Acyclic Diastereoselection: Methodology and Synthesis

无环非对映选择：方法与合成

基本信息

批准号：
7914485
负责人：
WILLIAM R ROUSH
金额：
$ 38.9万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-02-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7914485
关键词：
13-deoxytedanolide Aldehydes Antarctic Antimitotic Agents Area Biological Biological Factors Boranes Cell Line Cells Chemistry Colon Carcinoma Complex Coupling Databases Development Esters Exhibits Family Foundations Generations Glycolipids Glycols Goals Grant Green Algae HCT116 Cells Human In Vitro Inhibitory Concentration 50 Kinetics Laboratories Lead Libraries MCF7 cell Melanoma Cell Methodology Methods Organic Synthesis Pharmaceutical Preparations Pharmacologic Substance Plague Process Progress Reports Public Health Reaction Reagent Relative (related person)Research Resolution Solutions Source Staging Stereoisomer Structure Structure-Activity Relationship System Technology Tubulin Urochordata amphidinol 3 analog apoptolidin base chemotherapeutic agent cytotoxic cytotoxicity drug candidate enantiomer falls hemiketal indexing insight marine natural product melanoma member novel peloruside A polymerization programs propadiene small molecule stereochemistry tedanolide tetrafibricin

项目摘要

This proposal focuses on research in the area of acyclic diastereoselective synthesis, with emphasis on the development of novel allylmetal reagents for application to the total synthesis of stereochemically complex natural products. It is expected that this methodology will facilitate synthesis of analogs and SAR studies of biologically active natural products, and other drug-like small molecules. Specific goals are: (I) Development of New Methodology Involving Allylboron Reagents. The double allylboration reaction is a powerful method for the stereocontrolled synthesis of 1,5-diol systems from aldehyde precursors, and has particular promise and utility in fragment assembly of complex synthetic intermediates in synthetic problems. Further development of this methodology is proposed. The discovery in the previous grant period that the Soderquist borane, TDDB-H (I- 13), effects hydroboration of allenes to give the kinetically stable (Z)-g-borylallylborane I-8b provides the foundation for generation of a range of new reagents that will significantly broaden the scope and utility of the double allylboration (and related double allylmetalation) process. The full scope of allylstannation reactions of allylstannanes 33 and I-22 be explored. This chemistry will provide solutions to fragment assembly processes that cannot be achieved by using first- generation double allylboration reactions. Building off the highly enantioselective hydroborations of allenes (and especially the enantioconvergent hydroboration reactions of racemic allenes) discovered in the previous grant period, the development of additional double allylmetalating reagents involving the enantioselective hydroborations of racemic allenylsilane I-23, allenylboronate I-28, and the kinetic resolution of I-34 will be pursued. The enantioselective hydroboration of achiral allenes such as I-38 and I-40 will also be studied. The greatest utility of the enantioselective allene hydroboration chemistry lies in the ability to generate bifunctional allylborane products that can be used for several C-C bond formation reactions, especially in the context of convergent fragment assembly. (II) Total Syntheses of Nigricanoside A. Nigricanoside is a potent, antimitotic glycolipids isolated from the green alga Avrainvillea nigricans, but the relative and absolute stereochemical of nigricanoside A has not been defined. Palmerolide A is a new enamide- containing polyketide that has remarkable selectivity against melanoma cell lines, with a selectivity index of e103 for the most sensitive cells. The nigricanosides and palmerolide A have structurally related 1,2,5-trialkoxypentene units that will be synthesized in a stereochemically general manner by using the chiral reagent III-3 deriving from hydroboration of racemic allene III-2. Subsequent manipulations of the allylboration product, III-4, will permit any stereoisomer (either enantiomer or diastereomer) of the 1,2,5-trialkoxypentene units of these natural products to be assembled in a concise, stereodivergent manner. This technology will be used to generate NMR database libraries (III-22 and III-23) which will permit the full stereochemistry of nigricanoside A to be assigned. This technology will also lead to concise, stereochemically controlled syntheses of nigricanoside A and selected analogs (stereoisomers). (III) Completion of Projects From the Preceding Grant Period. Total syntheses of peloruside A and amphidinol 3 that were pursued in the preceding grant period will be completed. New methodology, falling under aim (I), will be used to complete these syntheses, which have already progressed to very late stages.

该提案重点关注无环非对映选择性合成领域的研究，其中重点开发新型烯丙基金属试剂用于全合成立体化学复杂的天然产物。预计该方法将有助于类似物的合成以及生物活性天然产物和其他类药物的 SAR 研究小分子。具体目标是： (I) 涉及烯丙基硼试剂的新方法的开发。双烯丙基硼化反应是立体控制合成 1,5-二醇体系的有效方法来自醛前体，并且在复杂的片段组装中具有特殊的前景和实用性合成问题中的合成中间体。该方法的进一步发展是建议的。在上一个资助期间发现 Soderquist 硼烷，TDDB-H (I- 13)，进行丙二烯的硼氢化反应，得到动力学稳定的 (Z)-g-硼基烯丙基硼烷 I-8b 为产生一系列新试剂奠定了基础，这些新试剂将显着拓宽双烯丙基硼化（和相关的双烯丙基金属化）工艺的范围和实用性。这探索烯丙基锡烷 33 和 I-22 的烯丙基锡化反应的全部范围。这种化学反应将为片段组装过程提供解决方案，这是使用first-无法实现的生成双烯丙基硼反应。建立丙二烯（尤其是丙二烯）的高度对映选择性硼氢化反应外消旋丙二烯的对映聚合硼氢化反应）在之前的资助中发现在此期间，开发了额外的双烯丙基金属化试剂，涉及外消旋丙二烯基硅烷 I-23、丙二烯基硼酸酯 I-28 和将寻求 I-34 的动力学解决方案。非手性丙二烯的对映选择性硼氢化 I-38和I-40等也将被研究。对映选择性丙二烯的最大用途硼氢化化学在于能够生成双功能烯丙基硼烷产物，该产物可以可用于多种 C-C 键形成反应，特别是在收敛的情况下片段组装。 (II) Nigricanoside A 的全合成。Nigricanoside 是一种有效的抗有丝分裂药物从绿藻 Avrainvillea nigricans 中分离出的糖脂，但相对和绝对黑果苷 A 的立体化学尚未定义。 Palmerolide A 是一种新型烯酰胺- 含有聚酮化合物，对黑色素瘤细胞系具有显着的选择性， e103 对最敏感细胞的选择性指数。黑果苷和棕榈内酯 A 具有结构相关的 1,2,5-三烷氧基戊烯单元将在立体化学中合成使用衍生自外消旋丙二烯硼氢化的手性试剂 III-3 的一般方式 III-2.烯丙基硼化产物 III-4 的后续操作将允许产生任何立体异构体这些天然产物的 1,2,5-三烷氧基戊烯单元（对映体或非对映体）以简洁、立体发散的方式组装。该技术将用于生成 NMR 数据库（III-22 和 III-23）将允许完整的立体化学待分配的黑果苷A。这项技术还将带来简洁、立体化学黑果苷 A 和选定的类似物（立体异构体）的受控合成。（三）上一资助期项目完成情况。全合成上一资助期间追求的peloruside A 和amphidinol 3 将完成。属于目标 (I) 的新方法将用于完成这些综合，其中已经进展到很晚的阶段。