Synthesis of Berkeleylactone A by Ring‐Closing Alkyne Metathesis

Using some straightforward alkyne chemistry and an asymmetric dihydroxylation on a dienoate, the substrate for a ring-closing alkyne metathesis (RCAM) was assembled in a few steps. After semihydrogenation of the triple bond, the resulting macrolactone was converted to berkeleylactone A through acetal hydrolysis, allylic oxidation, thia-Michael addition, hydrogenation, and ester hydrolysis. The 8,9-didehydro analog was also prepared.

Abstract

A new route to the macrolactone antibiotic berkeleylactone A was developed. As a key step, a ring-closing alkyne metathesis (RCAM) of an ester substrate featuring 1-propynyl termini was used. The carboxylic part of the substrate was easily assembled using alkyne chemistry, like carboxylation of a diyne followed by isomerization of the ynoate section to a dienoate and dihydroxylation of the 4,5-double bond. The synthesis of the alcohol part of the ester started with opening of (R)-propylene oxide with an acetylide and was followed by two triple bond migrations. After successful RCAM which formed the C8−C9 bond, the triple bond was selectively hydrogenated to the corresponding alkene before the 4,5-diol was oxidized to the 5-hydroxy-4-oxo derivative. At this stage, the thioether was formed and the 8,9-double bond reduced. We also prepared the 8,9-didehydro analog of berkeleylactone A. However, it turned out that its antimicrobial activity was slightly reduced.

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