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The first total synthesis of (.+-.)-triumphalone (I) and its conversion to (.+-.)-isotriumphalone is presented resulting in a revision of the reported structure.

Stereoselective synthesis of both optically active cis- and fra/M-1-amino-2-hydroxycyclohexane-l-carboxylic acids (Ahhs) la and 1b was accomplished by an asymmetric version of the Strecker synthesis. Stereochemical aspects of their chiral induction processes are investigated.

Four novel peptides, polistes-mastoparan-R1, 2, 3, and polistes-protonectin, were isolated from the venom of a paper wasp, Polistes rothneyi iwatai. MALDI-TOF MS analysis of a small amount of the crude venom gave six molecular-related ion peaks. Among them, m/z 1565 was expected to be a novel peptide. Purification of the crude venom by HPLC gave two known kinins, Thr6-bradykinin and Ala-Arg-Thr6-bradykinin, and four novel peptides named polistes-mastoparan-R1, 2, and 3, and polistes-protonectin. Polistes-mastoparan-R1, 2, and 3 (Pm-R) were tetradecapeptides that possess high sequence homology with that of mastoparan. The sequence of polistes-protonectin was similar to that of protonectin isolated from a Brazilian paper wasp. Histamine-releasing activities of Pm-R1, 2, and 3 were more potent than that of mastoparan. Polistes-protonectin exhibited the most potent hemolytic activity in comparison with the four novel peptides and mastoparan.

Natural and unnatural compounds possessing an α,α-disubstituted α-amino acid substructure have received significant attention because of their structural complexity and potent biological activity. Many methods have been developed for the enantio- and diastereoselective synthesis of α,α-disubstituted α-amino acids, many of which are focused on the total synthesis of natural products and related bioactive compounds. This microreview highlights recent advances in synthetic methods utilized for the synthesis of (1) α-substituted serine analogs, which were extensively transformed into glutamate and enkephalin analogs, and (2) natural products such as lactacystin, manzacidins, kaitocephalin, altemicidin, sphingofungins, and neooxazolomycin. The key methods for the construction of these higher-order structures are the asymmetric Strecker synthesis and enolate-Claisen rearrangements used by our group, and aldol condensation of an enolate or bislactim, mercurio- or iodo-cyclization, alkylation of an oxazoline, rearrangement of a trichloroacetimidate, nitrene insertion into a C–H bond, carbene insertion into a C–N bond, a Diels–Alder reaction, Lewis acid-induced epoxide opening, and other methods by other groups. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

The synthesis of an amino acid analogue bearing a squaryl group as a carboxylic acid surrogate (sq-AA; 2) has been developed. Aminomalonate equivalent 6 was used as a nucleophilic synthon whose alkylation or conjugate addition reaction followed by deprotection and decarboxylation reaction gave sq-AAs.

We identified novel 10 multi-cysteine peptides, namely Magi 7-16, from the spider Macrothele gigas by simple random cDNA screening of the venom gland. Mass analysis of the crude venom detected the mass numbers of the cross-linked forms of all peptides, confirming their presence in the venom. Magi 11, a C-terminus amidated peptide, was chemically synthesized and was indistinguishable from the native peptide proving the feasibility of the method for peptide identification. Moreover, toxicological assays showed diverse lethal or paralytic activities of these peptide toxins on mice and/or insects.

The synthesis of four types of optically active β-carbon-substituted analogs of threo -β-hydroxy aspartate (THA) and a β-carbon-substituted analog of threo -β-benzyloxy aspartate (TBOA), which are potent blockers of excitatory amino acid transporters in the mammalian central nervous system, via the chirality-transferring ester–enolate Claisen rearrangement of α-acyloxytrialkylsilane is described.

Efficient synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740: 1 ) and its structurally related analogs (−)- 2 and (−)- 3 has been accomplished starting with (1 S ,2 R )-1-amino-2-hydroxycyclopentane- or cyclohexanecarboxylic acid ( 4 or 17 ) via an intramolecular cyclopropanation of α-diazo acetamide.

A series of optically active α,α-disubstituted α-amino acids have been synthesized starting with an achiral or a racemic α-hydroxy or α-diazo ketone. In the present synthesis, the key transformation is an asymmetric version of the Strecker synthesis. An α-acyloxy ketone having a chiral amino acid as the acyloxy group afforded cyclic α-amino nitrile in a highly stereoselective manner; in this reaction the amino group and the chirality were diastereoselectively transplanted into the internal ketone group via an imine-enamine equilibrium of the cyclic ketimine intermediate. Oxidation of the amino group followed by removal of the resulting imino group and hydrolysis of the nitrile group afforded α-hydroxymethyl α-amino acid. The use of L-amino acid as the acyloxy group gave R enantiomer, and its S enantiomer was obtained when D-amino acid was employed. Some problematic processes that remained in the Strecker synthesis, i.e., preparation of the starting α-acyloxy ketone and oxidative conversion of α-amino nitr...

Highly enantioselective synthesis of (2R)-α-(hydroxymethyl)glutamate ( 1 ), a selective agonist of mGluR2 and 3, was achieved in short steps using an asymmetric version of the Strecker synthesis. This was converted into its α-methoxymethyl- and α-benzyloxymethyl derivatives 2 and 3 , possible ligands as tools to investigate glutamate receptors, via protection of the sterically hindered amino group by means of phase transfer catalyst.

Stereoselective construction of a tetraol system corresponding to C-5, 6, 7, and 11 in tetrodotoxin was achieved. Epoxidation of allyl sulfide 3 followed by base-induced ring-opening reaction gave hydroxyallyl sulfone 6. Repetition of the above reactions gave 1,3-dihydroxyvinyl sulfone 8, which was transformed to protected tetraols 18 and 20 by a series of sequential reactions: 1) reductive removal of the phenylsulfonyl group, 2) inversion of the α-axial TBSoxy group to an β-equatorial position, and 3) dihydroxylation with Oso 4 .

An enolate-like intermediate A derived from 1,2-dioxo-3-isopropyloxy-4-methyl-3-cyclobutene ( 6 ) has proven to be a novel nucleophilic synthon for an aldol condensation reaction with an arylaldehyde to give a variety of 4-hydroxy-2,3-dioxocyclobut-1-enyl group (Sq group)-containing cinnamic acid derivatives.

The stereoselective total synthesis of (−)-funebrine from 2-butyn-1-ol was described. The crucial steps in the synthesis involved the stereoselective enolate Claisen rearrangement of the (S)-α-acyloxy-α-alkynylsilane 8, the Au-catalyzed regio- and stereoselective lactonization of the allenylsilane 7, and the Paal–Knorr pyrrole condensation using an unsymmetrical 1,4-diketone 4b.

A short total synthesis of (−)-kainic acid has been developed involving a novel diastereofacial differentiating Cu-catalyzed Michael addition–cyclization reaction, which provided access to a chiral pyrroline in a highly stereoselective manner. The chiral pyrroline was converted to (−)-kainic acid via the stereoselective 1,4-reduction of the pyrroline double bond in three steps.

A short total synthesis of (−)-kainic acid has been developed involving a novel diastereofacial differentiating Cu-catalyzed Michael addition–cyclization reaction, which provided access to a chiral pyrroline in a highly stereoselective manner. The chiral pyrroline was converted to (−)-kainic acid via the stereoselective 1,4-reduction of the pyrroline double bond in three steps.

Barbier-type allylation of unactivated aldimines with allyl bromides in the presence of indium powder took place rapidly in alcoholic solvents to give homoallylic amines in fair to good yields.

d -glucono 1,5-lactone was converted to O-protected d -gluconic acids. The latter were transformed to gluco-KDO derivatives using Barton ester-based radical chemistry with high diastereoselectivity.

Oxidation of α-amino nitrile 4 with ozone gave rise to a mixture of α-imino nitrile 5 and a novel fragmentation product of 6 in one-step. The mixture was converted to a variety of α-substituted α-amino acids 7 in high yields, which enabled the asymmetric transferring Strecker synthesis to be a widely useful method.

Syntheses of novel amino acids possessing a squaryl group, 1−3, in an optically active form are described. The syntheses of 1−3 were conducted by a concise route involving (1) an aldol addition of an enolate derived from Gly, l-Asp, or l-Glu to diisopropyl squarate (4) and (2) an efficient decarboxylation of the aldol adducts based on the electron-withdrawing property of the squaryl group. Introducing N-protected group to 2 and 3 and peptide formation reactions are also described.

9- trans -9-Desmethyl-9-fluororetinal analogs were synthesized by the four-components coupling approach. Horner-Emmons olefination of 3 afforded the undesired 2 E -isomer 5 which was transformed to 6 E -triene 8 via the Stille coupling reaction. Isomerization of 6 E -triene 8 with an iodine catalyst proceeded in a highly regioselective manner to give the 6 Z -isomer 9 . Wittig reaction of 13 derived from oxidation of 9 followed by reduction and oxidation provided 13- cis -9-desmethyl-9-fluororetinal 17 . The 13- cis -analog 17 was regioselectively converted to the all- trans -isomer 19 by treatment with trifluoroacetic acid.

[reaction: see text] Four possible stereoisomers of manzacidin B were synthesized using stereochemically defined synthetic routes via the azide 7 and oxazoline 11 starting with the (R)-alpha-methyl Garner aldehyde 5. Comparisons of the spectroscopic data of the synthetic isomers 4a-d with those of the natural manzacidin B revised the proposed structure 3 to (4S,5S,6R)-4d.

An efficient insertion reaction of α-diazoketone to various carboxylic acids was achieved by using Cu(acac) 2 as a catalyst. Treatment of the diazo compound with a carboxylic acid (1.2 equiv) in the presence of Cu(acac) 2 (0.1 equiv) at room temperature afforded the corresponding ketoester in good yield. Various kinds of functional groups were tolerated under the reaction conditions.

Olefination of dialkyl squarates 1–5 with several ylides 6 and phosphonates 7 gave the corresponding alkylidene products 8–12 . In the case of Horner-Emmons reactions, stereoselective formation of Z -alkylidene products was observed. An acid-catalyzed hydrolysis of 8–12 gave squarylacetic acid esters 13 .

[reaction: see text] Total synthesis of the potent AMPA/KA receptor antagonist (-)-kaitocephalin (1) and its three diastereomers has been accomplished. The synthesis features strictly substrate-controlled operations to alpha-formylglutamate 3 starting with alpha-hydroxymethylglutamate 4. The requisite 2R,3S,7R-stereocenters were efficiently constructed by manipulation of stereoselective reactions: dihydroxylation of 7 followed by azide substitution of the corresponding thionocarbonate 10 and Cu-mediated allylation of an acyliminium ion 21. All of the protecting groups in 26 were removed simultaneously by AlCl3/Me2S to give 1.

The presented method gives access to the E-isomers of α,β-dehydroamino acid esters in high yields and is complementary to the existing methods for the preparation of the thermodynamically more stable Z-isomers.

The Prins cyclization of hydroxy-substituted allenylsilanes such as (I) with carbonyl compounds is efficiently achieved with TmsOTf to yield 2,3-dihydrofuran structures.

Various hydrazone derivatives of α-keto esters were prepared. The carbonyl group was readily regenerated in high yield from phenylhydrazones through oxidative hydrolysis using hypervalent organoiodine(III) reagents—either bis(trifluoroacetoxy)-iodobenzene (BTIB) in aqueous acetonitrile or hydroxy(tosyloxy)iodobenzene (HTIB) in chloroform. α-Acetoxy phenyl- or methylazo compounds were readily synthesized by oxidation of the corresponding hydrazones with iodobenzene diacetate (IBDA) in dichloromethane or acetic acid. α-Methoxy phenyl- or methylazo compounds were also prepared by oxidation of the hydrazones in methanol. The mechanisms of the oxidation reactions are discussed.

A facile synthesis of 6-hydroxyindole-3-acetic acid 1a, which is the proposed aromatic subunit of NPTX-1∼6, is described. Radical cyclization of isonitrile 2 successfully afforded 9 in high yield. The aromatic subunit of NPTX-1∼6 was confirmed as 4-hydroxyindole-3-acetic acid 12 by comparison of the 1H-NMR spectra with those of authentic 4- and 6-hydroxyindole-3-acetic acids.

An application of the Barton ester based radical reactions in carbohydrate chemistry is described. The chain-elongation reaction with ethyl α-trifluoroacetoxy acrylate 2 , followed by treatment with phenylhydrazine provided 3-deoxy-α-hydrazono-octulosonates 8a,b , derivatives of KDO and its gluco -isomer in good yield.

Basic enzyme: The tetraprenyl-β-curcumene synthase homologue from the alkalophilic Bacillus clausii catalyses conversions of a geranylfarnesyl diphosphate and a hexaprenyl diphosphate into novel head-to-tail acyclic sesterterpene and triterpene. Tetraprenyl-β-curcumene synthase homologues represent a new family of terpene synthases that form not only sesquarterpene but also sesterterpene and triterpene.

Activated manganese dioxide (MnO 2 ) was found to be an efficient oxidant in the conversion of oximes to carbonyl compounds. The utility of this method in synthesis was demonstrated by the conversion of galactose to its acyclic aldose derivative 5.

An intense indole N-H stretching vibrational band at 3486 cm-1 in the difference Fourier transform infrared spectrum is one of the characteristic features of the L intermediate of bacteriorhodopsin [Maeda, Sasaki, Ohkita, Simpson, & Herzfeld (1992) Biochemistry 31, 12543]. This band is now assigned to tryptophan-182. The Trp182-->Phe (W182F) protein shows specific features in the difference spectrum in the visible region upon L formation, and exhibits great delay in the L-M conversion. Fourier transform infrared difference spectra further indicate that while the intensity of the C-methyl in-plane bending vibration at 1009 cm-1 is lost in the L intermediate of the wild type, its intensity remains high in the W182F protein. The intensity of the N-H stretching vibration upon L formation is diminished considerably in an artificial bacteriorhodopsin containing 9-desmethylretinal. It also exhibits delayed M formation. These results suggest that Trp182 interacts with the retinal side chain through the 9-methyl group, and thereby affects the L-to-M conversion.

The regioselectivity of the process is found to be specific for the silyl group, since the -tBu analogue (IX) produces a pyrrole skeleton.

Juvenile hormone (JH), which occurs in several forms in different insects, is one of the most important insect hormones. The structure of JH in Heteroptera has not been elucidated until recently, although insects in this suborder have long been used as experimental animals for JH research. Here we review the structure determination of a novel JH in a stink bug,Plautia stali, which was named juvenile hormone III skipped bisepoxide [JHSB3: methyl (2R,3S,10R)-2,3;10,11-bisepoxyfarnesoate], based on the arrangement of two epoxides at C2,3 and C10,11 with a skipped double bond at C6,7.

An efficient conversion of allyl sulfide 6 prepared from (-)-quinic acid (5) to gabosines was achieved by a series of sequential reactions: i) Mislow-Evans rearrangement, ii) SeO 2 oxidation, iii) conjugate addition of sodium hydroxide or sodium acetate, and iv) elimination of the methoxymethyloxy group.

Kaempferia parviflora (KP), a Zingiberaceae plant, is used as a folk medicine in Thailand for the treatment of various symptoms, including general pains, colic gastrointestinal disorders, and male impotence. In this study, the inhibitory activities of KP against xanthine oxidase (XOD) were investigated. The extract of KP rhizomes showed more potent inhibitory activity (38% at 500 µg/ml) than those of the other Zingiberaceae plants tested. Ten methoxyflavones were isolated from the KP extract as the major chemical components and their chemical structures were elucidated by X-ray crystallography. The structurally confirmed methoxyflavones were subjected to the XOD inhibitory test. Among them, 3,5,7,4',5'-pentamethoxyflavone and 3',4',5,7-tetramethoxyflavone showed inhibitory activities (IC(50) of 0.9 and >4 mM, respectively) and their modes of inhibition are clarified as competitive/non-competitive mixed type. To the best of our knowledge, this is the first report to present the inhibitory activities of KP, 3,5,7,4',5'-pentamethoxyflavone and 3',4',5,7-tetramethoxyflavone against XOD.

The synthesis of the first example of a 13C-labeled analogue in the tetradotoxin congeners is described.

A novel silyl group-directed anti-SN2′ reaction of allylic alcohols under Mitsunobu reaction conditions is described. The Mitsunobu reaction of α-hydroxy-α-alkenylsilanes with a TBS or TIPS group gave the anti-SN2′ product, in which regio- and stereochemical outcomes of the reaction depended on the steric bulkiness of the silyl group.

α-Ketoacids and ketones can easily be regenerated in high yield from their phenylhydrazones via hydroxy azo compounds upon oxidation with hupervalent iodine reagents.

The reaction of α-trifluoroacetoxy acrylates and acrylonitriles with carbon radicals formed from carboxylic acids gives adducts that can be transformed into vic-diols, esters, amides, and homoaldehydes in good to high yield. Aldoses can be smoothly degraded to the corresponding nor- or bis-nor compounds using radical chemistry.

A stereocontrolled synthesis of (±)-diltiazem by applying nucleophilic addition of 2-aminothiophenol to α-alkoxycinnamic acid derivatives is described.

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Diphenyl disulfide is shown to be an efficient catalyst for the isomerization of (Z)-2-alkenoic esters to (E)-2-alkenoic esters in boiling tetrahydrofuran

Distereoface differentiating nucleophilic of thiophenol to olefins delivers a new concomitant asymmetric construction of two contiguous stereogenic centers and has been successfully applied to the asymmetric synthesis of (+)-diltiazem.