Synthesis Of Strigolactone (±)-GR24 And Its Analogues

Strigolactones (SLs), isolated from the root exudates of various plants, are a class of sesquiterpene taking isoprene as the basic unit, and generally include natural striga alcohols and some synthetic analogs. Typically, natural SLs are composed of a [6.5.5] tricyclic lactone (A-, B-and C-ring) connected to a furanone (D-ring) via an enol bridge. SLs have various distinctive biological functions including stimulating the germination of root parasitic plants, inducing the hyphal branching of arbuscular mycorrhizal fungi, regulating several developmental processes in higher plants and inhibiting proliferation of tumor cells. Due to their biological functions, SLs have bright prospects in biology, agriculture and pharmaceuticals.It is very difficult to obtain SLs from natural resources because of their poor stability and low level in the soil. Moreover, due to the high complexity of the structure of natural SLs, preparation of SLs through multi-step synthesis is also confronted with many difficulties such as low yield, high cost, and small scale. In order to resolve the source problem of SLs, chemists have developed several synthetic SLs, which are simple and stable in structure but still maintain good biological activity. GR24 is the first synthetic analog of Striga Alcohol, which shows good activity in promoting the germination of root parasitic plants, inducing the branching of arbuscular mycorrhizal fungi and inhibiting the branching of higher plants. The studies on the analog of GR24 also reveal that (-)-4-OH-ep/-GR24 performs superior to GR24 in the seed germination.Several synthetic approaches to GR24 and 4-OH-GR24 have been published. Despite of various highlights and advantages, these approaches are found with some disadvantages, including having long synthetic route, using expensive reagents or enzymes etc. Thus, facile and efficient methods for the syntheses of GR24 and its analogs are still in great need.This thesis focuses on the syntheses of (±)-GR24, (±)-4-OH-GR24 and their analogs with a new synthetic strategy. We first prepared (E)-4-(2-formyl phenyl)-3-butenoic acid, a key precursor of the cascade cyclization, through a 4-or 6-step transformation from benzoic acid or phthalic anhydride. Then, using an iron-catalyzed intramolecular cascade cyclization, we constructed the ABC-tricyclic core of 4-OH-GR24. Afterwards the ABC-lactone was coupled with furatone (D ring) via an enol bridge giving the target molecular (±)-4-OH-GR24 and its epimer. By adding different mucleophiles into the ring-closure reaction system, we have also achieved the construction of the tricyclic structure and the modification of C4-position of B ring in one pot. The newly synthesized analogs not only give a simpler structure of SLs with better performance in stability, but also contribute to reveal the working mechanism of SLs in plants.The thesis contains three sections:Part 1:A brief introduction about the discovery of SLs, its bioactivity, the prospect of its application and different reactions promoted by Lewis acid Fe(III) catalysts was given. A mini review of different synthetic methods of GR24 and 4-OH-GR24 was also included in the first part.Part 2:In this part, several novel GR24 analogs with different B ring have been designed. Based on the retrosynthetic analysis, the important precursor, (±)-4-(2-formyl phenyl)-3-butenoic acid, would be prepared using phthalic anhydride or benzoic acid as starting material through a several-step modification. Then, the ABC-tricyclic core of 4-OH-GR24 would be installation from the precursor via an optimized intramolecular cascade cyclization. The tricyclic lactone would react with ethyl formate followed by 5-bromo-3-methylfuran-2(5H)-one, leading to the final desired compound (±)-4-OH-GR24. By adding different nucleophiles, the modification on the structure of B ring in position 4 would be simultaneous achieved during the acid-catalyzed cyclization process.Part 3:Part three focuses on the syntheses of target molecules. Employing our strategy, (±)-4-OH-GR24 and (±)-GR24 have been synthesized successfully. Several ABC-tricyclic lactones with different substituting group in C4-position of B ring have been acquired as well.