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.     

Total synthesis of (+)-epiepoformin, (+)-epiepoxydon and (+)-bromoxone employing a useful chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexanecarboxylate

Enantioselective total synthesis of (+)-epiepoformin 1, (+)-epiepoxydon 2 and (+)-bromoxone 3 using a chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclo- hexanecarboxylate 6, is described. Since the synthesis afforded intermediates 18, 2 and 25, it accomplished a formal synthesis of (−)-theobroxide 19, (−)-phyllostine 22, (+)-herveynone 27 and (−)-asperpentyn 28. The usefulness of 6 for the synthesis of natural epoxycyclohexene derivatives was demonstrated.     

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.     

Synthesis of a regioisomeric analogue of the 3C-protease inhibitor thysanone via a Hauser annulation strategy

Hauser annulation of 3-cyano-5,7-dimethoxy-(3H)-isobenzofuran-1-one 4 with ethyl acrylate as a method to access activated naphthoquinone 3, a key intermediate for the synthesis of thysanone 1, proved unreliable. In contrast to this, Hauser annulation of regioisomeric 3-cyano-4,6-dimethoxy-(3H)-isobenzofuran-1-one 13 with ethyl acrylate proceeded readily affording ethyl 5,7-dimethoxy-1,4-naphthoquinone 12, after oxidation of the initial dihydroxynaphthalene 16. Allylation of naphthoquinone 12 followed by reductive methylation and Wacker oxidation afforded ketone 11 that underwent CBS reduction to (2′S)-alcohol 19 followed by cyclisation to lactone 20. Reduction of the lactone followed by oxidative demethylation afforded (1S,3S)-6,8-dimethoxy-1-hydroxy-3-methylpyrano[2,3-c]-1,4-naphthoquinone 22, a regioisomeric analogue of the 3C-protease inhibitor thysanone 1.     

Synthesis, characterization and anticancer activity of new chiral Pd(II)-complexes derived from unsymmetrical α-diimine ligands

A set of new diastereopure unsymmetrical α-diimine ligands 2a-d derived from methylglyoxal and optically pure primary amines 1a-d afforded the new chiral Pd(II)-complexes (S,S)-3a, (S,S)-3b, (S,S)-3c, and (1S, 2S, 3S, 5R)-3d. All compounds have been characterized by IR, ¹H, and ¹³C NMR spectroscopies along with MS-FAB⁺ spectrometry. The crystal and molecular structure for the complexes 3a, 3b and 3d have been fully confirmed by single-crystal X-ray studies. Likewise, complexes 3a-d have also been screened for their in vitro cytotoxicity against different classes of cancer: leukemia (K-562 CML), colon cancer (HCT-15), human breast adenocarcinoma (MCF-7), central nervous system (U-251 Glio) and prostate cancer (PC-3) cell lines.     

Synthesis and evaluation of new chiral diols based on the dicyclopentadiene skeleton

The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo(2R)-1a alcohol. The endo(2S)-1b alcohol was obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey's general procedure respectively, afforded with high diastereoselectivity the C₂ symmetry diols (2R,2′R)-2a and (2S,2′S)-2b, with endo oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2′R)-2a and (2S,2′S)-2b was tested towards the LiAlH₄ reduction of acetophenone. The C₂ symmetry appears to play a fundamental role.     

Synthesis of (E)-diethyl 6,6′-(diazene-1,2-diyl)bis(5-cyano-2-methyl-4-phenylnicotinates), a new type of 2,2′-azopyridine dyes

An unexpected, but simple method for the efficient synthesis of new 2.2′-azopyridine dyes, such as (E)-diethyl 6,6′-(diazene-1,2-diyl)bis(5-cyano-2-methyl-4-phenylnicotinates) (2, 4, 6, 8, 10, and 12), based on the treatment of ethyl 6-amino-5-cyano-2-methyl-4-arylnicotinates (1, 3, 5, 7, 9, and 11) with NBS/benzoyl peroxide, is described. The X-ray diffraction analysis and the UV-vis absorption spectra of dye 2 are reported and discussed.     

Enantioselective synthesis of indolizidine and quinolizidine derivatives from chiral non-racemic bicyclic lactams

Chiral non-racemic bicyclic lactams 2b,c, derived from (R)- and (S)-phenylglycinol, were used in the enantioselective synthesis of (−)-lupinine and 5-epitashiromine, respectively. The efficiency of the synthesis relied on the high diastereoselectivities of formation and reduction of compounds 2b,c.     

Bioactive meroditerpenes and indole alkaloids from the soil fungus Neosartorya fischeri (KUFC 6344), and the marine-derived fungi Neosartorya laciniosa (KUFC 7896) and Neosartorya tsunodae (KUFC 9213)

Two new metabolites including a new aszonalenin analogue (1c) and a new meroditerpene (3) were isolated, together with aszonalenin (1a), acetylaszonalenin (1b), 13-oxofumitremorgin B (2), aszonapyrone A (4b) and helvolic acid, from the culture of the soil fungus Neosartorya fischeri (KUFC 6344). While the ethyl acetate extract of the culture of the diseased coral-derived fungus Neosartorya laciniosa (KUFC 7896) furnished aszonapyrone B (4a), aszonapyrone A (4b), tryptoquivaline L and 3′-(4-oxoquinazolin-3-yl) spiro[1H-indole-3,5′-oxolane]-2,2′-dione, the ethyl acetate extract of the culture of the marine sponge-associated fungus Neosartorya tsunodae (KUFC 9213) yielded a new analogue of chevalone C (5) and helvolic acid. The structures of the new compounds were established based on 1D and 2D NMR spectral analysis as well as HR-ESIMS. Compounds 1a–c, 2, 3, 4a, 4b and 5 were evaluated for their in vitro growth inhibitory activity on the MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A375-C5 (melanoma) cell lines by the protein binding dye SRB method.     

Syntheses and bioactivities of tricyclic pyrones

In search of compounds that ameliorate the toxicity of amyloid-β (Aβ) peptides, new derivatives of tricyclic pyrones (1-7) were synthesized and their biological activities evaluated. The carboxylic ester and amide derivatives 1-4 were synthesized from a selective carboxylation of C3 methyl of (5aS,7S)-{7-Isopropenyl-3-methyl-1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyran (8) with LDA followed by benzyl chloroformate or carbon dioxide to provide ester 1 and carboxylic acid 9, respectively. Three isomeric tricyclic pyrone, 5-7, containing adenine moiety at C7 side chain were synthesized from the alkylation of mesylate 13 with adenine, and displacement of chloropurine 15 with amine 14. Although C3-benzyloxycarbonylmethyl analogs 1-3 have marginal ACAT and CETP activities, their modified aspartate analog 4 and C3-methyl-C7-(N3-adeninyl)-2-propyl analog 6 show a significant effect in protecting against neuron-cell death from the toxicity of intracellular accumulation of Aβ or Aβ-containing C-terminal fragments (CTF) of amyloid β precursor protein (APP). N9-Adenine analog 5 is 20-fold less effective than N3-adenine derivative 6 in the protection of neuron-cell death induced by Aβ, while N10-adenine analog 7 was inactive. As a result of this study, compounds 4 and 6 will well serve as lead compounds for further studies of the mechanism of action of Aβ-and CTF-induced neuron-cell death, studies which should enhance the future development of new drugs for the prevention and treatment of AD.     

Total synthesis of (+)-kalafungin using a tandem Michael-Dieckmann approach

A stereoselective synthesis of the antibiotic kalafungin 1 is reported. A key step involved the tandem Michael-Dieckmann reaction between methyl 2-methoxy-6-methylbenzoate 11 and the α,β-unsaturated lactone (R)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-4-methoxy-5,6-dihydropyran-2-one 10, which was prepared from (S)-aspartic acid. The C5 alkyl substituent was introduced by the use of methylmagnesium bromide and subsequent stereoselective reduction. A sequence of oxidations followed by acid-catalyzed epimerization delivered (+)-kalafungin 1.     

Tulearins A, B, and C; structures and absolute configurations

The relative configuration of tulearin A (1) is determined by X-ray diffraction analysis of a cyclic carbonate derivative 2 and the absolute configuration (2R,3R,5S,8S,9S,15R,17S) from the 9-MTPA-esters 1R and 1S is determined using the modified Mosher’s method. A mechanism for the unexpected formation of carbonate 2 is suggested. Two N-phenyltriazolinedione derivatives 3 and 4 are also prepared. Two additional tulearins, B and C (5 and 6) are isolated in very small amounts and their structures are elucidated by spectroscopic means.     

An efficient synthesis of 4H,5H-pyrano[3,4-c]pyran-4,5-diones from a suitably functionalized 2H-pyran-2-one

An efficient synthesis of ethyl 7-aryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-dione-1-carboxylate 5, and ethyl 6-aryl-3-cyano-2H-pyran-2-one-4-acetate 6 has been delineated by reaction of suitably functionalized 2H-pyran-2-ones 1 with ethyl acetoacetate 2.     

Absolute configuration of gomadalactones A, B and C, the components of the contact sex pheromone of Anoplophora malasiaca

Absolute configuration of gomadalactones A (1), B (2) and C (3), the pheromone components of the white-spotted longicorn beetle (Anoplophora malasiaca) was assigned as (1S,4R,5S)-1, (1R,4R,5R)-2 and (1S,4R,5S,8S)-3 by comparing their published CD spectra with those of (1R,5R)-(+)-4,4,8-trimethyl-3-oxabicyclo[3.3.0]oct-7-ene-2,6-dione (4) and (1S,5R,8S)-(+)-4,4,8-trimethyl-3-oxabicyclo[3.3.0]octane-2,6-dione (5) prepared from (R)-(−)-carvone (6).     

S-Transalkylation/ring closing metathesis as a route to azathiamacrocycles incorporating 2,2′-bipyridine subunits

A new route to cyclophanes 6a,b incorporating 2,2′-bipyridine subunits has been elaborated using as the key steps (1) S-transalkylation of 6,6′-bis(methylsulfanyl)-2,2′-bipyridines 2a,b with ethyl bromoacetate resulting in the formation of 6,6′-bis[(ethoxycarbonyl)methylsulfanyl]-2,2′-bipyridines 3a,b and (2) ring-closing metathesis of the corresponding alkenyl ethers 5a,b.     

Regioselective Baeyer-Villiger lactonization of 2-substituted pyrrolidin-4-one. Synthesis of statine

Nine 2-substituted pyrrolidin-4-ones 4a-i were obtained via a series of functional group transformation of known prolinol 5 by facile six kinds of methodologies. The target structure of 1,3-amino alcohols 2a-i was constructed in the regioselective Baeyer-Villiger lactonization of ketones 4a-i and reduction of the resulting 4-substituted tetrahydro-1,3-oxazin-6-ones 3a-i. A new and straightforward synthesis of (3S,4S)-statine (6) has been established starting from trans-(2S,4R)-4-hydroxyproline (1).     

Enantioselective alkylation and protonation of prochiral enolates in the asymmetric synthesis of β-amino acids

Achiral 1-benzoyl-3-methylperhydropyrimidin-4-one (1) was deemed a useful, potential precursor for the enantioselective synthesis of α-substituted β-amino acids. Pyrimidinone 1 was prepared from inexpensive β-aminopropanoic acid in 62% overall yield. Prochiral enolate derivative 1 -Li was alkylated in good yield and moderate enantioselectivity in the presence of chiral amines (S)-8, (S,S)-9, (S,S)-10, or (−)-sparteine. The enantioselectivity of the alkylation process is highest in toluene as the solvent and in the presence of lithium bromide as additive. The racemic alkylated derivatives 2 and 3 were readily metallated with LDA to give prochiral enolates 2-Li and 3-Li, that were reprotonated with novel chiral phenolic acids (S)-11, (S,S)-12, (S)-13, and (S,S)-14 in moderate enantioselectivity in the case of 2-Li and good enantioselectivity in the case of 3-Li. The acid (6N HCl) hydrolysis of enantioenriched 2 and 3 proceeded in good yield and without racemization to afford α-alkyl-β-amino acids 4 and 5, respectively.     

Studies on the Synthesis of Reidispongiolide A: Stereoselective Synthesis of the C(22)-C(36) Fragment

A highly stereoselective synthesis of the C(22)-C(36) fragment 2 of reidispongiolide A is described. This synthesis features the highly stereoselective mismatched double asymmetric crotylboration reaction of the aldehyde derived from 5 and the new chiral reagent (S)-(E)-7 that provides 12 with >15:1 dr. Subsequent coupling of the derived vinyl iodide 3 with aldehyde 16 provided allylic alcohol 17, that was elaborated by three steps into the targeted reidispongiolide fragment 2.     

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.     

Synthesis and electrochemical studies of ferrocene-dithiafulvalenes (Fc-DTF) and 1,1′-bis(dithiafulvalenyl)ferrocene (DTF-Fc-DTF). An approach towards new conducting organic materials

Novel π-conjugated donor compounds based on the strong electron-donating ferrocene moiety and dithiafulvalene donors exhibited increased electron donor ability. The ferrocenylketones 4a,b, 5, 8 and 9 were synthesized via described methods, and allowed to react with 2-dimethoxyphosphinyl-1,3-benzodithiole (13) in the presence of n-BuLi at −78°C in dry THF to afford the corresponding ferrocene-dithiafulvalenes 14a,b, 18, 19 and 1,1′-bis(benzo-1,3-dithiol-2-ylidene)ethyl]ferrocene (15). Electrochemical properties of these new donor compounds were studied using cyclic voltammetry (CV) and UV-Vis spectra. CV and absorption spectra of the new compounds were studied in comparison with ferrocene (6) and dibenzo-tetrathiafulvalene DB-TTF 3. Two-electron and three-electron redox behaviors were observed as two waves. The absorption spectra showed a red-shift with a slight increase in the absorption intensities.