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Studies Towards a Second-Generation Synthesis of the Aplyronines 10.17863/CAM.13755 Anzicek, Nika Paterson, Ian The aplyronines are a family of 24-membered macrolides of polyketide origin, isolated from the Japanese sea hare Aplysia kurodai. They exhibit an exceptional biological activity profile, acting through an actin and tubulin dual-targeting mechanism, with subnanomolar growth inhibitory potency against a diverse range of cancer cell lines. These characteristics render the aplyronines ideal payloads for antibody-drug conjugates but their prohibitively low natural abundance calls for an efficient total synthesis to overcome the supply issue. This dissertation describes the efforts towards developing a second-generation Paterson synthesis of the macrocyclic core of the aplyronines, focused on improving the scalability and selectivity of key transformations. Chapter 1 details the isolation, biological background and previous synthetic efforts towards the aplyronines to illustrate their therapeutic potential and the challenges associated with material sourcing by chemical synthesis. Chapter 2 presents the existing body of work on the aplyronine project within the Paterson group, highlighting the lessons learned over the past two decades and shortcomings to be addressed. Chapter 3 discusses a revised protecting group strategy towards the C1-C27 macrocyclic alcohol 159 with fewer manipulation steps. A refined reaction sequence featuring titanium aldol methodology and an enzymatic desymmetrisation process delivered multigram stocks of the C15-C27 aldehyde 161 upon scale- up, testifying to the robustness of the devised route. Synthesis of the C1-C14 northern fragment 253 closely followed the existing boron aldol approach with optimisation of the C11-C12 alkylation step, geared towards enhancing the regioselectivity. Chapter 4 describes the coupling of the two major fragments using an Horner-Wadsworth-Emmons reaction to assemble the C1-C27 backbone of the cyclic aplyronine core and suitably adjusted endgame steps to enable a one-step oxidative unmasking of the macrolactonisation sites. The first-generation intermediate 159 was accessed via site-specific Yamaguchi esterification and orthogonal deprotection of the C27 allyl carbonate. Discussion in Chapter 5 includes the appendage of the C28-C34 side chain 118, prepared by the known sequence, and suggestions for the future direction of the second-generation route with the outlook of linker appendage for the purposes of antibody-drug conjugate development. University of Cambridge 2017-10-03 Thesis Doctoral Doctor of Philosophy (PhD) en Public Scholarship, Development, Disability and Maintenance Fund of the Republic of Slovenia https://www.repository.cam.ac.uk/handle/1810/267831 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/1c5d3de5-bb76-4fa4-8845-f75dd0db836d/download 87eda9de84448d1f82354d60eee3eb5f https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d300970b-8cda-498f-987b-ffb522249888/download 0f1cf2b1e1ca9b2069d997aefa8331ca https://www.rioxx.net/licenses/all-rights-reserved/ Organic Chemistry Total Synthesis Retrosynthesis Protecting Groups Aldol Reactions Aplyronines Marine Natural Products Cancer Treatment Antibody-Drug Conjugates