The cyclopentane core framework 23 of pactamycin (1) was synthesized in 14 steps from symmetric cyclohexadiene 11. Our synthetic strategy features Rh-mediated catalytic desymmetrization of 10 via aziridination and then regioselective ring-opening reaction of sulfonylaziridine 9 with NaN3, ring-contraction of cyclohexene 14 by ozonolysis followed by intramolecular aldol reaction, and stereoselective construction of the sequential tetrasubstituted carbons by dihydroxylation and methylation reaction. Stereospecific incorporation of amine on tetrasubstituted carbon was achieved by Curtius rearrangement and subsequent carbamide formation.

An efficient total synthesis of TAN1251C was accomplished by employing a Ugi four-component accumulation reaction and a Dieckmann condensation to construct the spiro-fused cyclohexanone and γ-lactam ring. Diastereoselective reduction by side-chain-controlled hydrogenation of enamide 15 or Zn reduction of oxime 23 enabled construction of the amino group with the desired stereochemistry.

We accomplished divergent synthesis of potent kinase inhibitor BAY 61-3606 (1) and 27 derivatives via conjugation of imidazo[1,2-c]pyrimidine and indole ring compounds with aromatic (including pyridine) derivatives by means of palladium-catalyzed cross-coupling reaction. Spleen tyrosine kinase (Syk) and germinal center kinase (Gck, MAP4K2) inhibition assays showed that some of the synthesized compounds were selective Gck inhibitors.Download high-res image (101KB)Download full-size image

An efficient and versatile synthetic method for labile polyphenols was established using 2-nitrobenzenesulfonate (Ns) as a protecting group for phenol. This methodology provides regio- and stereoselective access to a range of methylated catechins, such as methylated epigallocatechin gallates, that are not readily available from natural sources. In addition, biomimetic synthesis of theaflavins from catechins was accomplished using Ns protection to minimize undesired side reactions of electron-rich aromatic rings during oxidation, enabling construction of the complex benzotropolone core in a single-step oxidative coupling reaction. Availability of these compounds will aid detailed structure–biological activity relationship studies of catechins.

Covering: up to 2014 The ecteinascidin family comprises a number of biologically active compounds, containing two to three tetrahydroisoquinoline subunits. Although isolated from marine tunicates, these compounds share a common pentacyclic core with several antimicrobial compounds found in terrestrial bacteria. Among the tetrahydroisoquinoline natural products, ecteinascidin 743 (Et-743) stands out as the most potent antitumor antibiotics that it is recently approved for treatment of a number of soft tissue sarcomas. In this article, we will review the backgrounds, the mechanism of action, the biosynthesis, and the synthetic studies of Et-743. Also, the development of Et-743 as an antitumor drug is discussed.

Total synthesis of SB-203207 (1) was achieved, beginning with a desymmetrical C–H insertion reaction of a diazoester bearing our recently developed chiral auxiliary. Utilizing the optically active bicyclo[3.3.0]octane ring, four stereogenic centers were efficiently constructed in sequence. Finally, mild oxidation of 27 to carboxylic acid via a cyanohydrin intermediate and hydrolysis of cyanide to carboxyamide in the presence of the labile enamide group completed an efficient total synthesis of 1.

Practical total syntheses of acromelic acids A (1) and B (2), which have potent neuro-excitatory activity, were accomplished in 13 (36% total yield) and 17 steps (6.9% total yield), respectively, from 2,6-dichloropyridine (8). Regioselective transformation of symmetric 8 provided nitroalkenes 15 and 16. The pyrrolidine ring was efficiently constructed by Ni-catalyzed asymmetric conjugate addition followed by intramolecular reductive amination.

The total synthesis of hedyotol A (1), a natural product isolated from Hedyotis lawsoniae (DC.) Wight et Arn. (Rubiaceae), was accomplished in a highly stereocontrolled manner. Key steps include an l-proline-catalyzed cross-aldol reaction and the biomimetic construction of a furofuran lignan skeleton through a quinomethide intermediate.

A practical total synthesis of kainoid MFPA (5) was achieved in only six steps, via a novel Ni-catalyst-mediated asymmetric conjugate addition reaction. Furthermore, a fluorescein-based fluorescent ionotropic glutamate receptor probe 28 was efficiently synthesized from a precursor derived from a synthetic intermediate of 5.

We describe a practical, large-scale synthesis of the “fairy-ring” plant-growth regulator 2-azahypoxanthine (AHX), and its biologically active hydroxyl metabolite (AOH) and riboside derivative (AHXr). AHXr, a biosynthetic intermediate, was synthesized from inosine via a biomimetic route. Biotinylated derivatives of AHX and AHXr were also synthesized as probes for mechanistic studies.

Chemoselective hydrogenation of unsaturated compounds bearing an o-nitrobenzenesulfonyl (Ns)-amide moiety, affording the corresponding saturated compounds, was accomplished efficiently without loss of the nitro group by using the Pd/MS3A catalyst and a H2 balloon. Partial hydrogenation of alkynes bearing an Ns group to corresponding cis alkenes was achieved with the combination of the Pd/BN catalyst and an additive (diethylenetriamine or acetic acid).

Asymmetric bromolactonization of prochiral cyclohexadiene derivatives with N-bromosuccimide proceeded in the presence of (DHQD)2PHAL as a chiral catalyst to afford the corresponding bromolactones with up to 93% ee. This reaction was also applicable to the kinetic resolution of a racemic cyclic ene-carboxylic acid, where the starting material was recovered with high enantioselectivity.

The efficient total syntheses of (+)-methoxyphenylkainic acid (3) and (+)-phenylkainic acid (4) were achieved using a rhodium carbenoid-mediated intermolecular C−H insertion reaction. Complete stereoselective construction of the kainoid skeleton was accomplished by utilizing the stereochemistry at the C-4 position as a pivotal stereogenic center.

A practical synthesis of nobiletin, a polymethoxylated citrus flavone, was accomplished by utilizing our novel flavone synthesis. Synthetic nobiletin was labelled by selective demethylation and rapid incorporation of 11C atom. Positron emission tomography images successfully visualized the brain distribution, which may provide therapeutic benefits in the treatment of Alzheimer's disease.

A concise synthesis of APDOEGCg (3) was accomplished. Due to the reactivity of its amine group, the compound could be easily converted to the fluorescein probe 21 and immunogen probe 22 efficiently. We then demonstrated the usefulness of the probes for imaging studies and the generation of antibodies.

Efficient synthesis of the tricyclic key intermediate 2 for (−)-FR901483 1 was accomplished. The precursor of the intramolecular aldol reaction 4b is constructed by the Ugi 4CC reaction and subsequent intramolecular Dieckmann condensation. This approach allows a fully stereocontrolled total synthesis of (−)-FR901483, which would provide various derivatives.Efficient synthesis of the tricyclic key intermediate 2 for (−)-FR901483 1 was accomplished using an intramolecular aldol reaction and an Ugi 4CC reaction.

The regioselective synthesis of chafurosides A (1) and B (2) from the same methyl ketone 5 was accomplished using a novel protecting group strategy. Both flavone rings were constructed from β-diketone intermediate 4, which was readily obtained by condensation of an acyl donor and ketone 5. Construction of the dihydrofuran ring was achieved via an intramolecular Mitsunobu reaction.

Regioselective synthesis of methylated epigallocatechin gallate from epigallocatechin was accomplished using a 2-nitrobenzenesulfonyl (Ns) group as a protecting group for phenols. This methodology provided several methylated catechins, which are naturally scarce catechin derivatives.The regioselective synthesis of methylated epigallocatechin gallate from epigallocatechin is reported.

The stereocontrolled total synthesis of (−)-myriocin 1 is reported. Optically active epoxide 9 was converted from symmetrical cyclohexadiene 8, utilizing an enzymatic kinetic resolution. The three sequential stereogenic centers of 1 were constructed by a regioselective epoxide-opening reaction and a Hofmann rearrangement. Elongation of the side chain was efficiently accomplished by the Julia–Kocienski reaction.(1R,2S,6S)-Methyl 2-[(tert-butoxycarbonyloxy)methyl]-7-oxabicyclo[4.1.0]hept-3-ene-2-carboxylateC14H20O6[α]23 = + 34.7 (c 1.01, CHCl3)Source of chirality: pig liver esterase [PLE-A (AMANO)]Absolute configuration: (1R,2S,6S)(1S,5S,6S)-Methyl 1-[(tert-butyldiphenylsilyloxy)methyl]-6-hydroxy-5-(methoxymethoxy)cyclohex-2-enecarboxylateC27H36O6Si[α]23 = + 11.2 (c 1.04, CHCl3)Source of chirality: pig liver esterase [PLE-A (AMANO)]Absolute configuration: (1S,5S,6S)(1S,5S,6S)-Methyl 1-[(tert-butyldiphenylsilyloxy)methyl]-5,6-bis(methoxymethoxy)cyclohex-2-enecarboxylateC29H40O7Si[α]23 = −23.8 (c 1.05, CHCl3)Source of chirality: pig liver esterase [PLE-A (AMANO)]Absolute configuration: (1S,5S,6S)(1S,5S,6S)-1-[(tert-Butyldiphenylsilyloxy)methyl]-5,6-bis(methoxymethoxy)cyclohex-2-enecarboxamideC28H39NO6Si[α]23 = −16.8 (c 1.01, CHCl3)Source of chirality: pig liver esterase [PLE-A (AMANO)]Absolute configuration: (1S,5S,6S)(S)-4-[(tert-Butyldiphenylsilyloxy)methyl]-4-[(5S,6S)-6-(2-hydroxyethyl)-2,4,7,9-tetraoxadecan-5-yl]oxazolidin-2-oneC28H41NO8Si[α]23 = −17.6 (c 1.01, CHCl3)Source of chirality: pig liver esterase [PLE-A (AMANO)]Absolute configuration: (4S,5S,6S)(S)-4-[(tert-Butyldiphenylsilyloxy)methyl]-4-{(5S,6S)-6-[2-(1-phenyl-1H-tetrazol-5-ylsulfonyl)ethyl]-2,4,7,9-tetraoxadecan-5-yl}oxazolidin-2-oneC35H45N5O9SSi[α]23 = −16.0 (c 0.77, CHCl3)Source of chirality: pig liver esterase [PLE-A (AMANO)]Absolute configuration: (4S,5S,6S)(R)-4-{(5S,6S)-6-[(E)-9-(2-Hexyl-1,3-dioxolan-2-yl)non-2-enyl]-2,4,7,9-tetraoxadecan-5-yl}-4-(hydroxymethyl)oxazolidin-2-oneC28H51NO9[α]23 = −13.3 (c 1.01, CHCl3)Source of chirality: pig liver esterase [PLE-A (AMANO)]Absolute configuration: (4R,5S,6S)(5R,8S,9S)-9-Hydroxy-8-[(E)-10-oxohexadec-2-enyl]-3,7-dioxa-1-azaspiro[4.4]nonane-2,6-dioneC22H35NO6[α]23 = −44.3 (c 0.30, CHCl3)Source of chirality: pig liver esterase [PLE-A (AMANO)]Absolute configuration: (5R,8S,9S)(−)-MyriocinC21H39NO6[α]23 = −1.4 (c 0.13, MeOH)Source of chirality: pig liver esterase [PLE-A (AMANO)]Absolute configuration: (2R,3S,4S)

A biphenanthryl ether with substituents in the bay regions was efficiently synthesized for the first time. The unique stereostructure of 1 was clarified. Its twisted conformation and optical behavior as well as its characteristic supramolecular helical structure, which is constructed through a C–H⋯F hydrogen bonding network in the solid state, are discussed.

The Heck reaction of an unsymmetrically substituted [3]cumulene has been investigated. Although a carbonyl conjugated alkene is present, the arylpalladium species selectively inserts into the C3–4 double bond, and a subsequent C–H activation reaction with a neighboring phenyl group gives the indene derivatives with a tetrasubstituted olefin moiety.

•2-Azahypoxanthine (AHX) or imidazole-4-carboxamide (ICA) increased yield of wheat.•AHX treatment of wheat seeds significantly increased yield.•Yield increase was due to the increase in number of ears.•AHX or ICA mitigated to decrease tillers under high temperature.Two-year field examinations to see effects of the principle components of a fungus causing “fairy rings” phenomena on lawns, 2-azahypoxanthine (AHX) and imidazole-4-carboxamide (ICA), on wheat were performed. The treatment of AHX or ICA was performed, in the early (seedling treatment, seed soaking treatment) and late (field treatment) developmental stages, and the resulting number of ears and grain weight per plant increased. AHX treatment increased the number of ears before tillering and ICA treatment increased the number after tillering. The high temperature during tillering stage in 2011 was a stress condition for wheat production in fields. The results indicated that AHX and ICA increased number of tillers and then number of ears, resulting in the increase of the grain yield even though under high-temperature stress.

A concise synthesis of APDOEGCg (3) was accomplished. Due to the reactivity of its amine group, the compound could be easily converted to the fluorescein probe 21 and immunogen probe 22 efficiently. We then demonstrated the usefulness of the probes for imaging studies and the generation of antibodies.

We describe a practical, large-scale synthesis of the “fairy-ring” plant-growth regulator 2-azahypoxanthine (AHX), and its biologically active hydroxyl metabolite (AOH) and riboside derivative (AHXr). AHXr, a biosynthetic intermediate, was synthesized from inosine via a biomimetic route. Biotinylated derivatives of AHX and AHXr were also synthesized as probes for mechanistic studies.

A practical synthesis of nobiletin, a polymethoxylated citrus flavone, was accomplished by utilizing our novel flavone synthesis. Synthetic nobiletin was labelled by selective demethylation and rapid incorporation of 11C atom. Positron emission tomography images successfully visualized the brain distribution, which may provide therapeutic benefits in the treatment of Alzheimer's disease.