Naturally Occurring Cyclobutanes: Their Biological Significance and Synthesis

Although naturally occurring cyclobutanes have been known for a century, until a few decades ago nearly all were limited to a some hydrocarbons such as α- and β-pinene, caryophyllene, or simple derivatives of these. However, with the development of more sophisticated analytical and spectroscopic techniques, the isolation and structural characterization of new compounds have resulted in a large growth of known cyclobutane derivatives both simple ones and some being rather complex having the cyclobutane moiety as part of their structure. The biological significance of several of these is now known, but for others more thorough studies are desired, necessitating syntheses of these since they are found only in minute amounts. Originally photoaddition reactions were used for the synthesis of the cyclobutane moiety. In the mid-60s separate groups found different methods for the easy formation of dichloroketene in situ together with alkenes, making these methods a thermal alternative. However, although both the photoaddition and ketene addition methods may be efficient methods for their use, they also have some severe limitations. For these reasons and due to the wealth of new cyclobutane compounds a quest for alternative methods is always in demand. In this review isolation, structural elucidation, and some biological activities will be reported. Syntheses, including some new methods for the syntheses of cyclobutanes, will also be mentioned. To limit the scope of the review, terpenes whose structures have been well known prior to approximately 2000 are not accounted for. These include compounds such as α- or β-pinene, copaene, caryophyllene, longipinene, and their most simple derivatives. Only a few leading references are included herein. Readers interested in these compounds can find reviews covering them elsewhere.