2001 Fiscal Year Annual Research Report

タンデム反応を駆使した複素環生物活性化合物の効率的な触媒的不斉合成法の開発

Research Project

Project/Area Number	13029024
Research Institution	The University of Tokyo
Principal Investigator	大嶋孝志東京大学, 大学院・薬学系研究科, 助手 (10313123)
Co-Investigator(Kenkyū-buntansha)	金井求東京大学, 大学院・薬学系研究科, 講師 (20243264) 柴崎正勝東京大学, 大学院・薬学系研究科, 教授 (30112767)
Keywords	触媒的不斉マイケル反応 / タンデム反応 / ストリキニーネ / ALB触媒 / La-linked-BINOL触媒 / インドール形成反応
Research Abstract	触媒的不斉反応とタンデム反応を駆使した多元素環状生物活性化合物(ストリキニーネ)の効率的な触媒的不斉合成法の開発検討を行った。具体的には触媒的不斉マイケル反応によりE環上に不斉炭素を構築し、Znによるニトロ基の還元を引き金とする3工程タンデム反応によってB, D環を一挙に構築する逆合成解析を行った。(1)触媒的不斉マイケル反応による不斉炭素の構築当研究室で開発されたALB触煤、また新たに開発したLa-linked-BINOL触媒はともに触媒的不斉マイケル反応を触媒する優れた触媒であり、ALB触媒は反応性の高さ、La-linked-BINOL触媒は基質一般性の高さと錯体の安定性という特徴を有している。今回全合成での利用を鑑みそれぞれの触媒の実用性向上の検討を行った。○ALB触媒今回反応を極めて高濃度で行うことで収率および不斉収率の低下を伴うことなく触媒の反応性を大きく向上させることに成功した。最終的にほとんど無溶媒に近い条件で反応を行うことにより0.1mol%の触媒でキログラムスケールの反応が24時間以内に完結し、分液および再結晶操作のみで光学的に純粋なマイケル付加体を91%収率で得ることができた。これは現在報告されている触媒的不斉炭素-炭素結合形成反応としては最も実用的で有効な反応の一つである。○La-linked-BINOL触媒はα位に様々置換基を有するマロン酸エステルにおいても>99%eeの不斉収率を実現する唯一の触媒であるものの触媒量の低減が求められていた。種々検討の結果、触媒量を低減した場合には触媒に対して0.01Mの反応濃度が最適であることが分かり、現在までのところ2.5mol%の触媒量で満足のいく結果が得られるようになった。またHFIP:(CF_3)_2CHOHが添加剤として効果的であることも分かってきており、メカニズムの解明とともにさらなる最適化を行っている。(2)3行程タンデム反応によるB, D環の構築光学的に純粋なマイケル付加体を用い、E-選択的側鎖の導入、位置選択的エノン形成反応、Stille反応を経て合成したアリルアルコールをトリフレート経由でアミノ化し、後処理後そのままZnによるニトロ基の還元を行うと、アミンの1,4-付加反応、続くインド-ル形成反応が速やかに進行し、一挙にB, D環が構築された4環性の化合物を得ることができた。精製方法も含め種々検討を行った結果、この3工程タンデム反応はアリルアルコールから77%収率で進行するようになった。B, D環の形成反応を段階的に行った場合、ヒドロキシメチル基を有しないモデル化合物を用いた場合ですら10行程が必要であったことからもタンデム反応が有効であることが分かる。続くC環の構築はDMTSFと処理することで40-50%収率で進行しており、現在ストリキニーネへの変換の検討を行っている。

Research Products

(24 results)

All Other

All Publications (24 results)

[Publications] N.Yoshikawa et al.: "Direct Catalytic Asymmetric Aldol Reactions Promoted by Novel Heterobimetallic Catalysts Possessing Strong Bronsted Base : A New Strategy for the Development of Lewis Acid-Bronsted Base Bifunctinal Catalysts"Tetrahedron. 57. 2569-2579 (2001)
[Publications] H.Nogami et al.: "Enantioselective Strecker-type reaction promoted by polymer-supported bifunctional catalyst"Tetrahedron Lett.. 42. 279-283 (2001)
[Publications] Y.Hamashima et al.: "Catalytic enantioselective cyanosilylation of ketones : improvement of enantioselectivity and catalyst turn-over by ligand tuning"Tetrahedron Lett.. 42. 691-694 (2001)
[Publications] S.Yamasaki et al.: "Novel Multiaction of Zr Catalyst : One-Pot Synthesis of β-Cyanohydrins from Olefins"J.Am.Chem.Soc.. 123. 1256-1257 (2001)
[Publications] N.Yoshikawa et al.: "Direct Catalytic Asymmetric Aldol Reaction : Synthesis of Either syn-or anti-α,β-Dihydroxy Ketones"J.Am.Chem.Soc.. 123. 2466-2467 (2001)
[Publications] T.Nemoto et al.: "Catalytic Asymmetric Epoxidation of Enones Using La-BINOL-Triphenylarsine Oxide Complex : Structural Determination of the Asymmetric Catalyst"J. Am. Chem. Soc.. 123. 2725-2732 (2001)
[Publications] M.Shibasaki et al.: "Multifunctional Asymmetric Catalysis"Chem.Pharm.Bull.. 49. 524-551 (2001)
[Publications] N.Kumagai et al.: "Direct Catalytic Enantio-and Diastereoselective Aldol Reaction Using a Zn-Zn-Linked-BINOL Complex : A Practical Synthesis of syn-1,2-Diols"Org.Lett.. 3. 1539-1542 (2001)
[Publications] G.Manickam et al.: "Anti-and Syn-Selective Cyanosilylation Reactions Promoted by a Sugar-Based Bifunctional Catalyst : Stereoselective Syntheses of Essential Building Blocks for HIV Protease Inhibitors and Bestatin"Synlett. 5. 617-620 (2001)
[Publications] K.Yamada et al.: "The First Enantioselective and Diastereoselective Catalytic Nitro-Mannich Reaction : A New Entry to Chiral Vicinal Diamines"Synlett. SI. 980-982 (2001)
[Publications] M.Takamura et al.: "Catalytic Enantioselective Reissert-Type Reaction : Development and Application to the Synthesis of a Potent NMDA Receptor Antagonist(-)-L-689,560 Using a Solid-Supported Catalyst"J.Am.Chem.Soc.. 123. 6801-6808 (2001)
[Publications] T.Suzuki et al.: "Catalytic asymmetric aldol reaction of ketones and aldehydes using chiral calcium alkoxides"Tetrahedron Lett.. 42. 4669-4671 (2001)
[Publications] S.Yamasaki et al.: "Zirconium Alkoxides in Catalysis"Chem.Eur.J.. 7. 4066-4073 (2002)
[Publications] S.Matsunaga et al.: "Linked-BINOL -an Approach towards Practical Asymmetric Multifunctional Catalysis -"Adv.Synthe.Catal.. 343. 1-13 (2001)
[Publications] T.Nemoto et al.: "Catalytic Asymmetric Synthesis of α, β-Epoxy Esters, Aldehydes, Amides, and γ, δ-Epoxy β-Keto Esters : Unique Reactivity of α, β-Unsaturated Carboxylic Acid Imidazolides"J.Am.Chem.Soc.. 123. 9474-9475 (2001)
[Publications] M.Kanai et al.: "Development and Application of Enantioselective Lewis Acid-Lewis Base Bifunctional Catalyst"Journal of Synthetic Organic Chemistry, Japan. 59. 767-778 (2001)
[Publications] K.Yabu et al.: "Switching Enantiofacial Selectivites Using One Chiral Source : Catalytic Enantioselective Synthesis of the Key Intermediate for(20S)-Camptothecin Family by(S)-Selective Cyanosylation of Ketones"J.Am.Chem.Soc.. 123. 9908-9909 (2001)
[Publications] K.Funabashi et al.: "Enantioselective Construction of Quaternary Stereocenter through a Reissert-Type Reactiion Catalyzed by an Electronically Tuned Bifunctional Catalyst : Efficient Synthesis of Various Biologically Significant compounds"J.Am.Chem.Soc.. 123. 10784-10785 (2001)
[Publications] A.Okada et al.: "Highly regioselective synthesis of cyclic enol silyl ethers using ring-closing metathesis"Tetrahedron Lett.. 42. 8023-8027 (2001)
[Publications] N.Kumagai et al.: "Enantioselective 1,4-Addition of Unmodified Ketone Catalyzed by a Bimetallic Zn-Zn-Linked-BINOL Complex"Org.Lett.. 3. 4251-4254 (2001)
[Publications] A.Sekine et al.: "An Enantioselective Formal Synthesis of 4-demethoxydaunomycin Using the Catalytic Asymmetric Ring Opening Reaction of meso-epoxide with p-anisidine"Tetrahedron. 58. 75-82 (2001)
[Publications] N.Tsuritani et al.: "Catalytic Asymmetric Syntheses of ICI-199441 and CP-99994 Using Nitro-Mannich Reaction"Chem.Lett.. (in press).
[Publications] T.Nemoto et al.: "Catalytic Asymmtrtic Epoxidation of α, β-Unsaturated Carbonyl Compounds"Journal of Synthetic Organic Chemistry, Japan. 60. 94-105 (2002)
[Publications] Y.Xu et al.: "A Practical Large-Scale Synthesis of Enantiomerically Pure 3-[Bis(methoxy-carbonyl)methyl]cyclohexanone via Catalytic Asymmetric Michael Reaction"Tetrahedron. (in press).

2001 Fiscal Year Annual Research Report

タンデム反応を駆使した複素環生物活性化合物の効率的な触媒的不斉合成法の開発

Principal Investigator

大嶋 孝志 東京大学, 大学院・薬学系研究科, 助手 (10313123)

Research Products

[Publications] N.Yoshikawa et al.: "Direct Catalytic Asymmetric Aldol Reactions Promoted by Novel Heterobimetallic Catalysts Possessing Strong Bronsted Base : A New Strategy for the Development of Lewis Acid-Bronsted Base Bifunctinal Catalysts"Tetrahedron. 57. 2569-2579 (2001)

[Publications] H.Nogami et al.: "Enantioselective Strecker-type reaction promoted by polymer-supported bifunctional catalyst"Tetrahedron Lett.. 42. 279-283 (2001)

[Publications] Y.Hamashima et al.: "Catalytic enantioselective cyanosilylation of ketones : improvement of enantioselectivity and catalyst turn-over by ligand tuning"Tetrahedron Lett.. 42. 691-694 (2001)

[Publications] S.Yamasaki et al.: "Novel Multiaction of Zr Catalyst : One-Pot Synthesis of β-Cyanohydrins from Olefins"J.Am.Chem.Soc.. 123. 1256-1257 (2001)

[Publications] N.Yoshikawa et al.: "Direct Catalytic Asymmetric Aldol Reaction : Synthesis of Either syn-or anti-α,β-Dihydroxy Ketones"J.Am.Chem.Soc.. 123. 2466-2467 (2001)

[Publications] T.Nemoto et al.: "Catalytic Asymmetric Epoxidation of Enones Using La-BINOL-Triphenylarsine Oxide Complex : Structural Determination of the Asymmetric Catalyst"J. Am. Chem. Soc.. 123. 2725-2732 (2001)

[Publications] M.Shibasaki et al.: "Multifunctional Asymmetric Catalysis"Chem.Pharm.Bull.. 49. 524-551 (2001)

[Publications] N.Kumagai et al.: "Direct Catalytic Enantio-and Diastereoselective Aldol Reaction Using a Zn-Zn-Linked-BINOL Complex : A Practical Synthesis of syn-1,2-Diols"Org.Lett.. 3. 1539-1542 (2001)

[Publications] G.Manickam et al.: "Anti-and Syn-Selective Cyanosilylation Reactions Promoted by a Sugar-Based Bifunctional Catalyst : Stereoselective Syntheses of Essential Building Blocks for HIV Protease Inhibitors and Bestatin"Synlett. 5. 617-620 (2001)

[Publications] K.Yamada et al.: "The First Enantioselective and Diastereoselective Catalytic Nitro-Mannich Reaction : A New Entry to Chiral Vicinal Diamines"Synlett. SI. 980-982 (2001)

[Publications] M.Takamura et al.: "Catalytic Enantioselective Reissert-Type Reaction : Development and Application to the Synthesis of a Potent NMDA Receptor Antagonist(-)-L-689,560 Using a Solid-Supported Catalyst"J.Am.Chem.Soc.. 123. 6801-6808 (2001)

[Publications] T.Suzuki et al.: "Catalytic asymmetric aldol reaction of ketones and aldehydes using chiral calcium alkoxides"Tetrahedron Lett.. 42. 4669-4671 (2001)

[Publications] S.Yamasaki et al.: "Zirconium Alkoxides in Catalysis"Chem.Eur.J.. 7. 4066-4073 (2002)

[Publications] S.Matsunaga et al.: "Linked-BINOL -an Approach towards Practical Asymmetric Multifunctional Catalysis -"Adv.Synthe.Catal.. 343. 1-13 (2001)

[Publications] T.Nemoto et al.: "Catalytic Asymmetric Synthesis of α, β-Epoxy Esters, Aldehydes, Amides, and γ, δ-Epoxy β-Keto Esters : Unique Reactivity of α, β-Unsaturated Carboxylic Acid Imidazolides"J.Am.Chem.Soc.. 123. 9474-9475 (2001)

[Publications] M.Kanai et al.: "Development and Application of Enantioselective Lewis Acid-Lewis Base Bifunctional Catalyst"Journal of Synthetic Organic Chemistry, Japan. 59. 767-778 (2001)

[Publications] K.Yabu et al.: "Switching Enantiofacial Selectivites Using One Chiral Source : Catalytic Enantioselective Synthesis of the Key Intermediate for(20S)-Camptothecin Family by(S)-Selective Cyanosylation of Ketones"J.Am.Chem.Soc.. 123. 9908-9909 (2001)

[Publications] K.Funabashi et al.: "Enantioselective Construction of Quaternary Stereocenter through a Reissert-Type Reactiion Catalyzed by an Electronically Tuned Bifunctional Catalyst : Efficient Synthesis of Various Biologically Significant compounds"J.Am.Chem.Soc.. 123. 10784-10785 (2001)

[Publications] A.Okada et al.: "Highly regioselective synthesis of cyclic enol silyl ethers using ring-closing metathesis"Tetrahedron Lett.. 42. 8023-8027 (2001)

[Publications] N.Kumagai et al.: "Enantioselective 1,4-Addition of Unmodified Ketone Catalyzed by a Bimetallic Zn-Zn-Linked-BINOL Complex"Org.Lett.. 3. 4251-4254 (2001)

[Publications] A.Sekine et al.: "An Enantioselective Formal Synthesis of 4-demethoxydaunomycin Using the Catalytic Asymmetric Ring Opening Reaction of meso-epoxide with p-anisidine"Tetrahedron. 58. 75-82 (2001)

[Publications] N.Tsuritani et al.: "Catalytic Asymmetric Syntheses of ICI-199441 and CP-99994 Using Nitro-Mannich Reaction"Chem.Lett.. (in press).

[Publications] T.Nemoto et al.: "Catalytic Asymmtrtic Epoxidation of α, β-Unsaturated Carbonyl Compounds"Journal of Synthetic Organic Chemistry, Japan. 60. 94-105 (2002)

[Publications] Y.Xu et al.: "A Practical Large-Scale Synthesis of Enantiomerically Pure 3-[Bis(methoxy-carbonyl)methyl]cyclohexanone via Catalytic Asymmetric Michael Reaction"Tetrahedron. (in press).

大嶋孝志東京大学, 大学院・薬学系研究科, 助手 (10313123)