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Synthesis and Molecular Editing of Callyspongiolide, Part 1: The Alkyne Metathesis/ trans ‐Reduction Strategy
Author(s) -
Mata Guillaume,
Wölfl Bernhard,
Fürstner Alois
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201804987
Subject(s) - alkyne , reduction (mathematics) , metathesis , chemistry , combinatorial chemistry , computer science , organic chemistry , catalysis , mathematics , polymerization , polymer , geometry
A path‐scouting investigation into the highly cytotoxic marine macrolide callyspongiolide is reported that capitalizes on the selective formation of the C10−C11 alkene site. While the closure of the macrocycle by ring closing alkyne metathesis (RCAM) with the aid of a molybdenum alkylidyne complex was high yielding, the envisaged semi‐reduction of the cycloalkyne to the corresponding E ‐alkene proved challenging. The reasons are likely steric in origin, in that the methyl branches on either side of the alkyne seem to prevent effective coordination of the substrate to the ruthenium catalyst, which must carry a bulky Cp* ligand to ensure high trans ‐selectivity. This notion is supported by the preparation of a callyspongiolide analogue, in which the two methyl groups in question are excised; its formation by RCAM followed by trans ‐hydrostannation/proto‐destannation was straightforward. In parallel work the formation of the fully functional building block 54 showed that the presence of an unprotected ‐OH group allows even hindered substrates to be processed: the protic group adjacent to the triple bond engages with a chloride ligand on the ruthenium catalyst in hydrogen bonding and hence assists in substrate binding. Moreover, the preparation of an alkynylogous callyspongiolide analogue is described.