Abstract
The union of two powerful transformations, directed C-H activation and decarboxylative cross-coupling, for the enantioselective synthesis of vicinally functionalized alkyl, carbocyclic, and heterocyclic compounds is described. Starting from simple carboxylic acid building blocks, this modular sequence exploits the residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult to prepare. The tactical use of these two transformations accomplishes a formal vicinal difunctionalization of carbon centers in a way that is modular and thus, amenable to rapid diversity incorporation. A simplification of routes to known preclinical drug candidates is presented along with the rapid diversification of an antimalarial compound series.
Highlights
Starting from simple carboxylic acid building blocks, this modular sequence exploits the residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult to prepare
As the most ubiquitous functional group in organic chemistry, carboxylic acids and their derivatives have naturally risen to the top in terms of directed C–H functionalization reactions available to the practitioner (Fig. 1A) [25,26,27,28,29]
We present a strategy for the net vicinal difunctionalization of cyclic and acyclic systems via sequential functionalization initiated by stereoselective C–H activation followed by decarboxylative cross-coupling to form a variety of C–C and C–X bonds, including aryl [42, 43], alkenyl [44], alkynyl [45], alkyl [26, 46], and boryl [47, 48]
Summary
The recent development of robust methods to decarboxylate such systems and programmably replace them with new C–C and C–B bonds in a stereochemically predictable way, a formal type of C–C activation, opens opportunities to leverage the power of carboxylate-directed C–H activation chemistry. This combination of one- [32] and two-electron disconnections would enable pathways to potentially valuable chiral acyclic building blocks, such as 3, that could be considered “retrosynthetically opaque,” as it is not immediately apparent how a simple building block, like 3-(3-bromophenyl) propanoic acid [4], could be used as its precursor (Fig. 1B) [33]. Application to a promising series of heretofore inaccessible azetidine-based antimalarial agents is disclosed
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