The construction of seven and eight-membered carbocycles remains challenging despite their ubiquity in natural products and medicinal therapeutics, including paclitaxel.1 The Ovaska lab has developed a proven methodology that mitigates detrimental entropic and enthalpic factors via a microwave-assisted tandem 5 and 6-exo dig cyclization of 4 and 5-hexyn-1-ols followed by a [3,3]-sigmatropic rearrangement to access various cycloheptanoid and cyclooctanoid ring systems. The reaction proceeds in a stereoselective manner, and allows for the construction of various complex ring systems. However, in order to apply the reaction to the synthesis of 8-membered rings, an electron-withdrawing group must be installed on the triple bond terminus (preferably a cyano group), and could benefit from the introduction of further functionalizable handles.2 Herein, we have developed an efficient route that incorporates ketal functionalities alpha to the hydroxyl group, allowing for easy access to a,b-unsaturated ketone-incorporated eight-membered rings. This novel methodology allows for rapid and reliable access to further functionalized cyclooctanoid-containing natural products and pharmaceuticals.
(1) Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; et al. Total Synthesis of Taxol. Nature 1994, 367 (6464), 630–634.
(2) Feldman, A. W.; Ovaska, S. I.; Ovaska, T. V. Facile Access to Cyclooctanoid Ring Systems via Microwave-Assisted Tandem 6-Exo Dig Cyclization-Rearrangement Sequence. Tetrahedron 2014, 70 (27–28), 4147–4155.
Alley, Kimberly, "Utilization of the Thorpe-Ingold Effect to Access Ketal-Functionalized Cyclooctanoids via Tandem 6-exo dig Cyclization-Claisen Rearrangement" (2018). Chemistry Honors Papers. 25.
The views expressed in this paper are solely those of the author.