天然产物 Lycojaponicumin D 和 Bufospirostenin A 的全合成研究

天然产物的化学全合成一直以来都是合成化学领域的一个重要的分支， 受
到化学界的广泛关注。 由于人们对天然产物进行构效关系研究、 药理研究、 临
床实验都需要大量的样品， 而从自然界中分离得到的天然产物往往来源不稳定，
且难以大量获得。 因此， 利用全合成手段， 高效、 迅速制备天然产物， 以满足
其药物研发需求显得至关重要
石松科生物碱是一类长期受到合成化学家和生物学家们广泛关注的、 所属
众多、 结构奇特、 有着广泛生理活性的天然产物。 Lycojaponicumin D 是从石松
科苔藓里分离得到的石松科生物碱。 它具有 5/7/6/6 四环核心骨架， 含有四个手
性中心， 其中两个是季碳中心。 本文运用组内发展的 Type II [5+2]分子内环加
成反应作为关键反应， 成功构建了 5/7/6 桥环体系。 值得一提的是， 本文利用烯
胺参与的 Type II [5+2]环加成反应， 得到了挑战性较大的双环[4.3.1]核心骨架，
这是文献从未报道过的， 合成较具创新性。 而在合成后期， 其 C12 以及 C15 手
性构型与天然产物不符， 为此设计了修正构型的策略， 后续的转化正在进行中。
Bufospirostenin A 是从中华大蟾蜍中分离得到的甾醇类天然产物。 它具有
挑战较大的 5/7/6/5 四环核心骨架， 十一个手性中心， 以及一个独特的螺环缩酮
结构。 初步的活性研究表明， 该化合物对钾钠泵有良好的抑制活性。 本文设计
了以 Hajos-Parrish 酮衍生物为原料， 以联烯和炔参与的 Pauson-Khand 反应为关
键步骤， 成功合成了 5/7/6/5 四环核心骨架， 同时引入了两个双键， 为合成后期
的转化提供了便利。 进一步的合成研究正在推进中。
 

The total synthesis of natural products has been an important branch in the field
of synthetic chemistry for a long time and has received extensive attention from the
chemical community. As we all know, people need a large amount of bioactive
compounds for structure–activity relationship studies, pharmacological assays, and
clinical experiments. However, the bioactive natural products are often unsustainable
and cannot be obtained in large quantities. In this regard ， it is very important to
prepare natural products efficiently by means of total synthesis.
The Lycopodium alkaloids are a class of natural products with numerous
structures, a wide range of physiological activities, and have long been widely
concerned by synthetic chemists and biologists. Lycojaponicumin D was isolated
from the moss of the Lycopodium japonicum in 2012. It possesses a 5/7/6/6 tetra-ring
skeleton and four stereocenters, two of which are quaternary carbon centers. In this
thesis, the Type II [5+2] intramolecular cycloaddition developed by Prof. Li’s group
was successfully used as a key reaction to construct a 5/7/6 bridged ring system. It is
worth to mention that the novel [5+2] cycloaddition reaction involving an enamine
moiety, which has not been reported yet, successfully afforded the extremely
challenging bicyclic [4.3.1] skeleton. At the late stage of the synthesis, it was found
that the configurations at C12 and C15 are incorrect. So an alternative strategy was
designed to reverse the configurations and the studies addressing this issue are
currently underway.
Bufospirostenin A is a sterol compound isolated from Bufo bufo gargarizans in
2017. It contains a challenging 5/7/6/5 tetra-ring skeleton and eleven stereogenic
centers along with a unique spiro structure. Preliminary bioactive studies indicate that
the compound has good inhibitory activity against Na+/K+-ATPase. We developed a
synthetic route using Hajos-Parrish ketone derivatives as starting material to construct
the 5/7/6/5 tetracyclic core skeleton with the Pauson-Khand reaction as the key step.
The allenic Pauson-Khand reaction furnished the fused 5/7 bicyclic ring in one step
and introduced two double bonds, which facilitates further transformations. The
synthetic study towards the total synthesis of Bufospirostenin A is progressing.
 

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