We previously reported a new and an effective method for the construction of eight- to twelve-membered ketones by ring closure. The present method was developed with an intention of synthesizing natural products involving medium-membered ring system. As the first application of the method to medium-membered natural products synthesis, we report here the syntheses of (±)-isocaryophyllene (1) and (±)-caryophyllene (2) having unsaturated nine-membered ring. When the mesylate 9 (R=Ms) prepared from 3 was treated with t-BuOK in t-BuOH, demasking of the thiol protecting group and the concomitant cyclization took place and the thirteen-membered lactam sulfide 10Z was obtained in 56% yield. The LDA-promoted intramolecular cyclization of the corresponding sulfoxide 11Z afforded the nine-membered keto sulfoxide 12Z in quantitative yield. Epimerization of the ketone 13 derived from 12Z at C_1-position, followed by the Wittig reaction produced (±)-isocaryophyllene (1). On the other hand, (±)-caryophyllene (2) was stereoselectively synthesized starting from the cyclobutene 14. Treatment of the sulfone 25 having the desired trans-substituents on the cyclobutane ring with the E-chloride 28E prepared from the thiocarbamate 26 afforded 29 and the subsequent cyclization of 34 derived from 29 with t-BuOK in t-BuOH followed by oxidation afforded the lactam sulfoxide 35. In the same way as described in the synthesis of 1, (±)-caryophyllene (2) was successfully synthesized from 35 through intramolecular cyclization.
