Synthetic Studies on Forskolin and Its Related Compounds

毛喉素及其相关化合物的合成研究

• 批准号: 01571164
• 负责人: HASHIMOTO Shun-ichi
• 金额: $ 1.34万
• 依托单位: Teikyo 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: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01571164/
• 关键词: Forskolin; Adenylate Cyclase; Structure-activity Relatioship; Total Synthesis; Labane diterpene; Butenolide; Intramolecular Diels-Alder Reaction; 分子内DielsーAlden反応; 分子内Diels-Alder反応

The labane diterpene forskolin, isolated from the roots of the Indian herb Coleus forskolii, has been shown to be hypotensive agent with spasmolytic, cardiotonic, and platelet aggregation inhibitory activity, and also demonstrated to be a unique and potent stimulator of the enzyme adenylate cyclase in various tissues. Owing to its therapeutic potential for glaucoma, congestive heart failure and bronchial asthma coupled with a substantial structural challenge, forskolin has elicited considerable synthetic attention. There have been synthesized more than 100 analogues from forskolin and its congeners, and through structure-activity relationships of them the region involving 1alpha-OH, 9alpha-OH, and 11-carbonyl has been suggested to be responsible for the above biological activities. We embarked upon an investigation directed towards the total synthesis of forskolin and its analogues otherwise difficult to prepare from natural forskolin with an aim to gain more information of structure-a … More citivity relationships and to differentiate a variety of activities forskolin exhibits. The activitiy of (<plus-minus>)-forskolin obtained by our total synthesis for adenylate cyclase in rat cerebral cortical membranes was half as potent as of natural forskolin, while (<plus-minus>)-1, 6, 7-trideoxyforskolin was totally inactive as we expected. Our attention was focused on the activity of (<plus-minus>)-6, 7-dideoxyforskolin, since it was not determined whether the presence of 6beta-OH and 7beta-OH is important or not for the activity. The result obtained with the synthesized molecule showed total inactivity, and so the presence of 6betaーOH and/or 7betaーOH was proposed to be crucial for the activity. With the above results in hand, we then directed our efforts to the total synthesis of (-)-forskol in natural form and the synthesis of its derivatives from the homochiral,versatile tricyclic lactone intermediate constructed by salient intramolecular DielsーAlder reaction of the butenolide. We have now found that the homochiral lactone with four asymmetric centers was efficiently constructe starting with the (S)-propargyl alcohol obtainable through (S)-BINAL-H reduction of the corresponding acetylenic ketone and successive recrystallization. The project on this line is goi Less

从印度草本植物毛喉鞘蕊花（Coleus forskolii）的根中分离出的唇形科二萜毛喉素（labane diperene forskolin）已被证明是具有痉挛、强心和血小板聚集抑制活性的消肿剂，并且还被证明是各种组织中腺苷酸环化酶的独特且有效的刺激剂。由于其对青光眼、充血性心力衰竭和支气管哮喘的治疗潜力，加上大量的结构挑战，毛喉素引起了相当大的综合关注。目前已合成了100多个forskolin及其类似物，通过构效关系分析，认为1 α-OH、9 α-OH和11-羰基区域可能与上述生物活性有关。我们开始了一项研究，目的是获得更多的结构信息，以全合成forskolin及其类似物，否则很难从天然forskolin制备 ...更多信息 社会关系，并区分各种活动福斯科林展品。全合成的（±<plus-minus>）-forskolin对大鼠大脑皮层膜腺苷酸环化酶的活性只有天然forskolin的一半，而（±<plus-minus>）-1，6，7-trideoxyforskolin完全没有活性。我们的注意力集中在（±<plus-minus>）-6，7-双脱氧毛喉素的活性上，因为还没有确定6 β-OH和7 β-OH的存在对活性是否重要。用合成的分子获得的结果显示完全无活性，因此6 β-OH和/或7 β-OH的存在被认为是活性的关键。有了上述结果，我们将努力方向转向天然形式的（-）-forskol的全合成及其衍生物的合成，这些衍生物是由丁烯酰亚胺的分子内Diels-Alder桤木反应构建的纯手性多功能三环内酯中间体。我们发现，从（S）-炔丙醇出发，通过（S）-BINAL-H还原相应的炔酮，再经重结晶，可有效地合成具有四个不对称中心的纯手性内酯。在这条线上的项目是goi减

项目成果

Shun-ichi Hashimoto: "A Rapid and Efficient Synthesis of 1, 2-trans-beta-Linked Glycosides via Benzyl or Benzoyl-Protected Glycopyranosyl Phosphates" J. Chem. Soc., Chem. Commun. 685-687 (1989)

Shun-ichi Hashimoto：“通过苄基或苯甲酰保护的吡喃糖基磷酸酯快速高效合成 1, 2-反式-β-连接糖苷”J. Chem。

橋本 俊一: "A Stereocontrolled Synthesis of(±)ー1,6,7ーTrideoxyforskolin" J.Chem.Soc.,Chem.Commun.24-25 (1987)

Shunichi Hashimoto：“(±)－1,6,7－Trideoxyforskolin 的立体控制合成”J.Chem.Soc.,Chem.Commun.24-25 (1987)

橋本 俊一: "A Total Synthesis of(±)ーForskolin" J.Am.Chem.Soc.110. 3670-3672 (1988)

桥本俊一：“(±)－毛喉素的全合成”J.Am.Chem.Soc.110 3670-3672 (1988)。

橋本 俊一: "A Mild and Rapid 1,2ーTransーGlycosidation Method via BenzoylーProtected Glycopyranosyl P,PーDiphenylーNー(pーToluenesulfonyl)phosphinimidates" Heterocycles. 30. 775-778 (1990)

Shunichi Hashimoto：“通过苯并保护的吡喃葡萄糖基 P,P-二苯-N-(对甲苯磺酰基)次膦酰亚胺酯进行温和快速的 1,2-反式糖苷化方法” 30. 775-778 (1990)。

橋本 俊一: "A Stereocontrolled Synthesis of(±)ー6,7ーDideoxyforskolin"

桥本俊一：“(±)－6,7－双脱氧毛喉素的立体控制合成”