Ireland-Claisen rearrangement of cyclopentanecarboxylates and studies directed toward the total synthesis of subergorgic acid

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Yin, Jiandong

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The purpose of this project is to explore the Ireland-Claisen rearrangement of five-membered ring ester substrates, and its application to the total synthesis of subergorgic acid. Previous investigations by the Gilbert group showed that alkenyl 2-methylcyclopentanecarboxylates and alkenyl 2- methoxycyclopentanecarboxylates undergo the rearrangement with complete refacial selectivity for the former, whereas the facial selectivity was mostly lost for the latter. The current studies confirmed these results and additionally demonstrated excellent diastereoselectivity in the rearrangement of the substituted alkenyl 2-methylcyclopentanecarboxylates. The high stereoselectivity is attributed to high diastereoselectivity in the formation of kinetic enolates from substrate esters, followed by [3,3]-sigmatropic rearrangement preferentially through a chair-like transition state. The high diastereoselectivity of this type of Ireland-Claisen rearrangement served as the fundamental basis of our approach to the synthesis of subergorgic acid, and in practice effected the stereochemical control for four out of the total of five asymmetric centers present in the molecule. The subsequent construction of rings A and C of subergorgic acid was attempted through several strategies, but each met with obstacles. Although most of these were overcome, it was not possible to accomplish the desired goal largely because of steric factors. Although our intended approach did not provide a short, viable route to the total synthesis of subergorgic acid, it did afford valuable insights regarding the IrelandClaisen rearrangement in five-membered ring systems. The formation of spirocompounds from both sterically and stereoelectronically demanding systems as seen in this work has the potential to serve as a general strategy for synthesis of such sub-units in both natural and unnatural products.




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