Synthesis of Complex Terpenes

复杂萜烯的合成

• 批准号: 8242687
• 负责人: PHIL S BARAN
• 金额: $ 36.01万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242687
• 关键词: Address; Alzheimer' s Disease; Anabolism; Anti-Bacterial Agents; Area; Biological; Biological Factors; Biological Testing; Carbon; Characteristics; Chemicals; Communicable Diseases; Complex; Development; Diterpenes; Exhibits; Family; Family member; Glycols; Hydrocarbons; Hydrogen Bonding; Hydroxyl Radical; Hydroxylation; Lead; Logic; Malignant Neoplasms; Methodology; Methods; Mixed Function Oxygenases; Nature; Oxidases; Oxidation-Reduction; Paclitaxel; Pathway interactions; Pharmaceutical Preparations; Phase; Reaction; Route; S Phase; Series; Site; Skeleton; System; Taxane Compound; Techniques; Terpenes; Testing; Therapeutic; Work; analog; dehydrogenation; desaturase; interest; methyl group; operation; oxidation; public health relevance; taxane

DESCRIPTION (provided by applicant): Although there has been sustained interest in the field of C-H bond oxidation, there is still a need for new methods and strategies for the functionalization of Csp3-H bonds in complex hydrocarbon systems. Within the context of a two-phase approach to terpene synthesis (a logic derived from the biosynthetic pathway of complex terpenoids), the carbogenic framework generated in the synthetic cyclase phase would be subjected to a series of Csp3-H oxidations en route to a highly oxidized terpene target. This "oxidase phase" would use a strategic combination of known Csp3-H oxidation techniques, but it would naturally highlight gaps in current methodology, eliciting invention and discovery. Specifically, the ent-atisane and taxane families of diterpenoids were chosen due to their large arrays of oxidative diversity found in Nature, and two methods in Csp3-H functionalization are proposed herein in order to minimize the number of steps and non-strategic redox fluctuations toward their total syntheses. To this end, a hydroxyl-directed desaturation reaction (to act as a "desaturase mimic") and a hydroxyl-directed methyl group hydroxylation reaction (to act as a "hydroxylase mimic") would be developed in the course of these synthetic endeavors. The ent-atisane and taxane families exhibit biological activities in almost every conceivable therapeutic area. Because of its similarity to biosynthesis, the "oxidation level ascent" within these terpene families would naturally lead to the synthesis of related family members and closely related analogs during the pursuit of highly oxidized ent-atisane (e.g., ent-atisenol) and taxane (e.g., Taxol(R)) targets. The scalable, enantioselective synthesis of a lowly oxidized ent-atisane or taxane core similar to the ones employed in Nature, followed by a short series of sequential, site-selective Csp3-H oxidations, would allow for a divergent synthesis that could target large quantities of scarce biologically active natural products and non-natural analogs for use in the fields of cancer, Alzheimer<s and infectious disease. This proposal is organized into three parts: 1) The first section describes the development of a hydroxyl-directed, net dehydrogenation reaction, which would serve useful in the synthetic approach toward both ent-atisanes and taxanes; 2) the second part details a short, enantioselective synthesis of the ent-atisane framework, subsequent Csp3-H oxidation sequences en route to various family members, as well as a hydroxyl-directed methyl group hydroxylation reaction, which would allow access to a characteristic syn- 1,3-diol motif that pervades terpenoid frameworks in general; 3) the final section describes an efficient enantioselective synthesis of the taxane skeleton for its subsequent use as an oxidase phase substrate, in order to target diverse bioactive taxanes as well as the commercial drug Taxol(R). PUBLIC HEALTH RELEVANCE: The ent-atisane and taxane families exhibit biological activities in almost every conceivable therapeutic area due to its large array of structural diversity. The scalable, enantioselective synthesis of a lowly oxidized ent-atisane or taxane core similar to the ones employed in Nature, followed by sequential, site-selective Csp3-H oxidations, would allow for a divergent synthesis that could target many ent-atisanes and taxanes from common intermediates. This work aims to synthesize large quantities of scarce biologically active natural products and non-natural analogs for use in the fields of cancer, Alzheimer's and infectious disease, as well as to fill gaps in the chemical toolbox of current Csp3-H oxidation techniques.

描述(申请人提供)：尽管人们对C-H键氧化领域一直感兴趣，但对于复杂碳氢化合物体系中Csp3-H键的官能化，仍然需要新的方法和策略。在两阶段合成萜烯的方法(这是从复杂萜类化合物的生物合成途径衍生出来的逻辑)的背景下，在合成环化酶阶段产生的碳基框架将在通往高度氧化的萜烯靶标的过程中经历一系列Csp3-H氧化。这一“氧化阶段”将使用已知的Csp3-H氧化技术的战略组合，但它自然会突出当前方法中的空白，引发发明和发现。具体地说，由于在自然界中发现了大量的氧化多样性，因此选择了二萜类化合物的齿-蒂烷和紫杉烷家族，并在此提出了两种Csp3-H官能化方法，以最小化步骤数和对其总合成的非战略性氧化还原波动。为此，在这些合成过程中，将发展一个羟基导向的去饱和反应(作为“去饱和酶模拟物”)和一个羟基导向的甲基羟基化反应(作为一个“羟基酶模拟物”)。硫杂环己烷和紫杉烷类化合物在几乎所有可以想象到的治疗领域都显示出生物活性。由于其与生物合成相似，这些萜烯家族中的“氧化水平上升”将自然导致相关家族成员和密切相关类似物的合成，以追逐高度氧化的反-蒂烷(例如，ent-atisenol)和紫杉烷(例如，紫杉醇(R))目标。类似于在自然中使用的方法，可扩展的、对映体选择性地合成低氧化的环戊二烷或紫杉烷核心，然后进行短系列的顺序的、位置选择性的CSP3-H氧化，将允许进行发散的合成，从而针对大量稀有的生物活性天然产物和非天然类似物，用于癌症、阿尔茨海默氏病和传染病领域。该建议分为三个部分：1)第一部分描述了羟基导向的净脱氢反应的发展，这将有助于对合成正蒂烷和紫杉烷的方法；2)第二部分详细描述了短的、对映选择性地合成庚烷骨架，随后的Csp3-H氧化序列在通往不同家族成员的途中，以及羟基导向的甲基羟基化反应，这将允许获得一个特征的SYN-1，3-二醇基序，该基序普遍地贯穿于萜类骨架；3)最后一节描述了一种高效的紫杉烷骨架的对映选择性合成，以便随后将其用作氧化酶相底物，以针对不同的生物活性紫杉烷以及商业药物紫杉醇(R)。 与公共卫生相关：由于其结构的多样性，硫杂环己烷和紫杉烷家族在几乎所有可以想象到的治疗领域中都显示出生物活性。类似于自然界中使用的方法，可扩展的、对映体选择性地合成低氧化的庚烷或紫杉烷核心，然后进行顺序的、位置选择性的Csp3-H氧化，将允许进行发散合成，该合成可以从共同的中间体中靶向许多庚烷和紫杉烷。这项工作旨在合成大量稀有的生物活性天然产物和非天然类似物，用于癌症、阿尔茨海默氏症和传染病领域，并填补目前Csp3-H氧化技术的化学工具箱中的空白。