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Alkyllithium Cyclizations in Organic Snythesis

有机合成中的烷基锂环化

基本信息

批准号：
6879156
负责人：
SCOTT D. RYCHNOVSKY
金额：
$ 23.15万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2007-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6879156
关键词：
alkyl nitrile alkylation biological products chemical cleavage chemical structure function chemical synthesis chemical transfer reaction cyclization ketal lithium organic chemicals piperidine pyrans spirane stereochemistry stereoisomer

项目摘要

DESCRIPTION (provided by applicant): Synthetic chemistry is the technology underlying modern drug development. The successful mapping of the human genome was the first step towards identifying new receptors and pathways to treat chronic diseases. The path from bimolecular targets to realizing improvements in human health usually requires the synthesis of small molecule agonists, antagonists, or inhibitors. In this proposal we will develop a potentially powerful method to synthesize small nitrogen and oxygen spiro rings. New synthetic methods such as this one are an enabling technology for improving human health. The reductive cleavage of nitrile is a rarely used method for generating alkyllithium reagents. In many six-membered rings this reaction is completely stereoselective, and the resulting alkyllithium will couple with electrophiles with retention of configuration. We propose to use this reductive lithiation reaction, in combination with facile alkylations adjacent to nitrile groups, to develop a general and stereoselective synthesis of spiro rings. This method will be developed to prepare the spiro-tetrahydropyran rings. These reductive cyclization reactions will be used in a general synthesis of contrathermodynamic spiroacetals, structures commonly found in complex natural products. The third area of development is in the synthesis of spiropiperidines, where modification of the substrate will allow either configuration of the spiropiperidine to be prepared selectively. The synthetic targets for this proposal are segments of natural products and natural products themselves. Segments of altohyrtin (spongistatin) and azaspiracid will be prepared using the approach to contrathermodynamic spiroacetals. Histrionicotoxin and pinnaic acid will be prepared using the spiropiperidine method. These compounds are of interest to synthetic and medicinal chemists, and have the types of rigid, polycyclic and polar structures found to show high bioactivity in many assays.

描述（由申请人提供）：合成化学是一种技术，现代药物开发的基础人类基因组的成功绘制是确定新的受体和治疗途径的第一步慢性病从双分子靶到实现改进的途径通常需要合成小分子激动剂，拮抗剂或抑制剂。在本提案中，我们将开发一种潜在的合成小氮氧螺环的有效方法。新像这样的合成方法是一种能够改善人体健康腈的还原裂解是一种很少使用的生成腈的方法。烷基锂试剂。在许多六元环中，该反应完全立体选择性，并且所得烷基锂将与亲电试剂偶联并保持构型。我们建议利用这种还原锂化反应，结合与腈基相邻的容易的烷基化，发展了螺环的通用和立体选择性合成。该方法将被开发用于制备螺-四氢吡喃环。这些还原环化反应将用于一般合成反热力学螺缩醛，结构常见于复杂的自然产品.第三个发展领域是综合螺哌啶，其中底物的修饰将允许选择性地制备螺哌啶的构型。该提案的合成目标是天然产品的部分，天然产品本身。altohyrtin（海绵抑素）片段和 azaspiracid将使用逆热力学方法制备螺缩醛将使用以下方法制备Histrionicotoxin和pinnaic acid：螺哌啶法这些化合物对于合成和制备具有重要意义。药物化学家，并有刚性，多环和极性的类型在许多测定中发现具有高生物活性的结构。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cyclization via carbolithiation of alpha-amino alkyllithium reagents.

DOI：
10.1021/ol801523r
发表时间：
2008-09-18
期刊：
Organic letters
影响因子：
5.2
作者：
Bahde RJ;Rychnovsky SD
通讯作者：
Rychnovsky SD

Total synthesis of lepadiformine alkaloids using N-Boc α-amino nitriles as trianion synthons.

DOI：
10.1021/jo300161x
发表时间：
2012-04-06
期刊：
The Journal of organic chemistry
影响因子：
0
作者：
Perry MA;Morin MD;Slafer BW;Rychnovsky SD
通讯作者：
Rychnovsky SD

Generation and utility of tertiary alpha-aminoorganolithium reagents.

叔α-氨基有机锂试剂的产生和应用。

DOI：
10.1021/ol049039p
发表时间：
2004
期刊：
Organic letters.
影响因子：
0
作者：
Wolckenhauer,ScottA;Rychnovsky,ScottD
通讯作者：
Rychnovsky,ScottD

Reductive spiroannulation of nitriles with secondary electrophiles.

DOI：
10.1021/ol050567q
发表时间：
2005-04
期刊：
Organic letters
影响因子：
5.2
作者：
Matthew D. Morin;S. Rychnovsky
通讯作者：
Matthew D. Morin;S. Rychnovsky

Fully substituted carbon centers by diastereoselective spirocyclization: stereoselective synthesis of (+)-lepadiformine C.

DOI：
10.1021/ja104250b
发表时间：
2010-07-21
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Perry, Matthew A.;Morin, Matthew D.;Slafer, Brian W.;Wolckenhauer, Scott A.;Rychnovsky, Scott D.
通讯作者：
Rychnovsky, Scott D.