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 and evaluation of 1-deoxy-8-epi-castanospermine, 1-deoxy-8-hydroxymethyl castanospermine, and (6S,7S,8R,8aR)-8-amino-octahydroindolizine-6,7-diol

A short, versatile, and enantioselective synthesis of 1-deoxy-8-epi-castanospermine (5), 1-deoxy-8-hydroxymethyl castanospermine (6), and (6S,7S,8R,8aR)-8-amino-octahydroindolizine-6,7-diol (7) is achieved from a common template 12. The key step utilized is PET provoked amine radical cyclization of 11 to 12 in excellent diastereoselectivity. The exocyclic double bond at C-8 of the template is functionalized to obtain 5-7 as exclusive diastereomers. 1-Deoxy-8-epi-castanospermine exhibited inhibition of α- and β-galactosidase and β-glucosidase. Compounds 6 and 7 were found to be weak inhibitors of β-glucosidase.     

New polyesters from Talaromyces flavus

Six new polyesters, talapolyesters A–F (1–4, 14, and 16), together with 11 known ones 15G256ν (5), 15G256ν-me (6), 15G256π (7), 15G256β-2 (8), 15G256α-2 (9), 15G256α-2-me (10), 15G256ι (11), 15G256β (12), 15G256α (13), 15G256α-1 (15), and 15G256ω (17), were isolated from the wetland soil-derived fungus Talaromyces flavus BYD07-13, and their structures were determined by NMR and MS spectroscopic data. Among them, 1–4 and 16 were assembled in a different manner from that of the known 256 polyesters. All the polyesters are composed of (R)-2,4-dihydroxy-6-(2-hydroxypropyl)benzoic acid and (R)-3-hydroxybutyric acid/(S)-3,4-dihydroxybutyric acid residues. The absolute configurations of the residues were determined by alkaline hydrolysis. The cytotoxicity against five tumor cell lines of these compounds was examined, and a tight structure–activity relationship is proposed.     

Synthesis and structural characterization of enantiopure exo and endo six-membered oxazoline-derived palladacycles

Direct palladation of (S)-4-benzyl-2-methyl-2-oxazoline (1) and (S)-2-benzyl-4-tert-butyl-2-oxazoline (2) using Pd(OAc)₂ in MeCN afforded the corresponding μ-acetato-dimeric complexes with six-membered exo and endo palladacycles, respectively. The same complexes were obtained by reacting coordination complexes Pd(1)₂(OAc)₂ and Pd(2)₂(OAc)₂ with Pd(OAc)₂ in MeCN. Metalation of (S)-2,4-dibenzyl-2-oxazoline (3) with Pd(OAc)₂ in AcOH, MeCN or CH₂Cl₂ resulted in the regiospecific formation of the six-membered endo palladacycle. The obtained μ-acetato-dimeric complexes were converted to the corresponding μ-chloro-dimeric derivatives 7, 11 and 13 by treatment with LiCl in acetone. The mononuclear PPh₃ adducts 8, 12 and 14 were obtained by reacting dimers 7, 11 and 13 with PPh₃ in benzene. NMR spectroscopy data supported the proposed structures of all complexes and suggested that exo and endo palladacycles in 8 and 12 have rigid boat conformations in CHCl₃. The X-ray crystal structures of the μ-acetato dimer 6 with the exo palladacycle and the PPh₃ adduct 14 with the endo metalacycle revealed boat conformation of both palladacycles and chiral twisted conformations δ(S) and λ(S), respectively, of the oxazoline rings in the solid state.     

Organocatalytic asymmetric Friedel–Crafts reaction of 1-naphthols with isatins: an enantioselective synthesis of 3-aryl-3-hydroxy-2-oxindoles

An organocatalytic enantioselective Friedel–Crafts reaction of 1-naphthols with isatins has been developed employing bifunctional thiourea–tertiary amine organocatalysts. A variety of isatin derivatives react well with 1-naphthols in the presence of Cinchona derived thiourea 1a to provide biologically important chiral 3-aryl-3-hydroxy-2-oxindoles (3a–zg) in good yield (70–84%) and moderate to good enantioselectivity (37–83%).     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-component domino reaction

An efficient, three-component domino reaction of dimedone 1, aromatic aldehydes (2a–o), and 1,3-cyclohexanedione 1a in the regio-selective synthesis of 3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones (3a–o) is reported. The desired product, 3 is efficiently promoted by ascorbic acid as an organo catalyst.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

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).     

Solvent-free reactions of N,N′-thiocarbonyldiimidazole with ferrocenylcarbinols

The efficient and simple routes for the synthesis of various ferrocenyl derivatives from ferrocenylcarbinols and N,N′-thiocarbonyldiimidazole (TCDI) are described. It involves grinding the two substrates in a Pyrex tube with a glass rod at room temperature. The reaction of ferrocenylmethanol (1a) provided S,S-bis(ferrocenylmethyl)dithiocarbonate (1b), whose crystal structure and a plausible mechanism for its formation are also reported. The reaction of 1-ferrocenyl-1-phenylmethanol (2a) and 1-ferrocenylbutanol (2b) gave the products 2c and 2d, respectively. The reaction of ω-ferrocenyl alcohols 4-ferrocenylphenol (3a) and 6-ferrocenylhexan-1-ol (3b) yielded the products 3c and 3d, respectively. Reaction of 1,1′-ferrocenedimethanol (3e) afforded 3f in moderate yield, and by contrast, it was not similar to 1b. Reaction of [4-(trifluoromethyl)phenyl]methanol (4a) provided the thiocarbonate 4b in good yield.     

The stereoselective synthesis of (E)-octafluoro-1,3,5-hexatriene and (3E,5E,7E)-dodecafluoro-1,3,5,7,9-decapentaene

(E)-(1,2-Difluoro-1,2-ethenediyl)bis[tributylstannane], 3, readily undergoes a Pd(PPh₃)₄/CuI-catalyzed cross-coupling reaction with iodotrifluoroethene to yield (E)-octafluoro-1,3,5-hexatriene, 4, in high isomeric purity. (1Z,3E,5Z)-(1,2,3,4,5,6-Hexafluoro-1,3,5-hexenetriyl)bis[tributylstannane], 7, was sequentially prepared from (1Z,3E,5Z)-(1,2,3,4,5,6-hexafluoro-1,3,5-hexenetriyl)bis[triethylsilane], 5, which was prepared via a Pd(PPh₃)₄/CuI-catalyzed cross-coupling reaction of 3 with (E)-1,2-difluoro-1-iodo-2-triethylsilylethene, 6. Pd(PPh₃)₄/CuI cross-coupling of 7 with iodotrifluoroethene gave (3E,5E,7E)-dodecafluoro-1,3,5,7,9-decapentaene, 8.     

Cyclization of N,N-diethylgeranylamine N-oxide in one-pot operation: preparation of cyclic terpenoid-aroma chemicals

Acid promoted cyclization of the geranylamine N-oxide (E)-4 followed by base-catalyzed intramolecular aldol condensation afforded 1-acetyl-4,4-dimethyl-1-cyclohexene (7) in one-pot operation. Reduction of 7, which possess strong fruity odor, followed by lipase-catalyzed kinetic resolution furnished the acetate (R)-26 (>49.9% yield, >99% ee) and the recovered alcohol (S)-25 (>49.9% yield, >99% ee, herbal odor).     

Synthesis of N,N-di(arylmethylidene)arylmethanediamines by flash vacuum pyrolysis of arylmethylazides

Flash vacuum pyrolysis of arylmethylazides 7a-d gave 2,4-diazapentadienes 5a-d in high yield (76-92%). The thermal cyclization of 5a-d gave cis-imidazolines 1a-d, further heating or Swern oxidation of 1a-d gave dehydrogenated products, imidazoles 2a-d.     

Dimolybdenum complexes containing anions of N,N′-bis(pyrimidine-2-yl)formamidine and N-(2-pyrimidinyl)formamide

The reactions of Mo₂(O₂CCH₃)₄ with different equivalents of N,N′-bis(pyrimidine-2-yl)formamidine (HL1) and N-(2-pyrimidinyl)formamide (HL2) afforded dimolybdenum complexes of the types Mo₂(O₂CCH₃)(L1)₂(L2) (1) trans-Mo₂(L1)₂(L2)₂ (2) cis-Mo₂(L1)₂(L2)₂ (3) and Mo₂(L2)₄ (4). Their UV–Vis and NMR spectra have been recorded and their structures determined by X-ray crystallography. Complexes 2 and 3 establish the first pair of trans and cis forms of dimolybdenum complexes containing formamidinate ligands. The L1 ligands in 1–3 are bridged to the metal centers through two central amine nitrogen atoms, while the L2 ligands in 1–4 are bridged to the metal centers via one pyrimidyl nitrogen atom and the amine nitrogen atom. The Mo–Mo distances of complexes 1 [2.0951(17) Å], 2 [2.103(1) Å] and 3 [2.1017(3) Å], which contain both Mo?N and Mo?O axial interactions, are slightly longer than those of complex 4 [2.0826(12)–2.0866(10) Å] which has only Mo?O interactions.     

Stereochemical challenges in characterizing nitrogenous spiro-axane sesquiterpenes from the Indo-Pacific sponges Amorphinopsis and Axinyssa

An investigation was conducted to identify the structures and bioactive properties of five compounds isolated from the Halichondrida sponges Amorphinopsis foetida and Axinyssa aplysinoides. All compounds possessed the spiro-axane sesquiterpene core and all were substituted at C-2 with nitrogen containing functionality. The stereochemistry of one known compound has been revised to (2R,5R,10S)-2-formamido-6-axene (3). It exhibited mild selective solid tumor and mild antibacterial activity and was found from Axinyssa. A second known substance whose stereochemistry has also been revised, (2R,5R,10S)-2-isothiocyanato-6-axene (4) plus its undescribed diastereomer (5) were isolated from Amorphinopsis. Both sponges were the source of two new N-phenethyl-2-formamido-6-axene diastereomeric compounds 6 and 7. No solid tumor or antibacterial activity was found for 4-7.     

6,7-Seco-ent-kaurane-type diterpenoids from Isodon eriocalyx var. laxiflora

Twenty nine 6,7-seco-ent-kaurane-type diterpenoids including 18 new ones, laxiflorolides C–T (1–18), along with 21 known ones were obtained from Isodon eriocalyx var. laxiflora. Laxiflorolides E–G (3–5) are the first identified naturally occurring 6,7-seco-ent-kauranoids that feature a 3,6-epoxy unit, and laxiflorolide M (11) is the first identified naturally occurring 6-nor-6,7-seco-ent-kauranoid. The absolute configurations of compounds 1, 3, 6, and 11 were determined by single-crystal X-ray diffraction analyses. The cytotoxic activity of the isolates was evaluated by an MTT assay.     

Regioselective synthesis of novel 4-aryl-2-ethylthio-7-methyl pyrazolo[1,5-a]-[1,3,5]-triazines

Pyrazolo[1,5-a]-[1,3,5]-triazines 6a-d were obtained by an efficient one-step reaction from S,S-diethyl aroyliminodithiocarbonates 4a-d and 5-amino-3-methylpyrazole 5 or by an alternative two-step reaction from 5 and aroyl isothiocyanates 8a-d to give initially the thiourea derivatives 9a-d, which after S-ethylation and cyclization afforded compounds 6a-d. The intermediate 7a isolated from reaction between 4a and 5 permitted us to establish the orientation.     

New natural products in the discorhabdin A- and B-series from New Zealand-sourced Latrunculia spp. sponges

A survey of the secondary metabolite chemistry profiles of New Zealand sponges of the genus Latrunculia has yielded new members of the discorhabdin A- and B-type families. The structure elucidation of (+)-(6R,8S)-1-thiomethyldiscorhabdin G^∗/I (5) and both enantiomers of 16a,17a-dehydrodiscorhabdin W (6) are reported. Absolute configurations were assigned by comparison with a dataset of recently reported electronic circular dichroism spectra of discorhabdin alkaloids. A stereochemical correction of the recently reported natural product (+)-3-dihydrodiscorhabdin A from (3S,5R,6S,8S)-(7) to the C3-epimeric (+)-(3R,5R,6S,8S)-(8) and assignment of absolute configuration is also presented. Semi-synthesis of (+)-(3S,5R,6S,8S)-(7) from (+)-discorhabdin A provided further evidence for this structure revision. Cytotoxicity data is reported for 5-8.     

N-Arylmethyl-7-azabicyclo[2.2.1]heptane derivatives: synthesis and reaction mechanisms

N-Arylmethyl-7-azabicyclo[2.2.1]heptane (I) derivatives have been synthesized by deprotection of N-protected, N-(arylmethyl)cyclohex-3-enamines, bromination of the resulting secondary cyclohex-3-enamines, followed by base-promoted cyclization (route a), or by bromination of N-protected, N-(arylmethyl)cyclohex-3-enamines followed by deprotection and base-mediated cyclization (route b). In these protocols we have observed that the bromination of the key intermediates (12, 13, and 19) is stereoselective leading to major trans-3-cis-4-dibromides (14, 17, and 20), whose mild base-mediated heterocyclization (on compound 14), or the two-step acid hydrolysis plus base-promoted cyclization (on compounds 17 and 20), gave products 6 and 7 in good yield. A mechanistic investigation using DFT has been carried out to explain the results observed in this work.     

Four new ginkgolic acids from Ginkgo biloba

Four new compounds, 2-hydroxy-6-(12′-hydroxyheptadec-13′(E)-en-1-yl)benzoic acid (1), 2-hydroxy-6-(13′-hydroxyheptadec-11′(E)-en-1-yl)benzoic acid (2), 2-hydroxy-6-(10′-hydroxypentadec-11′(E)-en-1-yl)benzoic acid (3), and 2-hydroxy-6-(11′-hydroxypentadec-9′(E)-en-1-yl)benzoic acid (4) were isolated from the leaves of Ginkgo biloba and the structures of new ginkgolic acids were deduced on the basis of spectroscopic methods and chemical means. Compounds 1 and 2, and 3 and 4 examined as an inseparable mixture of hydroxyl and double bond positional isomers, were ultimately defined by total synthesis. Compounds 1–4 showed moderate lipid droplets accumulation inhibitory activity on mouse pre-adipocyte cell line, MC3T3-G2/PA6.