Synthetic studies on taxane skeleton, taxol and its derivatives

紫杉烷骨架、紫杉醇及其衍生物的合成研究

• 批准号: 09672170
• 负责人: NAGAOKA Hiroto
• 金额: $ 1.92万
• 依托单位: MEIJI PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672170/
• 关键词: taxane skeleton; taxol; fragmentation reaction; nitrile oxide; synthesis; intramolecular cyclization; タキソ-ル

Taxol【○!R】 (paclitaxel), a typical taxane diterpene, is one of the most attractive synthetic targets in organic chemistry because of its unique structural features, as well as its antileukemic and tumor inhibiting activity. Recently, the total synthesis of taxol has been accomplished by six groups in succession, however, the efforts for developing an efficient synthetic method of taxanes are continuously being made. We now report a new synthetic route for the taxane skeleton using a fragmentation reaction and an intramolecular nitrile oxide cyclization reaction as key steps.First, we have confirmed the viability of intramolecular nitrile oxide cyclization for the construction of A/B ring system. The cyclization reaction of a model compound, 4-(5'-nitropentyl) cyclohexene derivative, promoted by p-chlorophenyl isocyanate and a catalytic amount of triethl amine was found to form directly the A/B ring system which has a bridgehead double bound in A ring and an oxime group in B ring.Next, the synthesis of the key intermediate consisting of A/C ring and its intramolecular cyclization to produce the taxane skeleton were investigated. The C ring unit was constructed by the fragmentation reaction of bicyclo [2.2.2] octane derivative prepared from D-mannitol in stereoselective manner. Connection of the C ring moiety with 4,6,6-trimethyl-2,4-cylohexadienyl group provided A/C ring system, which was easily converted into the key intermediate. The crucial cyclization reaction of the compound with p-chlorophenyl isocyanate gave the taxane skeleton in optically active form.

紫杉醇[0！R](紫杉醇)是一种典型的紫杉烷二萜化合物，由于其独特的结构特征以及抗白血病和抑瘤活性，是有机化学中最具吸引力的合成目标之一。近年来，紫杉醇的全合成已陆续由六个基团完成，但开发一种高效的紫杉烷合成方法仍在不断努力。我们现在报道了一条合成紫杉烷骨架的新路线，该路线以裂解反应和分子内氧化腈环化反应为关键步骤。首先，我们证实了分子内氧化腈环化反应用于构建A/B环体系的可行性。模型化合物4-(5‘-硝基戊基)环己烯在对氯苯基异氰酸酯的催化下与一定量的三乙胺直接环合，形成A环桥头双键、B环有肟基的A/B环系。其次，研究了由A/C环组成的关键中间体的合成及其分子内环化反应生成紫杉烷骨架。以D-甘露醇为原料，以立体选择性的方式合成了双环[2.2.2]辛烷衍生物，通过裂解反应构建了C环单元。C环部分与4，6，6-三甲基-2，4-环己二烯基连接形成A/C环体系，容易转化为关键中间体。该化合物与对氯苯基异氰酸酯发生关键的环化反应，得到具有光学活性的紫杉烷骨架。

项目成果

Yoshimasa Hirai: "Efficient Synthesis of the Taxane C Ring by Fragmantation Reaction of a Bicyclo[2.2.2]octane Derivative"Tetrahedron Letters. 38. 4997-5000 (1997)

Yoshimasa Hirai：“通过双环[2.2.2]辛烷衍生物的碎裂反应有效合成紫杉烷C环”四面体字母。

Yoshimasa Hirai: "Efficient Synthesis of the Taxane C Ring by Fragmentation Reaction of a Bicyclo[2.2.2]octane Derivative" Tetrahedron Letters. 38・28. 4997-5000 (1997)

Yoshimasa Hirai：“通过双环[2.2.2]辛烷衍生物的裂解反应有效合成紫杉烷C环”四面体快报38・28（1997）。

Yoshimasa Hirai: "Efficient Synthesis of the Taxane C Ring by Fragmentation Reaction of a Bicyclo [2.2.2] octane Derivative"Tetrahedron Letters. 38. 4997-5000 (1997)

Yoshimasa Hirai：“通过双环[2.2.2]辛烷衍生物的裂解反应有效合成紫杉烷C环”四面体字母。

Yoshimasa Hirai: "Efficient Synthesis of the Taxane C Ring by Fragmentation Reaction of a Bicyclo[2.2.2]octane Derivative" Tetrahedron Letters. 38. 4997-5000 (1997)

Yoshimasa Hirai：“通过双环[2.2.2]辛烷衍生物的裂解反应有效合成紫杉烷C环”四面体字母。