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Ring-Closing Alkyne Metathesis of 1,3-Diynes: Total Syntheses of Ivorenolide A and B & Studies towards the Total Synthesis of Rhizoxin D/Ringschluss-Alkin-Metathese von 1,3-Diinen: Totalsynthese von Ivorenolide A und B & Studien zur Totalsynthese von Rhizoxin D

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Ungeheuer,  Felix
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Ungeheuer, F. (2016). Ring-Closing Alkyne Metathesis of 1,3-Diynes: Total Syntheses of Ivorenolide A and B & Studies towards the Total Synthesis of Rhizoxin D/Ringschluss-Alkin-Metathese von 1,3-Diinen: Totalsynthese von Ivorenolide A und B & Studien zur Totalsynthese von Rhizoxin D. PhD Thesis, Technische Universität, Dortmund.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-60E9-9
Abstract
Ivorenolide A and B are representatives of a novel class of polyacetylenic natural products featuring a 1,3-diyne motif embedded in a macrocyclic core. Biological surveys revealed their promising immunosuppressive activity. Both compounds might serve as possible lead structures in the evolutionary process of developing novel highly active drugs. The application of the recently reported ring-closing alkyne metathesis of 1,3-diynes (RCDM) allowed the cyclization of a broad variety of acyclic 1,3-diynes. Application of this methodology culminated in the total syntheses of ivorenolide A and B. The total synthesis of ivorenolide B represented the first unsymmetrical RCDM between a terminal and a methyl capped 1,3-diyne and the total synthesis of ivorenolide A was the first cyclization of a bis-propargylic 1,3-diyne. Rhizoxin D and related family members are a class of polyketide macrolides which exhibit a wide array of interesting biological properties. A novel strategy for the total synthesis of this class of antitumor macrolides was established. The strategy relied on RCDM as the key transformation followed by a specifically developed selective conversion of the resulting 1,3-diyne to the corresponding (E,E)-1,3-diene via hydroxyl group directed trans-hydrostannation. The highly decorated macrocyclic core of rhizoxin D represented a remarkably challenging substrate for RCDM as it exhibits a multitude of oxygen functionalities as well as several sites of unsaturation and significant ring strain due to the annulated δ-lactone as well as to the (E) configured olefin. After the syntheses of both fragments and their successful assembly, the utilization of molybdenum alkylidyne complex C5 allowed the RCDM to proceed smoothly to give the cyclized 1,3-diyne. This example highlights the versatility of this transformation, rendering it a valuable alternative to established methods such as olefin metathesis.