Synthesis of the Apoptosis-Inducing Alkaloid Monanchocidin

诱导细胞凋亡的生物碱Monanchocidin的合成

• 批准号: 8565642
• 负责人: Ryan Lloyd Patman
• 金额: $ 3.16万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-23 至 2014-03-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8565642
• 关键词: Address; Adverse effects; Alkaloids; Alkylation; Alkynes; Apoptosis; Biological; Biological Factors; Cell Nucleus; Complex; Coupling; Cyclization; Development; Disease; Family; Family member; Fatty Acids; Goals; Guanidines; Inhibition of Cancer Cell Growth; Lead; Malignant Neoplasms; Marines; Metals; Methodology; Methods; Natural Resources; Nature; Palladium; Production; Public Health; Reaction; Reagent; Relative (related person); Research; Resources; Route; Scheme; Side; Structure; Synthesis Chemistry; Testing; Transition Elements; analog; cancer therapy; cancer type; chemotherapy; combat; flexibility; improved; innovation; member; novel; stereochemistry

DESCRIPTION (provided by applicant): Many medicinal reagents for the treatment of cancer originate from natural resources. To obtain sufficient quantities of these molecules and to improve their biological profile it is often necessary to produce these compounds synthetically. Monanchocidin, a member of the crambescidin family, is an attractive target for synthesis due to its complex structure and promising inhibition of cancer cell growth. An innovative strategy is proposed to address the synthesis of this molecule employing palladium catalyzed asymmetric allylic alkylation (AAA) and a novel hydroguanidination/cyclization sequence. The objective of this proposal is to develop a concise enantioselective synthesis of monanchocidin using newly developed reactions. We hypothesize that the pentacyclic guanidine can be rapidly assembled stereoselectively by developing a transition metal catalyzed hydroguanidination reaction. The specific aims of this project are; (1) to utilize palladium-catalyzed asymmetric allylic alkylation to construct the pyrolidine core of monanchocidin and other crambescidin family members, (2) develop and implement a novel transition-metal catalyzed hydroguanidination-spirocyclization method to assemble the pentacyclic guanidine, (3) develop an expedient synthetic route to access the fatty acid side chain in monanchocidin, and (4) develop a fragment coupling strategy that provides an efficient and modular route toward the first total synthesis of monanchocidin. The proposed research will be executed in an efficient manner by synthesizing key fragments enantioselectively and coupling them to the pyrolidine core of monanchocidin; assembled via palladium catalyzed asymmetric allylic alkylation (AAA). A novel method for construction of the pentacyclic guanidine of monanchocidin will be developed using a transition metal catalyzed hydroguanidination. An examination of transition metals typically used in hydroamination reactions will be conducted and the most efficient of these will be further optimized and employed in the proposed synthesis.

描述（由申请人提供）：许多用于治疗癌症的药物源自自然资源。为了获得足够数量的这些分子并改善其生物学特征，通常有必要合成产生这些化合物。 Monanchocidin是Crambescidin家族的成员，由于其复杂的结构和有望抑制癌细胞生长的抑制作用，是合成的有吸引力的靶标。提出了一种创新的策略来解决该分子的合成，该分子采用钯催化的不对称烯丙基烷基化（AAA）和一种新型的加氢酶化/环化序列。该提案的目的是使用新开发的反应开发一种简洁的对映选择性合成。我们假设可以通过开发过渡金属催化的加氢酶反应来立体选择五边形鸟嘌呤。该项目的具体目的是； （1）利用钯催化的不对称烯丙基烷基化来构建单鼠肽和其他crambescidin家族成员的吡咯烷核心，（2）开发和实施一种新型的过渡金属催化催化的水真相化方法，以促进速度促进促进硫酸硫酸的方向促进，以汇集速度，以促进合成（3），（3） Monanchocidin和（4）制定了一种碎片耦合策略，该策略提供了一种有效而模块化的途径，通向蒙乔基素的第一个总合成。拟议的研究将通过合成关键片段对映射并将其耦合到Monanchocidin的吡咯烷核心，以有效的方式执行。通过钯催化的不对称烯丙基烷基化（AAA）组装。将使用过渡金属催化的加氢酶来开发一种构建甲恰基素五边形鸟嘌呤的新方法。将对通常用于氢化反应中使用的过渡金属进行检查，其中最有效的效率将进一步优化并在拟议的合成中使用。