instead of an endocyclic double bond. Investigation of the kinase-inhibiting properties of the synthesized derivatives revealed that the C-2 epimer 30 of nakijiquinone C is a potent and selective inhibitor of the KDR receptor, a receptor tyrosine kinase involved in tumor angiogenesis. Molecular modeling studies based on the crystal structure of KDR and a model of the ATP binding site built from a crystal structure of FGF-R revealed an insight into the structural basis for the difference in activity between the natural product nakijiquinone C and the C-2 epimer 30.     

Cyclization into hydrindanones using samarium diiodide

Samarium(II) iodide has been employed to promote vinylogous pinacol coupling reaction of aldehyde onto alpha,beta-unsaturated ketones. The diastereoselectivity of 6-endo products was changed by addition of a proton source and/or HMPA and by the reaction temperature. The cyclization reactions described herein provide a general approach to the syntheses of 3,3-dimethylhydrindanes with a cis-relationship between the OH at C-4 and the proton at C-3a with good diastereoselectivity and under mild reaction conditions.     

Cal-B-catalyzed alkoxycarbonylation of a-ring stereoisomeric synthons of 1alpha,25-dihydroxyvitamin D3 and 1alpha,25-dihydroxy-19-nor-previtamin D3: a comparative study. first regioselective chemoenzymatic synthesis of 19-nor-A-ring carbonates

A comparative study of alkoxycarbonylation processes of both 19-nor-A-ring and A-ring stereoisomers of 1alpha,25-dihydroxyvitamin D3 analogues catalyzed by Candida antarctica lipase B (CAL-B) has been described. The presence of the methyl group in the A-ring at C-2, as in 3-6, has a determining role in the regioselectivity of the biocatalysis, mainly allowing the hydroxyl group at C-5 position to react. For the 19-nor-A-ring stereoisomers 7-10, which lack the C-2 methyl group, the configurations at C-3 and C-5 have a high influence in the selectivity exhibited by CAL-B. Thus, each couple of enantiomers showed opposing regioselectivities depending on the C-3 configuration. When C-3 possesses an (S)-configuration, enzymatic alkoxycarbonylations took place at the C-5-(R) or C-5-(S) hydroxyl groups. However, if the chiral centers at C-3 are (R), CAL-B alkoxycarbonylated the C-3-(R) hydroxyl group independently of the configuration at C-5. The corresponding carbonates are useful A-ring precursors of 1alpha,25-dihydroxyvitamin D3 analogues, selectively modified at the C-1 or C-3 positions. In addition, an improved synthesis of cis A-ring synthons 5 and 6 is described using a Mitsunobu methodology.     

Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach

Inherently racemic DHPMs have been resolved using chemical resolution methodology by appending enantiopure chiral auxiliary at N-1 or N-3 position of the DHPMs, leading to the formation of both diastereomers, which were separated chromatographically to obtain both enantiomers (ee upto 99.9%) of DHPMs, after removal of the auxiliary. Absolute configuration of the enantiomers has been assigned.     

8-Methyl-7-substituted-1,6-naphthyridine-3-carboxylic acids as New 6-desfluoroquinolone antibacterials

1,6-Naphthyridine-8-methyl-7-substituted-3-carboxylic acids were synthesized as new 6-desfluoro-quinolone antibacterials in which the usual fluorine atom at C-6 position was replaced by an endocyclic nitrogen atom. Comparing the antibacterial activity of these 6-azaquinolones with our previous 6-amino and 6-hydrogen counterparts, they resulted always less active. However, the presence of methyl group at C-8 position ensure good Gram-positive antibacterial activity, with minimum inhibitory concentrations values on the same order of ciprofloxacin for piperidinyl derivative 3d and tetrahydroisoquinolinyl derivative 3c.     

Substitution of 6-aminopenicillanic acid at the 6 carbon atom

The hydroxyalkylation of the penicillin nucleus at C-6 with benzaldehyde and formaldehyde is reported. 6-aminopenicillanic acid (6-APA) ( 2 ) was used as starting material. Protection of the functional groups and activation of the C-6 position were effected by converting 6-APA successively into the Schiff base 13 , the methyl ester 14 and the copper complex 15 . The latter gave with benzaldehyde the C-6 monosubstituted complex 17 , and with formaldehyde the disubstituted complex 18 . The direct α-hydroxybenzylation of 6-APA at C-6 was also carried out with an excess of benzaldehyde at pH 7,5 leading to the SCHIFF base 19 . Mild hydrolysis of 19 gave 6-amino-6-(α-hydroxybenzyl)-penicillanic acid ( 21 ). Phenylacetylation of the latter yielded the penicillin G analogue 22 . Direct reaction of 6-APA with formaldehyde took place only in the presence of salicylaldehyde, giving the oxazolidine 24 , from which the amino acid 25 could not be obtained. The new compounds showed only weak antibacterial activity as compared with penicillin G.     

Synthesis and evaluation of 2-Nonylaminopyridine derivatives as PPAR ligands

To find novel PPAR ligands, we prepared several 3-{3 or 4-[2-(nonylpyridin-2-ylamino)ethoxy]phenyl}propanoic acid derivatives which were designed based on the structure of our previous PPARgamma ligand 1. In PPAR binding affinity assays, compound 4, which had an ethoxy group at the C-2 position of the propanoic acid of 1, showed selective binding affinity for PPARgamma. Compound 3, with an ethyl group at the C-2 position, was found to be a PPARalpha/gamma dual ligand. Compound 6, the meta isomer of 1, has been shown to be a PPARalpha ligand. The introduction of methyl (7) and ethyl (8) groups to the C-2 position of the propanoic acid of 6 further improved PPARalpha-binding potency. In cell-based transactivation assay, compounds 3 and 4 showed dual-agonist activity toward PPARalpha and PPARgamma. Compound 6 was found to be a triple agonist and compound 8 proved to be a selective PPARalpha agonist. In the human hypodermic preadipocyte differentiation test, it was demonstrated that the maximal activity of compounds 3 and 4 was higher than that of rosiglitazone.     

Bioconversion of ilicic alcohol and derivatives with cultures of filamentous fungi

Aspergillus niger cultures monohydroxylate ilicic alcohol in C-3 in a cis position with respect to the methyl groups at C-4 and C-10, and trans position with respect to the hydroxyl group of C-4. Furthermore, Aspergillus niger cultures reduce ilicic aldehyde to its corresponding alcohol.     

Anticancer effect of A-ring or/and C-ring modified oleanolic acid derivatives on KB, MCF-7 and HeLa cell lines

New A-ring or/and C-ring modified methyl oleanolate derivatives were prepared. New simple method of synthesis of 3,12-diketone (3) from methyl oleanonate (2) was worked out. The obtained new compounds were tested for cytotoxic activity on KB, MCF-7 and HeLa cell lines. The derivatives had acetoxy, oxo or hydroxyimino function at the C-3 position and in some cases oxo, hydroxyimino or acyloxyimino group at the C-12 position. Almost all of the compounds showed strong cytotoxic activity, higher than unchanged oleanolic acid. The most active substances turned out to be the derivatives with acyloxyimino function, especially 4 and 8d.     

Aza- and carbo-[3+3] annulations of exo-cyclic vinylogous amides and urethanes. Synthesis of tetrahydroindolizidines and an unexpected formation of hexahydroquinolines

[3+3] Annulations of exo-cyclic vinylogous amides and urethanes with vinyl iminium salts are described here. We observed an intriguing dichotomy in their reaction pathways. For pyrrolidine- and azepane-based vinylogous amides or urethanes, aza-[3+3] annulation would dominate to give tetrahydroindolizidines, whereas, unexpectedly, for piperidine-based vinylogous amides or urethanes, carbo-[3+3] annulation was the pathway, leading to hexahydroquinolines. The origin for such a contrast is likely associated with a switch in the initial reaction pathway between C-1,2-addition and C-1,4-addition.     

Preparation of glycine-conjugated bile acids and their gas/liquid chromatographic analysis on an aluminum-clad flexible fused silica capillary column.

This paper describes a method for the direct gas/liquid chromatographic (GC) analysis of 46 glycine-conjugated bile acids, which differ from one another in the number, position and configuration of the hydroxyl groups at positions C-2, C-3, C-4, C-6, C-7 and/or C-12. Free bile acids were converted quantitatively on a micro scale to ethyl ester-trimethylsilyl (Et-TMS) and methyl ester-dimethylethylsilyl (Me-DMES) ether derivatives of the corresponding glycine conjugates. The Et-TMS and Me-DMES ethers of the glycine conjugates were chromatographed on an aluminum-clad flexible fused silica capillary column coated with a thin film (0.1 micron) of chemically bonded and cross-linked methylpolysiloxane. Relative retention time (RRT) and methylene unit (MU) values were determined for the 46 compounds and their GC behaviour was discussed. The derivatization procedure and the retention data would be useful for the direct GC identification of unknown glycine-conjugated bile acid mixtures extracted from biological samples.     

Reversed-phase high-performance thin-layer chromatography of mono-, di- and trisubstituted bile acid methyl esters

A comparative study is reported on separation of series of mono-, di-, and trisubstituted methyl 5β-cholanates, which differ only in the position and stereochemistry of hydroxyl or keto groups at position and stereochemistry of hydroxyl or keto groups at positions C-3, C-7, and/or C-12, by reversed-phase [with chemically-bonded (C-18) silica gel] and normal-phase (silica gel) high-performance thin-layer chromatography (HPTLC). Methnol (or acetonitrile)/water systems were employed as mobile phase. Reversed-phase HPTLC found to be particulary effective for separation of the stereoisomers of di- and trisubstituted compounds whereas the less polar monosubstituted isomers are well resolved in normal-phase HPTLC.     

Manganese(III) Acetate Oxidation of Alkyl Substituted 1-(Phenylsulfonyl)indoles

Methyl substituted 1-(phenylsulfonyl)indolines undergo tandem oxidation of the indoline ring and a C-2 methyl group. If there is no alkyl substituent at the C-2 position, nuclear acetoxylation can occur to afford oxindoles.     

Functicnalization of 4-Hydroxy-6-Methyl-2-Pyrone at C-5 Through [2,3] Sigmatropic Rearrangements of Allylic Sulphonium Ylides

Functionalization at C-5 of the triacetic acid lactone methyl ether, 7, has been achieved by a transfer from the C-6 position. Thus, treatment of sulfides 12 with an excess of ethyl diazoaceta-te provides the pyrones 15 through [2,3] sigmatropic rearrangements.