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Synthesis of Complex Terpenes

复杂萜烯的合成

基本信息

批准号：
8636031
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
项目类别：
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

项目摘要

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).

描述（由申请人提供）：尽管人们对C-H键氧化一直很感兴趣，但在复杂烃体系中，Csp3-H键的功能化仍然需要新的方法和策略。在萜烯合成的两相方法（复杂萜类化合物的生物合成途径的逻辑）的背景下，在合成环化酶阶段产生的碳基框架将在到达高度氧化的萜烯目标的过程中遭受一系列Csp3-H氧化。这个“氧化酶阶段”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。具体来说，二萜类化合物的正atisane和紫杉烷家族的选择是因为它们在自然界中发现了大量的氧化多样性，本文提出了两种Csp3-H功能化方法，以尽量减少其总合成的步骤数量和非战略性氧化还原波动。为此，在这些合成努力的过程中，将开发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“羟化酶模拟物”）。正atisane和紫杉烷家族在几乎所有可能的治疗领域都表现出生物活性。由于其与生物合成的相似性，这些萜烯家族中的“氧化水平上升”将自然导致在追求高度氧化的正丁烯烷（例如，正丁烯醇）和紫杉烷（例如，紫杉醇(R)）目标时合成相关家族成员和密切相关的类似物。类似于《Nature》中所使用的低氧化的正atisane或紫杉烷核心的可扩展、对端选择性合成，然后是一系列短序列的、位点选择性的Csp3-H氧化，将允许一种不同的合成，可以针对大量稀缺的生物活性天然产物和非天然类似物，用于癌症、阿尔茨海默病和传染病领域。本论文分为三个部分：1)第一部分描述了一种羟基导向的净脱氢反应的发展，这将有助于对-atisanes和紫杉烷的合成方法；2)第二部分详细介绍了一个简短的、对映选择性的正atisane框架合成，随后的Csp3-H氧化序列在通往各种家族成员的过程中，以及一个羟基导向的甲基羟基化反应，这将允许获得一个普遍存在于萜类框架中的特征的syn- 1,3-二醇基序；3)最后一节描述了一种有效的对映选择性合成紫杉烷骨架，用于其随后作为氧化酶相底物，以靶向多种生物活性紫杉烷以及商业药物紫杉醇(R)。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Scalable, enantioselective synthesis of germacrenes and related sesquiterpenes inspired by terpene cyclase phase logic.

DOI：
10.1002/anie.201206904
发表时间：
2012-11-12
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
影响因子：
16.6
作者：
Foo, Klement;Usui, Ippei;Goetz, Daniel C. G.;Werner, Erik W.;Holte, Dane;Baran, Phil S.
通讯作者：
Baran, Phil S.

A practical and catalytic reductive olefin coupling.

DOI：
10.1021/ja4117632
发表时间：
2014-01-29
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Lo JC;Yabe Y;Baran PS
通讯作者：
Baran PS

A unified approach to ent-atisane diterpenes and related alkaloids: synthesis of (-)-methyl atisenoate, (-)-isoatisine, and the hetidine skeleton.

DOI：
10.1021/ja507321j
发表时间：
2014-09-10
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Cherney, Emily C.;Lopchuk, Justin M.;Green, Jason C.;Baran, Phil S.
通讯作者：
Baran, Phil S.

Functionalized olefin cross-coupling to construct carbon-carbon bonds.

DOI：
10.1038/nature14006
发表时间：
2014-12-18
期刊：
NATURE
影响因子：
64.8
作者：
Lo, Julian C.;Gui, Jinghan;Yabe, Yuki;Pan, Chung-Mao;Baran, Phil S.
通讯作者：
Baran, Phil S.

Improving physical properties via C-H oxidation: chemical and enzymatic approaches.

DOI：
10.1002/anie.201407016
发表时间：
2014-11-03
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
影响因子：
16.6
作者：
Michaudel, Quentin;Journot, Guillaume;Regueiro-Ren, Alicia;Goswami, Animesh;Guo, Zhiwei;Tully, Thomas P.;Zou, Lufeng;Ramabhadran, Raghunath O.;Houk, Kendall N.;Baran, Phil S.
通讯作者：
Baran, Phil S.