ACYCLIC DIASTEREOSELECTION--METHODOLOGY AND SYNTHESIS

无环非对映选择--方法和合成

• 批准号: 2643506
• 负责人: WILLIAM R ROUSH
• 金额: $ 12.71万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2643506
• 关键词: aldehydes; allyl compound; antibiotics; antineoplastic antibiotics; boron; boronic acids; catalyst; chemical synthesis; croton oil; drug design /synthesis /production; enol; enolate; ketones; macrolide antibiotics; propionates; silanes; stereochemistry; stereoisomer

DESCRIPTION: It is proposed to continue investigations in the area of acyclic diastereoselective synthesis, with emphasis on crotylmetalation reactions and fragment assembly aldol reactions in the context of natural products synthesis. Specific goals are: 1. Development of New Methodology for the Synthesis of Anti, Anti Dipropionates. The reactions of b-hydroxy aldehydes with (Z)-crotyltrifluorosilane 36 and (Z)-crotylsilacyclobutanes 112-114 will be developed for the synthesis of anti, anti dipropionates, which are difficult to synthesize by other methods. 2. Stereochemical Studies of Methyl Ketone Aldol Reactions. (i) The involvement of boat-like transition states in methyl ketone aldol reactions will be probed by using the 2H-labeled enol silane 122 as precursor to lithium, boron and titanium enolates. (ii) A synthesis of the C(13)-C(25) segment of scytophycin C will be performed with emphasis on the aldol reaction of 125 and 126. The data that emerge from this study will complement results obtained in the rutamycin series, and should greatly increase the ability to make stereochemical predictions about other complex fragment couplings. 3. New Methodology for Fragment Coupling. Tartrate prenylboronates 136e,z will be developed for use in aldehyde allylboration reactions. The resulting adducts 137 will be elaborated to chiral methallylboronates 138 and then coupled with chiral aldehydes. It is expected that the diastereofacial selectivity of 138 will be large enough to dominate the diastereofacial preferences of most aldehydes. This methodology thus should constitute a general strategy for fragment coupling. 4. Completion of a Total Synthesis of Damavaricin D. This total synthesis, which is at an advanced stage, will be completed in the next grant period. A biomimetic strategy for the synthesis of streptovaricin C from damavaricin C (naturally derived) also will be explored. 5. Completion of a Total Synthesis of Bafilomycin A1. The synthesis, which has progressed to the stage of the macrocycle 85, will be completed by a late stage aldol reaction of methyl ketone 158 and chiral aldehyde 159. 6. Synthesis of Tedanolide. This project will give additional insight into the fragment assembly aldol problem. The crotylboration of meso dialdehyde 190 and the regioselective introduction of trisubstituted olefins via E2 reactions in conformationally flexible systems also will be explored.

描述：建议继续在以下领域进行调查： 无环非对映选择性合成，重点是巴豆基金属化 反应和片段组装羟醛缩合反应的背景下， 天然产物合成 具体目标是：1。开发新 反式，反式二丙酸酯的合成方法学。 的 b-羟基醛与（Z）-巴豆基三氟硅烷36和 （Z）-巴豆基硅环丁烷112-114将被开发用于合成 反，反二丙酸酯，这是很难合成的其他 方法. 2.甲基酮羟醛缩合反应的立体化学研究。 (i)船状过渡态对甲基酮的参与 将通过使用2 H-标记的烯醇硅烷122探测羟醛缩合反应 作为锂、硼和钛烯醇化物的前体。 (ii)合成 的C（13）-C（25）片段的scytophycin C将与 重点是125和126的羟醛缩合反应。 这些数据来自 这项研究将补充在芸香霉素系列中获得的结果， 将大大提高立体化学预测的能力 关于其他复杂的片段连接。 3.碎片的新方法 偶合器. 酒石酸异戊二烯基硼酸酯136 e，z将被开发用于 醛烯丙基硼化反应。 得到的加合物137将是 制备成手性甲基烯丙基硼酸酯138，然后与手性甲基烯丙基硼酸酯138偶联。 醛类。 预期138的非对映体选择性 将大到足以支配大多数人的非对映体偏好， 醛类。 因此，这一方法应构成一项总战略 用于片段偶联。 4.达玛瓦菌素的全合成 D. 这一全面综合工作已进入后期阶段， 在下一个补助期内完成。 一种仿生策略， 从达玛瓦里菌素C（天然衍生物）合成静脉曲张链菌素C 也将被探索。 5.完成全面综合报告 巴弗洛霉素A1。 合成，这已经发展到阶段的 大环85，将通过甲基的后期羟醛缩合反应完成 酮158和手性醛159。 6.替丹酮的合成 这 项目将提供更多的洞察片段组装羟醛 问题. 内消旋二醛190的巴豆基硼化反应和 通过E2反应区域选择性引入三取代烯烃 在构象灵活的系统中也将被探索。