Synthesis of 5-endo-, 5-exo-, 6-endo- and 6-exo-hydroxylated analogues of epibatidine

A convenient, high-yield synthesis of N-Boc-7-azabicyclo[2.2.1]hept-5-en-2-one (7) was developed by SmI₂-mediated desulfonylation of 6. Thus, 5-endo-, 5-exo-, 6-endo-, and 6-exo-hydroxylated epibatidine analogues 2a,b and 3a,b were synthesized from 7 by using a Pd(PPh₃)₄-catalyzed reductive Heck coupling reaction and SmI₂-mediated reduction of the carbonyl group as the key steps. Other reaction conditions for the reductive Heck procedure and the reduction step were also investigated.     

o-(Trialkylstannyl)anilines and their utility in Migita-Kosugi-Stille cross-coupling: direct introduction of the 2-aminophenyl substituent

We have developed shelf- and air-stable ortho-stannylated aniline reagents that can directly be coupled with alkenyl and aryl halides via Migita-Kosugi-Stille cross-coupling. We report (i) the efficient preparation of o-(tributylstannyl)aniline (2a) and o-(trimethylstannyl)aniline (2b), (ii) the comparison of the reactivities of 2a and 2b with those of related organostannanes in cross-coupling reaction with an alkenyl halide, and (iii) the cross-coupling of 2a and 2b with a series of arylhalides and triflate.     

Efficient microwave-assisted synthesis of 1-(1H-indol-1-yl)-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents

New conazole antifungals, in the series of triazole alcohols 23a-d and 24a-e incorporating an indole moiety substituted at 5-position by halogens, a cyano or 4-methoxyphenyl group, have been synthesized by ring opening of corresponding oxiranes 15 and 16. These dihalogeno intermediates and their congeneers could be prepared in high yields by Corey-Chaykovsky reaction under microwave irradiation.     

Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin

A convergent synthesis of (4R,15R,16R,21S)-rollicosin (1) and (4R,15S,16S,21S)-rollicosin (2) was accomplished. Hydroxy lactone 6a and/or 6b were synthesized from 4-pentyn-1-ol, and α,β-unsaturated lactone 7 was synthesized from γ-lactone 8 and 5-hexen-1-ol. Inhibitory activity of these compounds was examined with bovine heart mitochondrial complex I.     

Stereocontrolled conversion of some optically active (4S,5R)-dihydroisoxazoles into acyclic 3-acetamido-1,2-diols

Optically active (4S,5R)-dihydroisoxazoles 5a-c (90-91% ee) have been prepared by reaction of the epoxyketones 4a-c with hydroxylamine. Reduction of compounds 5a and 5b using lithium aluminium hydride took place exclusively from the Re face to give (1R,2S,3S)-1,3-disubstituted-3-aminopropane-1,2-diols 6a and 6b. These amino-diols were characterised by N-acetylation and the stereochemical sense of the hydride reduction was confirmed by conversion of amides 7a and 7b into α-amino acid derivatives 10a and 10b.     

Synthesis, structure and dynamic stereochemistry of (O → Si)-chelate N-(trifluorosilylmethyl)-[N-(S)-(1-phenylethyl)]acetamide and 1-(trifluorosilylmethyl)-2-oxoperhydroazepine: Retention of the O → Si coordination in the adduct with KF and 18-crown-6

The novel compounds, N-(trifluorosilylmethyl)-[N-(S)-(1-phenylethyl)]-acetamide (1a) and 1-(trifluorosilylmethyl)-2-oxoperhydroazepine (1b) have been prepared from the corresponding NH-compounds using ClCH₂SiCl₃/Et₃N or ClCH₂SiCl₃/(Me₃Si)₂NH followed by methanolysis or hydrolysis of the reaction mixture in the presence of Lewis bases, and then BF₃ etherate. Potassium-(18-crown-6)-(2-oxoperhydroazepinomethyl)tetrafluorosilicate (2) was synthesized by reaction of the trifluoride (1b) with KF in the presence of 18-crown-6. Using ¹⁹F, ²⁹Si NMR and X-ray diffraction techniques it was established that the silicon atom is pentacoordinate in the trifluorides (1a, b) and hexacoordinate in the adduct 2. Thus the internal coordination of the O → Si bond present in the trifluoride (1b) is retained in the adduct 2.The stereochemical non-rigidity of the trifluorides (1a, b) and the N-(trifluorosilylmethyl)-N-methylacetamide (1c) was investigated using dynamic ¹⁹F NMR spectroscopy. The activation barriers for permutational isomerization are in the range 9.5-10 kcal mol⁻¹. Lower values of ΔG^# for permutation of trifluorides (1a-c) compared to the monofluorides with the coordination core OSiC₃F together with small negative values for the activation entropy implies a non-dissociative mechanism. Quantum-chemical analysis suggests a mechanism involving a turnstile rotation.     

(R)-2,3-Cyclohexylideneglyceraldehyde: a novel template for simple entry into both cis- and trans-2,5-disubstituted tetrahydrofurans

Sharpless asymmetric dihydroxylation at the terminal olefin of benzoates 3a and 3b, using both AD-mix α and AD-mix β afforded only one diastereomer of diols 5a and 5b, respectively. Diols 5a and 5b were easily transformed into cis- and trans-2,5-disubstituted tetrahydrofurans 7 and 14, respectively, which were subsequently converted into known compounds 12 and 19.     

A facile synthesis of (6S,1′S)-(+)-hernandulcin and (6S,1′R)-(+)-epihernandulcin

A facile total synthesis of (+)-hernandulcin (1) was accomplished from (−)-isopulegol in 6 steps with 15% overall yield. Epoxidation of (−)-isopulegol with m-chloroperbenzoic acid followed by opening of the epoxide 3a with prenyl Grignard afforded the tertiary alcohol 4a with correct C-6 and C-1′ stereochemistry as a major product. Oxidation of the secondary alcohol in compound 4a to the ketone 5a was accomplished in high yield by using TPAP and N-methylmorpholine N-oxide. Conversion of the ketone 5a to α,β-unsaturated ketone via organoselenium intermediate gave (+)-hernandulcin (1). This method was also successfully applied to the synthesis of (+)-epihernandulcin (2).     

Asymmetric transfer hydrogenation of aromatic ketones with the ruthenium(II) catalyst derived from C2 symmetric N,N′-bis[(1S)-1-benzyl-2-O-(diphenylphosphinite)ethyl]ethanediamide

Asymmetric transfer hydrogenation of ketones with chiral molecular catalysts is realized to be one of the most magnificent tools to access chiral alcohols in organic synthesis. A new chiral phosphinite compound N,N′-bis[(1S)-1-benzyl-2-O-(diphenylphosphinite)ethyl]ethanediamide (1), has been synthesized by the reaction of chlorodiphenylphosphine with N,N′-bis[(1S)-1-benzyl-2-hydroxyethyl]ethanediamide under argon atmosphere. The oxidation of 1 with aqueous hydrogen peroxide, elemental sulfur or grey selenium in toluene gave the corresponding oxide 1a, sulfide 1b and selenide 1c, respectively. Pd, Pt and Ru complexes were obtained by the reaction of 1 with [MCl₂(cod)] (M: Pd 1d, Pt 1e) and [Ru(p-cymene)Cl₂]₂1f, respectively. All these new complexes were characterized by using NMR, FT-IR spectroscopies and microanalysis. Additionally, as a demonstration of their catalytic reactivity, the ruthenium complex 1f was tested as catalyst in the asymmetric transfer hydrogenation reactions of acetophenone derivatives with iPrOH was also investigated.     

Asymmetric synthesis of both enantiomers of syn-(3-trifluoromethyl)cysteine derivatives

The use of several chiral trifluoromethylated building blocks 1a, 1b, 9a and 9b was attempted to synthesize of syn-(3-trifluoromethyl)cysteine. A novel and efficient enantioselective synthesis of both enantiomers of syn-(3-trifluoromethyl)cysteine derivatives 12a and 12b was successfully achieved.     

Microwave-assisted Hantzsch thiazole synthesis of N-phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines from the reaction of 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones and thioureas

N-Phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines (6a-q) have been synthesized by the Hantzsch thiazole reaction of 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones (4a-e) with suitably substituted thioureas using microwave heating. The ethanones (4a-e) were prepared by the reaction of 6-phenylimidazo[2,1-b]thiazoles (3a-e) with chloroacetylchloride in refluxing 1,4-dioxane whereas the thiazoles (3a-e) were synthesized by the reaction of 2-bromo-1-phenylethanones (2a-e) with thiazol-2-amine in refluxing acetone.     

Click reactions of 2H-azaphosphirene chromium and molybdenum complexes and a surprisingly facile access to a 2H-1,4,2-diazaphosphole derivative

Ring expansion reactions of 2H-azaphosphirene chromium and molybdenum complexes 1a,b with dimethyl cyanamide, triflic acid, and, subsequently at ambient temperature, with triethylamine gave a mixture of the respective 2H-1,4,2-diazaphosphole complex 2a,b and the non-ligated heterocycle 3. If the deprotonation with NEt₃ was carried out at low temperature, the selective formation of complexes 2a,b was observed, which were isolated in excellent yields and fully characterized (including single-crystal X-ray crystallography). Experimental and computational results revealed that the P, Cr and P, Mo bonds of 2H-1,4,2-diazaphosphole complexes are significantly weakened upon N-protonation of the heterocyclic ligand. When mixtures of 1a,b, TfOH, and Me₂NCN were warmed to ambient temperature, the primarily formed N-protonated of 2H-1,4,2-diazaphosphole complexes 4a,b could be observed by ³¹P NMR spectroscopy. The latter underwent decomplexation to give the N-protonated free ligand 5, which could be isolated and characterized by multinuclear NMR experiments. The neutral non-ligated heterocycle 3 was isolated from a one-pot reaction of 1b with TfOH and Me₂NCN by adding NEt₃ to a solution of intermediately formed 5.     

(N-7-Azaindolyl)oligothiophenes: synthesis, characterization, and photophysical properties

The synthesis of a new series of mono- and oligothiophenes capped by 7-azaindoles such as 2-(N-azaindolyl)thiophene (1), 2-(N-azaindolyl)-5′-(bromo)oligothiophenes (2a-4a), and 2,5′-bis(N-azaindolyl)oligothiophenes (2b-4b) has been investigated. The reaction of 7-azaindole with 2-bromothiophene under the modified Ullmann condensation conditions led to the formation of 1. Simple extension of the same method to the reaction of 2,5′-dibromooligothiophenes in the presence of 4-5 M excess of 7-azaindole led to the formation of 2a-4a and 2b-4b in moderate overall yields (40-55%). All compounds were fully characterized by analytical and various spectroscopic techniques. The structures of 2b, 3b, and 4b were determined by X-ray diffraction analyses. All three compounds show several intermolecular C(π)?H interactions leading to the formation of herringbone packing in the solid-state structure. The UV absorption spectra of 1-4 consist of three characteristic electronic transitions corresponding to n→π^∗ and π→π^∗ transitions arising out of the π-conjugation of the entire molecule as well as local aromatic units. The emission spectra of the same compounds show intense fluorescence bands at the wavelengths between 422 and 495 nm. The length of the thiophene chain and the presence of bromine atom influence the band position of both absorption and emission spectra. While the extension in π-conjugation causes the reduction in the band gap, the bromine atom shifts the electronic transition energy to the blue region. The cyclic voltammetric measurements were performed with 1-4, which show that the compounds exhibit a typical pseudo-reversible redox wave with E_ox in the range 0.6-1.2 V.     

Diastereoselective route to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane, a pheromone component of the wasp Paravespula vulgaris

A diastereoselective approach to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane 1 and 1a is described. The route starts with an alkylation reaction among the cyclopentanone N,N-dimethylhydrazone 6 and the chiral iodides (R)-3 or (S)-3, derived from the enantiomers of ethyl β-hydroxybutyrate, controlling the estereocenter at C-2 of the molecules. The alkylated products 7 and 7a were easily transformed into the 1,8-O-TBS-1,8-dihydroxy-5-nonanones 9 and 9a in four steps, and a subsequent stereoselective spiroketalization, in acidic media, afforded a Z:E mixture (1:2) of compounds 1 and 1a.     

Concise and practical synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars

The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from d-glucose are described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed by intramolecular reductive amination of amino-aldehyde.     

N-(Propargyl)diazenecarboxamides for ‘click’ conjugation and their 1,3-dipolar cycloadditions with azidoalkylamines in the presence of Cu(II)

Propargyl functionalized diazenes 1 were prepared by two different approaches and were examined as alkyne click components in copper-catalyzed azide-alkyne cycloadditions (CuAAC) with 2-(azidomethyl)pyridine 5a and four α-azido-ω-aminoalkanes C2-C5 (5b-e). Whereas the reactions with azidoalkylamines 5b-e reached completion with copper(II) sulfate without the need of reducing agent typically in no more than few minutes, 2-(azidomethyl)pyridine 5a required the addition of metallic copper and much longer reaction times (2-24 h). This difference in the reactivity was studied and addressed in terms of base effect and proximity effect to CuAAC.     

Methylene-2-ethynylcyclopropanes: synthesis and biological activity of (Z)- and (E)-9-{[2-ethynyl-2-(hydroxymethyl)cyclopropylidene]methyl}adenine and -guanine

Synthesis of methylene-2-ethynylcyclopropane analogues of nucleosides 12a, 12b, 13a, and 13b is described. Ethyl methylenecyclopropane carboxylate 14 was hydroxymethylated to give alcohol 15, which was reduced to diol 16. Selective protection with tert-butyldimethylsilyl group gave derivative 17, which was oxidized to aldehyde 18. Wittig reaction with CBr₄ gave dibromoalkene 19. Elimination of both bromine atoms afforded methylene-2-ethynylcyclopropane 20. Bromoselenenylation using N-bromosuccinimide and diphenyldiselenide gave intermediate 21. Alkylation of adenine and 2-amino-6-chloropurine with 21 provided the Z,E-isomeric mixtures 22a and 22c. Oxidation afforded selenoxides 23a and 23c. Mild thermolysis furnished methylenecyclopropanes Z-24a, E-24a, and 24c. Deprotection and separation of Z,E-isomers gave adenine analogues 12a and 13a, and 2-amino-6-chloropurine intermediates 12c and 13c. Hydrolytic dechlorination of 12c and 13c afforded guanine analogues 12b and 13b. Adenine Z-isomer 12a inhibits replication of Epstein-Barr virus through its cytotoxicity. The E-isomer 13a is a substrate for adenosine deaminase.     

Photochromic properties of tetrakis(2-methylthien-3-yl)ethene and its tetrakis(methylthio) derivative

The photoreaction of tetrakis(2-methylthien-3-yl)ethene (1a) and its tetrakis(methylthio) derivative 1b was investigated in the context of a potentially new chromic system responsive to both photoexcitation and electron transfer. UV irradiation of 1 at low conversion leads to production of its cyclic isomer 2 while 2 returns to 1 upon vis irradiation, representative of facile photochromic behavior. In contrast, UV irradiation at high conversion transforms 1b to rearranged product 3b via the intermediacy of 2b.     

Pummerer-type reactions in the (2-methylsulfanyl-2-phosphonyl) thiopyran 1-oxide series

Two (3,6-dihydro-2-methylsulfanyl-2H-thiapyran-2-yl)phosphonate derivatives have been chemoselectively oxidized on the thiopyran sulfur. The obtained allylic six-membered cyclic sulfoxides 2a and 2b were reacted under Pummerer reaction conditions leading to new thiopyran derivatives (4a and 6b, respectively). In both studied cases, the nucleophilic attack of β,γ-unsaturated thionium ion intermediate took place regioselectively at the γ-position (even when occupied by a methyl substituent like in 2b). An unexpected second product 7b was however obtained from substrate 2b (having the dimethyl-substituted double bond). Dephosphorylation of 7b under basic conditions led to an original conjugated tri-unsaturated trifluromethylcarbonyl thiopyran product (8b). These results represent new original examples of the Pummerer reaction.     

Synthesis, characterization and in vitro DNA binding studies of tin(IV) complexes of tert-butyl 1-(2-hydroxy-1-phenylethylamino)-3-methyl-1-oxobutan-2-yl carbamate

Tin(IV) complexes 1(a and b) and 2(a and b) of valine derived peptide derivatives were synthesized and characterized on the basis of elemental analysis, IR, ¹H, ¹³C, ¹¹⁹Sn NMR, ESI-MS spectra and molar conductance measurements. The C-Sn-C angle was estimated from ^I3C and ¹H NMR data ¹J(¹¹⁹Sn, ^I3C) = 623 Hz; solution ²J(¹¹⁹Sn, ¹H) = 93.04 Hz to be 149.9°. In vitro binding studies of complexes 1 and 2 under physiological conditions at room temperature with CT-DNA were carried out employing UV-visible, fluorescence, circular dichroism and viscometric studies. The binding affinity of the complexes was quantified by calculating the K_b values and it follows the order 2a > 1a > 2b > 1b. To further examine the specific mode of binding, the interaction of complexes 2(a and b) were carried out with 5′GMP and 5′TMP by using absorption and NMR (¹H, ³¹P) spectroscopy. The supercoiled pBR322 plasmid DNA cleavage activity of the complexes was ascertained by gel electrophoresis assay. The complexes cleave supercoiled pBR322 plasmid DNA efficiently into its nicked form at micromolar concentrations.