Allenic [2 + 2 + 1] Reactions Enabling Syntheses of Natural Products with 7-Membe

艾伦酸 [2 2 1] 反应能够合成具有 7-Membe 的天然产物

• 批准号: 7943031
• 负责人: Kay M Brummond
• 金额: $ 31.39万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943031
• 关键词: ATP phosphohydrolase; Acetates; Action Potentials; Apoptosis; Biocompatible Materials; Biological; Biological Factors; Calcium; Cardiac; Cell Membrane Permeability; Cells; Complex; Cytosol; Endoplasmic Reticulum; Esters; Family; Goals; Human; Kinetics; Medical; Methods; Molecular; Nerve; Oxygen; Pharmaceutical Preparations; Phase; Preparation; Process; Property; Protocols documentation; Pump; Reaction; Research; Route; Site; Skeletal Muscle; Skeleton; Sodium Channel; System; Thapsigargin; Therapeutic; Time; Transition Elements; analog; androgen independent prostate cancer; butenolide; cancer cell; drug discovery; flexibility; guanacastepene; inhibitor/antagonist; interest; member; novel; programs; propadiene; rhodotoxin; sodium ion; tool

Ready access to seven-membered rings systems will facilitate the synthesis of biologically important compounds possessing this ring system. Three carbocyclic cores of three targets, thapsigargin, grayanotoxin III and guanacastepene J, will be synthesized to demonstrate the synthetic utility, efficiency, and flexibility of the allenic cyclocarbonylation reaction. Realization of the goals of this proposal will provide a more general understanding of allenes and transition-metal catalyzed cyclocarbonylation reactions. Moreover, the long-term goals of this project are the application of this strategy to the total synthesis of thapsigargin, guanacastepene J and grayanotoxin III that will feature access to novel intermediates and analogs enabling new biological studies. The long-term goals are not within the scope of this proposal. The specific aims of this proposal include: 1) Extending the scope of the allenic Pauson-Khand reaction to include more densely functionalized precursors including, but not limited to allenol esters. Cyclocarbonylation of allenol esters provides rapid access to ¿-acetoxy cyclopentadienones. The rapid isomerization of allenol acetates under the Rh(I)-catalyzed conditions will be explored for the enantioselective preparation of ¿-acetoxy cyclopentadienones using dynamic kinetic asymmetric transformation (DYKAT). 2) Synthesizing the carbocyclic framework of thapsigargin using the Pauson-Khand reaction of an allenol ester. Thapsigargin is a highly oxygenated carbocycle that is particularly well suited for this method that features well-timed introductions of oxygen functionality limiting the number of protection and deprotection steps. Moreover, the DYKAT protocol developed in Aim 1 will be exploited as a potential means of achieving a diastereoselective allenic Pauson-Khand reaction. Thapsigargin posseses interesting biological activity functioning as a subnanomolar inhibitor of sarcoplasmic and endoplasmic reticulum Ca+2 ATPase (SERCA). 3) Synthesizing the carbocyclic core of guanacastepene J, a member of the guanacastepene family, but a compound in which the biological activity has not been established due to very limited quantities. The synthesis features an allenic Pauson- Khand reaction using an unusual ¿-allenylidene butenolide. 4) Synthesizing the carbocyclic core of grayanotoxin III via a route that features a highly functionalized allene-yne precursor to generate a molecularly complex skeleton. Grayanotoxin is an important molecular tool for deciphering the mechanism for gating functions of the sodium ion channels.

随时进入七元环系统将促进合成

项目成果

Rh(I)-catalyzed cyclocarbonylation of allenol esters to prepare acetoxy 4-alkylidenecyclopent-3-en-2-ones.

• DOI: 10.1021/jo901459t
• 发表时间: 2009-11-06
• 期刊: The Journal of organic chemistry
• 作者: Brummond KM;Davis MM;Huang C
• 通讯作者: Huang C

Chiral nonracemic alpha-alkylidene and alpha-silylidene cyclopentenones from chiral allenes using an intramolecular allenic Pauson-Khand-type cycloaddition.

使用分子内丙二烯 Pauson-Khand 型环加成反应从手性丙二烯得到手性非外消旋 α-亚烷基和 α-甲硅烷基环戊烯酮。

• DOI: 10.1021/jo016305t
• 发表时间: 2002
• 期刊: The Journal of organic chemistry
• 作者: Brummond,KayM;Kerekes,AngelaD;Wan,Honghe
• 通讯作者: Wan,Honghe

Structural basis for the synergy of 4'- and 2'-modifications on siRNA nuclease resistance, thermal stability and RNAi activity.

• DOI: 10.1093/nar/gky703
• 发表时间: 2018-09-19
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Harp JM;Guenther DC;Bisbe A;Perkins L;Matsuda S;Bommineni GR;Zlatev I;Foster DJ;Taneja N;Charisse K;Maier MA;Rajeev KG;Manoharan M;Egli M
• 通讯作者: Egli M

Conditions for a Rh(I)-catalyzed [2 + 2 + 1] cycloaddition reaction with methyl substituted allenes and alkynes.

Rh(I) 催化的与甲基取代的丙二烯和炔烃的 [2 2 1] 环加成反应的条件。

• DOI: 10.1016/j.tetlet.2015.01.075
• 发表时间: 2015
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Wells,SarahM;Brummond,KayM
• 通讯作者: Brummond,KayM

A redox economical synthesis of bioactive 6,12-guaianolides.

• DOI: 10.1021/ol400904y
• 发表时间: 2013-06-07
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Wen, Bo;Hexum, Joseph K.;Widen, John C.;Harki, Daniel A.;Brummond, Kay M.
• 通讯作者: Brummond, Kay M.