Sesterterpenes and phenolic alkenes from the Thai sponge Hyrtios erectus

Sesterterpene, erectusolide A (1), six phenolic alkenes, erectuseneols A?F (2–7) and nine known compounds, luffalactone (8), luffariolide E (9), (6E)- and (6Z)-neomanoalide 24,25-diacetates (10 and 11), 6,6-dimethylundecane-2,5,10-trione (12), threo- and erythro-cavernosines (13 and 14), (4E,6E)-dehydromanoalide (15), echinoclerodane A (16), were isolated from the marine sponge Hyrtios erectus. Compound 13 was isolated for the first time from a natural source. The structures of these compounds were elucidated on the basis of spectroscopic analysis. The phenolic alkenes 3 and 7, the sesterterpenes 8–11 and 15, and compounds 12–14 were evaluated for cytotoxic activities against six cancer cell lines, MOLT-3, HepG2, HeLa, HuCCA-1, A549, and MDA-MB-231.     

Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Efficient preparations of (R)-(−)-apomorphine (R)-1 and (R)-(−)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.     

Lipase mediated resolution of 1,3-butanediol derivatives: chiral building blocks for pheromone enantiosynthesis. Part 3

(R,S)-1,3-Butanediol 5 was kinetically resolved by enzymatic acetylation with vinyl acetate under the presence of Chirazyme™ L-2, c–f, yielding (S)-1-O-acetyl-1,3-hydroxybutane 6 and (R)-1,3-di-O-acetyl-1,3-butanediol 7 with enantiomeric excesses of 91% (E=67.3). Compounds 6 and 7 were easily transformed into the corresponding (S)-3-O-(2-methoxyethoxymethyl)-3-hydroxybutanal 10 and (R)-3-benzyloxybutanal 19, through a protection–deprotection and functional group interchange methodology. Subsequent reaction of 10 and 19 with 3-(methoxycarbonylpropionylmethylene)triphenylphosphorane afforded methyl (E,S)-8-O-(2-methoxyethoxymethyl)-4-oxo-5-nonenoate 12 and (E,R)-8-benzyloxy-4-oxo-5-nonenoate 20. The alkenes 19 and 20 were then catalytically hydrogenated to the corresponding saturated esters 13 and 21. Treatment of 13 and 21 with 1,2-ethanedithiol/F₃B·OEt₂ afforded dithioketals 14 and 22, which were respectively reduced to (S)-1,8-dihydroxy-4-nonanone ethylidenedithioketal 15 and (R)-8-O-benzyl-1,8-dihydroxy-4-nonanone ethylidenedithioketal 23. Finally, deprotection of 15 by catalytic hydrogenation under acidic conditions gave the expected (5S,7S)-(−)-7-methyl-1,6-dioxaspiro[4.5]decane 1. The (5R,7R)-(+)-1 enantiomer was analogously prepared from 23. Both compounds were formed by this procedure with an e.e. of 91%.     

Biogenetically related caged ent-kaurane diterpenoids from Isodon eriocalyx var. laxiflora

Two novel caged ent-kauranoids, neolaxiflorins D (1) and E (2), along with three other new ent-kauranoids, neolaxiflorins F–H (3–5), and a known one, eriocalyxin B (6), were obtained from Isodon eriocalyx var. laxiflora. Neolaxiflorin D (1) is the first 15,16-seco-16,17-dinor-ent-kaurane diterpenoid, and neolaxiflorin E (2) is the first 15,16-seco-17-homo-ent-kauranoid. The absolute configurations of ent-kauranoids 1 and 2 were determined by single-crystal X-ray diffraction analyses. Structural analysis of intermediate compounds 3–5 indicated that eriocalyxin B (6) is a biogenetic precursor of caged ent-kauranoids 1 and 2 as illustrated. The cytotoxic activity of the new compounds was evaluated by an MTT assay.     

Stereoselective synthesis of novel N-(α-l-arabinofuranos-1-yl)-l-amino acids

In lead detoxification, the α-anomer of N-glycocyl-l-amino acid is more potent than its β-anomer. Here a six-step-reaction route for stereoselectively preparing N-(α-l-arabinose-1-yl)-l-amino acids is reported. Treating l-arabinose with acetic anhydride and sodium acetate provided 1,2,3,5-tetra-O-acetyl-l-arabinofuranose in 90% yield. After removing the 1-acetyl group, the thus formed 2,3,5-tri-O-acetyl-l-arabinofuranose and N-(2-nitrophenylsulfonyl)-l-amino acid t-butylesters were treated with triphenylphosphine to perform Mitsunobu dehydration and form 2,3,5-tri-O-acetyl-l-arabinofuranosyl-l-[N-(2-nitrophenylsulfonyl)]amino acid t-butylesters 2a–f, and the ratios of their α- to β-anomer ranged from 8/1 to 9/1. Chromatographic separation provided epimerically pure 2a–f-α and 2a–f-β. In the presence of CF₃CO₂H, 2a–f-α and 2a–f-β were converted to α- and β-anomers of N-(2,3,5-tri-O-acetyl-l-arabinofuranosyl)-N-(2-nitrobenzenesulfonyl)-l-amino acids, 3a–f-α and 3a–f-β, in 87–92% yields. While in the presence of NaOCH₃, 3a–f-α and 3a–f-β were converted to α- and β-anomers of N-(l-arabinofuranosyl)-N-(2-nitrobenzenesulfonyl)-l-amino acids, 4a–f-α and 4a–f-β, in 90–96% yields. Treating 4a–f-α and 4a–f-β with N-ethyldiisopropylamine (DIPEA) and thiophenol, their 2-nitrophenylsulfonyl groups were removed, and the α- and β-anomers of N-(l-arabinose-1-yl)-l-amino acids were formed in 70–79% yields. The bioassay confirmed that the lead detoxification activity of the α-anomer was significantly higher than that of the β-anomer.     

Chemoenzymatic synthesis of both enantiomers of 3-hydroxy- and 3-amino-3-phenylpropanoic acid

Ethyl (S)-3-hydroxy-3-phenylpropionate (S)-2 was obtained by the asymmetric reduction of ethyl 3-phenyl-3-oxopropionate 1 with the yeast Saccharomyces cerevisiae (ATCC 9080). The kinetic resolution of racemic ethyl 2-acetoxy-3-phenyl-propionate rac-3 with the same microorganism, gave after hydrolysis ethyl (R)- and (S)-3-hydroxy-3-phenylpropionates (R)-2 and (S)-2 which were converted by a straightforward series of reactions to the enantiomers of 3-amino-3-phenyl-propionic acids (S)-6 and (R)-6. The asymmetric reduction and hydrolytic kinetic resolution were also tested with several other whole cell systems under a variety of conditions.     

Enantioselective cyanosilylation of aldehydes catalysed by a diastereomeric mixture of atropisomeric thioureas

New bifunctional atropisomeric thioureas 1 were synthesised and tested as both a mixture of diastereomers (aR/aS)-(R,R)-1 and as single diastereomers (aR)-(R,R)-1 and (aR)-(S,S)-1, in the organocatalysed, enantioselective, cyanosilylation of a range of aldehydes (aromatic and aliphatic). Moderate enantiomeric excesses (up to 69% ee) and quantitative yields were obtained. The best results were achieved using a mixture of thiourea diastereomers (aR/aS)-(R,R)-1 instead of the single diastereomers alone.     

Synthesis of ethyl and t-butyl (3R,5S)-dihydroxy-6-benzyloxy hexanoates via diastereo- and enantioselective microbial reduction

Previously we have demonstrated the reduction of ethyl diketoester 4 to the corresponding dihydroxy ester 6a by Acinetobacter sp. SC13874. Recently we screened more than 100 cultures for microbial reduction of both the ethyl and t-butyl diketoesters 4 and 5. Most yeast cultures showed a preference for reduction at the C-3 with low enantioselectivity. Among the three Acinetobacter strains screened, Acinetobacter sp. SC13874 reduced both compounds 4 and 5 to the corresponding (3R)- and (5S)-monohydroxy compounds. Monohydroxy compounds were isolated and their absolute configurations determined. (3R)- and (5S)-Monohydroxy compounds were reduced further to the corresponding dihydroxy esters 6a and 8a to provide alternate routes for the synthesis of compounds 14a and 16a, potential intermediates for the synthesis of HMG-CoA reductase inhibitors. Cell suspensions of Acinetobacter sp. SC13874 reduced the ethyl diketoester 4 to a mixture of desired syn and undesired anti diastereomers. The desired syn-(3R,5S)-dihydroxy ester 6a was obtained with an enantiomeric excess (ee) of 99% and a diastereomeric excess (de) of 63%. Cell suspensions reduced the t-butyl diketoester 5 to a mixture of mono- and dihydroxy esters with the dihydroxy ester showing an ee of 87% and de of 51% for the desired syn-(3R,5S)-dihydroxy ester 8a. Three different ketoreductases were purified to homogeneity, and their biochemical properties compared. Reductase I only catalyzes the reduction of ethyl diketoester 4 to its monohydroxy products 10 and 11, whereas reductase II catalyzes the formation of dihydroxy products 6 and 7 from monohydroxy substrates 10 and 11. A third reductase (III) was identified, which catalyzes the reduction of diketoester 4 to syn-(3R,5S)-dihydroxy ester 6a.     

Practical method for crystalline-liquid resolution of chrysanthemic acids utilizing chiral 1,1′-binaphthol monoethyl ethers directed for process chemistry

We have developed an efficient practical resolution method for (1R,3R)-trans-chrysanthemic acid 1 and (1R,3S)-trans-2,2-dimethyl-3-(2,2-dichloroethenyl)cyclopropanecarboxylic acid 2, based on the preliminary results of the simpler analogues, (1R)-2,2-dichlorocyclopropanecarboxylic acid 3 and (1R)-2,2-dimethylcyclopropanecarboxylic acid 4, using a crystalline-liquid separation procedure (without column chromatography) with chiral 1,1′-binaphthol monoethyl ethers (R)-5b as the key auxiliary. Direct esterifications of 1, 2, 3, and 4 with (R)-5b gave four sets of (1R)- and (1S)-diastereomeric esters 8, 9, 6, and 7, respectively, with markedly different melting points. All of these diastereomers were easily obtained using a simple and one-step crystalline-liquid separation. The separated diastereomers 8 and 9 were easily hydrolyzed to the desired enantiopure acids 1 (>98%) and 2 (>99%), respectively, with recovery of (R)-5b (>90%).     

Transformations of S-substituted 5,7-dimethyl-4а,5а-diphenyl-3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-2-ones under treatment of 1,2-benzoquinones and photochemical properties of reaction products

For the first time 5,7-di-tert-butyl-1,3-dimethyl-3a,9a-diphenyl-3,3a-dihydro-1H-benzo[5,6][1,4]dioxino[2,3-d]imidazol-2(9aH)-one 13 and complex 9 of 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol with 1,3-dimethyl-4,5-diphenyl-1H-imidazol-2(3H)-one 10a were prepared by the reactions of 3-alkylthio-5,7-dimethyl-4a,7a-diphenyl-4a,5,7,7a-tetrahydro-1H-imidazo[4,5-e]-1,2,4-triazin-6(4H)-ones with 3,5-di-tert-butyl-1,2-benzoquinone 1 and 4,6-di-tert-butyl-3-nitro-1,2-benzoquinone 2, respectively. Photochemical transformations of compounds 9 and 10a as well as products of its photooxygenation involving singlet oxygen under UV irradiation: urea 16, isomeric 1,3-dimethyl-4,5-diphenylimidazolidin-2-ones 17 and 17′, and compound 18 were studied by the spectral-kinetic method. Data on the absorption and fluorescence properties of synthesized compounds and their photoproducts were obtained.     

Antifouling and cytotoxic constituents from the South China Sea sponge Acanthella cavernosa

A bioassay-guided chemical investigation of the South China Sea sponge Acanthella cavernosa resulted in the isolation of eight new diterpenoids, kalihinols M–T (1–8), together with seven known analogues (9–15). These compounds featured a trans-decalin ring bearing a tetrahydrofuran or a tetrahydropyran ring at C-7. Compounds 1 and 2, with a formamide functionality beared at C-4, extended the structure breadth of this diterpenoid family. The absolute stereostructures of 1–14 were determined by a combination of 2D NMR and CD spectroscopic analysis and single crystal X-ray diffraction. Compounds 1 and 2 were confirmed to have the configurations of 4S, 5S, whereas 3–14 were determined as 4R, 5R. Compounds 3–14 displayed significant antifouling activity against the barnacle Balanus amphitrite larvae, and the cytotoxic activities of 3–14 were evaluated against the H1299, A549, PC3, CT-26, and HCT-116 cancer cell lines.     

Highly diastereoselective approach to novel phenylindolizidinols via benzothieno analogues of tylophorine based on reductive desulfurization of benzo[b]thiophene

Chiral tetra- and hexahydro[1]benzothieno[2,3-f]indolizines 3–5, 9, and 11 were synthesized easily from benzo[b]thiophene-2-carboxaldehyde (1) and (S)-glutamic acid (2) in good overall yields and both high enantio- and diastereomeric purities. Applying a diastereoselective reductive desulfurization of benzo[b]thiophene followed by lactam reduction, epimeric alcohols 4a and 4b were readily converted into (7R or S,8aS)-phenylindolizidinols 6a,c. During these studies, the reduction of benzothienoindolizines 3–5, 9, 11, and 12, was investigated and the results obtained are also discussed.     

Inclusion and selectivity of amides by p-terphenyl derivative bearing adamantanecarboxylic acid

Hydrogen-bonding compound (1), which is composed of p-terphenyl and adamantanecarboxylic acid, acted as a host molecule for three amides, respectively, forming crystals. Crystals containing the amides (1a and 1b) were produced from N,N-dimethylformamide (DMF) and N,N-diethylformamide (DEF) in 1:2 host:guest complexation stoichiometry, respectively, whereas guest-free crystals (1c) were generated from N-methylformamide (NMF). In the crystal structures of 1a and 1b, carboxylic acids of 1 interact with oxygen atoms of the amide guests through hydrogen bonds to afford network and layer architectures. Crystals 1a and 1b were given from equimolar binary mixtures of DMF or DEF and NMF, respectively. Further, from a mixture of DMF and DEF, guest-inclusion crystals 1d different from 1a and 1b were formed, where DMF was preferentially accommodated. Competition experiments revealed that the selectivity order of 1 for the amide guests was DMF?>?DEF???NMF.     

Stereoselective and versatile approach for the synthesis of gossyplure and its components

Efficient synthetic routes to gossyplure and its components (1a and 1b) were formulated. The three key units viz the alkynol 3, the bromide 5, and the alkanal 13 were derived from easily accessible starting materials. Alkylation of 3 with 5, and subsequent semihydrogenation followed by oxidation, provided the C₁₁-alkenal 8 which was subjected to a stereocontrolled Wittig reaction with a C₅-phosphonium salt, to yield directly the desired pheromone (1a + 1b). The synthesis of its individual components involved the manipulation via an acetylenic intermediate, viz the alkynol 14 which was obtained through alkylation of 3. A sequence of well-established reactions on 14, then provided the corresponding (E)- and (Z)-alkenylphosphonium salts which upon a (Z)-specific Wittig olefination with the C₇-aldehyde (13), led to the stereoselective synthesis of 1a and 1b.     

Continuous-flow enzymatic resolution strategy for the acylation of amino alcohols with a remote stereogenic centre: synthesis of calycotomine enantiomers

Both enantiomers of calycotomine (R)-5 and (S)-5 were prepared through the CAL-B-catalysed asymmetric O-acylation of N-Boc-protected (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol [(±)-3)]. The optimum conditions for the enzymatic resolution were determined under continuous-flow conditions, while the preparative-scale resolution of (±)-3 was performed as a batch reaction with high enantioselectivity (E >200). The resulting amino alcohol (S)-3 and amino ester (R)-4, obtained with high enantiomeric excess (ee = 99%), were transformed into the desired calycotomine (S)-5 and (R)-5 (ee = 99%). A systematic study was carried out in a continuous-flow system on the O-acylation of tetrahydroisoquinoline amino alcohol homologues (±)-1 to (±)-3 containing a remote stereogenic centre.     

Total synthesis of lycopene-5,6-diol and γ-carotene-5′,6′-diol stereoisomers and their HPLC separation

Lycopene-5,6-diol stereoisomers (1a,b) and (2a,b) and γ-carotene-5′,6′-diol stereoisomers (3a,b) and (4a,b) were synthesized by a stepwise C₁₅ + C₁₀ + C₁₅ double Wittig reaction strategy. The key compounds erythro(anti)-C₁₅-dihydroxy aldehydes 17a,b and their threo(syn)-stereoisomers 23a,b were prepared via Sharpless asymmetric epoxidation of geraniol and nerol followed by acidic hydrolysis of the epoxides in a stereospecific manner. The enantiomerically enriched anti-isomers were obtained by way of recrystallization of 2,3-epoxygeranyl 3,5-dinitrobenzoates 9a,b, whereas syn-isomers were obtained as enantiomerically pure forms via recrystallization of dihydroxyneryl 3,5-dinitrobenzoates 21a,b. In order to determine the absolute stereochemistry of natural products, HPLC separation methods for each enantiomers 1a,b–4a,b were established by using a column carrying a chiral stationary phase.     

Phloroglucinol derivatives and a chromone glucoside from the leaves of Myrtus communis

Seven new phloroglucinol derivatives, myrtucommunins A–D (1–4), 6-methylisomyrtucommulone B (5), 4-methylmyrtucommulone B (6), and 2-isobutyryl-4-methylphloroglucinol 1-O-β-d-glucopyranoside (7), and one new chromone derivative, undulatoside A 6′-O-gallate (8), were isolated from the leaves of Myrtus communis (Myrtaceae). Myrtucommunins A–D (1–4) were conjugates of polymethylated acylphloroglucinol and flavonol rhamnoside. The absolute configurations of the rhamnosyl moieties for 1–4 were confirmed to be l in each case by HPLC analyses, while those of the aglycones were assigned by comparisons of the experimental and TDDFT calculated ECD spectra. 6-Methylisomyrtucommulone B (5) and 4-methylmyrtucommulone B (6) were assigned as 6/6/6 tricyclic acylphloroglucinol derivatives with a racemic nature. Antimicrobial activities of 1–8 and related known compounds were evaluated.     

Chromatographic enantioseparation of racemic α-(1-naphthyl)ethylammonium perchlorate by a Merrifield resin-bound enantiomerically pure chiral dimethylpyridino-18-crown-6 ligand

Three novel chiral pyridino-18-crown-6 ligands (S,S)-1, (S,S)-2 and (S,S)-3 were prepared and (S,S)-1 was attached to a Merrifield resin. The resulting adsorbent (S,S)-5 was used as a chiral stationary phase in the chromatographic enantioseparation of racemic α-(1-naphthyl)ethylammonium perchlorate. Also, a new chiral pyridono-18-crown-6 ligand (S,S)-6, used for the synthesis of (S,S)-1 and (S,S)-2, was prepared in two different ways.     

Photodimerization-induced transition of helixes to vesicles based on coumarin-12-crown-4

Rational construction of fine-tuning and precisely controllable topological nanostructures based on supramolecular self-assembly system remains a challenge. Herein, coumarin-12-crown-4 (1) as a building block was synthesized by one-pot method and showed reversible high stereo-selective photodimerization (anti-head-to-head dimer (anti-HH-1): syn-head-to-head dimer (syn-HH-1) = 10.8:1) and photocleavage. Helical nanobelts were formed by the self-assembly of 1 through asymmetrical H-bonds, which were in concordance with the crystal state superstructure. Upon irradiation with 365 nm light, these nanobelts transformed into nanoballs which were constructed by three building blocks. Further, we investigated the photoreaction of 1 and got two pure covalent dimers (anti-HH-1 and syn-HH-1). The anti-HH-1 self-assembled into hollow micro-vesicles. The transformation of superstructures based on photo-controlled multiple blocks shines a light to the research on the relationship between molecules and superstructures.     

Resolution,absolute configuration and antifilarial activity of coumarinyl amino alcohols

The resolution of racemic coumarinyl amino alcohols 5–10 was achieved by using the inexpensive and readily accessible chiral resolving agent N-carbethoxy-l-proline (S)-11. Direct esterification of rac-5–10 with (S)-11 furnished diastereomeric esters, which were easily separated by column chromatography. The obtained diastereomers yielded the desired enantiopure coumarinyl amino alcohols (S)-(+)-5–10 and (R)-(?)-5–10 in good yields with high enantiomeric excess on saponification. The absolute configurations were determined by X-ray crystal analysis and/or by comparison of the specific rotations. Furthermore, in in vitro antifilarial motility inhibition assays, enantiopure coumarins (S)-(+)-9, (R)-(?)-9 and (S)-(+)-10, (R)-(?)-10 were found to be less efficient in affecting the viability of macrofilariae of Brugia malayi than their racemic forms 9 and 10, respectively, indicating the synergistic effect of the enantiomers in evoking antifilarial action.