Studies On The Total Synthesis Of Chromanone Natural Products

Chromanones and its derivatives are widely distributed in many natural products, including monomeric and dimeric chromanone lactones, tetrahydroxanthones, Elaeocarpines and so on. These natural products have many biological activities such as anti-inflammatory, antibacterial, antifungal activity etc.Therefore, the total synthesis of these natural products has been much concerned by organic synthesis chemists. In this paper, as a guide, our specific research work begins from the total synthesis of these natural products. The main contents include the following three chapters.Chapter 1 Research overview of chromanone lactone natural productsIn this chapter, we turn first to review the isolation, structural characteristics and biological activity of these chromanone lactone natural products, as well as recent total synthetic research stating from organic synthetic chemists. On the basis of analysis of chromanone lactone core skeleton structure, we proposed a strategy and direction of total synthesis study of such natural products.Secondly, Microdiplodiasone was chosen to be representative molecule, and then we designed and attempted three different synthetic routes in its total synthesis research: 1) asymmetric IOM route catalyzed by chiral thiourea; 2) asymmetric IOM route induced by chiral sulfoxide; 3) Michael addition route of FOTMS to 2-methyl chromone derivatives. Three key precursors 1-118, 1-128 and 1-119’ were synthesized. We know the fact that 2-methylchromone have lower activity. These laid a foundation for the follow-up work.Chapter 2 Michael addition reaction of FOTMS to chromone and its application in the total synthesis of chromanone lactone natural productsFirst, we were to review briefly the research overview of Michael addition reaction of chromone and FOTMS, respectively. We then explored and developed a general strategy for the construction of 2-γ-lactone chromanone skeletons via a TMSI-promoted Michael addition of FOTMS to chromones. This protocol has a high yield(55%-94%) and diastereoselectivity(1:1-20:1) and broad substrate scope, including chromone, thiochromone and quinolone and tolerates a large range of functional groups.Secondly, the applicability of this sequence is demonstrated through the efficient total syntheses of(±)-Lachnone C(7 steps 24.4% overall yield),(±)-Microdiplodiasone(5 steps 29.7% overall yield),(±)-Blennolide C(5 steps 21.6% overall yield), and(±)-Gonytolide C(5 steps 35.7% overall yield) and G(7 steps 30.1% overall yield), and formal total synthesis of(±)-Diversonol. Compared with the previously reported synthetic routes of these natural products, we greatly reducing the synthetic steps to improve the efficiency of synthesis.We further explored the total synthesis of dimeric chromanone lactone Gonytolide A, which was based on the strategy of the double Michael addition of FOTMS to bischromone. We first builded a critical bischromone compound 2-80, then synthesized the precursor compound 2-88 of target molecule using the above method.At last, a attemption to build chiral centers of chromanone skeleton in the 2-position and the γ- position of lactone ring has been carried out through a organic catalytical asymmetric Michael addition of FOTMS to chromone. Specific research work includes the following five parts: 1) Michael addition reaction catalyzed by chiral thiourea; 2) Michael addition reaction catalyzed by cinchona catalyst; 3) Michael addition reaction catalyzed by cinchona PTC catalyst; 4) Michael addition reaction catalyzed by iodonium ion; 5) Michael addition reaction of double catalytic activation with silicon-based Lewis Acid and chiral Lewis Base.The chiral thiourea catalyst, cinchona catalyst, cinchona PTC catalyst for the Michael addition reaction of FOTMS to chromone is invalid. The addition reaction catalyzed by iodonium ion has a high yield, but no enantioselectivity. While Michael addition reaction of double catalytic activation with silicon-based Lewis Acid and chiral Lewis Base can be made up to 78% yield, 24% ee value. These findings established a solid foundation for us to further accomplish asymmetric total synthesis of lactone chromanone natural products. At present, we are still trying to carry out this part of the work.Chapter 3 Study on the total synthesis of ElaeocarpineIn this chapter, we turn first to review the isolation, structural characteristics and biological activity of Elaeocarpines natural products and recent total synthetic research state. On the basis of analysis of Elaeocarpine alkaloids core tetracyclic skeleton structure, we proposed and designed a strategy established on the basis of catalytic asymmetric three-component Michael-Imino-Aldol one-pot reaction to construct such a key total synthesis precursor of these natural product.We designed a simple and efficient three-component tandem reaction route in the total syntheses of Elaeocarpine and Isoelaeocarpine. The key precursor 5-methyl-chromone 3-23 and halogenated sulfinimine 3-27 and 3-29 have been synthesized. Then three-component Michael-Imino-Aldol model reaction has been achieved in the form of one-pot reaction, and expected key precursor 3-47 has also been synthesized simultaneously. we are still trying to carry out the cyclization reaction in late stage.