The field of total synthesis has a rich history and a vibrant future. Landmark advances and revolutionary strides in the logic of synthesis have put the practicing chemist in the enviable position of being able to create nearly any molecule with enough time and effort. The stage is now set for organic chemists to aim for "ideality" in the way molecules are synthesized. This perspective presents a simple and informative definition of "ideality" and demonstrates its use during the self-evaluation of several syntheses from our laboratory.

Seven-membered rings fused with an indole are termed cyclohepta[b]indoles. Compounds exhibiting this structure motif display a broad spectrum of biological activities, ranging from inhibition of adipocyte fatty-acid-binding protein (A-FABP), deacetylation of histones, inhibition of leukotriene production p53, antituberculosis activities, and anti-HIV activities. These biological profiles are found in natural products containing the cyclohepta[b]indole motif, as well as in pharmaceuticals that contain this structure motif. Therefore, the biology of molecules derived from the skeleton of cyclohepta[b]indoles, as well as cyclopenta- and cyclohexa[b]indoles, has attracted considerable interest from the pharmaceutical industry as potential therapeutics in recent years. This is reflected by more than two dozen patents that have been issued in the past decade, solely based on the cyclohepta[b]indole structure motif. The efficient preparation of highly functionalized and unsymmetrically substituted cyclohepta[b]indoles has therefore become of central interest for synthetic organic chemists. Historically, this structure motif most often has been prepared by means of a Fischer indole synthesis. Although very robust and useful, this reaction poses certain limitations. Especially unsymmetrically functionalized cyclohepta[b]indoles are not suitable for a Fischer indole type synthesis, since product mixtures are inevitable. Therefore, novel methodologies to overcome these synthetic obstacles have been developed in recent years. This Account introduces all natural products and pharmaceutical compounds exhibiting the cyclohepta[b]indole motif. The structural variability within cyclohepta[b]indole alkaloids in combination with the broad range of organisms where these alkaloids have been isolated from, strongly suggests that the cyclohepta[b]indole is somehow a "privileged" structure motif. The organisms producing these compounds range from evergreen trees (actinophyllic acid) to cyanobacteria (ambiguinines). The synthetic methodologies to construct these molecular scaffolds (natural and unnatural in origin) are in turn highlighted and discussed with regard to their potential to access highly functionalized and unsymmetrical cyclohepta[b]indoles, for which they specifically have been designed. The methods are classified with respect to reaction type and whether or not they are enantioselective. Finally, the syntheses of cyclohepta[b]indole natural products are presented, thereby in each case, focusing on the construction of this structure motif in the course of the respective total synthesis. As a conclusion, we end by contrasting the methodological progress in the field with the actual successful application of the newly developed methods to the synthesis of complex structures to pinpoint the urgent requirement for further synthetic development for efficient synthetic design of this "privileged" structure motif.

Canataxpropellane belongs to the medicinally important taxane diterpene family. The most prominent congener, Taxol, is one of the most commonly used anticancer agent in clinics today. Canataxpropellane exhibits a taxane skeleton with three additional transannular C–C bonds, resulting in a total of six contiguous quaternary carbons, of which four are located on a cyclobutane ring. Unfortunately, isolation of canataxpropellane from natural sources is inefficient. Here, we report a total synthesis of (–)-canataxpropellane in 26 steps and 0.5% overall yield from a known intermediate corresponding to 29 steps from commercial material. The core structure of the (–)-canataxpropellane (2) was assembled in two steps using a Diels–Alder/ortho-alkene-arene photocycloaddition sequence. Enantioselectivity was introduced by designing chiral siloxanes to serve as auxiliaries in the Diels–Alder reaction.

Dimeric pyrrole-imidazole alkaloids represent a rich and topologically unique class of marine natural products. This full account will follow the progression of efforts that culminated in the enantioselective total syntheses of the most structurally ornate members of this family: the axinellamines, the massadines, and palau’amine. A bio-inspired approach capitalizing on the pseudo-symmetry of the members of this class is recounted, delivering a deschloro derivative of the natural product core. Next, the enantioselective synthesis of the chlorocyclopentane core featuring a scalable, catalytic, enantioselective Diels–Alder reaction of a 1-siloxydiene is outlined in detail. Finally, the successful divergent conversion of this core to each of the aforementioned natural products, and the ensuing methodological developments are described.

SummaryThis review summarizes the application of the divinylcyclopropane–cycloheptadiene rearrangement in synthetic organic chemistry. A brief overview of the new mechanistic insights concerning the title reaction is provided as well as a condensed account on the biological relevance of the topic. Heteroatom variants of this rearrangement are covered briefly.