Studies On The Synthesis Of Chromene Type Natural Products And Their Analogues

Bioactive natural products as drug lead compounds have always been an important source for new drug development.However,new drug development becomes more and more difficult along with the threat of drug resistance.The study of natural products with novel structures,biological activities and unique mechanisms of action as lead compounds can greatly promote the development of new drugs.Chromene-type proanthocyanidins have unique biological activities and have broad application prospects in the fields of health food,cosmetic and medicine.Therefore,it can lay the foundation for the subsequent research on pharmacology and pharmacodynamics through the total synthesis study of this active natural products.This thesis selects chromene natural products bisflavanol,pocyanidin B and pocyanidin A with important biological activities as total synthesis target.At the same time,the synthetic method of benzopyran parent skeleton was studied based on the total synthesis of natural products.The total synthesis of bisflavanol natural products talienbisflavan A,bis-8,8′-catechinylmethane and bis-8,8′-epicatechinylmethane was achieved based on flavan-3-ol convergent coupling strategy.An efficient and highly stereoselective synthesis of tetra-O-benzyl catechin was developed using a cheap and readily available commercial caffeic acid as the raw material.The newly developed regioselective methylenation of flavan-3-ol was used as the key coupling reaction to construct the basic methylene skeleton in a single step.The inversion of the configuration of two hydroxyl groups was accomplished by the“oxidation-reduction”strategy,followed by side chain esterification,O-Bn deprotection reaction.The first total synthesis of talienbisflavan A,bis-8,8′-epicatechinylmethane and the concise synthesis of bis-8,8′-catechinylmethane was realized.The efficient and green synthesis of bisflavanol natural products and their derivatives was achieved using the acid catalyzed self-coupling reaction as the key coupling reaction.C8-methylol flavan-3-ols were synthesized from flavan-3-ols using the regioselective Vilsmeier-Haack reaction and LiBH₄ reduction.Subsequently,the dimeric products were obtained by the self-copling reaction using TfOH as the catalyst.Finaly,we obtained twenty bisflavanol natural product derivatives with different substituent groups.At the same time,four bisflavanol natural products were synthesized by removal the protecting groups.The synthesis study of relatively complex procyanidin B₁ and A₁ were conducted based on the synthesis of the before mentioned bisflavanol compounds.Asymmetric epoxidation ofα,β-unsaturated ketones and direct epoxide ring-opening of catechins were investigated.The common ring-closing precursor skeleton was synthesized by the coupling of regioselective epoxy ring opening alkoxylate with tetrabenzyl catechin under Yb（OTf）₃ catalyzed condition.The diversity synthesis of procyanidin B₁,A₁ and their diastereomers were achieved using the common intermediate.This study has set a solid foundation for the future stereoselective synthesis research.The synthetic method of the parent benzopyran skeleton was studied based on the total synthesis of chromene natural products,and a series of chromene natural products analogues were synthesized.2-（2H-chromene）-oxazoles were obtained by Sn（OTf）₂ catalyzed tandem reaction of 2H-chromene hemiacetal withα-isonitrile acetamide.After optimization of the reaction conditions,twenty representative 2-（2H-chromene）-oxazoles were synthesized to verify the substrate scope of the method.Finally,a possible mechanism of the reaction was proposed.