Total synthesis of haplomintrins A and B and studies on enantioselective quinone Diels-Alder reactions

单倍明特林A和B的全合成及对映选择性醌Diels-Alder反应的研究

• 批准号: 456623941
• 负责人: Dr. Stefan Wiesler
• 金额: --
• 依托单位: Department of Chemistry
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/456623941?language=en
• 关键词: Total; synthesis; haplomintrins; studies; enantioselective

The total synthesis of natural products (secondary metabolites) still remains an ongoing challenge and important part of organic chemistry, as natural products and their derivatives can often be used to identify new drugs or drug candidates. In order to accomplish the synthesis of mostly complex target frameworks, one typically relies on well-established reactions and methods. However, to tackle potential synthetic hardships or to circumvent a lack of existing approaches, new methods must be developed.One main class of plant secondary metabolites are terpenoids, some of which also possess significant biological activity. In 2015 Lou et al. reported two novel labdane-type diterpenoids, haplomintrins A and B, which they discovered from the Chinese liverwort Haplomitrium mnioides. The main objective of the present research proposal is to accomplish the first enantioselective total synthesis of haplomintrins A and B. In this vein, it is planned to carry out an enantioselective quinone Diels-Alder reaction as key step, using literature-known chiral catalysts. In addition, it should be tested whether a Nakada-type β-keto imide enables an improved chiral induction of copper bis(oxazoline) complexes, especially if the known chiral catalyst systems fail in this challenging quinone Diels-Alder reaction. With the Diels-Alder adduct in hand, a regio- and stereoselective addition of lithium furylacetylene to one of the carbonyl groups of the cis-decalin system is envisioned. The next step in the total synthesis of haplomitrin B is the transformation into the trans-decalin system, followed by cationic or radical deoxygenation and a subsequent alkynoic acid lactonization. Since one potential problem associated with the deoxygenation is the loss of stereo information at the propargylic position, it is also proposed to carry out the lactonization first. Then the deoxygenation of the structurally more rigid compound should not influence the stereo information. In order to prepare for further synthetic difficulties an alternative lactonization strategy is proposed involving a reduction of the propargyl group, followed by a hydroboration and lactonization of the resulting alcohol with the methylester. Finally, the last step toward haplomintrin B is a photoinduced [2+2] cycloaddition for which Lou et al. conducted some preliminary studies.With haplomintrin B in hand, a late-stage C–H functionalization by means of a Hartwig silylation should lead to haplomintrin A. Therefore, the carbonyl group of haplomintrin B should be stereoselectively converted to a hydroxy group using SmI2 as reducing agent. After subsequent silylation of the hydroxy group, the addition of RhCl(Xantphos) should provide the oxasilolane with the methyl group in δ-position. The subsequent Fleming-Tamao oxidation then leads to the δ-hydroxylated compound. Finally, a sequence of Swern oxidation, Pinnick oxidation and esterification should furnish haplomintrin A.

天然产物（二级代谢产物）的总合成仍然是有机化学的持续挑战和重要的一部分，因为天然产物及其衍生物通常可用于鉴定新药或候选药物。为了完成大部分复杂的目标框架的综合，通常依赖于建立的反应和方法。但是，为了应对潜在的综合困难或避免缺乏现有方法，必须开发新的方法。一种主要的植物二次代谢产物是萜类化代谢物，其中一些也可能具有重要的生物学活性。在2015年Lou等。报道了两种新型的Labdane型二萜类化合物，单倍蛋白A和B，他们从中国利弗沃特单倍替林Mnioid中发现。本研究建议的主要目的是完成单倍替氏蛋白A和B的第一个对映选择性的总合成。在这种静脉中，计划使用文献 - 知名的手性催化剂来作为关键步骤进行对映选择性奎因酮Diels-alder反应。此外，应测试中Nakada型β-Keto Imide是否可以改善铜双（恶唑氨酸）复合物的手性诱导，尤其是在此挑战Quinone Diels-Alder反应中，已知的手性催化剂系统失败。随着Diels-Alder的添加，设想在顺式甲基乙烯系统的一个羰基中，将锂乙二醇的区域性和立体选择性添加到了CIS-Decalin System的一个。单倍蛋白B的总合成的下一步是转化为跨核蛋白系统，其次是阳离子或自由基脱氧和随后的藻酸乳酸化。由于与脱氧相关的一个潜在问题是在宣传位置失去立体声信息，因此还建议首先进行乳酸化。那么结构上更刚性化合物的脱氧化不应影响立体信息。为了准备进一步的综合难度，提出了替代的乳沉积策略，涉及propargyl群的减少，然后与甲基酯一起进行液化和乳酸化。最后，向单倍蛋白B进行的最后一步是Lou等人的光诱导的[2+2]环加成。进行了一些初步研究。在手握单倍链蛋白B的情况下，通过hartwig silylation的后期C – H官能化应导致单倍链蛋白A。因此，使用SMI2 AS REDICICS AS REDICENIC AS REDICENCERS的HYDROXY组立体地将单倍氨基蛋白B组定为carbonyl carbonyl carbonyl carbonyl carbonyl carbonyl carbonyl carbonyl。在随后的羟基硅烷基化后，添加RhCl（Xantphos）应在δ位中向甲基提供甲基。然后，随后的fleming-tamao氧化导致δ-羟基化化合物。最后，一系列细胞氧化，固定氧化和酯化应提供单倍蛋白A。