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(+)-Phomopsolide C

A short total synthesis of (+)-Phomopsolid with the key steps chemoselective CM and RCM.

Ring-size selective RCM and chemoselective CM as key bond forming reactions in the total synthesis of (+)-Phomopsolide C The phomopsolides belong to a series of related 6-substituted 5,6-dihydro-5-hydroxypyran-2-ones and are a new class of natural products possessing an effective antiboring/antifeeding activity against the elm bark beetle, which is responsibe for Dutch elm disease. In our approach to phomopsolide C, a ring-size selective ring closing metathesis (RCM) and a highly regio- and chemoselective cross metathesis (CM) comprised the key bond-forming reactions. To allow for flexibility in our synthetic plan, we envisaged two pathways to phomopsolide C. Pathway A was based on a tandem RCM/CM. Selectivity in this conversion would require RCM to occur first, giving exclusively the six-membered ring with only one pendant double bond available for CM. In pathway B, CM and RCM occur in separate steps to provide an 8-substituted precursor for RCM. Model studies on the ring closing behaviour have shown that we are able to control the size selectivity of the RCM by altering the electronic environment of double bonds. Finally, it was the electron withdrawing side chain of the natural product precursor which controlled the reaction outcome, directing the metathesis to the sterically less hindered, more electron rich double bond, forming exclusively the desired six membered ring, according to pathway B. Selectivity in CM was obtained by tuning the relative steric environments of the double bonds. Using the Hoveyda-Blechert catalyst, CM yielded exclusively the desired regioisomer in 89% with PG´ being the trityl group. Using the optimised model study conditions, RCM proceeded in 68% to give the six membered ring, which after esterification and trityl removal gave (+)-phomopsolide C. In conclusion, we have developed an efficient and practical synthetic route to (+)-phomopsolide C, which is easy to carry out and involves the use of easily accessible starting materials.

S. Michaelis, S. Blechert, Total Synthesis of (+)-Phomopsolide C by Ring-Size Selective Ring-Closing Metathesis/Cross-Metathesis, Org. Lett. 2005, 7, 5513-5516. [DOI]

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