Total Synthesis And Biological Activities Discovery Of Thaxtomin

Total synthesis of natural product has always been an effective protocol for exploring new research field and discovering new biological chemicals. Natural products Thaxtomins attracted extensive attention due to their new structural backbones and herbicidal mode of action. Thaxtomin A, the most predominant, active and structural typical member, was first isolated from potato tuber slices infected with cultures of S. Scabies in1989. It was used as a selective agent to discard scab-susceptible genotypes and thus elevate the overall levels of common scab resistance in the potato breeding populations. Furthermore, it is effective in rice fields with no phytotoxicity to rice. However, the uneconomically preparation procedure and its structure is difficult to synthesized and therefore structural modification limit the discovery and commercialization of Thaxtomin A. The most characteristic structural feature of Thaxtomin A is4-nitro-indole and C-hydroxydiketopiperazine scaffold. In fact, such C-hydroxydiketopiperazine scaffold exists in several classes of natural products. The challenge of synthesis Thaxtomin A is the construction of C-hydroxydiketopiperazine. Despite of the scattering appearance of the synthesis of C-hydroxydiketopiperazine scaffold in literature, it has never been well studied, especially on factors affecting the cyclization and stereochemistry. Thus, a facile synthetic approach to produce the C-hydroxydiketopiperazine scaffold will be most desirable for total synthesis and further structural modification of these natural products. Furthermore, the chemical synthesis may shed light on the synthesis of other natural products which bearing C-hydroxydiketopiperazine scaffold and how the stereochemical properties of chiral pesticide Thaxtomin A play a role in its biological activities, which has never been answered previously.In this work, we report a facil synthesis procedure of the C-hydroxydiketopiperazine scaffold, and the chemical properties and stereochemisdtry were well studied. The protocol provided hemiaminal product via intramolecular nucleophilic cyclization of an amide towards a ketoamide group under a concerted catalytic condition using Et3N/MgBr2·Et2O. The first total synthesis of Thaxtomin A was achieved by employing this protocol. The convenient purification procedure of Thaxtomin A from diastereoisomeric mixtures and the conversion of iso-Thaxtomin A into Thaxtomin A in situ make large scale production possible. We also prepared three other stereoisomers of Thaxtomin A through the same synthetic route. The biological test results indicated that natural product Thaxtomin A has obvious growth inhibitory activity on dicotyledon weeds B. Campestris and A. retroflexus, mirror-Thaxtomin A has simmilar anti-fungi activity as fungicide Chlorothalonil, iso- Thaxtomin A has higher anti-TMV activity than antiviral drug Ribavirin, mirror-iso-Thaxtomin A exhibited the same level of activity as Ribavirin. Futhermore, Thaxtomin A also showed excellent anti HIV-RT activity. The mouse cytokine array panel experiment showed that Thaxtomin A could stimulate or inhibit many cytokines. The excellent bioactivities and strict stereoselective properties of the four stereoisomers indicated that the C-hydroxydiketopiperazine scaffold represents a rich resource for developing new biologically active chemicals. The strategy of synthesis C-hydroxydiketopiperazine we discovered shed light on the synthesis of other natural products which bearing C-hydroxydiketopiperazine scaffold.As a continuation of our research on the discovery of their herbicidal properties, Thaxtomin C and a series of thaxtomin analogues were synthesized, and the SAR was initially studied. The bioassay results indicated that Thaxtomin A, Thaxtomin C, T-8, T-13exhibited apparently herbicidal activity, indicating these four compounds might have the potential to be developed as new herbicide for weed control of crop field. In addition, the anti-human pathogenic bacteria activities of all synthesized compounds were tested. The results showed that Thaxtomin C exhibited moderate activity, but other compounds have no activity.