Chemoselectivity: the mother of invention in total synthesis

Abstract

IUPAC defines chemoselectivity as "the preferential reaction of a chemical reagent with one of two or more different functional groups", a definition that describes in rather understated terms the single greatest obstacle to complex molecule synthesis. Indeed, efforts to synthesize natural products often become case studies in the art and science of chemoselective control, a skill that nature has practiced deftly for billions of years but man has yet to master. Confrontation of one or perhaps a collection of functional groups that are either promiscuously reactive or stubbornly inert has the potential to unravel an entire strategic design. One could argue that the degree to which chemists can control chemoselectivity pales in comparison to the state of the art in stereocontrol. In this Account, we hope to illustrate how the combination of necessity and tenacity leads to the invention of chemoselective chemistry for the construction of complex molecules. In our laboratory, a premium is placed upon selecting targets that would be difficult or impossible to synthesize using traditional techniques. The successful total synthesis of such molecules demands a high degree of innovation, which in turn enables the discovery of new reactivity and principles for controlling chemoselectivity. In devising an approach to a difficult target, we choose bond disconnections that primarily maximize skeletal simplification, especially when the proposed chemistry is poorly precedented or completely unknown. By choosing such a strategy--rather than adapting an approach to fit known reactions--innovation and invention become the primary goal of the total synthesis. Delivery of the target molecule in a concise and convergent manner is the natural consequence of such endeavors, and invention becomes a prerequisite for success.

Figure 1

Representative natural products synthesized in the Baran research group (2003 - 2008).

Figure 2

Oxysceptrin and nakamuric acid: natural products obtained by chemoselective oxidation of sceptrin (1).

Scheme 1

An oxaquadricyclane fragmentation leads to the first total synthesis of sceptrin (1) and an unusual cyclobutane fragmentation delivers the cyclohexyl pyrrole-imidazole alkaloids ageliferin (2) and nagelamide E (3).

Scheme 2

Enantioselective access to sceptrin and ageliferin.

Scheme 3

Incorporation of a strategically-simplifying late-stage chemoselective intermolecular oxidation facilitates the total synthesis of axinellamines A (4) and B (5), massadine (6), and massadine chloride (7).

Scheme 4

Another strategically simplifying transformation, indole-enolate oxidative coupling, provides an entry into the hapalindole and fisherindole alkaloids, including welwitindolinone A (11).

Scheme 5

A peculiar fifth ring (49) is found to undergo Norrish fragmentation, delivering the sterically crowded indole alkaloid, ambiguine H (12), which was synthesized without recourse to protecting groups.

Scheme 6

Intra- and intermolecular enolate heterocoupling in total synthesis: The stephacidin alkaloids and bursehernin.

Scheme 7

Inquiry into a revised chartelline biosynthesis leads to the discovery of a remarkable [1,5]-sigmatropic rearrangement (65→66) and an unusual, non-catalyzed decarboxylation (67→15)

Scheme 8

The discovery of an alcohol-directed gem-dihalogenation, strategic masking of functionality in a unique orthoamide steroid skeleton, and late-stage chemoselective reduction enable the synthesis of cortistatin A (16)

Scheme 9

A unique cascade sequence for forming the heterocyclic core and a pyrone Diels-Alder macrocyclization lead to a short synthesis of haouamine A (17)

Scheme 10

A new method for oxidative C-N bond formation between indoles and anilines (80→82) enables a 4-step synthesis of psychotrimine (18).