Asymmetric Total Synthesis of Neoxaline

Trimble L.A., Sumarah M.W., Blackwell B.A., Wrona M.D., Miller J.D.

Two diastereomeric metabolites (16R) and (16S)-hydroxyroquefortine C were characterized from Penicillium crustosum DAOM 215343. The 16S metabolite is reported for the first time along with evidence for the absolute stereochemistry of both. The metabolites were originally detected by LC–NMR and the structures of the subsequently isolated metabolites were elucidated by HRMS and NMR.

KONDA Y., ONDA M., HIRANO A., OMURA S.

Oxaline (1) has been isolated from Penicillium species Fg-234 and the structure of the compound (2) obtained by treatment of 1 with hydrochloric acid is deduced on the basis of spectral data. Neoxaline (9) isolated from Aspergillus japonicus Fg-551 has a structural framework similar to that of 1.

Kang J., Fang X., Chen X., Zhao G., Ren A., Xu J., Yang W.

A synthetic green fluorescent protein analogue showed Zn2+-induced fluorescence in organic solvents (Φ = 0.07 at r.t. and up to 0.3 at low temperature). The experimental observations and theoretical calculations suggest that Zn2+ binding inhibits the free rotation of an aryl–alkene bond, which allows excited molecules to relax through the emission pathway instead of the thermodynamic pathway. The solvent influenced the fluorescence intensities and wavelengths by direct or indirect interactions with the molecules.

Du L., Feng T., Zhao B., Li D., Cai S., Zhu T., Wang F., Xiao X., Gu Q.

Four new alkaloids, including two new meleagrin analogs, meleagrin D (1) and E (2), and two new diketopiperazines, roquefortine H (3) and I (4), were isolated from a deep ocean sediment-derived fungus Penicillium sp. Meleagrin D (1) and E (2) possess unprecedented acetate–mevalonate-derived side chains on the imidazole moiety. These new meleagrins showed weak cytotoxicity against the A-549 cell line, whereas meleagrin B (5) and meleagrin (6), which were isolated previously from the same strain, induced HL-60 cell apoptosis or arrested the cell cycle through G2/M phase, respectively. The results indicate that the distinct substitutions on the imidazole ring significantly influence the cytotoxicity of the meleagrin alkaloids.

Sravan Kumar J., Jonnalagadda S.C., Mereddy V.R.

An efficient methodology for the preparation of α-hydroxyamides via boric acid mediated addition of isonitriles on to aldehydes has been developed. The reaction of isonitriles with α-boronobenzaldehyde takes place under intramolecular catalysis conditions to provide functionalized benzoxaboroles.

Du L., Li D., Zhu T., Cai S., Wang F., Xiao X., Gu Q.

Four new alkaloids, including two new meleagrin analogs, meleagrins B (2) and C (3), and two new diketopiperazines, roquefortines F (5) and G (6), together with six new diterpenes, conidiogenones B–G (7–12), were isolated from a deep ocean sediment derived fungus Penicillium sp. The structures and stereochemistry of the new compounds were elucidated by spectroscopic methods. The cytotoxicity of the new compounds against the HL-60, A-549, BEL-7402, and MOLT-4 cell lines was evaluated.

Shangguan N., Hehre W.J., Ohlinger W.S., Beavers M.P., Joullié M.M.

The first total synthesis of roquefortine C is achieved by implementation of a novel elimination strategy to construct the thermodynamically unstable E-dehydrohistidine moiety. Molecular modeling studies are presented which explain the instability of the roquefortine C structure compared to that of isoroquefortine C.

Wan L., Tius M.A.

The allene ether version of the Nazarov cyclization was used to construct the cyclopentane dione portion of madindolines A and B. The racemic cyclopentane dione from the Nazarov cyclization was converted to an enol ether that was combined with the chiral, nonracemic hydroxyfuroindoline in a Mannich reaction. Deprotection and oxidation led to (+)-madindoline A and (+)-madindoline B. [reaction: see text].

Overy D.P., Phipps R.K., Frydenvang K., Larsen T.O.

Overy, D. P., Phipps, R. K., Frydenvang, K., Larsen, T. O. (2006). Epi-Neozaline, a chemotaxonomic marker for Penicillium tulipae. Biochemical Systematics and Ecology, 34, (4), 345-348. Sponsorship: Danish Research Council (grant No. 9901295)

Overy D.P., Nielsen K.F., Smedsgaard J.

Three strains of each of the seven taxa comprising the Penicillium series Corymbifera were surveyed by direct injection mass spectrometry (MS) and liquid chromatography–MS for the production of terrestric acid and roquefortine/oxaline biosynthesis pathway metabolites when cultured upon macerated tissue agars prepared from Allium cepa, Zingiber officinale, and Tulipa gesneriana, and on the defined medium Czapek yeast autolysate agar (CYA). A novel solid-phase extraction methodology was applied for the rapid purification of roquefortine metabolites from a complex matrix. Penicillium hordei and P. venetum produced roquefortine D and C, whereas P. hirsutum produced roquefortine D and C and glandicolines A and B. P. albocoremium, P. allii, and P. radicicola carried the pathway through to meleagrin, producing roquefortine D and C, glandicolines A and B, and meleagrin. P. tulipae produced all previously mentioned metabolites yet carried the pathway through to an end product recognized as epi-neoxaline, prompting the proposal of a roquefortine/epi-neoxaline biogenesis pathway. Terrestric acid production was stimulated by all Corymbifera strains on plant-derived media compared to CYA controls. In planta, production of terrestric acid, roquefortine C, glandicolines A and B, meleagrin, epi-neoxaline, and several other species-related secondary metabolites were confirmed from A. cepa bulbs infected with Corymbifera strains. The deposition of roquefortine/oxaline pathway metabolites as an extracellular nitrogen reserve for uptake and metabolism into growing mycelia and the synergistic role of terrestric acid and other Corymbifera secondary metabolites in enhancing the competitive fitness of Corymbifera species in planta are proposed.

Sunazuka T., Shirahata T., Tsuchiya S., Hirose T., Mori R., Harigaya Y., Kuwajima I., Ōmura S.

The stereoselective synthesis of tetracyclic intermediate, the indoline spiroaminal 3 for neoxaline (1) and oxaline (2), has been accomplished. The key step of the stereoselective synthesis of 3 was the Lewis acid mediated transcyclization of 4 to the diaminal 18, and the tungstate-catalyzed oxidation of 18 to obtain the nitrone 19, which easily cyclizes to the indoline spiroaminal framework 3. [structure: see text]

Sunazuka T., Yoshida K., Kojima N., Shirahata T., Hirose T., Handa M., Yamamoto D., Harigaya Y., Kuwajima I., Ōmura S.

Total synthesis of (−)-physovenine has been achieved in a concise manner starting from optically active (−)-3a-hydroxyfuroindoline. Total synthesis of calabar bean alkaloid (−)-physovenine (−)- 3 has been achieved in a concise manner starting from optically active (−)-3a-hydroxyfuroindoline (−)- 2 , synthesized via modified Sharpless epoxidation of tryptophol 1 . Our strategy involved a stereospecific radical substitution reaction and regioselective oxidation at the C5 position.

Koizumi Y., Arai M., Tomoda H., Ōmura S.

Oxaline and neoxaline, fungal alkaloids, were found to inhibit cell proliferation and to induce cell cycle arrest at the G 2 /M phase in Jurkat cells. CBP501 (a peptide corresponding to amino acids 211–221 of Cdc25C phosphatase), which inhibits the G 2 checkpoint, did not affect the G 2 /M arrest caused by oxaline, suggesting that oxaline causes M phase arrest but not G 2 phase arrest. The Cdc2 phosphorylation level of oxaline-treated cell lysate was lower than that of the control cells, indicating that oxaline arrests the M phase. Oxaline disrupted cytoplasmic microtubule assembly in 3T3 cells. Furthermore, oxaline inhibited polymerization of microtubule protein and purified tubulin dose-dependently in vitro. In a binding competition assay, oxaline inhibited the binding of [ 3 H]colchicine to tubulin, but not that of [ 3 H]vinblastine. These results indicate that oxaline inhibits tubulin polymerization, resulting in cell cycle arrest at the M phase.

Sai H., Ogiku T., Ohmizu H.

Highly stereoselective syntheses of (E)-α,β-dehydroamino acids and (E)-α,β-dehydropeptides have been achieved in good yields by stereospecific dehydration of threo-β-hydroxy-α-amino acid derivatives using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and CuCl 2 .

Hirose T., Sunazuka T., Shirahata T., Yamamoto D., Harigaya Y., Kuwajima I., Ōmura S.

[reaction: see text] A short and efficient total synthesis of (+)-madindolines A (1) and B (2), potent and selective inhibitors of interleukin 6, has been achieved. The synthesis features a key chelation-controlled 1,4-diastereoselective acylation to generate the quaternary carbon and an intramolecular acylation of allylsilane to build up the cyclopentene unit.

Bates R.W., Pham T.L., Sae-Lao P.

Mapinta S., Kongjaroon S., Trisrivirat D., Kesornpun C., Wu J., Chaiyen P., Weeranoppanant N.

In this work, a chemo-enzymatic reaction was developed to synthesize indole-3-acetic acid (IAA) in a continuous flow mode.

Chen J., Chen Z., Yu M., Xu Z., Li C.

AbstractHerein, a novel and efficient protocol for the synthesis of polycyclic spiroindolines is realized through a 1,2‐acyloxy migration‐cyclization cascade starting from ester‐tethered 1,2,3‐triazoles. [6,5,5,6] and [6,5,6,6] ring skeleton are constructed in moderate to excellent yields.

Rippel R., Leitão F., Georgieva M.K., Mamede R., Gomes C.S., Rodrigues C., Fernandes A.R., Lourenço A., Ferreira L.M., Branco P.

A novel approach has been developed for the efficient synthesis of the unsymmetrical (2-aminopyrrolidin-1-yl)carboxamidine alkaloidal core found in Cernumidine (1) and its analogs (20a, 20c, 20f, 20i-o). The key transformation...

Li S., Liu X., Tung C., Liu L.

Sunazuka T.

Scheuplein N.J., Bzdyl N.M., Lohr T., Kibble E.A., Hasenkopf A., Herbst C., Sarkar-Tyson M., Holzgrabe U.

Chen C., Chen J., Wang H., Xu Z., Duan S., Li C.

Luo P., Dai J., Ye R., Zhu L., Deng Y., Peng F., Shao Z.

Catalytic asymmetric reactions of acetaldehyde, an inexpensive and versatile two-carbon nucleophile, still remain a challenge. Herein, chiral acyclic secondary aminocatalysts are developed as a means to address the difficult asymmetric reactions of acetaldehyde. The chiral acyclic secondary aminocatalysts exhibit unique reactivity and selectivity, which are not observable by using chiral cyclic secondary aminocatalysts or primary aminocatalysts. The activity is demonstrated by introducing previously challenging chemical transformations such as asymmetric Mannich reactions and switching enantioselectivity where the same absolute configuration of chiral catalysts are used. In general, the chiral acyclic catalysts improve activity and enantioselectivity, broadening the possible substrate scope. This work lays the foundation for the transformation of acetaldehyde with chiral acyclic secondary aminocatalysis and future work surrounding this class of aminocatalyst.

Moriyama K., Oka Y.

Banfi L., Basso A., Lambruschini C., Moni L., Riva R.

This perspective aims at celebrating the 100th anniversary of the discovery of the Passerini three component reaction. After being nearly neglected for many years, now this reaction has become quite popular, thanks to the achievements of the last 30 years, which have revealed several chances of exploitation in organic synthesis. Though not being comprehensive, this review means to show the various ways that have been used in order to expand the utility of the Passerini reaction. Post-MCR transformations to give heterocycles or peptidomimetics, variants through single component replacement, stereochemical issues, and applications in total syntheses will be especially covered.

Lin Z., Xue Y., Liang X., Wang J., Lin S., Tao J., You S., Liu W.

The interest in indole dearomatization, which serves as a useful tool in the total synthesis of related alkaloid natural products, has recently been renewed with the intention of developing new methods efficient in both yield and stereoselective control. Here, we report an enzymatic approach for the oxidative dearomatization of indoles in the asymmetric synthesis of a variety of furoindolines with a vicinal quaternary carbon stereogenic center. This approach depends on the activity of a flavin-dependent monooxygenase, TsrE, which is involved in the biosynthesis of bicyclic thiopeptide antibiotic thiostrepton. TsrE catalyzes 2,3-epoxidation and subsequent epoxide opening in a highly enantioselective manner during the conversion of 2-methyl-indole-3-acetic acid or 2-methyl-tryptophol to furoindoline , with up to > 99% conversion and > 99% ee under mild reaction conditions. Complementing current chemical methods for oxidative indole dearomatization, the TsrE activity-based approach enriches the toolbox in the asymmetric synthesis of products possessing a furoindoline skeleton.

Lin Z., Xue Y., Liang X., Wang J., Lin S., Tao J., You S., Liu W.

An enzymatic approach for oxidative indole dearomatization is reported. TsrE, a flavin-dependent monooxygenase involved in the biosynthesis of bicyclic thiopeptide antibiotic thiostrepton, catalyzes 2,3-epoxidation and subsequent epoxide opening during the conversion of 2-methyl-indole-3-acetic acid or 2-methyl-tryptophol to furoindoline, with up to >99 % conversion and >99 % ee under mild reaction conditions.

Hewage R.T., Huang R., Lai S., Lien Y., Weng S., Li D., Chen Y., Wu S., Chein R., Lin H.

Meleagrin B is a terpene-alkaloid hybrid natural product that contains both the conidiogenone and meleagrin scaffold. Their derivatives show diverse biological activities. We characterized the biosynthesis of (-)-conidiogenone B (1), which involves a diterpene synthase and a P450 monooxygenase. In addition, an α,β-hydrolase (Con-ABH) was shown to catalyze an aza-Michael addition between 1 and imidazole to give 3S-imidazolyl conidiogenone B (6). Compound 6 was more potent than 1 against Staphylococcus aureus strains.

Tan H., Wang Y.

An efficient one-pot multicomponent reaction for the synthesis of novel tetrasubstituted hexahydroimidazo[1,2-a]pyridines starting from readily available cinnamaldehydes, ethylenediamines, and 1,3-dicarbonyl compounds catalyzed by AcOH is described. Two new cycles and four new bonds are constructed with all reactants being efficiently utilized in this transformation. The products could be obtained in 1-3 h under ambient conditions exclusively as a single isomer (trans). Single-crystal X-ray analysis confirmed the trans derivative as the only isomer.