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Advances in Alkyne Metathesis: Catalysts with Multivalent Siloxy Ligands & Formal Total Synthesis of (+)-Aspicilin & Stabilization of α-Helical Peptide Structures


Schaubach,  Sebastian
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Schaubach, S. (2016). Advances in Alkyne Metathesis: Catalysts with Multivalent Siloxy Ligands & Formal Total Synthesis of (+)-Aspicilin & Stabilization of α-Helical Peptide Structures. PhD Thesis, Technische Universität Dortmund, Dortmund.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002A-F005-1
Development of New Two-Component Alkyne Metathesis Catalysts
The last couple of years have seen considerable progress in alkyne metathesis. This development led to catalysts with remarkable activity and functional-group tolerance as demonstrated in highly advanced applications.[1] However, substrates with (multiple) protic sites still cause problems. Therefore we submitted the current catalyst generation based on Mo-alkylidynes with monodentate siloxy ligands to an extensive screening. The acquired information was then used for the design of a new catalyst generation based on multidentate siloxy ligands. We have established an efficient, scalable method to form tridentate silanols of type 3 via hydrosilylation of triolefin precursors 1 with chlorosilanes 2 and subsequent hydrolysis (Scheme 1).
The catalysts are generated in situ from the known molybdenum alkylidyne[2] 4 and silanols 3a-c by ligand exchange (Scheme 2). Gratifyingly they show excellent stability and tolerate substrates containing free alcohols and highly coordinating groups. Their potential was further underlined by the ring closing alkyne metathesis (RCAM) reaction of diynes with two protected or unprotected hydroxy groups in propargylic positions. Moreover, they enabled three natural product syntheses where other commonly used catalysts failed.

Stabilization of α-Helical Peptides Using RCAM
Hydrocarbon-stapled peptides are a promising tool for targeting challenging protein-protein interactions, that are not accessible via classic small molecule approaches.[3] One way to enforce an α-helical conformation is the introduction of an all-hydrocarbon macrocyclic bridge connecting two turns of a helix (Scheme 3).[4] To accomplish this goal a hydrocarbon tether was introduced by RCAM using immobilized precursors 5. Impressingly all (protected) functionalities present in the 20 proteinogenic amino acids were tolerated.
Additionally, we successfully accomplished the synthesis of adjacent and intertwined bicyclic peptides via tandem ring closing olefin metathesis (RCM) and RCAM reactions. In order to further functionalize the macrocyclic scaffolds the immobilized alkyne was submitted to hydration, dibromination and azide-alkyne cycloadditions, which allowed us to introduce sidechains containing biomolecules such as sugars or biotin.

Formal Total Synthesis of (+)-Aspicilin
We have demonstrated the feasibility of constructing an E,E-diene in a macrocyclic molecule within a formal synthesis (+)-Aspicilin (7). In this synthesis we found that the 18-membered macrocyclic core structure 9 could be achieved via RCAM at high reaction temperature and under strict control of the reaction time (Scheme 4). Furthermore, we applied a newly developed hydrostannylation methodology for the first time on a macrocyclic 1,3-enyne.[5] The formal synthesis of (+)-Aspicilin was completed in 14 steps with an overall yield of 10% for the longest linear sequence of ten steps.