Natural products are the most important source of active biological products. This chapter presents some of the most relevant synthesis of natural products that contain spirocyclic motifs. It focuses on (+)-calafianin, pseurotin A, -ushikulide A, -acutumine, and spirotryprostatin. Porco's research group designed a total synthesis process in which the key step was asymmetric nucleophilic epoxidation. Hayashi et al. reported a total synthesis of pseurotin A using an acid-catalyzed hemiacetalization, followed by dehydration as key steps for the creation of the spirocenter. Osada et al. obtained spirotryprostatin B from the fermentation broth of the fungus Aspergillus fumigatus in 1996. Spirotryprostatin B is an extremelycomplex alkaloid that appears to arise biosynthetically by phenylation of a diketopiperazine derived from tryptophan and proline. These synthesesare important examples of how organic synthesis has evolved and improved to overcome the structural challenges presented by natural products. © 2022 John Wiley and Sons, Inc. All rights reserved.