Abstract
The polycyclic cembranoids and norcembranoids are a large family of diterpenoids isolated from soft corals, which are believed to originate from the macrocyclic furanocembranoids through the biosynthesis in marine organisms. These macrocyclic and polycyclic natural products feature interesting carbocyclic skeletons including a furan heterocycle or its dearomatized moiety between C3−C6 and a butenolide moiety encompassing C10−C12−C20. Due to their unique structures as well as the promising bioactivities they displayed, numerous synthetic chemists made a variety of efforts towards the traditional synthesis and biomimetic synthesis of members of the cembranoids and norcembranoids family. Meanwhile, computational chemists have taken theoretical approaches to provide different perspectives.This thesis describes our studies on the biosyntheses of several novel polycyclic diterpenes including mandapamate, isomandapamate, rameswaralide, plumarellide, ineleganolide and sinulochmodin C, from macrocyclic precursors, e.g., bipinnatin J and deoxypukalide, through density functional theory (DFT) calculations. This thesis contains seven chapters: research background (chapter 1), fundamentals in quantum chemistry (chapter 2), our research outcomes (chapter 3−6) and conclusion (chapter 7).
Chapter 1 introduced the background of related marine natural products including isolation, structures, synthetic attempts and computational studies. Chapter 2 gave a preliminary introduction to the fundamentals in quantum chemistry. In the next four chapters, we provided detailed computational studies. In Chapter 3, DFT (B3LYP-D3(BJ) and ωB97X-D) calculations have been used to assess the stereochemical outcomes of the proposed biosynthetic pathways of mandapamate and isomandapamate. Our calculations revealed that the topological shift between macrocyclic conformers is vital in controlling the stereoselectivity of the downstream steps towards the isomeric mandapamates. A stepwise 4+2 type process is energetically favored over a concerted [4+2] pathway and is consistent with the stereochemistries found in the natural products. In Chapter 4, DFT (M06-2X and ωB97X-D) calculations showed that the biosynthesis pathway to the complex fused-ring system in rameswaralide involved with a [4+3] transannular cyclization from a macrocycle polyene intermediate is highly possible. Meanwhile, an alternative pathway by a [4+2] cycloaddition including an alpha-ketol rearrangement step became untenable. The following ring opening of the cyclic hemiketal intermediate and the topological shift between the macrocyclic polyene conformers are critical steps leading to the thermodynamically favored isomer of rameswaralide. In Chapter 5, DFT (M06-2X and ωB97X-D) calculations are in line with the experimental observations which revealed that the pathways towards the anticipated plumarellide-based ring system are energetically unfavorable. In addition, the structure difference between the final polycycles is theoretically explained by the DFT calculations. Our calculations also suggest that synthesizing a macrocyclic precursor with trans-double bond at C13 and C14 would be preferred. In Chapter 6, DFT (M06-2X and ωB97X-D) calculations revealed that two of the four potential pathways towards the formation of the polycyclic C19-norcembranoids ineleganolide and sinulochmodin C are energetically favored, whose mechanism involved with two-step transannular Michael reactions under basic condition. Our calculations are in line with Pattenden’s synthetic work and give credence to the proposed biosynthesis speculation from 5-episinuleptolide to ineleganolide and sinulochmodin C. Chapter 7 draws a conclusion of the above work.
| Date of Award | 15 Oct 2025 |
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| Original language | English |
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| Supervisor | Bencan Tang (Supervisor), Jonathan D. Hirst (Supervisor) & Michael J. Stocks (Supervisor) |