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  Collective Total Synthesis of Casbane Diterpenes: One Strategy - Multiple Targets

Löffler, L. E. (2021). Collective Total Synthesis of Casbane Diterpenes: One Strategy - Multiple Targets. PhD Thesis, Technische Universität, Dortmund.

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 Creators:
Löffler, Lorenz E.1, Author           
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1Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445584              

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 Abstract: Terpenes are a class of secondary natural products containing a fascinating diversity of unsaturated carbon skeletons. The casbane family belongs to the macrocyclic diterpenes and exhibit various biological activities. Some casbane diterpene producing plants are used in traditional Chinese medicine. These rare metabolites have been isolated from biologically unrelated organisms all over the world. Despite their promising biological activities and their structural diversity, only preliminary biological activity studies were conducted; previous classic total synthesis approaches were limited to the simplest member, the parent casbene. Based on a modular construction of the macrocyclic diterpene framework in combination with a versatile late-stage diversification, the convergent synthesis of several family members was accomplished: in nuce One Strategy – Multiple Targets. The casbane natural product family is structurally characterised by its 14-membered unsaturated macrocycle with a fused gem-dimethyl cyclopropane, which naturally appears in all four configurations. The cis-configured cyclopropane motif was prepared enantioselectively by a rhodium catalyst-controlled cyclopropanation. The corresponding trans derivative was accessed by subsequent epimerisation. The ring-closing alkyne metathesis enabled the cyclisation towards the 14-membered macrocycle in the presence of several alkenes and the cyclopropane unit. This demonstrated the orthogonality of alkyne metathesis towards alkene metathesis. Furthermore, the tolerance towards the cyclopropane unit, which was in conjugation with the catalytically transformed C≡C triple bond, was shown for the first time. Several natural products (depressin, euphorhylonal A, and yuexiandajisu A) were obtained after subjecting the resulting macrocyclic alkynes to regio- and stereoselective semi-reductive manipulations and late-stage diversifications. This synthesis of these natural products established the versatility of the herein developed synthetic strategy. Comparison of the analytical data of the natural product euphorhylonal A with those of the synthesised diastereomers showed significant divergences. The configuration of euphorhylonal A was found to be misassigned. Using computational chemistry, the correct configuration (relative) of euphorhylonal A was predicted in high confidence and the absolute configuration was clarified by total synthesis. The successful preparation of the terpene framework enabled the synthetic approach of twice oxygenated casbane diterpenes, including a hydroxy functionality in the “southern” sector. An enantioselective bisborylation with subsequent mono-oxidation was employed to incorporate the hydroxy functionality. This introduction marked a key step towards the total synthesis of 2-epi-10-hydroxydepressin. Future investigations towards the 14-membered macrocycle and synthesis of additional casbane diterpenes are expected to demonstrate the robustness of this synthetic strategy. The successful preparation of the terpene framework enabled the synthetic approach of twice oxygenated casbane diterpenes, including a hydroxy functionality in the “southern” sector. An enantioselective bisborylation with subsequent mono-oxidation was employed to incorporate the hydroxy functionality. This introduction marked a key step towards the total synthesis of 2-epi-10-hydroxydepressin. Future investigations towards the 14-membered macrocycle and synthesis of additional casbane diterpenes are expected to demonstrate the robustness of this synthetic strategy. The preparation of the gem-dimethyl cyclopropane using the dirhodium catalyst, [Rh2(5S-MEPY)4], was first described by Doyle and co-worker. The synthesis of these important catalysts was optimised in terms of yield and practicality, following previous achievements of the group. In contrast to the [Rh2(5S-MEPY)4] catalyst, the closely related bismuth-rhodium carboxamidate complex [BiRh(5S-MEPY)4] showed no observable reactivity in cyclopropanations with diazoacetate compounds. This surprising difference in reactivity was investigated by simulating their electronic structures using a computational approach and by comparing their structures in the solid state. The geometric structures of both complexes showed dissimilar ligand orientations, forming a narrow environment at the binding site of the bismuth-rhodium complex. The computed molecular orbitals and the corresponding energy levels showed varied energetic distribution as well as a significant increase of the HOMO/LUMO gap. Furthermore, the frontier orbitals exhibit a dissimilar population at the metal centres (Figure 4). This constitution disfavours the diazo decomposition and carbene formation.

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Language(s): eng - English
 Dates: 2021-10-192021-10-19
 Publication Status: Published in print
 Pages: 231
 Publishing info: Dortmund : Technische Universität
 Table of Contents: -
 Rev. Type: -
 Identifiers: -
 Degree: PhD

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