Abstract
Organic synthesis is a central theme of chemistry research and play an indispensable role in chemistry, medicine, biology, materials, and the interfaces of these disciplines. The more efficiency and greenness of organic synthesis is a long-lasting research focus and receiving more and more attentions relevant to the global challenge of sustainability. This PhD thesis, consisting of three chapters of research work, describes the development of more efficient and greener synthetic strategies and methodologies for chemical synthesis of valuable organic molecules including some structurally complex bioactive natural products.Chapter one describes the development of more efficient chemical synthesis of anthracimycins. With the rise of muti-drug resistant bacteria (surperbugs) and the fall of discovery and development of structurally new antibiotics. Marine natural product anthracimycin was reported to be a new class of macrolide compounds with novel structure and potent antibacterial activity, which has attracted extensive attentions including total synthesis. However, the only total synthesis is not efficient in terms of steps (20 steps) and overall yield (only 0.4 mg obtained by the total synthesis). This chapter presents a 10-step protecting-group free asymmetric total syntheses of anthracimycin and anthracimycin B (first total synthesis) and obtained 25 mg of anthracimycin and 14 mg of anthracimycin B. Our convergent strategy features (i) one-pot sequential Mukaiyama vinylogous aldol/intramolecular Diels–Alder reaction to construct trans-decalin skeleton with high yield and excellent endo/exo selectivity and (ii) Z-selective ring-closing metathesis to forge the 14-membered ring. In vitro antibacterial evaluation suggested that our synthetic samples exhibited excellent antibacterial potency against Gram-positive strains and MRSA biofilm. This work secures the supply of rarely accessible anthracimycins and lays the fundamental ground for further development of anthracimycins into clinically used antibiotics.
Chapter two reports the chemical synthesis of anticancer steroid natural product withanolide D. Steroids play a very crucial role on regulating the human endocrine system have been used therapeutics for treatments of many human diseases and disorders. Withanolide D was isolated in 1968 from withania sonznifera with strong antitumour activity and chemically synthesized with 21 steps. Chapter two presents the development of a a 11-step synthesis of withanolide D. Our synthetic route features (i) Diels–Alder reaction of singlet O2 with the cyclic diene to functionalize aldol/transesterification to forge the lactone with tetra-substituted alkene. Our work represents the most efficient endeavors with shortest synthetic steps, and permits supply of samples and analogues for further biological evaluation in the future.
Chapter three describes the development of one-pot oxidative coupling of arenes with arylboronic acids by merging Fenton-bromide system with Suzuki-Miyaura coupling reaction. Suzuki coupling of haloarenes with arylboronic acids was widely used in both research labs and industry. However, haloarenes needed and usually prepared by halogenation reaction, which is not only operationally risky but also produces lots of organic waste This chapter addresses this issue by developing a new oxidative coupling of arenes with arylboronic acids through merging our Fenton-bromide system with Suzuki-Miyaura reaction. This green oxidative Suzuki coupling features (1) using H2O2 as the terminal oxidant and H2O as the sole solvent (2) low cost and non-toxicity of chemical used, and (3) broad substrate scope. Inspired by our new oxidative Suzuki coupling, we further extended this conceptual method to accommodate dehydrogenative coupling with alkynes and alkenes, achieving the Fenton-bromide/ Songashira coupling and Fenton-bromide/ Heck reaction.
The last chapter is a brief summary of my PhD work.
| Date of Award | 2023 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Rongbiao TONG (Supervisor) |
Cite this
- Standard