天然白藜芦醇低聚物的不对称仿生合成

Oligostilbenes, a class of plant polyphenols, are formed in nature by oxidative oligomeriztion of resveratrol and its derivatives catalyzed by enzymes and have received considerable attention of synthetic chemists on account of their structural complexity and diverse biological activities. The research efforts on these oligomers over the past thirty years have achieved dramatic success and were mostly focused on the synthesis of their racemates. A quick access to the skeletons of most oligostilbenes is the coupling reactions of stilbene precursors under various oxidative conditions. Thus the regio- and stereo- selective oxidative coupling reaction will be applied in this project towards the asymmetric biosynthesis of several resveratrol oligomers. Our biosynthetic strategies are as follows: the tert-butyl positional protecting groups were firstly introduced to resveratrol monomers to impede the unexpected coupling modes and increase the yields of desired coupling products. Then different chiral auxiliary groups were introduced in the above precursors to realize asymmetric induction in the coupling reactions. The diastereoisomeric coupling products obtained were subjected to a series of deprotection reactions and necessary structural modifications to finally synthesize several optically pure resveratrol dimers. In addition, we will employ several chiral copper-amine complexes to catalyze the asymmetric oxidative coupling reactions of achiral resveratrol precursor so as to explore the chiral catalyst applicable for the asymmetric biosynthesis of oligostilbenes. The synthetic strategy in this project effectively overcame the disadvantages of traditional oxidative coupling reaction in the synthesis of oligostilbenes and was expected to prepare several optically active natural resveratrol oligomers in relative high yields so as to promote the development of this kind of innovative drugs.

二苯乙烯低聚物是由白藜芦醇及其衍生物在生物酶作用下相互偶合而形成的一类多酚化合物，因其结构复杂且生物活性多样而受到广泛关注，但目前大多局限于消旋物的合成。氧化偶联反应是构建二苯乙烯低聚物骨架最快捷的途径之一，本项目拟采用区域及立体选择性的氧化偶联反应合成策略，开展对几种白藜芦醇二聚物的不对称仿生合成研究。通过在白藜芦醇单体中同时引入叔丁基位置保护基与手性辅助基团, 实现偶联反应的区域及立体选择性控制。非对映异构的偶联产物经脱保护基反应及必要的结构修饰，有望合成结构多样的白藜芦醇二聚物。本项目还拟研究手性铜-氨配合物催化的白藜芦醇衍生物的不对称氧化偶联反应，探索适用于二苯乙烯类化合物氧化偶联反应的手性催化剂。本项目能有效克服传统氧化偶联方法合成二苯乙烯低聚物时的产物组成复杂、产率低且缺乏区域及立体选择性的缺点，可望以较高产率合成高光学纯度的天然白藜芦醇低聚物，以推动该类创新药物的发展。

二苯乙烯低聚物是由白藜芦醇及其衍生物在生物酶作用下相互偶合而形成的一类多酚化合物，因其结构复杂且生物活性多样而受到广泛关注，但目前大多局限于消旋物的合成。氧化偶联反应是构建二苯乙烯低聚物骨架最快捷的途径之一，本项目采用区域及立体选择性的氧化偶联反应合成策略，开展对几种白藜芦醇二聚物的不对称仿生合成研究。通过在白藜芦醇单体中引入不同的位置保护基，同时引入适当的手性辅助基团, 以期实现偶联反应的区域及立体选择性控制。在项目实施中，考察了叔丁基取代的乙酰化白藜芦醇在氧化偶联反应条件下的二聚产物结构及其在脱保护反应中形成的非天然白藜芦醇二聚物。深入研究了卤代白藜芦醇或溴代异丹叶大黄素单体在各种氧化条件下的偶联产物，并通过脱除二聚中间体上的卤素位置保护基，最终合成多种结构类型的天然二苯乙烯低聚体。另外以手性白藜芦醇仲丁基醚或溴代白藜芦醇仲丁基醚为偶联前体，分别探索了它们在酶催化下的氧化偶联反应，并通过脱除偶联产物中的各类保护基，合成了具有显著光学活性的二聚产物，为本项目拟定的研究目标的深入开展打下良好的基础。最后还考察了两种α-氰基白藜芦醇类单体的氧化偶联产物，探究双键上的氰基对自由基偶联反应的影响，合成了几种氰基取代的白藜芦醇二聚物。本项目通过在单体中引入不同类型的保护基，提高了偶联反应的区域及立体选择性，有效克服了传统氧化偶联方法合成二苯乙烯低聚物时的产物组成复杂、产率低等缺点，以较高产率合成了数十种结构多样的二苯乙烯二聚体，并在高光学活性的天然白藜芦醇低聚物的不对称仿生合成方面做了有益的探索，取得了有价值的阶段性成果，为该领域研究的深入开展提供了很好的借鉴性。