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

天然产物（次生代谢物）的全合成仍然是一个持续的挑战，也是有机化学的重要组成部分，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。为了完成大多数复杂目标框架的合成，人们通常依赖于成熟的反应和方法。然而，为了解决潜在的合成困难或规避现有方法的缺乏，必须开发新的方法。一类主要的植物次生代谢产物是萜类化合物，其中一些也具有显著的生物活性。2015年Lou等人报道了从中国苔类植物Haplomitrium mnioides中发现的两种新的labdane型二萜，haplomintrins A和B。本研究计划的主要目标是首次完成对映选择性全合成haplomintrins A和b。在此基础上，计划利用文献已知的手性催化剂，进行醌Diels-Alder反应作为关键步骤。此外，应该测试中田型β-酮亚胺是否能够改善铜双（恶唑啉）配合物的手性诱导，特别是如果已知的手性催化剂系统在这种具有挑战性的醌diols - alder反应中失败。有了Diels-Alder加合物，在顺式十氢化萘体系的一个羰基上，设想了一种区域和立体选择性加成的锂呋喃乙炔。haplomitrin B全合成的下一步是转化为反式十氢化萘体系，然后是阳离子或自由基脱氧和随后的炔酸内酯化。由于与脱氧相关的一个潜在问题是丙炔位置立体信息的丢失，因此也建议先进行内酯化。那么结构刚性较强的化合物的脱氧应该不会影响立体信息。为了准备进一步的合成困难，提出了一种替代内酯化策略，包括还原丙炔基，然后用甲基lester进行硼氢化和内酯化。最后，迈向haplomintrin B的最后一步是光诱导[2+2]环加成，Lou等人对此进行了一些初步研究。有了haplomintrin B，通过Hartwig硅基化进行的C-H后期官能化应该会导致haplomintrin a。因此，haplomintrin B的羰基应该以SmI2作为还原剂立体选择性地转化为羟基。在随后的羟基硅基化之后，RhCl（Xantphos）的加入应使草硅烷具有δ-位置的甲基。随后的弗莱明-塔茂氧化反应生成δ-羟基化化合物。最后，经过一系列的Swern氧化、Pinnick氧化和酯化反应，得到一种高纯度的蛋白a。

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.