Model Studies for a Ring-Closing Metathesis Approach to the Bafilomycin Macrolactone Core from a 2,2-Dimethoxy Tetraenic Ester Precursor

• Published in: European journal of organic chemistry 2013-12, Vol.2013 (36), p.8265-8278
• Main Authors: Chevalley, Alice, Prunet, Joëlle, Mauduit, Marc, Férézou, Jean-Pierre
• Format: Article
• Language: English
• Subjects: Cyclization; Macrocycles; Me­tath­esis; Natural products; Total synthesis
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201300559

A ring‐closing metathesis strategy is reported for the construction of the 16‐membered macrolactone core of the bafilomycins. One decisive key feature is the presence of a 2,2‐dimethoxyketal functionality at C‐2 that provides the required flexibility to the tetraenic ester precursor, allowing the ring‐closing metathesis reaction to take place. Three different model esters of increasing complexity were successfully subjected to the 1,3‐diene‐ene ring‐closing metathesis reaction. The best promoter for the simplest esters was the Grubbs first‐generation precatalyst. A Hoveyda–Grubbs‐type trifluoromethylamido‐containing precatalyst developed by Mauduit's group gave satisfactory results for the most complex ester. In all experiments, the 12‐Z‐configured isomer was obtained as the major product. Subsequent microwave‐promoted methanol elimination was achieved on the simplest model compound using camphorsulfonic acid (CSA) as a catalyst. Under these conditions, a E to Z isomerization of the double bond at C‐4, as well as ca. 50 % isomerization of the 12‐Z double bond into the corresponding 12‐E isomer, were observed. Thanks to the presence of a 2,2‐dimethoxyketal functionality at C‐2 of the ester precursors, models of the bafilomycin core were synthesized using a ring‐closing metathesis strategy. An indenylidene Ru complex gave the best results for the ring‐closing metathesis step on an advanced model ester. Finally, acid‐catalysed elimination of MeOH yielded the required tetraenic macrolactone.