Total synthesis of (-)-domoic acid, a potent ionotropic glutamate receptor agonist and the key compound in oceanic harmful algal blooms.

The stereo-controlled total synthesis of (-)-domoic acid is described. The critical construction of the C1'-C2' Z-configuration was accomplished by taking advantage of an unsaturated lactam structure. The side chain fragment was introduced in the final stages of synthesis through a modified Julia-Kocienski reaction, aiming for its efficient derivatization.

Total Synthesis of Sophoraflavanone H and Confirmation of Its Absolute Configuration.

Sophoraflavanone H (1) is a polyphenol with a hybrid-type structure containing 2,3-diaryl-2,3-dihydrobenzofuran and flavanone ring moieties. This compound and related analogues are promising leads for antimicrobial and antitumor drug development. Here we describe a total synthesis of 1 and its diastereomer. The dihydrobenzofuran and flavanone rings were constructed by a Rh-catalyzed asymmetric C-H insertion reaction and selective oxy-Michael reaction. The absolute configuration of 1 was established by X-ray crystallographic analysis and CD spectral investigation of synthetic derivatives.

Lipase-catalyzed asymmetric synthesis of naphtho[2,3-c]furan-1(3H)-one derivatives by a one-pot dynamic kinetic resolution/intramolecular Diels-Alder reaction: Total synthesis of (-)-himbacine.

One-pot sequential reactions using the acyl moieties installed by enzymatic dynamic kinetic resolution of alcohols have been little investigated. In this work, the acryloyl moiety installed via the lipase/oxovanadium combo-catalyzed dynamic kinetic resolution of a racemic dienol [4-(cyclohex-1-en-1-yl)but-3-en-2-ol or 1-(cyclohex-1-en-1-yl)but-2-en-1-ol] with a (Z)-3-(phenylsulfonyl)acrylate underwent an intramolecular Diels-Alder reaction in a one-pot procedure to produce an optically active naphtho[2,3-c]furan-1(3H)-one derivative (98% ee). This method was successfully applied to the asymmetric total synthesis of (-)-himbacine.

Synthetic Study on Pactamycin: Stereoselective Synthesis of the Cyclopentane Core Framework.

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.

Total Synthesis of TAN1251C via Diastereoselective Construction of the Azaspiro Skeleton.

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.

Stereoselective construction of 2-vinyl 3-hydroxybenzopyran rings: total syntheses of teadenols A and B.

Total syntheses of teadenols A and B, isolated from fermented tea, were accomplished in a highly stereocontrolled manner. Key steps were an organocatalytic asymmetric α-aminoxylation reaction of an aldehyde and a palladium-catalyzed intramolecular allylic substitution with phenol. In the latter reaction, we utilized the different conformational preferences of cyclic and acyclic carbonate precursors to obtain cis- and trans-fused benzopyran rings, respectively, via intramolecular etherification.

Practical Synthesis of Spermine, Thermospermine and Norspermine.

Polyamines, such as spermine (1), thermospermine (2) and norspermine (3), are widely distributed in nature, and have multiple biological activities. In addition, many of their conjugates have potential for pharmacological use. Here, we present a solid-phase synthesis using our nitrobenzenesulfonyl (Ns) strategy, which can provide 1, 2 and 3 on a gram scale. This approach should be suitable for facile construction of a diverse library of polyamines.

Central-axial-central chirality transfer: asymmetric synthesis of highly substituted indenes bearing a stereogenic quaternary carbon center from optically active propargyl alcohols.

An asymmetric synthesis of highly substituted indenes 3, bearing a quaternary stereogenic carbon center, has been developed via the central-axial-central chirality transfer from optically active propargyl alcohols 1. This transformation involves the addition/rearrangement of 1 and ynamides 2 to give tetra-substituted allenes 4 and further cyclization of 4.

Efficient intramolecular cyclizations of phenoxyethynyl diols into multisubstituted α,ß-unsaturated lactones.

AgOTf-catalyzed intramolecular cyclization of phenoxyethynyl diols proceeded under mild conditions to afford the multisubstituted α,ß-unsaturated-γ-lactones in 55-98% yields. This method was also applicable to the synthesis of α,ß-unsaturated-δ-lactones. A similar cyclization proceeded when AgOTf was replaced with a stoichiometric amount of N-bromosuccinimide to furnish the α-bromo-substituted α,ß-unsaturated lactones.

A Penicillium sp. F33 metabolite and its synthetic derivatives inhibit acetyl-CoA:1-O-alkyl-sn-glycero-3-phosphocholine acetyltransferase (a key enzyme in platelet-activating factor biosynthesis) and carrageenan-induced paw edema in mice.

Acetyl-CoA:1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) acetyltransferase is a key enzyme in the biosynthesis of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) in inflammatory cells. Substances which inhibit this enzyme are of therapeutic interest. In this study, we screened for new inhibitors of lyso-PAF acetyltransferase with anti-inflammatory effects. In a metabolite from Penicillium sp. F33, we isolated an acetyltransferase inhibitor identified as dihydrofumigatin (2-methoxy-1,3,4-trihydroxy-5-methylbenzene) from high resolution mass spectrometer and NMR data. Dihydrofumigatin had strong acetyltransferase inhibitory activity, but was not stable in aqueous solution. Thus, we chemically synthesized its oxidized form fumigatin (3-hydroxy-2-methoxy-5-methyl-1,4-benzoquinone) and derivatives thereof, and evaluated their inhibitory effects. Strong inhibitory activity was observed for saturated fatty acid esters of fumigatin; the order of inhibition was 3-decanoyloxy-2-methoxy-5-methyl-1,4-benzoquinone (termed FUD-7, IC50 = 3 µM)>2-methoxy-5-methyl-3-tetradecanoyloxy-1,4-benzoquinone (termed FUD-8, IC50 = 20 µM)>3-hexanoyloxy-2-methoxy-5-methyl-1,4-benzoquinone (IC50 = 139 µM). Interestingly, these compounds also significantly suppressed the gene expression of lyso-PAF acetyltransferase/LPCAT2 in mouse bone marrow-derived macrophages stimulated by lipopolysaccharide (LPS). We further evaluated the effect of these substances on anti-inflammatory activity in vivo using the carrageenan-induced mouse paw edema test. FUD-7 and FUD-8 at 2.5 mg/kg showed significant, 47.9-51.7%, inhibition stronger than that of prednisolone at 10 mg/kg (41.9%). These results suggest that FUD-7 and FUD-8 are potent inhibitors with anti-inflammatory activity.

Discovery of aromatic components with excellent fragrance properties and biological activities: ß-ionols with antimelanogenetic effects and their asymmetric syntheses.

Both enantiomers of dihydro-ß-ionol and ß-ionol, contained in the aromatic components of Osmanthus flower and of Hakuto peach, were obtained with high optical purity by lipase-catalyzed kinetic resolution of the racemates. It was found that all these enantiomers had different characteristic favorable scents and high antimelanogenetic effects. The absolute configuration and the enantiomer ratios of dihydro-ß-ionol in the aromatic components of Osmanthus flower and of Hakuto peach were determined. The asymmetric synthesis of (R)-dihydro-ß-ionol, one of the most valuable raw materials for fragrance and flavor, was performed from inexpensive ß-ionone via lipase-catalyzed dynamic kinetic resolution followed by reduction.

Heteropolyacid-catalyzed direct deoxygenation of propargyl and allyl alcohols.

The combination of H(3)[PW(12)O(40)]·nH(2)O (1 mol %) and Et(3)SiH led to the direct catalytic deoxygenation of propargyl alcohols, in which proper solvent selection Cl(CH(2))(2)Cl vs CF(3)CH(2)OH was the key to obtaining better product yields. Under similar conditions, the deoxygenation of allyl alcohols proceeded to give thermodynamically stable alkenes with migration of the double bonds in good yields.

[Development of environmentally benign transformations via 1,3-transposition of hydroxyl group].

This review article describes our recent efforts to develop environmentally benign transformations of allyl and propargyl alcohols via the 1,3-transposition of their hydroxyl groups using combined catalyst systems. This methodology allows for successful transformation under mild conditions, which has never been achieved using each catalyst. Representative examples of this methodology include the following three reactions. First, the combination of oxo-vanadium compounds and lipases resulted in the dynamic kinetic resolution of racemic allyl alcohols to give optically active allyl esters in high yields. Second, Mo-Au-Ag combination catalysis dramatically accelerated the rearrangement of diverse propargyl alcohols into α,ß-unsaturated carbonyl compounds. Finally, the choice of suitable heteropoly acids for the rearrangement of propargyl alcohols led to the selective preparation of both (Z)- and (E)-enones.

One-pot synthesis of optically active allyl esters via lipase-vanadium combo catalysis.

The combination of vanadium-oxo compounds (3 or 4) with a lipase produced the regio- and enantioconvergent transformation of racemic allyl alcohols (1 or 2) into optically active allyl esters. In this system, the vanadium compounds catalyzed the continuous racemization of the alcohols along with the transposition of the hydroxyl group, while the lipase effected the chemo- and enantioselective esterification to achieve the dynamic kinetic resolution.

Cationic gold(I)-catalyzed intramolecular cyclization of gamma-hydroxyalkynones into 3(2H)-furanones.

The combination of (p-CF(3)C(6)H(4))(3)PAuCl and AgOTf generates a powerful catalyst for the intramolecular cyclizations of readily available gamma-hydroxyalkynones under mild conditions. The substituted 3(2H)-furanones are obtained in 55-94% yields. This method is also applicable to the preparation of 2,3-dihydro-4H-pyran-4-ones.

Cationic gold(I)-mediated intramolecular cyclization of 3-alkyne-1,2-diols and 1-amino-3-alkyn-2-ols: a practical route to furans and pyrroles.

The intramolecular cyclizations of the 3-alkyne-1,2-diols and the 1-amino-3-alkyn-2-ols with a low catalyst loading (0.05-0.5 mol %) of (Ph(3)P)AuCl-AgNTf(2) or (Ph(3)P)AuCl-AgOTf proceeded at room temperature to provide a variety of substituted furans and pyrroles in excellent yields (85-98% yields). This method is also fully applicable to the conversion of several dozen grams of the substrate using only 0.05 mol % each of the Au and Ag catalysts.