高選択的グリコシル化反応の開発とオリゴ糖鎖・配糖体の合成

　細胞表層に分布する複合糖質（糖脂質、糖タンパク質およびプロテオグリカン）糖鎖部が示す生理的意義および疾病との関わり、さらに抗がん性含糖抗生物質の活性発現に糖鎖部が不可欠なことが明らかにされるにつれ、有機合成化学の分野でも糖質合成の根幹をなすグリコシル化反応の開発およびオリゴ糖鎖の効果的構築法の開発が重要な課題となっています。
　一般にグリコシル化反応の成否は糖の種類に大きく左右される上に、糖供与体の脱離基および保護基、受容体水酸基の求核性、反応剤、溶媒等の要因が複雑に絡まるため、それを予見することさえ困難な場合も多いことが知られています。

　当研究室では上記要因の中でも糖供与体の脱離基が支配的要因を成すとの考えのもとに、従来にない特徴をもつ糖供与体の創製を目指し、特にリン原子を中心元素とする脱離基に着眼しました。リン原子は種々の元素で修飾容易なことから多様性に富む脱離基の設定が可能です。
　すでに、ホスファ−ト、ホスフィンイミダ−ト、ホスホロジアミドイミドチオア−トを脱離基に組み込んだ糖供与体を基盤とする高選択的グリコシル化反応を達成していますが、最近、３価のリンであるホスファイトを組み込んだ糖供与体が著しく高い反応性を示すことを見い出しました。これらの脱離基を組み込んだ各糖供与体は、反応性の違いを反映してそれぞれ特徴ある反応条件の設定を可能にします。
　したがって、この分野において究極の合成戦略と目される"armed/disarmed"糖供与体概念を基盤とした生物活性オリゴ糖鎖合成への展開が期待できます。

　また、これまでに開発したグリコシル化反応は極めて緩和な反応条件の設定を許容することから、副作用の軽減を目的とした含糖抗生物質および各種配糖体の糖質部の改変を試みるとともに、薬物ターゲッテイングあるいはプロドラッグの可能性を秘めた糖コンジュゲート医薬品（薬理活性物質あるいは医薬品 に糖を結合した複合体）の開発を行っていきたいと考えています。

総説・著書

• Stereocontrolled Construction of 1,2-cis-α-Glycosidic Linkages Using Glycosyl Diphenyl Phosphates and Synthesis of α-galactosylceramide KRN7000.
  H. Nambu, S. Nakamura, N. Suzuki, and S. Hashimoto, Trends Glycosci. Glycotechnol, 2010, 22 (123), 26-40.
  
  
• Phosphates, Phosphites and Other O−P Derivatives.
  S. Nakamura, H. Nambu, and S. Hashimoto, in Handbook of Chemical Glycosylation: Advances in Stereoselectivity and Therapeutic Relevance (Ed.: A. V. Demchenko), Wiley-VCH, Weinheim, 2008, pp. 223−259.
  
  
• 含リン脱離基を基盤とするグリコシル化反応．
  橋本俊一，中村精一，“グライコワード−グライコテクノロジー”，蟹江 治編，
  http://www.glycoforum.gr.jp/science/word/glycotechnology/GT-A01J.html, 1999.
  
  
• オリゴ糖鎖合成の新戦略．
  橋本俊一，中島 誠， ファルマシア，1996，32，1375−1380．[CiNii]
  
  
• 含リン脱離基を基盤とする高選択的グリコシル化反応．
  橋本俊一，本田 雄，柳谷由己，中島 誠，池上四郎，有機合成化学協会誌，1995，53，620−632．
  
  
• 新しいグリコシル化反応の設計．
  橋本俊一，“糖鎖 III 糖鎖の分子設計”，永井克孝代表編集，東京化学同人，1994, pp. 129−136．
  
  
• グリコシル化反応ー化学法．
  橋本俊一，池上四郎，“糖鎖工学ーこれからの生命科学”，木幡 陽，永井克孝，鈴木 旺，渋谷直人，小川智也編，産業調査会，1992，pp. 477−495．

最近の発表論文

• Glycosylation with 2-Acetoamide-2-deoxyglycosyl Donors at a Low Temperature: Scope of the Non-Oxazoline Method
  R. Arihara, K. Kakita, N. Suzuki, S. Nakamura, S. Hashimoto, J. Org. Chem., 2015, 88, 4259-4277. [DOI]
  
  
• Synthesis of the Tetrasaccharide Repeating Unit from Acinetobacter baumannii Sergroup 018 Capitalizing on Phosphorus-Containing Leaving Groups
  R. Arihara, K. Kakita, K. Yamada, S. Nakamura, S. Hashimoto, J. Org. Chem., 2015, 80, 4278-4288. [DOI]
  
  
• A Stereocontrolled Construction of 2-Azido-2-deoxy-1,2-cis-α-galactosidic Linkages Utilizing 2-Azido-4,6-O-benzylidene-2-deoxygalactopyranosyl Diphenyl Phosphates: Stereoselective Synthesis of Mucin Core 5 and Core 7 Structures.
  K. Kakita, T. Tsuda, N. Suzuki, S. Nakamura, H. Nambu, and S. Hashimoto, Tetrahedron., 2012, 68, 5005−5017. [DOI]
  
  
• Direct and Stereoselective Synthesis of 2-Azido-2-deoxy-β-D-Mannosides Using the Phosphate Method.
  S. Nakamura, T. Tsuda, N. Suzuki, and S. Hashimoto, Heterocycles, 2009, 77, 843−848. [Abstract]
  
  
• Catalytic Stereoselective Glycosidation with Glycosyl Diphenyl Phosphates: Rapid Construction of 1,2-cis-α-Glycosidic Linkages.
  M. Koshiba, N. Suzuki, R. Arihara, T. Tsuda, H. Nambu, S. Nakamura, and S. Hashimoto, Chem. Asian J., 2008, 3, 1664−1677. [DOI]
  
  
• Direct and Stereoselective Synthesis of β-D-Mannosides Using 4,6-O-Benzylidene-Protected Mannosyl Diethyl Phosphite as a Donor.
  T. Tsuda, R. Arihara, S. Sato, M. Koshiba, S. Nakamura, and S. Hashimoto, Tetrahedron, 2005, 61, 10719−10733. [DOI]
  
  
• Direct and Stereoselective Synthesis of 2-Acetamido-2-deoxy-β-D-glycopyranosides by Using the Phosphite Method.
  R. Arihara, S. Nakamura, and S. Hashimoto, Angew. Chem. Int. Ed., 2005, 44, 2245−2249. [DOI]
  
  
• A Highly Stereoselective Construction of 1,2-trans-β-Glycosidic Linkages Capitalizing on 2-Azido-2-deoxy-D-glycosyl Diphenyl Phosphates as Glycosyl Donors.
  T. Tsuda, S. Nakamura, and S. Hashimoto, Tetrahedron, 2004, 60, 10711−10737. [DOI]
  
  
• A Stereocontrolled Construction of 2-Azido-2-deoxy-1,2-trans-β-glycosidic Linkages Utilizing 2-Azido-2-deoxyglycopyranosyl Diphenyl Phosphates.
  T. Tsuda, S. Nakamura, and S. Hashimoto, Tetrahedron Lett., 2003, 44, 6453−6457. [DOI]
  
  
• Direct and Stereoselective Construction of β-Mannosidic Linkages Capitalizing on 4,6-O-Benzylidene-Protected D-Mannopyranosyl Diethyl Phosphite.
  T. Tsuda, S. Sato, S. Nakamura, and S. Hashimoto, Heterocycles, 2003, 59, 509−515. [Abstract]
  
  
• Chemoselective Glycosidation Strategy Based on Glycosyl Donors and Acceptors Carrying Phosphorus-Containing Leaving Groups: A Convergent Synthesis of Ganglioside GM₃.
  H. Sakamoto, S. Nakamura, T. Tsuda, and S. Hashimoto, Tetrahedron Lett., 2000, 41, 7691−7695. [DOI]
  
  
• A Facile Synthesis of 3'-Deoxy-3'-fluorothymidine via a Highly Stereoselective Glycosylation with 2,3-Dideoxy-3-fluoro-D-erythro-pentofuranosyl Diethyl Phosphite.
  J. Inagaki, H. Sakamoto, M. Nakajima, S. Nakamura, and S. Hashimoto, Synlett, 1999, 1274−1276. [DOI]
  
  
• An Extremely Mild and Stereocontrolled Construction of 1,2-cis-α-Glycosidic Linkages via Benzyl-Protected Glycopyranosyl Diethyl Phosphites.
  H. Tanaka, H. Sakamoto, A. Sano, S. Nakamura, M. Nakajima, and S. Hashimoto, Chem. Commun., 1999, 1259−1260. [DOI]
  
  
• N-Glycosylation with Glycosyl Diethyl Phosphites: A Highly Stereoselective Synthesis of 2'-Deoxy-β-ribonucleosides.
  S. Hashimoto, J. Inagaki, H. Sakamoto, A. Sano, and M. Nakajima, Heterocycles, 1997, 46, 215−220. [Abstract]
  
  
• "Armed-Disarmed" Glycosidation Strategy Based on Glycosyl Donors and Acceptors Carrying Phosphoroamidate as a Leaving Group: A Convergent Synthesis of Globotriaosylceramide.
  S. Hashimoto, H. Sakamoto, T. Honda, H. Abe, S. Nakamura and S. Ikegami, Tetrahedron Lett., 1997, 38, 8969−8972. [DOI]
  
  
• Oligosaccharide Synthesis Based on Glycosyl Donors and Acceptors Carrying Phosphorus-Containing Leaving Groups.
  S. Hashimoto, H. Sakamoto, T. Honda, and S. Ikegami, Tetrahedron Lett., 1997, 38, 5181−5184. [DOI]
  
  
• An Attempt at the Direct Construction of 2-Deoxy-β-glycosidic Linkages Capitalizing on 2-Deoxyglycopyranosyl Diethyl Phosphites as Glycosyl Donors.
  S. Hashimoto, A. Sano, H. Sakamoto, M. Nakajima, Y. Yanagiya, S. Ikegami, Synlett, 1995, 1271−1273. [DOI]
  
  
• An Extremely Mild and General Method for the Construction of 1,2-trans-β-Glycosidic Linkages via Glycopyranosyl Diethyl Phosphites with Participating Groups at C-2.
  S. Hashimoto, A. Sano, K. Umeo, M. Nakajima, S. Ikegami, Chem. Pharm. Bull., 1995, 43, 2267−2269. [Journal@rchive]
  
  
• An Extremely Mild and Stereocontrolled Construction of 1,2-trans-β-Glycosidic Linkages Capitalizing on Benzyl-Protected Glycopyranosyl Diethyl Phosphites as Glycosyl Donors.
  S. Hashimoto, K. Umeo, A. Sano, N. Watanabe, M. Nakajima, and S. Ikegami, Tetrahedron Lett., 1995, 36, 2251−2254. [DOI]
  
  
• A Stereocontrolled Construction of 2-Deoxy-β-glycosidic Linkages via 1,2-trans-β-Glycosidation of 2-Deoxy-2-[(p-methoxyphenyl)thio]glycopyranosyl N,N,N',N'-Tetramethylphosphoroamidates.
  S. Hashimoto, Y. Yanagiya, T. Honda, and S. Ikegami, Chem. Lett., 1992, 1511−1514. [Journal@rchive]
  
  
• An Efficient Construction of 1,2-trans-β-Glycosidic Linkages Capitalizing on Glycopyranosyl N,N,N',N'-Tetramethylphosphoroamidates as Shelf-Stable Glycosyl Donors.
  S. Hashimoto, Y. Yanagiya, T. Honda, H. Harada, and S. Ikegami, Tetrahedron Lett., 1992, 33, 3523−3526. [DOI]
  
  
• A New and General Glycosidation Method for Podophyllum Lignan Glycosides.
  S. Hashimoto, T. Honda, and S. Ikegami, Tetrahedron Lett., 1991, 32, 1653−1654. [DOI]
  
  
• An Extremely Mild and General Method for the Stereocontrolled Construction of 1,2-cis-Glycosidic Linkages via S-Glycopyranosyl Phosphorodiamidimidothioates.
  S. Hashimoto, T. Honda, and S. Ikegami, Tetrahedron Lett., 1990, 31, 4769−4772. [DOI]
  
  
• An Efficient Construction of 1,2-trans-β-glycosidic Linkages via Benzyl-Protected Glycopyranosyl P,P-Diphenyl-N-(p-Toluenesulfonyl)phosphinimidates.
  S. Hashimoto, T. Honda, and S. Ikegami, Chem. Pharm. Bull., 1990, 38, 2323−2325. [Journal@rchive]
  
  
• A Mild and Rapid 1,2-trans-Glycosidation Method via Benzoyl-Protected Glycopyranosyl P,P-Diphenyl-N-(p-Toluenesulfonyl)phosphinimidates.
  S. Hashimoto, T. Honda, and S. Ikegami, Heterocycles, 1990, 30, 775−778. [Abstract]
  
  
• A Rapid and Efficient Synthesis of 1,2-trans-β-Linked Glycosides via Benzyl- or Benzoyl-Protected Glycopyranosyl Phosphates.
  S. Hashimoto, T. Honda, and S. Ikegami, J. Chem. Soc., Chem. Commun., 1989, 685−687. [DOI]