Cyclobutanes in organic synthesis: Lewis acid-promoted ketene-alkene [2+2] cycloadditions, total synthesis of gracilioether F, and collaborative total synthesis of hippolachnin A.

摘要

Cyclobutanes are found in >2000 natural products, can be used in a variety of transformations, and serve an important role in medicinal chemistry as conformationally rigid structures and as bioisosteres. To provide access to functionalized cyclobutanes, we have developed Lewis acid-promoted ketene-alkene [2+2] cycloadditions for both mono- and disubstituted carbon ketenes. These reactions offer a number of advantages compared to thermal variants which include: increased reactivity, increased stereoselectivity, and in some instances, altered diastereoselectivity. This reaction has been studied both experimentally and computationally. The utility of these methods was highlighted in the first total synthesis of gracilioether F, a complex natural product.;A closely related cyclobutane-containing natural product, hippolachnin A was synthesized using a quadricyclane [2+2+2] cycloaddition. The use of quadricyclane allows for the formation of five of the six stereocenters present in hippolachnin A, and represents the first application of quadricyclane to natural product synthesis.