Dearomatization is a fundamental chemical transformation, and it underlies some of the most efficient tactics for generating threedimensional complexity from basic two-dimensional precursors. The dearomative toolbox, once restricted to only a handful of reactions, has begun to grow more sophisticated as novel methods are added, introducing more functionality under milder conditions and with more control over chemo-, regio-, and stereoselectivity than ever before. Over the past two decades, major developments in dearomative processes have bolstered significant total-synthesis endeavors and greatly expanded the scope and complexity of chemical building blocks accessible from feedstock arenes. In this Perspective, we highlight some of the recent advances and key challenges that remain in this vibrant area of organic chemistry.

This review explores the strategies and tactics of effective dearomative retrosynthetic logic, illustrated through numerous outstanding examples of contemporary natural product total synthesis.

The isomalabaricanes comprise a large family of marine triterpenoids with fascinating structures that have been shown to be selective and potent apoptosis inducers in certain cancer cell lines. In this article, we describe the successful total syntheses of the isomalabaricanes stelletin A, stelletin E, and rhabdastrellic acid A, as well as the development of a general strategy to access other natural products within this unique family. High-throughput experimentation and computational chemistry methods were used in this endeavor. A preliminary structure−activity relationship study of stelletin A revealed the trans-syn-trans core motif of the isomalabaricanes to be critical for their cytotoxic activity.

The first total syntheses of (±)-rhabdastrellic acid A and (±)-stelletin E, highly cytotoxic isomalabaricane triterpenoids, have been accomplished in a linear sequence of 14 steps from commercial geranylacetone. The exceptionally strained trans-syntrans-perhydrobenz[e]indene core characteristic of the isomalabaricanes is efficiently accessed in a selective manner through a rapid, complexity-generating sequence. This process features a reductive radical polyene cyclization, an unprecedented oxidative Rautenstrauch cycloisomerization, and umpolung α-substitution of a p-toluenesulfonylhydrazone with in situ reductive transposition. A late-stage cross-coupling in concert with a modular approach to polyunsaturated side chains renders this a general strategy for the synthesis of numerous family members of these synthetically challenging and hitherto inaccessible marine triterpenoids.