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.     

Velutabularins A-J, phragmalin-type limonoids with novel cyclic moiety from Chukrasia tabularis var. velutina

Velutabularins A-J, ten novel phragmalin-type limonoids, were isolated from the stem bark of Chukrasia tabularis var. velutina. In structures of 1-6, the tetrahydrofuran ring from dehydration of OH-15 and OH-17, ring C and 13/14/18-cyclopropanyl moiety formed an unprecedented 8-oxatricyclo[4,3,1^1,6]decane. Compounds 7-10 are derivates of 1-6 opening the tetrahydrofuran ring. All of these compounds possess a novel C-16/C-30 δ-lactone ring, which were reported in phragmalins rarely. The structures of these novel compounds were elucidated based on extensive 1D and 2D spectroscopic analysis. The absolute configuration of 5 and 9 were determined by the calculated electronic circular dichroism (ECD) method. The anti-inflammatory activities of major compounds (2, 4, 5, 9) were evaluated for inhibitory activity against lipopolysaccharide (LPS) induced nitric oxide (NO) production in macrophage (RAW264.7) cell line.     

Highly selective synthesis of 4(5)-aryl-, 2,4(5)-diaryl-, and 4,5-diaryl-1H-imidazoles via Pd-catalyzed direct C-5 arylation of 1-benzyl-1H-imidazole

Highly selective, practical, and efficient protocols for the preparation of 4(5)-aryl-1H-imidazoles 2, 2,4(5)-diaryl-1H-imidazoles 3, and 4,5-diaryl-1H-imidazoles 1 are described. A key step of these protocols is the regioselective synthesis of 5-aryl-1-benzyl-1H-imidazoles 9 by Pd-catalyzed direct C-5 arylation of commercially available 1-benzyl-1H-imidazole (8) with aryl halides. The three-step synthesis of compounds 3 from 8 also involves the Pd-catalyzed and Cu-mediated direct C-2 arylation of imidazoles 9 with aryl halides under base-free and ligandless conditions. On the other hand, the four-step synthesis of imidazoles 1 from 8 also involves the regioselective bromination of compounds 9 and a Suzuki reaction of the resulting 5-aryl-1-benzyl-4-bromo-1H-imidazoles 11 with arylboronic acids 5 under phase-transfer conditions, followed by N-debenzylation.     

New tricyclic geldanamycin analogues from an engineered strain of Streptomyces hygroscopicus JCM4427

Two tricyclic geldanamycin analogues, DHQ5 (1) and DHQ6 (2), were produced by a combinatorial mutant (AC15) contained a site-directed mutagenesis on the geldanamycin polyketide synthase (PKS) gene with inactivation of the post-PKS tailoring genes (gel7) of Streptomyces hygroscopicus JCM4427. The structural diversity of tricyclic geldanamycin analogues is due to the formation of unusual additional rings, which are formed by alkylation of the C-21 position by C-12 in DHQ5 (1) and by electrophilic addition of the C-15 hydroxyl group to the double bond (C-8-C-9), which leads to the migration of the double bond (to C-7-C-8) and the elimination of a carbamoyloxy group in DHQ6 (2).     

New oxindole and indole alkaloids from Gelsemium rankinii

Six new humantenine-type (1-6) and two new gelsemine-type (7, 8) oxindole alkaloids and one new indole alkaloid (9) were isolated from the leaves and branches of Gelsemium rankinii. The structures of the new alkaloids were determined by spectroscopic analyses. Among them, 6-hydroxyhumantenine (5) is the first example of a Gelsemium alkaloid with an oxygen function at C-6 position, and is a plausible biogenetic precursor of gelsemine-type alkaloids.     

Synthesis of 3,4,5-trisubstituted indoles via iterative directed lithiation of 1-(triisopropylsilyl)gramines

Directed lithiation of 1-(triisopropylsilyl)gramines 1 with tert-butyllithium followed by reaction with trimethylsilylmethyl azide produced 4-amino-1-(triisopropylsilyl)gramines 7. The N-tert-butoxycarbonyl derivatives 8 were lithiated selectively at C-5 with tert-butyllithium and the lithiated species were reacted with a variety of electrophiles to give 5-functionalized compounds, 9 and 10. A facile method to produce 3,4,5-trisubstituted indoles from readily available gramine derivatives is thereby established.     

Combined biotransformations of 4(20),11-taxadienes

Taxuyunnanine C (1) and its analogs (2 and 3), the C-14 oxygenated 4(20), 11-taxadienes from callus cultures of Taxus sp., were regio- and stereo-selectively hydroxylated at the 7β position by a fungus, Abisidia coerulea IFO 4011, and it was interesting that the longer the alkyl chain of the acyloxyl group at C-14 became, the higher the yield of 7β-hydroxylated product was. Besides the three 7β-hydroxylated products (5, 9, 17), other nine new products (7, 11, 12, 14, 15, 16, 18, 20 and 21) and six known products (4, 6, 8, 10, 13 and 19) were obtained. Subsequently, the acetylated derivatives (24 and 27) of 7β-and 9α-hydroxylated products of 1 were regio- and stereo-specifically hydroxylated at the 9α position by Ginkgo cells and 7β position by A. coerulea, respectively. Thus, the two specific oxidations have been combined. These bioconversions would provide not only valuable intermediates for the semi-synthesis of paclitaxel or other bioactive taxoids from 1 and its analogs, but also some useful hints for the biosynthetic pathway of taxoid in the natural Taxus plant.     

Synthesis, structural and conformational studies of Z- and E-isomers of fluorinated C-6 isobutenyl N-methyl thymine derivatives

A new series of conformationally restricted pyrimidine derivatives bearing C-6 isobutenyl side-chain (2-9) has been prepared. The novel fluoroalkenyl pyrimidine nucleoside mimetic 3 as model compound for development of tracer molecule in positron emission tomography (PET) was synthesized by fluorination reaction of methoxytritylated pyrimidine derivative using diethylaminosulfur trifluoride (DAST). Conversion of one hydroxyl group to methoxytritylated, fluorinated, mesylated and acetylated pyrimidine derivatives (2, 3, 5-7 and 9) afforded a mixture of Z- and E-isomers in which Z-isomers were predominant. Conformational study of 1, and its fluorinated structural congeners 3 and 4 by the use of NOE experiments revealed predominant conformation of compounds where vinyl H-1′ proton is spatially close to N-1 methyl and H-3′b methylene protons and on the other hand H-3′a methylene protons are close to C-5 methyl protons. The stereostructure of 1,3-dihydroxyisobutenyl N-methyl thymine 1 was unambiguously confirmed by X-ray crystal structure analysis.     

Chemistry of xanthorrhizol: synthesis of several bisabolane sesquiterpenoids from xanthorrhizol

(−)-Xanthorrhizol (1) isolated from the rhizomes of Curcuma xanthorrhiza has been transformed to several bisabolane-type sesquiterpenoids, in a stereoselective manner. 10R- and 10S-10,11-dihydro-10,11-dihydroxyxanthorrhizols (2, 3), (−)-curcuquinone (4), (−)-curcuhydroquinone (5), helibisabonol A (7) and allylic alcohol 8 have been prepared from xanthorrhizol in optically active forms. All the routes involved a Sharpless AD to introduce the stereogenic centre at C-10.     

Synthesis of podophyllotoxin analogues: δ-lactone-containing picropodophyllin, podophyllotoxin and 4′-demethyl-epipodophyllotoxin derivatives

Non-epimerizable cis and trans δ-lactone analogues of podophyllotoxin have been prepared. Thus the synthesis of the cis isomer 4 has been achieved in 8 steps and 4% overall yield from podophyllotoxin 1 via the reduction of the γ lactone ring into the trans diol, selective protection of the 4-OH and 11-OH as a benzylidene acetal, and Wittig elongation at C-13 with inversion of configuration at C-2. Same elongation at C-13 but via the formation of a mesylate and introduction of a cyano group, led to the trans δ-lactone 5 (7 steps from 1 and 6% overall yied) with a small amount of its C-4 epimer 6. The synthesis of non-epimerizable δ-lactone analogues of 4′-demethyl-epipodophyllotoxin 7 and of 4-demethyl podophyllotoxin 8 are also reported. The synthesis of 7 and 8 was based upon the reduction of the γ-lactone ring of 4′-demethyl-4-epipodophyllotoxin followed by selective protection at C-11 and elongation at C-13. (8-15% and 4% overall yields). Compounds 4, 5 and 7 did not display relevant cytotoxicity in vitro against L1210 murine leukemia.     

Withaphysanolide A, a novel C-27 norwithanolide skeleton, and other cytotoxic compounds from Physalis divericata

A novel C-27 norwithasteroid, withaphysanolide A (1) containing a pyran ring was isolated from the aerial parts of Physalis divericata. Four known withaphysalins (2-5) and five physalins (6-10) were also isolated. The structural assignment for 1 was done based on spectroscopic and single-crystal X-ray diffraction data. Logical biosynthetic pathways were postulated. Compounds 6, 7, and 10 displayed potent cytotoxic activity against HCT-116 and H460 human cancer cell lines, with IC₅₀ values less than 2.0 μM.     

Muchimangins E and F: novel diphenylmethyl-substituted xanthones from Securidaca longepedunculata

Two new highly oxygenated xanthones, named muchimangins E (1) and F (2), have been isolated from the root of Securidaca longepedunculata (Polygalaceae). Their structures were elucidated by the analyses of spectral data to be a novel xanthone with a diphenylmethyl substituent at C-2. Moreover, the structures of muchimangins B (4) and C (5) were revised by careful analysis of the spectral data and by comparing their NMR data with those of 1 and 2, to be xanthones with the diphenylmethyl substituent at C-2, not at C-4 reported previously.     

Revisiting diterpene lactones of Suregada multiflora

Phytochemical investigations on the organic extracts of the leaves of Suregada multiflora have led to the isolation of ten tetracyclic diterpene lactones 1-10, members of a rare class of abiatene diterpene lactones. Compounds 1-5 were found to be new. The structures of gelomulides F (11), D (12) and E (13) were revised on the basis of 2D NMR and X-ray diffraction evidences. Compounds 1 and 2 contain an epoxy linkage between C-8 and C-14, whereas compounds 3-5 were identified as 8,14-dihydroxy analogues of diterpene lactones. The stereochemical assignments in new compound 1 are based on X-ray diffraction analysis. Compounds 6 and 7 were identified as the known gelomulides A, G. The structures of compounds 7-9 were unambiguously confirmed by X-ray diffraction analyses.     

Absolute stereochemistry of antifouling cembranoid epimers at C-8 from the Caribbean octocoral Pseudoplexaura flagellosa. Revised structures of plexaurolones

Eight cembranoid epimers at C-8 (1-8) were isolated from the organic extract of the Colombian Caribbean octocoral Pseudoplexaura flagellosa. Compounds 2, 4, and 6 are reported for the first time. Although compounds 1, 3, 5, 7, and 8 have been reported previously, their structures and NMR assignments are revised, completed or corrected. The structures of these compounds were established on the basis of detailed analysis of their spectroscopic data. Furthermore, the relative configurations of compounds 1-3 and 7 were confirmed by single-crystal X-ray diffraction. The absolute configurations of compounds 1-8 were determined using a combination of the modified Mosher method and unambiguous chemical interconversions. Evaluation of their antifouling properties using quorum sensing inhibition (QSI) and biofilm inhibition bioassays showed that compounds 3, 6, and 7 have excellent QSI activity against Chromobacterium violaceum, as measured by inhibition of the production of violacein pigment, without interfering with its growth. Furthermore, compounds 3, 5, 6, and 8 exhibited inhibition of biofilm maturation without interfering in the growth of Pseudomonas aeruginosa, Vibrio harveyi, and Staphylococcus aureus. This is the first report of cembranoids as inhibitors of bacterial biofilm and as compounds that interfere with QS in C. violaceum.     

Attempts directed towards the synthesis and determination of the absolute stereochemistry of iso-cladospolide-B and cladospolides-B and C

Attempts to synthesise iso-cladospolide-B, cladospolide-B and cladospolide-C resulted in macrolides 1, 2 and 4 along with butenolide 3. Of the three stereogenic centres, the C-4/C-5 vic-diol was obtained from tartaric acid and d-glucose, while the C-11 stereocentre was created by Jacobsen’s method.     

Diterpenoids from Isodon pharicus

A phytochemical investigation of Isodon pharicus led to the isolation of a novel asymmetric ent-kauranoid dimer, bispseurata F (1), and three new diterpenoids, pharicinins A-C (2-4). Their structures were elucidated by extensive spectroscopic analysis. Compound 1 features a unique linkage pattern of C-17 with C-11′ to connect the two monomers. A possible biogenetic pathway of 1 was also proposed. Compounds 3 and 4 exhibited moderate inhibitory activity against NB4 and SH-SY5Y cell lines.     

Swiemahogins A and B, two novel limonoids from Swietenia mahogani

Two novel limonoids, swiemahogins A (1) and B (2) isolated from the twigs and leaves of Swietenia mahogany, are the first examples of andirobin and phragmalin types of limonoids, of which the D-ring δ-lactone is demolished and a rare γ-lactone is fused to the C-ring at C-8 and C-14. Their structures were elucidated by extensive spectroscopic means, and that of 1 was confirmed by single-crystal X-ray diffraction.     

3,4-seco-Diterpenoids from Trigonostemon flavidus

Phytochemical investigation on the stems of Trigonostemon flavidus resulted in the isolation of five new 3,4-seco-diterpenoids, trigoflavidones A-E (1-5), structurally related to the main co-occurring known 3,4-seco-sonderianic acid (6) and 3,4-seco-sonderianol (7). Compound 4 possesses new 3,4-seco rearranged ent-pimarane skeletal type, characteristic of a vinyl group at C-8, while 5 features a unique five-membered ring (C₁) fused with a cyclopropane ring (C₂). The structures of the new compounds were established by a combination of spectroscopic data and computational methods. Compounds 1-7 were tested for their cytotoxicities on HL-60, SMMC-7721, A-549, MCF-7, and SW480 human tumor cell lines.     

Synthesis of poinsettifolin A

A synthesis of poinsettifolin A (1), a prenylated flavonol isolated from Dorstenia poinsettifolia, is described. Two routes starting from quercetin were explored, and 1 could be prepared if a prenyl group first was incorporated at C-6 of the protected quercetin followed by a condensation with citral at C-8. The key synthetic steps are a Mitsunobu reaction, an europium (III)-catalysed Claisen rearrangement coupled with cross-metathesis, and a benzopyran-forming geranylation. The two geranylated 3,5,3′,4′-tetrahydroxyflavonols prepared, 1 and 3, were assayed for antileishmanial activity against Leishmania amazonensis and Leishmania braziliensis, and found to be active. Compound 3 showed cytotoxic activity against leukaemia and lung cancer cells while 1 lacked cytotoxicity.     

Didemnaketals D and E,bioactive terpenoids from a Red Sea ascidian Didemnum species

Two new spiroketals, didemnaketals D (1) and E (2) were isolated from a marine ascidian species belonging to the genus Didemnum. The structures of the compounds were elucidated by extensive 1D (¹H, ¹³C, and DEPT) and 2D (COSY, TOCSY, HSQC, HMBC, NOESY, and ROESY) NMR studies and high-resolution mass spectroscopic data. The new didemnaketals differ from the reported ones in which that they lack the methyl functionality at C-6 and the hydroxy moiety at C-21. Instead, they possess an ester moiety at C-6 in addition to new oxygen functionality at C-20 of the didemnaketals. Compounds 1 and 2 were evaluated for their protein kinase inhibitory activity against different kinases (CDK5, CK1, DyrK1A, and GSK3) at 10 μg/mL. Compounds 1 and 2 showed moderate activity against these kinases. In addition, the compounds displayed moderate antimicrobial activity against Staphylococcus aureus and Bacillus subtilis, respectively.