手性苯酞骨架导向的催化不对称高联烯硼基化－内酯化串联反应研究

Chiral phthalides are frequently found in naturally occurring substances, and exhibit a broad spectrum of biological activities. They also act as versatile building blocks in organic synthesis, particularly in the synthesis of functionalized naphthalenes, anthracenes, and naphthacene natural products. Thus the development of efficient synthetic methods for such type of compounds is highly desirable. Toward addressing the challenge of creating chiral quaternary stereogenic center at the 3-position of phthalides and regioselective synthesis of 1,3-butadienyl or homoallenyl phthalides from the same starting materials, we will study the reaction between methyl 2-carbonylbenzoates and 2,3-dienylboronic esters in an asymmetric manner. The only using of chiral Brønsted acids, or binary catalyst system containing Brønsted acids and metallic complexes are to be carried out, which will facilitate the asymmetric tandem homoallenylboration-lactonization reactions for chiral phthalides. The former catalytic protocol has already proved to be feasible to get chiral phthalides bearing a 1,3-butadienyl substitutent. The latter one will be further established to get optically pure 1,3-butadienyl or homoallenyl phthalides controlled by metal ions. Furthermore, the synthetic utilities of the catalytic adducts to chiral natural products (3-butylphthalide and Cryphonectric acid) will be launched. Reactions and processes monitored by NMR, Mass spectroscopy, X-ray, CD, and density functional theory (DFT) calculations will be carried out to elucidate the plausible mechanism.

手性苯酞骨架广泛存在于天然产物和具有生理活性分子中，还可以继续转化为其它类化合物，因此这类结构单元的构建受到广泛关注。本项目针对高联烯基硼酸酯与羰基加成反应的区域和对映选择性合成、及苯酞结构中3-位手性季碳构建两个难题，基于我们前期在醛的不对称高联烯基化加成反应的研究基础，采用简单易得的邻酰基苯甲酸甲酯和高联烯硼酸酯作为反应原料，利用催化不对称串联反应策略，通过研究手性有机磷酸，或手性磷酸与不同种类金属络合物组成的协同二元催化剂体系的催化效果，以期实现温和反应条件下、官能团兼容性好、高效、高区域和高对映选择性催化不对称高联烯基-内酯化串联环化反应，从而发展3-位1,3-丁二烯基和高联烯基取代手性苯酞分子的合成方法，进一步实现两个手性天然产物3-丁基苯酞和Cryphonectric acid的全合成。最后还将充分使用核磁共振、质谱、计算化学等仪器、分析手段深入探讨反应机理和立体控制。

不饱和硼酸酯是一类重要的功能基引入试剂，具有毒性低、稳定性好和被活化方式多、和结构类型多样等优点，因此受到广泛研究。采用双功能手性磷酸催化剂，提高醛的亲电性和控制醛烯丙基硼基化反应的对映选择性，反应操作方便，具有优良的产率和对映选择性；由芳基、烯基或烯丙基硼酸（酯），羰基化合物和胺的三组分反应制备苄基、烯丙基或高烯丙基胺的反应，称为Petasis反应或硼基Mannich反应（因反应机理与Mannich反应类似），目前催化不对称Petasis反应的例子不多，基于简单酮的Petasis反应未见文献报道。基于这些研究背景，在该项目的资助下，我们通过不饱和硼酸酯的设计，采用串联反应策略，实现了多类手性骨架分子的构建，完成了四种天然产物的合成，通过Brønsted酸催化首次实现了简单酮的Petasis反应，为相关分子的合成提供了新思路。总而言之，我们共发表标注基金资助 SCI 论文 22 篇，其中包括Angew. Chem. Int. Ed. (2篇)，Acs Catal.，Sci. Bull.，Coordin. Chem. Rev.等影响因子大于 10 的论文 5 篇，授权专利 2 项。已超额完成原预期目标。