Acyclic Diastereoselection: Methodology and Synthesis

无环非对映选择：方法与合成

• 批准号: 7727319
• 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
• 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/7727319
• 关键词: Aldehydes; Antimitotic Agents; Area; Biological; Biological Factors; Boranes; Cell Line; Cells; Chemistry; Colon Carcinoma; Complex; Databases; Development; Esters; Foundations; Generations; Glycolipids; Glycols; Goals; Grant; Green Algae; HCT116 Cells; Human; In Vitro; Inhibitory Concentration 50; Kinetics; Lead; Libraries; MCF7 cell; Melanoma Cell; Methodology; Methods; Pharmaceutical Preparations; Process; Reaction; Reagent; Relative (related person); Research; Resolution; Solutions; Source; Staging; Stereoisomer; Structure-Activity Relationship; System; Technology; Tubulin; amphidinol 3; analog; enantiomer; falls; indexing; novel; peloruside A; polymerization; propadiene; public health relevance; small molecule; stereochemistry

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.

这项建议侧重于非环非对映选择性合成领域的研究， 重点开发应用于全合成的新型烯丙基金属试剂 立体化学复杂的天然产品。预计这一方法将有助于 生物活性天然产物和其他类药物的类似物的合成和SAR研究 小分子。具体目标是： (I)开发涉及烯丙基硼试剂的新方法。双打 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 从醛的前体出发，在络合物的片段组装中具有特殊的前景和用途 合成问题中的合成中间体。这一方法的进一步发展是 建议。在前一个授权期内发现，索德奎斯特硼烷，TDDB-H(I- 13)，影响烯的氢硼化反应，得到动力学稳定的(Z)-g-硼基烯丙基硼烷I-8b 为一系列新试剂的产生奠定了基础，这些新试剂将显著扩大 双烯丙基硼(及相关的双烯丙基金属化)工艺的范围和用途。这个 探讨了烯丙基锡烷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，这些过程无法通过使用First- 生成双烯丙基硼反应。 以高对映体选择性的联烯氢化硼为基础(尤其是 在先前的授权中发现的外消旋烯的对映体会聚氢硼化反应) 期间，额外的双烯丙基金属化试剂的开发涉及到 外消旋烯基硅烷I-23，烯基硼酸根I-28的对映体选择性氢化 将寻求I-34的动力学解析。非手性联烯的对映选择性氢化反应 例如I-38和I-40也将被研究。对映选择性丙二烯的最大用途 氢化反应的化学在于能够产生双官能团的烯丙基硼烷产品 用于几个C-C键的形成反应，特别是在收敛的情况下 碎片组装。 (Ii)尼日利亚苷的全合成。尼日利亚苷是一种有效的抗有丝分裂物质。 从绿藻Avrainvillea nigricans中分离出的糖脂，但相对和绝对 黑木苷A的立体化学成分尚未定义。棕榈内酯A是一种新的烯胺类化合物。 含有对黑色素瘤细胞系具有显著选择性的聚酮，具有 对于最敏感的电池，选择性指数为e103。黑木素苷和棕榈酰内酯A 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 手性试剂III-3用于外消旋烯的氢硼化反应的一般方法 III-2.随后对烯丙基硼化产物III-4的操作将允许任何立体异构体 这些天然产物的1，2，5-三烷氧基戊烯单元(对映体或非对映异构体) 以简明的、立体的方式组装。这项技术将被用于产生 核磁共振数据库文库(III-22和III-23)，将允许完全立体化学 黑木皂苷A待指认。这项技术还将导致简明的、立体化学的 黑木苷A和选定类似物(立体异构体)的受控合成。 (3)完成上一批款期内的项目。全合成 将完成在前一个赠款期间进行的鬼臼糖苷A和苯并二醇3。 属于目标(一)的新方法将被用来完成这些合成，这些合成已经 已经发展到很晚的阶段。