Chemical Studies of alpha-Pyrone Meroterpenoids

α-吡喃酮类萜的化学研究

• 批准号: 08672444
• 负责人: SUNAZUKA Toshiaki
• 金额: $ 1.34万
• 依托单位: Kitasato University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08672444/
• 关键词: alpha-Pyrone; Meroterpenoid; ACAT; Total Synthesis; Coupling reaction; sesquiterpene; biomimetic; Structure-Activity Relationships; メロ-テルぺノイド; アリスカシン; メロ-テルペノイド; AChE

The first total synthesis of the microbial a-pyrone meroterpenoid, (+)-pyripyropene A (1), acyl-CoA : cholesterol acyltransferase (ACAT) inhibitor, which is effective and concise convergent approach (14 steps, 9.3% yield), designed to afford easy access to both the natural products and a variety of analogs, has been achieved. The key step is the coupling reaction between a-pyrone-pyridine moiety (4) and the acid chloride of sesquiterpene moiety (3) in the presence of Lewis acid to construct ketone (2). The sesquiterpene moiety has been synthesized via stereoselective reductive formylation, palladium associated carbonylation, and allylic oxidation started from (+)-Wieland-Wiescher ketone.(+)-Pyripyropene E (15) also has been synthesized from farnesyl acetate(9 steps, 9.6 % overall yield). The convergent and stereoselective route exploited a biomimetic polyene cyclization as the key transformation.We also made over 300 derivatives usuing theses synthetis scheme, and clarified the structure-activity relationships.

首次全合成微生物α-吡喃酮类萜，(+)-pyripyropene A (1)，酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂，这是一种有效而简洁的收敛方法（14步，9.3%产率），旨在方便地获得天然产物和各种类似物。关键步骤是α-吡喃酮-吡啶部分(4)与倍半萜部分的酰基氯(3)在路易斯酸存在下发生偶联反应，构建酮(2)。从 (+)-Wieland-Wiescher 酮开始，通过立体选择性还原甲酰化、钯相关羰基化和烯丙基氧化合成倍半萜部分。(+)-Pyripyropene E (15) 也从乙酸法尼酯合成（9 个步骤，总产率 9.6%）。收敛和立体选择性路线以仿生多烯环化为关键转化。我们还利用这些合成方案合成了300多个衍生物，并阐明了构效关系。

项目成果

砂塚敏明: "Chemical Modification of Pyripyropenes,I." J.Antibiotics. 49. 1133-1148 (1996)

Toshiaki Sunazuka：“吡啶罗平的化学修饰，I.抗生素”49。1133-1148（1996）

T.Sunazuka, S.Omura, et al, (3): "The Total synthesis of (+)-Pyripyropene A ; Potent Bioavailable Inhibitor of Acyl-CoA ; Cholesterol Acyltransferase" J.Org.Chem.60. 8126-8127 (1995)

T.Sunazuka、S.Omura 等人，(3)：“()-Pyripyropene A 的全合成；酰基辅酶 A 的有效生物利用抑制剂；胆固醇酰基转移酶”J.Org.Chem.60。

砂塚敏明: "Chemical Modification of Pyripyropenes.1." J.Antibiotics. 49. 1133-1148 (1996)

Toshiaki Sunazuka：“吡咯平的化学修饰。1。抗生素杂志”49。1133-1148（1996）

T.Sunazuka, S.Omura, et al: "Synthetic Study of alpha-Pyrone Meroterpenoids, Pyripyropenes" J.Syn.Org.Chem., Jpn.56. 478-488 (1998)

T.Sunazuka、S.Omura 等人：“α-吡喃酮 Meroterpenoids、Pyripyropenes 的合成研究”J.Syn.Org.Chem.，Jpn.56。

砂塚敏明: "Chemical Modification and Stracture-Activity Relationships of Pyripyropenes II" J.Antibiotics. 49. 1149-1156 (1996)

Toshiaki Sunazuka：“Pyripyropenes II 的化学修饰和结构-活性关系”J.Antibiotics 49。1149-1156 (1996)