Facile conversion of 2-azetidinones to 2-piperidones: application to a formal synthesis of Prosopis and Cassia alkaloids

Nonracemic 5,6-disubstituted 2-piperidones were prepared from readily accessible 3,4-disubstituted-2-azetidinones having pre-installed substituents by reductive ring opening of 2-azetidinones followed by stereoselective installation of Z-α,β-unsaturated ester and lactam formation. For the synthetic application to the naturally occurring piperidine alkaloids, such as Prosopis and Cassia alkaloids, 5-hydroxy-2-piperidones (+)-13 and (−)-24 were prepared from 2-azetidinones (−)-6b and (+)-18 via two-carbon ring homologation.     

N-Nosyl as a stereoselectivity-improving and easily removable group in the O-glycosylation of d-allal and d-galactal-derived allyl aziridines. Stereospecific synthesis of 4-amino-2,3-unsaturated-O-glycosides

The glycosylation of alcohols, phenol, and partially protected monosaccharides with the diastereoisomeric d-allal and d-galactal-derived N-nosyl aziridines 2α and 2β leads to the corresponding 4-N-(nosylamino)-2,3-unsaturated-α-O- (6α) and β-O-glycosides and disaccharides (6β), respectively, in a stereospecific substrate-dependent O-glycosylation process. The N-(nosylamino) group of 6α and 6β can easily be deprotected to give the corresponding 4-amino-2,3-unsaturated-O-glycosides 7α and 7β, with an increased value to our glycosylation protocol.     

Transformations of hispanolone. Novel Michael adducts with in planta activity against rice blast

Two novel Michael adducts 9α-cyano-15,16-epoxy-7β-hydroxylabda-13(16),14-dien-6-one (2) and 9α-cyano-15,16-epoxy-7-hydroxylabda-7,13(16),14-trien-6-one (3) and the reduction product of 2, 9α-cyano-15,16-epoxy-6β,7β-dihydroxylabda-13(16),14-diene (4), were synthesized from the naturally occurring labdane diterpene hispanolone (1). Compounds 2-4 exhibited in planta activity against the pathogenic rice blast fungus Magnaporthe grisea.     

Synthesis of d-gluco-, l-ido-, d-galacto-, and l-altro-configured glycaro-1,5-lactams from tartaric acid

The d-gluco-, l-ido-, d-galacto-, and l-altro-configured glycaro-1,5-lactams 1-4 were prepared from the known tartaric anhydride 5 via the aldehyde 6. These lactams are known (1) or potential (2-4) inhibitors of β-d-glucuronidases and α-l-iduronidases. Olefination of 6 to the (E)- and (Z)-alkenes 7 or 8, followed by reagent or substrate controlled dihydroxylation, lactonization, azidation, reduction, and deprotection led in 10 steps and in overall yields of 11-20% to the title lactams.     

Asymmetric synthesis of the 6-cyanoindole derivatives as non-steroidal glucocorticoid receptor modulators using (+)- and (−)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate

We have successfully synthesized enantiomerically pure (+)- and (−)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate (+)-1 and (−)-1, which are key intermediates of non-steroidal glucocorticoid receptor modulators, by employing a cinchona alkaloid catalyzed addition of 6-cyanoindole to ethyl trifluoropyruvate. The optimized method can be applied to large-scale synthesis. Furthermore, using the key intermediates (+)-1 and (−)-1, enantiomerically pure glucocorticoid receptor modulators (+)-3 and (−)-3 can be synthesized (>99% ee for both compounds). The glucocorticoid receptor binding affinity was influenced by the stereogenic center at the trifluoromethyl alcohol moiety; compound (−)-3 showed a higher binding affinity compared to (+)-3.     

Tandem reduction-olefination of triethyl 2-acyl-2-fluoro-2-phosphonoacetates and a synthetic approach to Cbz-Gly-Ψ[(Z)-CFC]-Gly dipeptide isostere

(Z)-α-Fluoro-α,β-unsaturated esters (Z)-7a-f were stereoselectively prepared by a tandem reduction-olefination of triethyl 2-acyl-2-fluoro-2-phosphonoacetates 6a-f with NaBH₄ in EtOH. A concise synthesis of Cbz-Gly-Ψ[(Z)-CFC]-Gly (26) as a dipeptide isostere was achieved via the tandem reduction-olefination of the corresponding 2-acyl-2-fluoro-2-phosphonoacetate 20.     

Effect of α-fluorination on asymmetric epoxidation of trans-olefins using α-fluorinated cyclohexanone dioxiranes

Epoxidations of trans-β-methylstyrene, trans-stilbene and trans-methyl p-methoxycinnamate using chiral dioxiranes derived from both enantiopure diastereomers of α-fluoro cyclohexanones, (2S, 5R)-3a-6a and (2R, 5R)-3e-6e are studied and compared. From ab initio calculations at the HF/6-31G^∗ level of conformational inter-conversion for (2S, 5R)-D5a and (2R, 5R)-D5e dioxiranes it was found that, due to the α-fluorine atom, conformer K1 is more stable in the case of (2S, 5R)-D5a while conformer K2 is more stable in the case of (2R, 5R)-D5e. However, in both cases, the more stable conformers, K1 and K2, undergo rapid inter-conversion. Therefore, based on slow epoxidation reactions and rapid ring inversion of six-membered ring dioxiranes the Curtin-Hammett principle holds. Conformation K2 with axial fluorine having been found to be more reactive, the inversion of configuration observed for the epoxides obtained with ketones 3e-6e (compared with ketones 3a-6a) could be rationalized from competitive reactions of K2 and K1 conformations leading to simultaneous production of both (−) and (+) epoxides in the case of ketones 3e-6e.     

A new approach for the asymmetric syntheses of 2-epi-deoxoprosopinine and azasugar derivatives

A new approach to 2-epi-deoxoprosopinine 11, 1-deoxygulonojirimycin 7, and l-gulono-1,5-lactam 9 was described. The C-2 hydroxymethyl group was introduced regioselectively using SmI₂ mediated coupling of (S)-3-silyloxyglutarimide 13b with either chloromethyl benzyl ether 16a or the Beau-Skrydstrup reagent 16b, followed by debenzylation and highly cis-diastereoselective reductive deoxygenation. Adoption of the Savoi's chemoselective ring-opening alkylation method allowed a highly diastereoselective introduction of the lipid side chain of 2-epi-deoxoprosopinine 11 in a straightforward manner. Dehydration followed by highly trans-diastereoselective dihydroxylation led to polyoxygenated lactam derivative 27 as a key intermediate for the syntheses of 7 and 9.     

Formation of chiral tertiary homoallylic alcohols via Evans aldol reaction or enzymatic resolution and their influence on the Sharpless asymmetric dihydroxylation

Enantioenriched tertiary homoallylic alcohol derivatives (S)-2c and (S)-2a were obtained via Evans aldol methodology and enzymatic resolution of racemic tertiary acetate 2e, respectively. In order to study asymmetric 1,3-induction of the stereogenic center present in 2, congener (R)-2a as well as its O-protected derivatives (R)-2b-d were submitted to Sharpless asymmetric dihydroxylation to yield the diastereomeric 1,2,4-triol derivatives (2R,4R)- and (2S,4R)-3a-d, revealing that neither the substrate nor the Sharpless catalyst exert any stereocontrol. Similar observations were made for the less bulky alkynyl-substituted derivative 12b. However, by using a directed dihydroxylation, the anti product (2R,4R)-3a was favored.     

The first synthesis of secondary sugar sulfonic acids by nucleophilic displacement reactions

The 4-deoxy-4-C-sulfonic acid and 6-deoxy-6-C-sulfonic acid derivatives of methyl α-d-gluco- and α-d-galactopyranosides were prepared by triflate-mediated nucleophilic displacement reactions, either with NaHSO₃ or with AcSK. The triflate esters of methyl 2,3,4-tri-O-benzyl- 1, methyl 2,3,6-tri-O-benzyl-α-d-glucopyranoside 9 and methyl 2,3,6-tri-O-benzyl-α-d-galactopyranoside 5 provided methyl 6-deoxy-6-C-sulfo-α-d-glucopyranoside 4, methyl 4-deoxy-4-C-sulfo-α-d-galactopyranoside 12 and α-d-glucopyranoside 8, respectively. The triflate derivative of methyl 2,3,4-tri-O-benzyl-α-d-galactopyranoside 13 gave methyl 3,6-anhydro-2,4-di-O-benzyl-α-d-galactopyranoside 14. Formation of the 3,6-anhydro derivative was prevented by using 3,4-O-isopropylidene acetal protection to obtain methyl 6-deoxy-6-C-sulfo-α-d-galactopyranoside 19. The aim of the research is to replace the sulfate esters by sulfonic acids in the repeating oligosaccharide units of glycosaminoglycans or in different oligosaccharide ligands.     

5,10:13,14-Disecosteroids: novel modified steroids containing 10- and 9-membered rings

In this paper a synthetic pathway to the modified 5,10:13,14-bisfragmentation cholestane derivatives 8-14 is described. The synthesis involves introduction of the 5α- and 14α-hydroxyl groups in the cholestane molecule and subsequent cleavage of the C(5)-C(10) bond in 5α,14α-dihydroxycholestan-3β-yl acetate (4) with the HgO/I₂ reagent and the C(13)-C(14) bond in the stereoisomeric 14α-hydroxy-5,10-secosteroids 5 and 6 with the Pb(OAc)₄/I₂ reagent. Complete and unambiguous ¹H and ¹³C NMR resonance assignments of the obtained secosteroids, as well as the solution conformations of their 10- and 9-membered rings were determined by extensive analysis of 1D and 2D NMR spectral data. The structures and the solid-state conformations of 5,10-secosteroids 5-7 were confirmed by X-ray analysis. All diseco-compounds have a novel 5,10:13,14-disecocholestane skeleton.     

Synthesis of enantiomerically pure Sb-chirogenic organoantimony compounds and their crystal structures

Sb-chirogenic organoantimony compounds (±)-5a-c bearing heteroatom moieties such as 4,4-dimethyl-2-oxazolinyl, methoxymethyl, and diphenylphosphanyl substituents on the o-position of an aryl group have been prepared by nucleophilic displacement of the ethynyl moiety on (1-naphthyl)(phenylethynyl)(p-tolyl)stibane (3) with aryllithium reagents (2a-c). The optical resolution of the racemic (±)-5a,b was attained via separation of a diastereomeric mixture of their palladium complexes (S)-7 formed from the reactions of (±)-5a,b with di-μ-chlorobis[(S)-dimethyl(1-ethyl-α-naphthyl)aminato-C²,N]dipalladium(II) (6). The enantiomerically pure Sb-chirogenic stibanes isolated here were optically stable, and no racemization on the chiral antimony center was observed even when they were allowed to stand at room temperature for over 72 h in chloroform. The structure of 5a,b including the absolute configuration was determined by single crystal X-ray analyses of (+)-5aB and antimony-palladium complex (7bB), respectively. The analyses also revealed the presence of intramolecular interaction between the antimony and sp²-nitrogen atoms in the molecule Sb(S)-(+)-5aB.     

Synthesis and characterization of novel pyridyl/naphthyl/(diphenyl)methylseleno substituted alkanoic acids: X-ray structure of 2-pyridylselenoethanoic acid, 2-naphthylselenoethanoic acid and 2-(diphenyl)methylselenoethanoic acid

A number of novel and synthetically important pyridyl/naphthyl/(diphenyl)methylseleno substituted alkanoic acids (20-25) have been synthesized using an efficient and operationally simple strategy. Starting substrates, ethyl pyridyl/naphthyl/(diphenyl)methylseleno substituted alkanoates (8-13) were easily prepared by treatment of ethyl chloroalkanoates 7(a-c) with nucleophilic selenium reagent RSeNa⁺, generated from the cleavage of dipyridyl/dinaphthyl/bis(diphenylmethyl) diselenide (1-6) with sodium borohydride in ethanol. The ethyl pyridyl/naphthyl/(diphenyl)methylseleno substituted alkanoates (8-13) on basic hydrolysis and subsequent acidification afford pyridyl/naphthyl/(diphenyl) methylseleno substituted alkanoic acids (20-25) in excellent yields. These selenoalkanoates (8-13) and selenoalkanoic acids (20-25) have been characterized by elemental analysis and various spectroscopic techniques viz. NMR (¹H, ¹³C and ⁷⁷Se), IR and mass spectrometry. The molecular structure of 2-pyridylselenoethanoic acid (20a), 2-naphthylselenoethanoic acid (23a) and 2-(diphenyl)methylselenoethanoic acid (24a) has also been established with the help of single crystal X-ray analysis.     

A novel dynamic kinetic resolution accompanied by intramolecular transesterification: asymmetric synthesis of a 4-hydroxymethyl-2-oxazolidinone from serinol derivatives

Reaction paths of the one-pot reaction of (R)-2-(α-methylbenzyl)amino-1,3-propanediol (1) and 2-chloroethyl chloroformate with DBU giving (4S,αR)-4-hydroxymethyl-3-(α-methylbenzyl)-2-oxazolidinone [(4S)-2] (94% de) were investigated. Intermediates of this reaction, 2-chloroethyl (2S)- and 2-chloroethyl (2R)-3-hydroxy-2-[(αR)-α-methylbenzyl]aminopropyl carbonates [(2S)-4 and (2R)-4], were synthesized individually. After the addition of DBU to the respective solution of the carbonate (2S)-4 and that of (2R)-4 in dichloromethane, the intramolecular transesterification between (2S)-4 and (2R)-4 and the diastereoselective intramolecular cyclization proceeded to afford (4S)-2 in high diastereomeric excess. Therefore, two monocarbonates (2S)-4 and (2R)-4 were kinetically resolved by this cyclization during the intramolecular transesterification between (2S)-4 and (2R)-4. We found that this process involved dynamic kinetic resolution accompanied by intramolecular transesterification.     

Steroid-based head-to-tail amphiphiles as effective iono- and protonophores

The synthesis of five steroid-oligo(ethyleneglycol) conjugates (1-5) has been accomplished starting from commercially available epi-androsterone (8) and known 3β-[(tert-butyldiphenylsilyl)oxy]-5α-23,24-bisnorchol-16-en-6α,7β,22-triol (27). The synthetic strategy was based on a convergent approach including stereoselective C-17 side chains construction and standard coupling reactions. The activities of the head-to-tail amphiphiles, once incorporated in 95:5 egg PC/PG vesicular membranes, have been assessed by direct determination of transported species by NMR techniques (²³Na⁺) and fluorescence spectroscopy (H⁺). The sodium and proton transmembrane transport was compared to those evaluated for the polyene macrolide antibiotic amphotericin B and those shown by the known related C₂-symmetric sterol-polyether conjugates 6 and 7.     

Naphthyridines. Part 3: First example of the polyfunctionally substituted 1,2,4-triazolo[1,5-g][1,6]naphthyridines ring system

Treatment of 1,2,4-triazoles (1) with diethylmalonate in bromobenzene gave 1,2,4-triazolo-[1,5-a]pyridines 2. Chlorination of 2 using POCl₃/DMF (Vilsmeier reagent) led to the isolation of 7-chloro-6-formyl-1,2,4-triazolo[1,5-a]pyridine derivative 4, which reacted with the stabilized ylid 5 to afford 6-ethoxycarbonylvinyl-1,2,4-triazolo[1,5-a]-pyridines 6. Azidation of 6 yielded the corresponding azido compound 7, (Scheme 2). Reduction of 7 with Na₂S₂O₄ gave the corresponding 7-amino compound 8, which cyclized in boiling DMF to give the novel 1,2,4-triazolo[1,5-g][1,6]naphthyridines 9. On the other hand, reacting 7 with one equivalent of PPh₃ (aza-Wittig reaction) in CH₂Cl₂ gave 7-imino-phosphorane derivative 10, and subsequent cyclization in boiling DMF afforded the new 1,2,4-triazolo[1,5-g][1,6]naphthyridine derivative 11 (Scheme 3). However, treatment of 10 with phenyl isothiocyanate in 1,2-dichlorobenzene at reflux temperature gave the new 1,2,4-triazolo[1,5-g][1,6]naphthyridine derivative 14 (Scheme 4). Refluxing 6 with excess of a primary amines 15a,b in absolute. EtOH yielded the corresponding 7-alkyl-amino-1,2,4-triazolo[1,5-a]pyridines 16a,b. These obtained amines 16a,b underwent intramolecular heterocyclization in boiling DMF to give the novel 9-alkyl-1,2,4-triazolo[1,5-g][1,6]-naphthyridines 17a,b, in excellent yields (Scheme 5).     

The microbiological transformation of steroidal saponins by Curvularia lunata

The microbiological transformation of polyphyllin I (compound I), polyphyllin III (compound II), polyphyllin V (compound III) and polyphyllin VI (compound IV) by Curvularia lunata into their corresponding subsaponins, for example, diosgenin-3-O-α-l-arabinofuranosyl (1→4)-β-d-glucopyranoside (compound V), diosgenin-3-O-α-l-rhamnopyranosyl (1→4)-β-d-glucopyranoside (compound VI), diosgenin-3-O-β-d-glucopyranoside (compound VII) and pennogenin-3-O-β-d-glucopyranoside (compound VIII), were studied in this paper. Curvularia lunata is able to hydrolyze terminal rhamnosyls that are linked by 1→2 C- bond to sugar residues of steroidal saponins at C-3 position with high activity and regioselectivity.     

Preparation of both enantiomers of β-(3,4-dihydroxybenzyl)-β-alanine, higher homologues of Dopa

β²-(3,4-Dihydroxybenzyl)-β-alanine [β²-Homo-Dopa, 1] is a novel β-amino acid homologue of Dopa, the most successful therapeutic agent in the treatment of Parkinson's disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of β-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired β-amino acids were purified by silica gel chromatography. Alternatively, enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-chain β-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary α-phenylethylamine. Finally, nearly enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-3-aminopropionic acid, rac-12, with (R)- or (S)-α-phenylethylamine, followed by catalytic hydrogenolysis.     

Facile generation method for conjugated allenyl esters based on retro-Dieckmann-type ring-opening reactions

α-Alkynyl-α-ethoxycarbonyl cyclopentanones 1a-c and cyclohexanones 2a-c were readily synthesized by the reaction of ethyl 2-oxocyclopentanonecarboxylate 6 and ethyl 2-oxocyclohexanonecarboxylate 7 with alkynyllead triacetates 5a-c obtained from lithium acetylides 4a-c and lead tetraacetate. Treatment of 1a-c and 2a-c with 1 N KOH in THF or with n-Bu₄N⁺OEt⁻ in EtOH and THF gave the corresponding conjugated allenyl esters 8a-c, 9a-c, 10a-c, and 11a-c in good to excellent yields, respectively.     

Bis-spiro-azaphilones and azaphilones from the fungi Chaetomium cochliodes VTh01 and C. cochliodes CTh05

Four new dimeric spiro-azaplilones, cochliodones A-D (1-4), two new azaphliones, chaetoviridines E and F (5 and 6), a new epi-chaetoviridin A (7), together with five known compounds, chaetoviridin A (8), ergosterol (9), chaetochalasin A (10), 24(R)-5α,8α-epidioxyergosta-6-22-diene-3β-ol (11), and ergosterol-β-d-glucoside (12) were isolated from the fungi Chaetomium cochliodes VTh01 and C. cochliodes CTh05. Structures and stereochemistry of the atropisomers 1-3 were determined by single-crystal X-ray diffraction analysis. Compounds 5, 10, and 11 exhibited antimalarial activity against Plasmodium falciparum, while 3, 5, 6, 10, and 11 showed antimycobacterial activity against Mycobacterium tuberculosis. In addition, 5 and 6 also showed cytotoxicity against the KB, BC1, and NCI-H187 cell lines.