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The sea conceals a mermaid’s grotto of useful chemicals-marine natural products of therapeutic potential. Marine sponges in particular are a rich source of natural products with structural diversity and novel biological activity. In recent times, there has been a growing interest in the synthesis of marine natural products. The present thesis entitled, “Synthesis of bioactive marine meroterpenoids: frondosins and liphagal” is an endeavor along the same lines and is organized under two parts –Part A and Part B. Part A: Studies towards the total synthesis of (±) frondosins A and B Frondosins A-E are IL-8 inhibiting marine meroterpenoids, with novel bicyclo[5.4.0]undecane framework, exhibiting anti-inflammatory and anti HIV-1 activities. A relatively simple and inherently flexible ring-closing metathesis (RCM) based strategy was employed to achieve the total synthesis of frondosins A (formal) and B in only 17 linear steps (total 13 operations) and 5% overall yield. A concise route, based on RCM, to the core structure of bioactive frondosins is amenable to ready appendage diversification and enables implementation of functionalization manoeuvres on all positions in the seven-membered ring of the bicyclic framework was also developed. A Diels-Alder strategy that led to the synthesis of 8-des-methyl norfrondosin A dimethyl ether is also delineated in Part A of the thesis. Part B: A concise synthesis of (±) liphagal Liphagal is a marine meroterpenoid displaying an unprecedented “liphagane” skeleton. It is a selective inhibitor of PI3K  and significantly toxic against a small panel of human tumor cell lines (LoVo, CaCo-human colon and MDA-468-human breast). A concise and straightforward biomimetic strategy towards liphagal and its 14-des-formyl analogue that awarded liphagal dimethyl ether in only eight steps from commercially available building blocks is described in Part B of the thesis.

Chapter One presents an overview of phosphorus reagents for the carbon homologations of aldehydes and ketones leading to functionalized carbonyl derivatives. Select examples are provided to exemplify the utility of carbon homologation methodology in synthesis and asymmetric organocatalysis and in the total synthesis of natural products. The directing effect of acetals on regioselective ylide formation is explored in Chapter Two. Evidence is presented for ylide formation through a complex induced proximity effect with lithium bases under coordinating conditions. Moreover, four-carbon donors represent a limit for useful directed ylide formation with trialkylphosphine-derived Wittig salts in carbonyl homologation reactions. A facile approach to the synthesis of methyl vinyl ketones (MVKs), using acetonyl tripropylphosphoranes under mild conditions, is reported in Chapter Three. A library of diversely functionalized MVKs was synthesized as a demonstration of the scope and generality of the methodology. The application of MVKs as substrates for organocatalysis and as building blocks for useful polyketide intermediates is briefly highlighted. In Chapter Four, the two-carbon homologation methodology that was presented in the previous chapter is applied to the synthesis of the polyketide olivetol and a series of O-methyl derivatives. Cyclic diketone intermediates were aromatized with catalytic iodine and DMSO as a terminal oxidant. Modification of the solvent system allowed for the selective synthesis of mono- or dimethyl ethers of methyl olivetolate. The selectivity of this aromatization is further explored in the final chapter with more complex substrates. Chapter Five focuses on the synthesis of the meroterpene phytocannabinoids found in Cannabis sativa. A synthetic strategy involving the sequential condensation/[3+3]-annulation of citral with cyclic 1,3-diketones synthesized in the previous chapter. This afforded non-aromatic meroterpenes that were subjected to acid-mediated thermal rearrangement and catalytic oxidative aromatization. Evidence for chemoselectivity of the aromatization methodology was demonstrated and a synthesis of methyl cannabinolate is presented. / Thesis / Doctor of Philosophy (PhD) / Methodologies for the extension of aldehydes to functionalized olefins and their application to the synthesis of cannabinolic acid methyl ester are presented.

3,5-Dimethylorsellinic acid (DMOA)-derived meroterpenoids are an extensive natural product family with significant structural complexity and diverse biological activity. Their structures feature various fused, bridged, spirocyclic skeletons and unconventional stereochemistries with significant strain, especially the trans-syn-trans fused drimane system, and extensive oxidative, skeletal rearrangements. Despite a long isolation history and extensive biosynthesis studies and encouraging biological activities, chemical synthesis of those natural products appeared only recently compared with other well-studied diterpene families such as the ent-kauranes, daphanes, and tiglianes. Thus, this thesis will present our work as an incremental advancement on the total syntheses of DMOA-derived meroterpenoids. In Chapter 1, a thorough biosynthetic relationship of DMOA-derived meroterpenoid subfamilies is reviewed and the most updated isolation and syntheses are covered with the purpose to provide the reader an understanding and appreciation of the origin of the exceptional diversity of DMOA-derived meroterpenoids. In Chapter 2, three generations of routes towards DMOA-derived spiromeroterpenoid are discussed in detail. The oxidative [3+2] cyclization approach was found to generate several complex dimers and the simplicission core. Lessons learned therein pointed to a successful strategy. In Chapter 3, a successful fragment coupling strategy culminated in a concise, modular, and collective synthesis of five spiromeroterpenoid natural products. The synthesis features a sterically hindered bis-neopentyl 1,2-addition coupling/oxidative Michael addition/MHAT reduction sequence to rapidly construct the conserved spirocycle with full stereo-control. The gateway natural product asnovolin A was secured in deca-milligram amounts which laid the foundation for chemoenzymatic synthesis of the highly oxidized spiromeroterpenoid novofumigatonin. In Chapter 4, significant progress was made towards the synthesis of the complex meroterpenoid andiconin. We developed a late stage de novo construction of the dearomatized biosynthetic precursor. A biomimetic radical fragmentation [4+2] cascade was designed to establish the highly congested [2.2.2] octane core of the natural product. / 2026-03-15T00:00:00Z

The tree and shrub species belonging to the Myrtaceae family are rich in structurally diverse meroterpenoids which possess anti-cancer, anti-malarial, anti-bacterial, anti-viral, and anti-inflammatory biological activities. Many of the natural products belonging to this family are derived from two common precursors: syncarpic acid and formyl phloroglucinol. The dissertation research described herein is focused on the total synthesis of two subclasses of natural products: syncarpic acid-derived meroterpenoids and formyl phloroglucinol meroterpenoids. The synthetic methodologies disclosed were developed to enrich the chemodiversity of these novel meroterpenoids by providing efficient access to such scaffolds and derivatives. Rhodomyrtusials A–C, the first examples of syncarpic acid-derived sesquiterpene meroterpenoids featuring a unique 6/5/5/9/4 fused pentacyclic ring system, were isolated from Rhodomyrtus tomentosa along with several biogenetically-related dihydropyran isomers. Two bis-furans and one dihydropyran isomer showed acetylcholinesterase (AChE) inhibitory activity. Herein, the bioinspired total syntheses of six isolates were achieved in six steps utilizing a reactive enetrione intermediate generated in situ from a readily available hydroxy-endoperoxide precursor are reported. Further evaluation of alkene reaction partners identified additional modes of reactivity for the enetrione, leading to the production of novel small molecule scaffolds. Furthermore, computational studies have identified a valid asynchronous, concerted pathway leading to the formation of the bis-furan containing natural products. Eucalyptusdimers A−C, three dimeric phellandrene-derived formyl phloroglucinol meroterpenoids featuring an unprecedented, fused skeleton between two phellandrene and two acylphloroglucinol subunits, along with one biogenetically related intermediate eucalyprobusone A, were isolated from the fruits of Eucalyptus robusta. These isolates also showed AChE inhibitory activity. A one-pot, three-component reaction was identified to achieve the synthesis of eucalyprobusone A and subsequent synthetic efforts towards eucalyptusdimers A and B via hetero-Diels Alder (HDA) [4+2] cycloaddition with known terpene, alpha-phellandrene are outlined. Initial efforts failed to promote the desired HDA cycloaddition, which led to alternate exploration of oxidative [4+2] cycloaddition chemistry. Using this revised strategy, the synthesis of several Eucalyptus metabolites including grandinol, euglobal IIc, and euglobal T1 was achieved. Future efforts and synthetic strategies to afford the eucalyptusdimers from these precursors are provided. / 2025-09-20T00:00:00Z