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Application of Sulfurane Chemistry in the Assembly of HIV Protease Inhibitors

硫烷化学在 HIV 蛋白酶抑制剂组装中的应用

基本信息

批准号：
7539773
负责人：
David Christopher Forbes
金额：
$ 20.24万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7539773
关键词：
Acetates Acetic Acid Acetic Acids Affect Alabama Aldehydes Alkenes Amprenavir Area Ascorbic Acid Atazanavir Aziridines Betaine Binding Biological Biological Factors Butane Butanes Carbon Carbon Dioxide Catalysis Chemistry Complement 3d Receptors Cyclopropanes Data Decarboxylation Development Environment Ethylene Oxide Exhibits Facility Construction Funding Category Funding Generations Glyceraldehyde Goals HIV Protease Inhibitors Imines In Situ Ketones Left Lopinavir Mannitol Methods Motion Nelfinavir Numbers Organic Chemistry Postdoctoral Fellow Preparation Public Health Reaction Reagent Research Resources Ritonavir Role Salts Saquinavir Savings Science Students Sulfides Sulfur Surveys System Technology Time Translating United States National Institutes of Health aziridine carboxylate cost cyclopropane fosamprenavir high school hydroxyethylene improved peptidomimetics programs promoter scaffold success teacher ylide

项目摘要

DESCRIPTION (provided by applicant): My research program lies primarily in the area of synthetic organic chemistry. A large component is dedicated toward the development of new synthetic methods. The success of the program is heavily dependent upon the involvement of motivated and talented undergraduate students. Funds requested through the NIH AREA program will allow for the involvement of high school chemistry teachers active in the statewide-funded program Alabama Science in Motion (ASIM), postdoctoral research associates, and undergraduate research students. Their involvement will, in terms of maturation, bring our research program to the next level. This is my first application to NIH. The construction of three-membered rings represents an extremely useful synthetic transformation for the introduction of functionality into organic molecules. Of the common disconnections available to assemble three-membered rings, the sulfur ylide approach offers potential advantages of atom efficiency, facility for stereocontrol and catalysis. Our research plans are to build upon preliminary data with the intent to explore catalysis, asymmetry, and natural product synthesis. By reversing the role of the sulfur atom, we will have a completely new method in the generation of sulfur ylides. The carboxylate dianions generated in situ will displace the halide bound to the sulfurane and generate carboxymethyl betaine functionality directly. Upon decarboxylation, the sulfur ylide will react with a host of ?-acceptors affording three-membered ring carbocycles. Advantages include the ease by which one can modify the ylide reagent. Developing this technology would be a significant advancement to the field as witnessed to date especially when using chiral nonracemic sulfurane promoters to conduct alkylidene transfers. Concurrent with the development of the sulfurane chemistry will be the application of the sulfur ylide technology in the preparation of HIV protease inhibitors. Our approach is conceptually unique in that it has as the key step, assembly of the hydroxyethylene three-carbon building block using butane-2,3-diacetals of glyceraldehyde (BDA). The BDA derivative will allow for stereospecific methylidene transfers. Once formed, the ring(s) can be opened and within two steps, the three-carbon building block found in the HIV protease inhibitors of amprenavir, atazanavir, fosamprenavir, lopinavir, nelfinavir, ritonavir, and saquinavir can be furnished. This approach significantly improves upon how these materials are currently prepared. PUBLIC HEALTH RELEVANCE: We have a synthetic plan which will offer the synthetic chemist the most efficient means to perform methylidene transfers onto a @-system. The materials prepared using this method will significantly streamline how modern HIV protease inhibitors are prepared. A savings in time and resources will ultimately translate to cost.

描述（由申请人提供）：我的研究计划主要是在合成有机化学领域。一个很大的组成部分致力于开发新的合成方法。该计划的成功在很大程度上取决于积极和有才华的本科生的参与。通过NIH区域计划申请的资金将允许高中化学教师积极参与全州资助的亚拉巴马科学运动（ASIM）计划，博士后研究助理和本科研究生。他们的参与将使我们的研究项目更上一层楼。这是我第一次申请NIH。三元环的构建代表了一种非常有用的将功能引入有机分子的合成转化。在组装三元环的常见断开方法中，硫叶立德方法提供了原子效率、立体控制和催化的便利性的潜在优势。我们的研究计划是建立在初步数据的基础上，旨在探索催化，不对称和天然产物合成。通过颠倒硫原子的作用，我们将在硫叶立德的生成中有一个全新的方法。原位生成的羧酸根二价阴离子将取代与硫烷结合的卤化物并直接生成羧甲基甜菜碱官能团。脱羧后，硫叶立德将与大量的？-提供三元环碳环的受体。优点包括可以容易地修饰叶立德试剂。发展这一技术将是一个重大的进步，该领域的见证，特别是当使用手性非外消旋硫烷促进剂进行亚烷基转移。随着硫烷化学的发展，硫叶立德技术将在制备HIV蛋白酶抑制剂中得到应用。我们的方法在概念上是独特的，因为它具有作为关键步骤，使用甘油醛（BDA）的丁烷-2，3-二缩醛组装羟基三碳结构单元。BDA衍生物将允许立体特异性亚甲基转移。一旦形成，环可以打开，并且在两个步骤内，可以提供在安普那韦、阿扎那韦、福沙那韦、洛匹那韦、奈非那韦、利托那韦和沙奎那韦的HIV蛋白酶抑制剂中发现的三碳结构单元。这种方法大大改进了目前制备这些材料的方法。公共卫生关系：我们有一个合成计划，它将为合成化学家提供最有效的方法来进行亚甲基转移到@-系统上。使用这种方法制备的材料将显著简化现代HIV蛋白酶抑制剂的制备方式。节省的时间和资源最终将转化为成本。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

2,6-Dichloro-1-[(1E)-2-(phenyl-sulfon-yl)ethen-yl]benzene.

2,6-二氯-1-[(1E)-2-(苯磺基)乙烯基]苯。

DOI：
10.1107/s1600536811011901
发表时间：
2011
期刊：
Acta crystallographica. Section E, Structure reports online
影响因子：
0
作者：
South,MichaelS;Obiako,AdirikaJ;Sykora,RichardE;Forbes,DavidC
通讯作者：
Forbes,DavidC

Synthesis of Chiral Aziridines through Decarboxylative Generation of Sulfur Ylides and their Reaction with Chiral Sulfinyl Imines.

DOI：
10.1080/00397910802654898
发表时间：
2009-01-01
期刊：
Synthetic communications
影响因子：
2.1
作者：
Forbes DC;Bettigeri SV;Amin SR;Bean CJ;Law AM;Stockman RA
通讯作者：
Stockman RA

Sulfenylation Chemistry using Polymer-Supported Sulfides.

DOI：
10.1016/j.tetlet.2009.02.009
发表时间：
2009
期刊：
TETRAHEDRON LETTERS
影响因子：
1.8
作者：
Forbes, David C.;Bettigeri, Sampada V.;Al-Azzeh, Nahla N.;Finnigan, Brian P.;Kundukulam, Joseph A.
通讯作者：
Kundukulam, Joseph A.

Forging Faculty Student Relationships at the College Level Using a Freshman Research Experience.

利用新生研究经验在大学层面建立师生关系。