Naphthospironone A是2010年由朱华结和文孟良课题组从云南大屯锡尾矿中一种拟诺卡氏放线菌的培养液中分离得到的新型萘醌类天然产物。该天然产物具有一定的细胞毒性及抗革兰氏阳性菌和阴性菌的活性。不同于已经报道的萘醌类天然产物，Naphthospironone A具有独特的螺[二环[3.2.1]辛烷-吡喃]的笼状分子骨架并且含有五个连续的手性中心，其中四个为氧杂的季碳手性中心。该天然产物合成难度较大，迄今为止只有一例研究完成了其ABD环模型结构的消旋体合成。

本论文在逆合成分析的基础上对Naphthospironone A的不对称全合成路线展开了探索。首先对课题组前期探索的螺环内酯中间体合成路线进行优化，采用汇聚式合成路线，利用连续的两步偶联反应将萘醌与C、D环片段连接，再利用环氧化和酸性条件下的环氧开环-内酯化高效构筑D环，得到了关键螺环内酯中间体。本论文又以该螺环内酯中间体为基础探究了一系列合成分子笼状骨架的策略，分别探索了先导入19位羟基再环化和先环化再导入19位羟基的两种路线，并最终成功通过溴代螺环内酯在氢化条件下还原脱溴引发的双键迁移和碱性条件下的分子内aldol反应实现了分子骨架的构筑，进而通过Mukaiyama水合反应成功导入了19位羟基。本论文还进一步探究了D环双键的导入策略，最终选择在溴代螺环内酯中间体中引入苯硫基并在环化形成分子骨架后氧化消除得到D环双键，进而最终以17步最长线性步骤实现了Naphthospironone A的首次不对称全合成。

本论文的研究工作成功实现具有复杂笼状骨架的Naphthospironone A的全合成，为下一步构效关系研究和结构优化提供了基础，也为其他聚酮类天然产物的合成提供了参考。

Naphthospironone A, a novel natural product in naphthoquinone family, was isolated by Zhu and Wen’s group in 2010 from the solid fermentation of an alkalophilic actinomycete which was found in a tin mine tailings area in Datun, Yunnan Province in southwest China. It exhibited moderate cytotoxicity and antibiotic activity against several Gram-positive and -negative bacteria. Unlike other reported naphthoquinones, Naphthospironone A has a unique spiro[bicyclo[3.2.1]octane-pyran] cage-like skeleton and contains five contiguous chiral carbons, four of which are quaternary oxygenated centers. Due to the synthetic challenge of naphthospironone A, only one study so far has constructed its racemic ABD ring model structure.

In this thesis, an asymmetric synthetic route for Naphthospironone A was explored on the basis of retrosynthetic analysis. Firstly, the previous synthetic route of the spirolactone intermediate explored by our group was optimized. A convergent synthetic route was adopted to connect naphthoquinone with C- and D-ring precursors using a sequential two-step coupling reactions. The D-ring was efficiently constructed through epoxidation and epoxy-ring opening/lactonization under acidic condition to afford the key spirolactone intermediate. Secondly, we explored a series of strategies to construct the cage skeleton, including introducing the 19-OH group before and after B-ring cyclization, respectively. The skeleton was successfully constructed through the double-bond migration triggered by the reductive debromination of bromospirolactone under hydrogenation, followed by the intramolecular aldol reaction under basic conditions. And the 19-OH group was successfully introduced by the Mukaiyama hydration reaction. Lastly, we investigated the strategy to install the double bond on D-ring. After extensive investigation, we finally chose to introduce a thiophenyl group on the bromospironolactone intermediate and afforded the D-ring double bond through an oxidation-elimination process after cyclization to form the cage-like skeleton. In summary, we achieved the first asymmetric total synthesis of Naphthospironone A via a process containing 17 steps in the longest linear sequence.

The successful work of the total synthesis of Naphthospironone A with a complex cage-like skeleton, not only paves the way for the next structure-activity relationship study and structure optimization, but also provides useful experience for the synthesis of other complex natural products in naphthoquinone family.