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The versatile methodology was developed for synthesizing kujigamberol B, a dinorlabdane diterpenoid isolated from the methanol extract of Kuji amber. A highly efficient intramolecular cyclization is followed by a Sonogashira-coupling reaction during the total synthesis. The synthesized compounds were evaluated for the growth-restoring activity against the mutant yeast (zds1Δ erg3Δ pdr1Δ pdr3Δ) and for the degranulation of RBL-2H3 cells. We found that in both activities, primary alcohol and secondary alcohol analogs are as active as kujigamberol B.

The enantioselective synthesis of violaceoid D, a cytotoxic phenolic compound isolated from the culture broth of Aspergillus violaceofuscus Gasperini, was achieved. The total synthesis involves stereoselective construction of the stereogenic center of violaceoid D via Sharpless asymmetric dihydroxylation, followed by Smiles rearrangement. The absolute configuration of natural violaceoid D was determined to be R from the specific rotation value. Synthesized violaceoid D and its analogs were evaluated for cytotoxicity against two human cancer cell lines, Jurkat and HCT116. Because the enantiomer of violaceoid D showed no cytotoxicity, it is plausible that violaceoid D binds selectively to specific target molecules, such as proteins in the cancer cells.

An efficient synthesis of both enantiomers of lycoperdic acid, a 4-hydroxyglutamic acid derivative from edible mushroom Lycoperdon perlatum, was achieved from a chiral aminoalcohol. The key steps were a stereoselective introduction of a C3 unit into a bicyclic ketone and oxidative cleavage of a cyclic vicinal diol into a dicarboxylic acid. This report provides the first synthesis of (−)-lycoperdic acid.

The structure of an anti-plant pathogenic and plant growth-promoting nonenolide, namely cremenolide, was revised by an efficient combination of DFT-based theoretical NMR calculations and synthesis of a target diastereomer. Initially, the planar structure of cremenolide was reconsidered by an individual analysis of the reported NMR spectra. Subsequently, the relative configuration was predicted using NMR calculations of all possible diastereomers based on the ωB97X-D functional. Finally, the relative configuration of cremenolide was unambiguously confirmed by preparation of the proposed structure.

The heterothallic group of the plant pathogen Phytophthora can sexually reproduce between the cross-compatible mating types A1 and A2. The mating hormone α2, produced by A2 mating type and utilized to promote the sexual reproduction of the partner A1 type, is known to be biosynthesized from phytol. In this study, we identified 2 biosynthetic intermediates, 11- and 16-hydroxyphytols (1 and 2), for α2 by administering the synthetic intermediates to an A2-type strain to produce α2 and by administering phytol to A2 strains to detect the intermediates in the mycelia. The results suggest that α2 is biosynthesized by possibly 2 cytochrome P450 oxygenases via 2 hydroxyphytol intermediates (1 and 2) in A2 hyphae and secreted outside.

Ishigamide was isolated as a metabolite of a recombinant strain of Streptomyces sp. MSC090213JE08 and its unsaturated fatty acid moiety has been confirmed in vitro to be synthesized by a type II PKS. Biosynthesis of such a highly reduced polyketide by a type II PKS is worthy of note. However, absolute configuration of ishigamide remained unknown. (R)-Ishigamide was synthesized enantioselectively employing Stille coupling and Wittig reaction between three units, vinyl iodide, stannyldienal, and Wittig salt. Stereochemistry of natural ishigamide was determined to be R by chiral HPLC analysis comparing with the synthesized standard.

An efficient synthetic pathway to acylpyrrolidinones via a nitro-Mannich reaction, followed by the intramolecular 1,3-dipolar cycloaddition of a nitrile oxide to an alkyne was developed. The syntheses of a leucine-derived tetramic acid and natural tetramide (+)-laccarin were achieved in five steps using aldehydes, 2-alkynamides and nitromethane as the carbon sources.

The enantioselective synthesis of aromatic bisabolanes, such as 1,3,5-bisabolatrien-7-ol, peniciaculin A and B, and hydroxysydonic acid, has been described. Our methodology for the total synthesis of aromatic bisabolanes involves the stereoselective construction of the C-7 stereogenic center via a Sharpless asymmetric dihydroxylation reaction, followed by a SmI2-mediated Julia olefination. Preliminary results obtained for the odor evaluation of 1,3,5-bisabolatrien-7-ol and the confirmation of the absolute configurations of peniciaculin A and B are also described.

The first synthesis of (7S,9R)-decarestrictine H and (7R,9R)-decarestrictine H as well as the improved synthesis of decarestrictine J were achieved. The overall yields of (7S,9R)-decarestrictines H and J were 20.9% each in nine to ten steps from (R)-Roche ester using a unified synthetic route via esterification with 3,3-ethylenedioxyhex-5-enoic acid and ring-closing metathesis, which were the key steps. The relative stereochemistry of decarestrictine H was determined to be 7,9-syn by comparing the spectral data of the natural product and synthetic epimers of decarestrictines H.

The crop destroyer Phytophthora uses mating hormones α1 and α2 to commence its sexual reproduction. The α1-induced sexual reproduction of the A2 mating type was unexpectedly found to be interfered with by the counterhormone α2 that the A2 type itself produces to induce the sexual reproduction of the A1 type. A plausible mechanism is proposed based on structure–activity relationships.

Formosusin A, a specific inhibitor of an X-family DNA polymerase (rat DNA polymerase β), was synthesized using a Sharpless asymmetric dihydroxylation as the key step for the preparation of a chiral building block. This Letter describes the first example of the total synthesis of formosusin A. The absolute configuration of the natural formosusin A was determined to be ( R ) from the specific rotation value. Racemization of formosusin A was observed under acidic conditions, suggesting that the reported natural product might have low optical purity.

Cochlearol A, a renoprotective meroterpenoid isolated from Ganoderma cochlear, was formally synthesized by intramolecular acetal formation. Its characteristic perhydro-3,9a-epoxybenzo[c]oxepine skeleton was stereoselectively constructed by intramolecular acetal formation employing spiroepoxide as a key intermediate, which was prepared via benzylic oxidation under Nicolaou’s conditions employing photochemically activated Pb(OAc)4 and introduction of epoxide under Concellon’s conditions using diiodomethane and methyllithium.

The stereochemistry of selective anticancer compound FE399 was determined to be rel-9R,14R,17R by theoretical and synthetic studies. Relative stereochemistry of FE399 was predicted by comparison of the 13C NMR chemical shifts of the natural sample with that predicted by theoretical calculation for each possible stereoisomer. The first synthesis of (9R,14R,17R)-(−)-FE399 was achieved using an amide formation of a dithiazocane with a hydroxy dodecanoic acid derivatives and sixteen-membered macrolactonization as key steps. The overall yield was 18% in ten steps from l -cysteine and (S)-glycidyl tosylate.

Both enantiomers of (Z)-2β-hydroxy-14-hydro-β-santalol, a potent anti-H. pylori agent, were synthesized and the absolute configuration of the natural product was determined to be 1R,2S,3R,4S. The bicyclo[2.2.1]heptane skeleton was efficiently constructed employing tandem radical cyclization of tethered precursor. Both enantiomers were prepared via optical resolution of racemic intermediate.

The stereochemistry of decarestrictine G was revised to be 5R,6R,9R from theoretical and synthetic studies. The presumable stereoisomer was estimated by comparison of the 1H NMR chemical shifts of the natural product with the calculated values based on density functional theory. With this finding, a synthetic study was performed, and the spectroscopic data for the synthetic (5R,6R,9R)-isomer was fully identical to those of the natural product. The synthesis of (5R,6R,9R)-(−)-decarestrictine G was achieved in 16.5% overall yield in six steps from methyl 3-oxohex-5-enoate via a ring-closing metathesis and a face-selective dihydroxylation of a ten-membered lactone system as the key steps.

In response to environmental stressors such as blast fungal infections, rice produces phytoalexins, an antimicrobial diterpenoid compound. Together with momilactones, phytocassanes are among the major diterpenoid phytoalexins. The biosynthetic genes of diterpenoid phytoalexin are organized on the chromosome in functional gene clusters, comprising diterpene cyclase, dehydrogenase, and cytochrome P450 monooxygenase genes. Their functions have been studied extensively using in vitro enzyme assay systems. Specifically, P450 genes (CYP71Z6, Z7; CYP76M5, M6, M7, M8) on rice chromosome 2 have multifunctional activities associated with ent-copalyl diphosphate-related diterpene hydrocarbons, but the in planta contribution of these genes to diterpenoid phytoalexin production remains unknown. Here, we characterized cyp71z7 T-DNA mutant and CYP76M7/M8 RNAi lines to find that potential phytoalexin intermediates accumulated in these P450-suppressed rice plants. The results suggested that in planta, CYP71Z7 is responsible for C2-hydroxylation of phytocassanes and that CYP76M7/M8 is involved in C11α-hydroxylation of 3-hydroxy-cassadiene. Based on these results, we proposed potential routes of phytocassane biosynthesis in planta.

Epicoccamides A and D were synthesized through a route that utilizes fragment coupling via olefin cross-metathesis as a key step. The right-hand segment of the epicoccamides was synthesized by a tandem O-acylation–migration reaction, and the left-hand segments were stereoselectively synthesized through a modified version of Crich’s β-selective mannosylation. The previously assigned absolute configuration of the epicoccamide D was confirmed, and that of epicoccamide A was assigned as (5S,2′S) based on the NMR and CD spectra. This Letter provides the first example of the total synthesis of epicoccamide A.

Communication among microorganisms is mediated by secretion and detection of microbial signaling molecules such as quorum-sensing pheromones and microbial hormones. The molecules elicit the regulation of important genes necessary for microbial survival and often play important roles in interspecies or even inter-kingdom communication. Recent progress in the study of the signaling molecules has enabled us to eavesdrop on microbial conversations to gain insight on their intercellular communication system. This review summarizes the recent advances in the chemistry and chemical biology of these important microbial signaling molecules: acyl-homoserine lactones (AHLs), AI-2, CAI-1 related α-hydroxy ketones (AHKs), ComX pheromones, diffusible signal factors (DSFs), diffusible extracellular factor (DF), and Phytophthora mating hormones.

The first enantioselective syntheses of ganomycin I, a meroterpenoid isolated from the Vietnamese mushroom Ganoderma colossum, and the related meroterpenoid fornicin A were accomplished. Our methodology for the total syntheses of these compounds featured the construction of the butenolide moiety by asymmetric dihydroxylation followed by Julia–Kocienski type olefin formation and ring-closing metathesis reactions. The absolute configurations of the two natural products were determined by comparisons of specific rotation. A cell-based assay of the synthetic compounds with transfected human embryonic kidney 293 tet-off (E-PR293) cells indicated that ganomycin I possesses cytotoxicity and fornicin A possesses weak anti-HIV-1 protease activity without cytotoxicity.

The first total syntheses of 5′-O-desmethylterphenyllin and three related p-terphenyls have been achieved. The methodology features a Suzuki–Miyaura coupling reaction with a hindered aryl chloride as the key step. Two of the four synthesized 5′-O-desmethylterphenyllins exhibit moderate TNF-α release-inhibitory activity toward RBL-2H3 cells.

The first total synthesis of virgineone aglycone has been achieved employing the tandem O -acylation–migration reaction and the olefin cross-metathesis as key steps for fragment couplings. The left-hand segment of virgineone was also synthesized. The absolute configuration of the reported virgineone aglycone was determined to be (2 S ,7 RS ,26 S ) based on NMR analyses and the specific rotation values of the synthetic compounds. The absolute configuration of the natural virgineone was presumed to be (2 S ,7 S ,26 S ) based on NMR analyses of the synthetic virgineone aglycone.

Synthesis of 2-homoprenyl-1-methyl-3-(5-methylfuran-2-yl)cyclopenta-2,4-dien-1-ol, the core framework of the proposed structure of the brown alga derived natural product sargafuran, was achieved in six steps from the commercially available 5-methylfurfural via the Piancatelli rearrangement of furylcarbinol. The concise synthetic route to the 1,2,3-trisubstituted cyclopentadienol is established. However, the 1H and 13C NMR spectral data of the synthetic analog of sargafuran suggest that the originally proposed structure of sargafuran must be incorrect. In addition, the structure of the natural sargafuran is also discussed.

The synthesis of two potent osteoclast-forming suppressing agents isolated from the Chinese mushroom Agrocybe chaxingu , demethylincisterol A 3 and chaxine A, was accomplished using ergocalciferol as the starting material. Our methodology for the synthesis of demethylincisterol A 3 and chaxine A featured the construction of a butenolide moiety by the intramolecular Horner–Wadsworth–Emmons reaction under Masamune–Roush conditions. This is the first reported synthesis of chaxine A.

The mating hormones α1 and α2 induce sexual reproduction of the phytopathogenic genus Phytophthora. To demonstrate the structural elements responsible to hormonal activity, 17 derivatives of α1 and α2 were synthesized and their hormonal activity (oospore-inducing activity) was evaluated. The terminal ester derivatives of α1 (diacetate and dibenzoate) retained the hormonal activity, whereas a dicarbamate derivative completely suppressed the activity. Even monocarbamates showed weak activities; among them the 1-O-carbamate was less active than 16-O-carbamate, suggesting that the 1-OH group is a little more important than 16-OH. Dihydro, dehydro, and demethyl derivatives exhibited the minimum level of activity. Surviving activity of 15-epi-α1 suggested a less importance of this stereochemistry. Contrary to α1, not only the terminal diacetate derivative but also monoacetates of α2 exhibited no or little activity. Among the monoacetates, 1-O-acetyl-α2 exhibited little yet relatively better activity than the others. No activity was observed for mono- and dicarbamoyl derivatives of α2. Dihydro α2 with the saturated double bond lost most of the activity. These findings suggest that both the mating hormones α1 and α2 require most of the functional (hydroxyl, keto, and olefinic) groups they possess in their natural form for inducing the sexual reproduction of Phytophthora.

Four stereoisomers of Phytophthora mating hormone α2 were synthesized using both enantiomers of citronellol as starting materials. The absolute configuration of the natural product was determined to be 7 S ,11 R ,15 R by oospore-inducing assays of the synthetic isomers. A concise synthetic procedure of α1 was also established using a common synthetic intermediate of α2.

The first synthesis of (±)-cyclic dehypoxanthine futalosine (cyclic DHFL), a biosynthetic intermediate in the futalosine pathway for menaquinones operating in microorganisms, has been achieved. Efficient growth of the Streptomyces coelicolor mutant, which lacks the cyclic DHFL synthetase gene (mqnC gene) was observed in the presence of synthetic (±)-cyclic DHFL.

Microbial signaling molecules such as autoinducers and microbial hormones play important roles in intercellular communication in microorganisms. Information transfer between the individual cells of a microorganism is one of the most important biological events among them. Researchers often suffer from extremely low levels of microbial signaling molecule contents, which prevent them from understanding chemistry and biology of intercellular communication in microorganisms. Chemical synthesis is a powerful tool to obtain sufficient amounts of sample and to clarify the structure of a molecule. This review focuses on the synthesis and stereochemistry-bioactivity relationships of five microbial signaling molecules, Vibrio cholerae autoinducer-1 (CAI-1), AI-2 precursor (DPD), an acylhomoserine lactone from Rhizobium leguminosarum (small bacteriocin), a diffusible extracellular factor of Xanthomondas campestris pv. campestris, and Phytophthora mating hormone α1.

Short-step syntheses of (2RS,8R,10R)-YM-193221 (1) and tyroscherin (2), which are biologically active compounds isolated from Pseudallescheria sp., were accomplished in six and eight steps from L-tyrosine. The relative stereochemistry of natural YM-193221 was determined to be 8R *,10R *.

A proposed structure for the diffusible extracellular factor (DF) of Xanthomonas campestris pv. campestris (Xcc) has been synthesized. Its MS spectrum and biological activity, however, contradict those of the natural product previously reported, suggesting that the structure for DF of Xcc must be reexamined.

Four stereoisomers of roseoside (vomifoliol glucosides) were synthesized using glucose as a chiral resolving reagent. The four synthetic stereoisomers exhibited inhibitory activity on leukotriene release from mouse bone marrow-derived cultured mast cells (BMCMC). The (6S)-isomers of roseoside were about twice as active as (6R)-isomers.

An asymmetric total synthesis of ent-sandaracopimaradiene, a biosynthetic intermediate of oryzalexins, via B-alkyl Suzuki-Miyaura coupling and Lewis acid-mediated B-ring formation as key steps was achieved.

A convergent synthetic strategy for abietane diterpenoids via B -alkyl Suzuki–Miyaura coupling and Lewis acid-mediated cyclization reactions is established. Asymmetric total synthesis of 12-deoxyroyleanone, an antileishmanial diterpene, is described.

The copulation release pheromone of the cowpea weevil, Callosobruchus maculatus, was re-isolated from about 30,000 virgin female. The natural pheromone was confirmed to be stereochemically impure by Ohrui–Akasaka-2D-HPLC methodology. The structure–activity relationship of the pheromone was also clarified.

Two stereoisomers of penazetidine A (1a), the azetidine alkaloid isolated from the Indo-Pacific marine sponge Penares sollasi, were synthesized by starting from (S)-serine and (R)-or (S)-citronellol. The natural penazetidine A must be either (2S,3R,4S,12′R)- or (2S,3R,4S,12′S)-1a.

The structure of the antibacterial sesquiterpene from Premna oligotricha was shown to be not 1 but 2 (relative stereochemistry) by the unambiguous synthesis of both (±)-1 and (±)-2.

A diastereomeric mixture and the four stereoisomers of 2,6-dimethyloctane-1,8-dioic acid (2), a copulation release pheromone of the cowpea weevil, Callosobruchus maculatus, were synthesized. The stereoisomeric purities of the four synthetic isomers of 2 were determined by the HPLC analyses of their bis-2-(2,3-anthracenedicarboximide)-1-cyclohexyl esters.

(E)-6-Ethyl-2,10-dimethyl-5,9-undecadienal was identified from female seed beetle, Callosobruchus rhodesianus (Pic), as an electroantennographic-detection (EAD) active compound in the male. The ratio of the (E)-6-ethyl-2,10-dimethyl-5,9-undecadienal and (3S,6E)-2,3-dihydrohomofarnesal, previously identified as a sex attractant pheromone, was estimated at approximately 1:4.5. In combination with the stereoisomer-activity relationship of 2,3-dihydrohomofarnesal, we suggest that this new compound might function as a minor sex attractant pheromone in C. rhodesianus.

Phytocassane A–E possess ent -cassane skeleton because synthetic (+)-2-deoxyphytocassane A with cassane skeleton showed the Cotton effects positive at 369 nm (due to the ring-C dienone chromophore) and negative at 289 nm (due to the ring-A carbonyl group), while the natural phytocassane A exhibited the opposite Cotton effects.

The first synthesis of a stereoisomeric mixture of hormone α1, the mating hormone of Phytophthora , was achieved, and the synthetic mixture was confirmed to be hormonally active.

Both the enantiomers of incrustoporin (2-p-tolyl-2-hexen-4-olide, 1) were synthesized by starting from methyl p-tolylacetate (2) and (S)-1,2-epoxybutane (3). The naturally occurring compound 1 was shown to possess the R configuration.

Vialinin A, a small compound isolated from the Chinese mushroom Thelephora vialis, exhibits more effective anti-inflammatory activity than the widely used immunosuppressive drug tacrolimus (FK506). Here, we show that ubiquitin-specific peptidase 5/isopeptidase T (USP5/IsoT) is a target molecule of vialinin A, identified by using a beads-probe method. Vialinin A inhibited the peptidase activity of USP5/IsoT and also inhibited the enzymatic activities of USP4 among deubiquitinating enzymes tested. Although USPs are a member of thiol protease family, vialinin A exhibited no inhibitions for other thiol proteases, such as calpain and cathepsin.

The first example of immobilized bakers' yeast mediated reduction of ketones in fluorous media is described. The use of fluorous media permits simple work-up and reuse of the solvent without any purification.

The first total synthesis of ent-cassa-12,15-diene, a putative precursor of diterpene phytoalexins, was accomplished.

The four stereoisomers of small bacteriocin, an autoinducer of the symbiotic nitrogen-fixing bacterium Rhizobium leguminosarum, were synthesized via a versatile methodology for 3′-hydroxyacyl homoserine lactones based on the Nagao asymmetric aldol reaction. The synthetic isomers were much less effective at inhibiting the growth of R. leguminosarum RBL5523 than the natural isomer, showing the importance of stereochemistry for activity.

An efficient and stereoselective synthesis of three stereoisomers of the sex pheromone of the cowpea weevil, Callosobruchus maculatus, is reported.

A versatile methodology for the synthesis of various terpenoids via B -alkyl Suzuki–Miyaura coupling as a key step is established. Synthesis of cordiaquinone J and K, new antifungal and larvicidal meroterpenoids, was achieved by using this methodology. The absolute configurations of cordiaquinone J and K were confirmed by the synthesis.

Total synthesis of cordiaquinone K, a new antifungal and larvicidal meroterpenoid, is reported. The absolute configuration of cordiaquinone K was confirmed by the synthesis.

A novel pyrrolidine amide (MQ-A3) isolated from the tropical convolvulaceous species was synthesized in 5 steps by starting from commercially available 12-bromododecanol and (S)-2-methylbutylbromide. The absolute configuration of the natural product was confirmed by a comparison of the specific rotation values.