高橋 孝志

Construction of the ABC ring system of taxanes via one-pot three-component coupling and intramolecular alkylation is accomplished. The 1,4-addition of a protected cyanohydrin ether to 2-methyl-2-cyclohexenone and subsequent addition of the resulting enolate to formaldehyde proceeded stereoselectively to provide the AC ring in 90% yield. The stereoselective reduction of the 2-keto group was achieved by using hydroxy-directed hydride reduction with LiAlH4. The intramolecular alkylation of the protected cyanohydrin ether furnished the ABC ring system of taxanes in 43% yield.

Construction of the ABC ring system of taxanes via one-pot three-component coupling and intramolecular alkylation is accomplished. The 1,4-addition of a protected cyanohydrin ether to 2-methyl-2-cyclohexenone and subsequent addition of the resulting enolate to formaldehyde proceeded stereoselectively to provide the AC ring in 90% yield. The stereoselective reduction of the 2-keto group was achieved by using hydroxy-directed hydride reduction with LiAlH4. The intramolecular alkylation of the protected cyanohydrin ether furnished the ABC ring system of taxanes in 43% yield.

The monoclonal antibody mAb.A2B5 is a marker for the detection of oligodendrocyte progenitor cells that differentiate into type-2 astrocytes and oligodendrocytes. It is also a useful antibody for separating these cells from other lineage populations. The epitope of this antibody is considered to be the gangliosides GT3 and GQ1c. In this study, we sought to define more precisely the structure of the epitope. Accordingly, we chemically synthesized defined oligosialic acid structures linked to phosphatidylethanolamine and bovine serum albumin and used these to determine the antigenic specificity. mAb.A2B5 recognized the Neu5Ac alpha 2 -> 8Neu5Ac alpha 2 -> 8Neu5Ac alpha -> structure on both glycolipids and glycoproteins. We then examined whether the mAb.A2B5 epitope exists on glycoproteins in developing mouse brains. Western blot analyses revealed the expression of four glycoproteins reactive with the mAb.A2B5, and their expression was dependent on the stage of neural development. All the immunoreactivity in these glycoproteins with mAb.A2B5 disappeared after sialidase treatment and were resistant to chloroform/methanol extraction. These epitopes were also detected in brain homogenates from both GD3 synthetase-null and GD3/GD2 synthetase double null mice. These findings show that the alpha 2,8-trisialic acid (triSia) unit recognized by mAb.A2B5 resides not only on gangliosides but also on glycoproteins in developing mouse brain. We postulate that the triSia structure on glycoproteins may be involved in oligodendrocyte differentiation, similar to the case with the alpha 2,8-triSia structure on gangliosides. Real time polymerase chain reaction analysis of the developmental expression of all known ST8Sia genes, which are responsible for the biosynthesis of alpha 2,8-linked Sia residues, showed that ST8Sia III gene expression correlated with expression of the triSia epitope. We suggest that ST8Sia III is the principal sialyltransferase responsible for synthesis of the alpha 2,8-triSia units on glycoproteins.

The monoclonal antibody mAb.A2B5 is a marker for the detection of oligodendrocyte progenitor cells that differentiate into type-2 astrocytes and oligodendrocytes. It is also a useful antibody for separating these cells from other lineage populations. The epitope of this antibody is considered to be the gangliosides GT3 and GQ1c. In this study, we sought to define more precisely the structure of the epitope. Accordingly, we chemically synthesized defined oligosialic acid structures linked to phosphatidylethanolamine and bovine serum albumin and used these to determine the antigenic specificity. mAb.A2B5 recognized the Neu5Ac alpha 2 -> 8Neu5Ac alpha 2 -> 8Neu5Ac alpha -> structure on both glycolipids and glycoproteins. We then examined whether the mAb.A2B5 epitope exists on glycoproteins in developing mouse brains. Western blot analyses revealed the expression of four glycoproteins reactive with the mAb.A2B5, and their expression was dependent on the stage of neural development. All the immunoreactivity in these glycoproteins with mAb.A2B5 disappeared after sialidase treatment and were resistant to chloroform/methanol extraction. These epitopes were also detected in brain homogenates from both GD3 synthetase-null and GD3/GD2 synthetase double null mice. These findings show that the alpha 2,8-trisialic acid (triSia) unit recognized by mAb.A2B5 resides not only on gangliosides but also on glycoproteins in developing mouse brain. We postulate that the triSia structure on glycoproteins may be involved in oligodendrocyte differentiation, similar to the case with the alpha 2,8-triSia structure on gangliosides. Real time polymerase chain reaction analysis of the developmental expression of all known ST8Sia genes, which are responsible for the biosynthesis of alpha 2,8-linked Sia residues, showed that ST8Sia III gene expression correlated with expression of the triSia epitope. We suggest that ST8Sia III is the principal sialyltransferase responsible for synthesis of the alpha 2,8-triSia units on glycoproteins.

We synthesized a series of N-1-substituted norcymserine derivatives 7a-p and evaluated their anti-cholinesterase activities. In vitro evaluation showed that the pyridinylethyl derivatives 7m-o and the piperidinylethyl derivative 7p improved the anti-butyrylcholinesterase activity by approximately threefold compared to N-1-phenethylnorcymserine (PEC, 2). A quantitative structure-activity relationship (QSAR) study indicated that logS might be a key feature of the improved compounds. (C) 2010 Elsevier Ltd. All rights reserved.

We synthesized carbamate-modified (-)-N-1-phenethylnorphysostigmine derivatives 3a-u and evaluated their anti-cholinesterase activities. In vitro evaluation showed that cyclohexylmethylcarbamate derivative 3u potently and selectively inhibits butyrylcholinesterase. (C) 2010 Elsevier Ltd. All rights reserved.

In this report, we describe the stereoselective synthesis of a combinatorial library comprised of 16 deoxyhexasaccharides that are related to a landomycin A sugar moiety, based on an orthogonal deprotection strategy. The use of an olivosyl donor containing a benzyl ether at the C3 position and benzoyl ester at the C4 position, and the olivosyl donor, a naphthylmethyl ether, and a p-nitrobenzylethyl or benzyl sulfonyl ester enabled the synthesis of a set of four diolivosyl units containing a hydroxyl group at the C3 or C4 position by a simple glycosylation and deprotection procedure. Using a phenylthio 2,3,6-trideoxyglycoside, alpha-selective glycosidation proceeded without anomerizat ion of the 2,6-dideoxy-beta-glycosides. In addition, alkylhydroquinone and levulinoyl groups were found to be an effective set of orthogonal protecting groups for the anomeric position and a hydroxyl group. The coupling of all combinations of trisaccharide units in a beta-selective manner was accomplished by activation of the glycosyl imidate with I-2 and Et3SiH. No cleavage of the acid-labile 2,3,6-trideoxyglycoside was observed under the conditions used for the reactions. Finally, all of the protected hexasaccharides were deprotected by hydrolysis of the esters, microwave (MW) assisted cleavage of the 2-trimethylsilylethoxymethoxy (SEM) ether, and a Birch reduction.

The synthesis of a bicyclic enediyne capable of photosensitive triggering and conjugated to a pyrrole-imidazole polyamide is described. Using UV irradiation, this hybrid molecule is shown to exhibit 100-fold stronger potency for DNA cleavage, in an in vitro assay, as compared to the enediyne without the DNA-localizing pyrrole-imidazole.

In this report, we describe the stereoselective synthesis of a combinatorial library comprised of 16 deoxyhexasaccharides that are related to a landomycin A sugar moiety, based on an orthogonal deprotection strategy. The use of an olivosyl donor containing a benzyl ether at the C3 position and benzoyl ester at the C4 position, and the olivosyl donor, a naphthylmethyl ether, and a p-nitrobenzylethyl or benzyl sulfonyl ester enabled the synthesis of a set of four diolivosyl units containing a hydroxyl group at the C3 or C4 position by a simple glycosylation and deprotection procedure. Using a phenylthio 2,3,6-trideoxyglycoside, alpha-selective glycosidation proceeded without anomerizat ion of the 2,6-dideoxy-beta-glycosides. In addition, alkylhydroquinone and levulinoyl groups were found to be an effective set of orthogonal protecting groups for the anomeric position and a hydroxyl group. The coupling of all combinations of trisaccharide units in a beta-selective manner was accomplished by activation of the glycosyl imidate with I-2 and Et3SiH. No cleavage of the acid-labile 2,3,6-trideoxyglycoside was observed under the conditions used for the reactions. Finally, all of the protected hexasaccharides were deprotected by hydrolysis of the esters, microwave (MW) assisted cleavage of the 2-trimethylsilylethoxymethoxy (SEM) ether, and a Birch reduction.

The synthesis of a bicyclic enediyne capable of photosensitive triggering and conjugated to a pyrrole-imidazole polyamide is described. Using UV irradiation, this hybrid molecule is shown to exhibit 100-fold stronger potency for DNA cleavage, in an in vitro assay, as compared to the enediyne without the DNA-localizing pyrrole-imidazole.

Naturally occurring antibiotics containing 9-membered enediynes have received considerable attention for many years due to their potent DNA-cleaving activity. We previously reported the design and synthesis of a synthetic, masked 9-membered enediyne that possesses DNA-cleaving activity. Despite the importance of the 9-membered enediynes, application of these molecules is limited by their difficult synthesis. Herein, we report an improved process for the generation of a synthetic, masked 9-membered enediyne that uses an automated synthesizer for the production of a key synthetic intermediate.

Naturally occurring antibiotics containing 9-membered enediynes have received considerable attention for many years due to their potent DNA-cleaving activity. We previously reported the design and synthesis of a synthetic, masked 9-membered enediyne that possesses DNA-cleaving activity. Despite the importance of the 9-membered enediynes, application of these molecules is limited by their difficult synthesis. Herein, we report an improved process for the generation of a synthetic, masked 9-membered enediyne that uses an automated synthesizer for the production of a key synthetic intermediate.

The stereoselective one-pot three-component coupling reaction was accomplished by 1,4-addition of the protected cyanohydrin ether 9f to cyclohexenone 10g and subsequent addition of the resulting enolate to formaldehyde in high yield for the formation of the AC ring system of taxanes. We found that the bulky substituents at the 10-position in the A ring prevent the desired 1,4-addition. Similarly, the bulky trialkylsiloxy groups at the 4-position in the C ring prevent the 1,4-addition and electron-donating alkoxy groups at the same position induce the undesired retro-Michael reaction. (C) 2009 Elsevier Ltd. All rights reserved.

The stereoselective one-pot three-component coupling reaction was accomplished by 1,4-addition of the protected cyanohydrin ether 9f to cyclohexenone 10g and subsequent addition of the resulting enolate to formaldehyde in high yield for the formation of the AC ring system of taxanes. We found that the bulky substituents at the 10-position in the A ring prevent the desired 1,4-addition. Similarly, the bulky trialkylsiloxy groups at the 4-position in the C ring prevent the 1,4-addition and electron-donating alkoxy groups at the same position induce the undesired retro-Michael reaction. (C) 2009 Elsevier Ltd. All rights reserved.

An efficient stereoselective synthesis of alpha(2,9) tetra- to disialic acids 1-3, using the 5,4-N,O-carbonyl protected thiosialoside 4, is described. The cyclic protecting group was effective for alpha-sialylation without the need for acetonitrile as the solvent. The donor 4 enabled the formation of a tetramer in excellent yield and selectivity. Deprotection of the cyclic protecting groups of the protected di- to tetrasialica acids proceeded smoothly to give the fully deprotected alpha(2,9) tetra- to disialic acids 1-3.

A concise and convergent total synthesis of the highly cytotoxic marine natural product apratoxin A is accomplished by an 18-step linear sequence. The high sensitivity of the thiazoline, bearing an adjacent P-hydroxyl group at the C35-position, results in the assembly process requiring the inclusion of appropriate protecting groups and the careful optimization o all individual transformations. In the synthesis of 3,7-dihydroxy-2,5,8,8-tetra-methylnonanoic acid (Dtena), three reagent-controlled asymmetric reactions enables us to introduce four chiral carbon centers in a dihydroxylated fatty acid moiety. Formation of the hindered ester and sterically-unfavorable N-methylamide bonds were successfully demonstrated. The thiazoline in apratoxin A was constructed by Tf(2)O and Ph(3)PO-mediated dehydrative cyclizatin, and final macrocyclizatin was achieved between N-methylisoleucine and proline residues. Moreover, an oxazoline analogue and a C34 epimer of apratoxin A have also been elaborated in a similar approach. This synthetic route would enable assembly of other analogues differing in stereo-centers of Dtena and their amino acids.

Efficient synthesis of the deoxysugar part of versipelostatin (VST) was achieved by direct and stereoselective glycosylation of the reduced VST aglycon. Activation of 2-deoxyglycosyl imidate with IBr under basic conditions enables alpha-selective glycosylation of beta-2-deoxylglycosides without anomerization. Comparison of the synthetic and natural VST products using NMR indicates that versipelostatin has a beta-D-digitoxose-(1,4)-alpha-L-oleandrose-(1,4)-beta-D-digitoxose trisaccharide. In addition, results of a biological assay indicate that the deoxyoligosaccharide unit of the synthetic glycoside was important for biological activity of the compound.

16 five-ring ester-type Br-substituted banana-shaped molecules were synthesized in a combinatorial manner using palladium-catalyzed carbonylative esterification on a polymer-support and their mesophase behavior was investigated.

A concise and convergent total synthesis of the highly cytotoxic marine natural product apratoxin A is accomplished by an 18-step linear sequence. The high sensitivity of the thiazoline, bearing an adjacent P-hydroxyl group at the C35-position, results in the assembly process requiring the inclusion of appropriate protecting groups and the careful optimization o all individual transformations. In the synthesis of 3,7-dihydroxy-2,5,8,8-tetra-methylnonanoic acid (Dtena), three reagent-controlled asymmetric reactions enables us to introduce four chiral carbon centers in a dihydroxylated fatty acid moiety. Formation of the hindered ester and sterically-unfavorable N-methylamide bonds were successfully demonstrated. The thiazoline in apratoxin A was constructed by Tf(2)O and Ph(3)PO-mediated dehydrative cyclizatin, and final macrocyclizatin was achieved between N-methylisoleucine and proline residues. Moreover, an oxazoline analogue and a C34 epimer of apratoxin A have also been elaborated in a similar approach. This synthetic route would enable assembly of other analogues differing in stereo-centers of Dtena and their amino acids.

Efficient synthesis of the deoxysugar part of versipelostatin (VST) was achieved by direct and stereoselective glycosylation of the reduced VST aglycon. Activation of 2-deoxyglycosyl imidate with IBr under basic conditions enables alpha-selective glycosylation of beta-2-deoxylglycosides without anomerization. Comparison of the synthetic and natural VST products using NMR indicates that versipelostatin has a beta-D-digitoxose-(1,4)-alpha-L-oleandrose-(1,4)-beta-D-digitoxose trisaccharide. In addition, results of a biological assay indicate that the deoxyoligosaccharide unit of the synthetic glycoside was important for biological activity of the compound.

16 five-ring ester-type Br-substituted banana-shaped molecules were synthesized in a combinatorial manner using palladium-catalyzed carbonylative esterification on a polymer-support and their mesophase behavior was investigated.

In this report, we describe an efficient convergent synthesis of the GP1c glycolipid epitope, which is one of the most complex c-series gangliosides. The a(2,3) and a(2,8) sialylations were accomplished by use of 5N,4O-carbonyl and 7,8-O-isopropyliden as well as 5N,4Ocarbonyl-and 7,8-di-O-chloroacetyl-protected sialyl donors in good yields with excellent a-selectivity, respectively. The two sialyl donors enable synthesis of the di- and trisialylgalactosides by simple glycosylation and deprotection. We synthesized the protected GP1c glycolipid epitope, which is a compact, rigid, branched structure, via direct coupling of tetarasaccharide and pentasaccharide units. Copyright © 2008 American Chemical Society.

S-alkylation reaction of a thiol group on a carbohydrate probe with 2-bromoacetamide-coated glass slide as a loading reaction was developed under physiological conditions, and the synthesis of carbohydrate microarrays using the immobilization reaction was achieved.

An efficient synthesis of alpha(2,9) trisialic acid has been achieved via one-pot glycosylation and polymer-assisted deprotection. The synthesis involves chemo- and regioselective alpha-sialylation of ethylthiosialoside with the S-benzoxazolyl (S-Box) sialyl donor. Use of a prelinker to link an activated ester and a vinyl ether via a carbon chain enables polymer-assisted deprotection of the protected trisialic acids.

S-alkylation reaction of a thiol group on a carbohydrate probe with 2-bromoacetamide-coated glass slide as a loading reaction was developed under physiological conditions, and the synthesis of carbohydrate microarrays using the immobilization reaction was achieved.

In this report, we describe an efficient convergent synthesis of the GP1c glycolipid epitope, which is one of the most complex c-series gangliosides. The alpha(2,3) and alpha(2,8) sialylations were accomplished by use of 5N,4O-carbonyl and 7,8-O-isopropyliden as well as 5N,4O-carbonyl- and 7,8-di-O-chloroacetyl-protected sialyl donors in good yields with excellent alpha-selectivity, respectively. The two sialyl donors enable synthesis of the di- and trisialylgalactosides by simple glycosylation and deprotection. We synthesized the protected GP1c glycolipid epitope, which is a compact, rigid, branched structure, via direct coupling of tetarasaccharide and pentasaccharide units.

We report high-resolution photoemission spectroscopy of newly-discovered iron-based layered superconductor La(O0.93F0.07)FeAs (Tc = 24 K). We found that the superconducting gap shows a marked deviation from the isotropic s-wave symmetry. The estimated gap size at 5K is 3.6 meV in the s- or axial p-wave case, while it is 4.1 meV in the polar p- or d-wave case. We also found a pseudogap of 15-20 meV above Tc, which is gradually filled-in with increasing temperature and closes at temperature far above Tc similarly to copper-oxide high-temperature superconductors. ©2008 The Physical Society of Japan.

We report high-resolution photoemission spectroscopy of newly-discovered iron-based layered superconductor La(O0.93F0.07)FeAs (T-c = 24 K). We found that the superconducting gap shows a marked deviation from the isotropic s-wave symmetry. The estimated gap size at 5 K is 3.6 meV in the s- or axial p-wave case, while it. is 4.1 meV in the polar p- or d-wave case. We also found a pseudogap of 15-20 meV above T-c, which is gradually filled-in with increasing temperature and closes at temperature far above T-c similarly to copper-oxide high-temperature superconductors.

Cyclic peptidic RGD models were efficiently synthesized by Pd(P(t-Bu)(3))(2)-catalyzed carbonylative macrolactamization in the presence of 4 angstrom molecular sieves under 10 atm of carbon monoxide.

Cyclic peptidic RGD models were efficiently synthesized by Pd(P(t-Bu)(3))(2)-catalyzed carbonylative macrolactamization in the presence of 4 angstrom molecular sieves under 10 atm of carbon monoxide.

Six-types of palladium-catalyzed coupling, Mizoroki-Heck, Migita-Stille, Sonogashira, carbonylative esterification, carbonylative Stille, and carbonylative Sonogashira reactions, were performed on a polymer support. The above coupling reactions of m- and p-substituted aromatic rings, followed by carbonylative esterification with m- and p-substituted anisol derivatives were carried out in a combinatorial manner. Acid cleavage from the polymer-support provided the conjugated aromatic ring systems 1 and 2, which are the core parts of rodlike liquid crystals. © 2008 American Chemical Society.

An effective hydrophilic scaffold composed of D-trihydroxyllysine-based olioopeptides and its application in the synthesis of the various ([1])In-DTPA conjugates with mono- to pentabisphosphonate units for use as bone tracers are described. The D-trihydroxyllysine derivative with three orthogonal protecting groups was conjugated with functional devices at the gamma position and allowed oligomerization based on peptide chemistry. The radiopharmaceutical complexes of (III)In(III) selected chelators, 4 and 8, were suitable for bone imaging. These results show that D-trihydroxyllysine 2 was an effective building block for the synthesis of multivalent ligands applicable to medical use.

Six-types of palladium-catalyzed coupling, Mizoroki-Heck, Migita-Stille, Sonogashira, carbonylative esterification, carbonylative Stille, and carbonylative Sonogashira reactions, were performed on a polymer support. The above coupling reactions of m- and p-substituted aromatic rings, followed by carbonylative esterification with m- and p-substituted anisol derivatives were carried out in a combinatorial manner. Acid cleavage from the polymer-support provided the conjugated aromatic ring systems I and 2, which are the core parts of rodlike liquid crystals.

An effective hydrophilic scaffold composed of D-trihydroxyllysine-based olioopeptides and its application in the synthesis of the various ([1])In-DTPA conjugates with mono- to pentabisphosphonate units for use as bone tracers are described. The D-trihydroxyllysine derivative with three orthogonal protecting groups was conjugated with functional devices at the gamma position and allowed oligomerization based on peptide chemistry. The radiopharmaceutical complexes of (III)In(III) selected chelators, 4 and 8, were suitable for bone imaging. These results show that D-trihydroxyllysine 2 was an effective building block for the synthesis of multivalent ligands applicable to medical use.

An optically active octahydroindole, the core unit of aeruginosins (Choi) was synthesized. The Diels-Alder reaction of Danishefsky's diene with methyl (Z)-2-acetamido-2,4-pentadienoates provided the adducts regioselectively in good yield. The adducts were converted to the L-Choi precursor by asymmetric hydrogenation, followed by acid cyclization. (c) 2007 Elsevier Ltd. All rights reserved.

An optically active octahydroindole, the core unit of aeruginosins (Choi) was synthesized. The Diels-Alder reaction of Danishefsky's diene with methyl (Z)-2-acetamido-2,4-pentadienoates provided the adducts regioselectively in good yield. The adducts were converted to the L-Choi precursor by asymmetric hydrogenation, followed by acid cyclization. (c) 2007 Elsevier Ltd. All rights reserved.

The synthesis of a spiro[4.4]nonane skeleton by the palladium-catalyzed domino cyclization of a linear 7-methylene-2,10-undecadienyl acetate is described. The pi-allylpalladium intermediate underwent intramolecular alkene insertion with high intraannular diastereoselectivity, followed by intramolecular Heck-type cyclization, leading to a spiro[4.4]nonane system. Oxidation of the allylic ether moiety and transformation of the vinyl group to an exo-methylene unit provided 3, which is the known synthetic intermediate of dimethyl gloiosiphone A (2).

The synthesis of a spiro[4.4]nonane skeleton by the palladium-catalyzed domino cyclization of a linear 7-methylene-2,10-undecadienyl acetate is described. The pi-allylpalladium intermediate underwent intramolecular alkene insertion with high intraannular diastereoselectivity, followed by intramolecular Heck-type cyclization, leading to a spiro[4.4]nonane system. Oxidation of the allylic ether moiety and transformation of the vinyl group to an exo-methylene unit provided 3, which is the known synthetic intermediate of dimethyl gloiosiphone A (2).

The glycosidation of a polymer-supported glycosyl donor, N-phenyltrifluoroacetimidate, with various glycosyl acceptors is reported. The application of the polymer-supported N-phenyltrifluoroacetimidate is demonstrated in the synthesis of vancomycin derivatives. 2-O-[2-(azidomethyl)benzoyl]glycosyl imidate was attached to a polymer support at the 6-position by a phenylsulfonate linked with a C13 alkyl spacer. Solid-phase glycosidation with a vancomycin aglycon, selective deprotection of the 2-(azidomethyl)benzoyl group, and glycosylation of the resulting 2-hydroxy group with a vancosamine unit were performed. Nucleophilic cleavage from the polymer support with acetate, chloride, azido, and thioacetate ions provided vancomycin derivatives in pure form after simple purification. The semisynthesis of vancomycin was achieved by deprotection of the acetate derivative.