A large number of caryophyllene-type sesquiterpenoids have been isolated from nature. Many of them show a wide range of biological and pharmacological activities. Recently, as highly oxygenated caryophyllene-type sesquiterpenoids, pestalotiopsin A and structurally related natural products such as pestalotiopsin B and C and taedolidol have been isolated from Pestalotiopsis sp. These natural products are characterized by their highly distorted bi- to pentacyclic structures, all including a gem-dimethylated cyclobutane ring as one constituent. Recently, the first asymmetric total synthesis of both enantiomers of pestalotiopsin A was completed by the authors and coworkers, thereby clarifying the previously unknown absolute stereochemistry of this natural product. These total syntheses were achieved by the following notable synthetic concepts: (1) chiral auxiliary-based symmetric synthesis of the functionalized cyclobutane derivatives through the Lewis acid-catalyzed [2 + 2] cycloaddition between dimethyl ketene diethyl ketal and propiolamide equipped with the Oppolzer's camphorsultam and (2) an intramolecular Nozaki-Hiyama-Kishi cross-coupling mediated by a Cr(II)/catalytic Ni(II) system for high-yielding nine-membered ring formation. In this chapter, the authors also summarize their synthetic approaches toward pestalotiopsin A and related caryophyllene-type sesquiterpenoids, reported so far by Procter and coworkers and Paquette and coworkers. The Procter group has utilized the SmI2-mediated reductive 4-exo-trig cyclization for the efficient construction of the polysubstituted cyclobutane moiety. The Paquette group has demonstrated the effectiveness of the zirconocene-mediated ring contraction strategy for access to the enantiomerically pure multiply functionalized cyclobutane moiety. The highlights of their synthetic endeavors aimed at the total synthesis of pestalotiopsin A are discussed in this chapter.