Synthetic Study Directed toward the Squalene Synthase Inhibitor Zaragozic Acid and Squalestatin

角鲨烯合酶抑制剂萨拉哥酸和角鲨烯他汀的合成研究

• 批准号: 06672119
• 负责人: TSUBUKI Masayoshi
• 金额: $ 1.22万
• 依托单位: Institute of Medicinal Chemistry Hoshi, University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06672119/
• 关键词: Zaragozic Acid; Squalestatin; Synthetic Study; Squalene Synthase Inhibitor; Furan; Wittig Rearrangement; Dendrolasin; Furylmethyl Ether; 3-Methylfuryl-2-methanol; 3-Furylethanol; グリセルアルデヒド; ジオキサビシクロオクタン

Studies toward the synthesis of the bicyclic core of the zaragozic acids (squalestatins) have been carried out by the utilization of verstile building blocks, chiral furylglycerols. The key features are the diastereoselective dihydroxylation followed by reduction of (2S, 3S)-6-tert-butyldimethylsiloxy-2-[(4S')-2', 2'-dimethyl-1', 3'-dioxolan-4'-y]-4, 5-bis (methoxymethoxy-methyl)-6H-pyran-3 (2H)-one to control the stereochemistries at the C4-C6 positions of the target molecule. Addition of lithium acetylide at the stereocenter C3 provided (3R, 4R, 5R, 6S)-1, 7-diacetoxy-4-benzyloxy-3-tert-butyldimethylsiloxy-8-nonyn-2-one-5, 6-bis[spiro-4'-(2', 2'-dimethyl-1', 3'-dioxolane)], a potent intermediate in the synthesis of the bicylic core of zaragozic acids (squalestatins).During the course of the synthetic studies, the Wittig rearrangement of furylmethyl ethers has been found. The Witting rearrangement of 3-furylmethyl ethers proceeded efficiently to give 3-methyl-2-furylmethanols or 3-furylethanols depending on the basicity of the butyllithium used. Synthesis of a furanosesquiterpenoid dendrolasin has been achieved with the 1, 2-rearrangement of 3-furylmethyl geranyl ether as a key step.

利用手性呋喃甘油作为构筑基团，合成了双环Zaragozic酸类化合物(角鲨酸酯)。主要特征是非对映选择性的二羟基化反应，然后通过还原(2S，3S)-6-叔丁基二甲基硅氧基-2-[(4S‘)-2’，2‘-二甲基-1’，3‘-二氧杂环戊烷-4’-y]-4，5-二(甲氧基甲氧基甲基)-6H-吡喃-3(2H)-酮来控制目标分子C4-C6位的立体化学。在(3R，4R，5R，6S)-1，7-diacetoxy-4-benzyloxy-3-tert-butyldimethylsiloxy-8-nonyn-2-one-5，6-双[螺环-4‘-(2’，2‘-二甲基-1’，3‘-二氧杂环戊烷)]的立体中心C_3上加成了乙炔锂。根据所用正丁基锂的碱度不同，3-呋喃甲醚的With重排反应可以有效地生成3-甲基-2-呋喃甲醇或3-呋喃乙醇。以3-呋喃甲基香叶基醚的1，2-重排反应为关键步骤，合成了一种呋喃倍半萜类树枝菌素。

项目成果

津吹政可: "Wittig Rearrangement of 3-Furylmethyl Ethers and Its Application to the Synthesis of Dendrolasin" J. Chem. Soc.,Chem. Commun.,. 2135-2136 (1995)

Masakazu Tsubuki：“3-呋喃基甲基醚的 Wittig 重排及其在 Dendrolasin 合成中的应用”J. Chem. Soc.，Chem. 2135-2136 (1995)

津吹政可: "Wittig Rearrangement of 3-Furylmethyl Ethers and Its Application to the Synthesis of Dendrolasin" J. Chem, Soc, Chem, Commun.2135-2136 (1995)

Masakazu Tsubuki：“3-呋喃基甲基醚的 Wittig 重排及其在 Dendrolasin 合成中的应用”J. Chem, Soc, Chem, Commun.2135-2136 (1995)

Masayoshi Tsubuki: "Wittig Rearrangement of 3-Furylmethyl Ethers and Its Application to the Synthesis of Dendrolasin" J.Chem. Soc., Chem. Commun.20. 2135-2136 (1995)

Masayoshi Tsubuki：“3-呋喃甲基醚的 Wittig 重排及其在 Dendrolasin 合成中的应用”J.Chem。