American Chemical Society
ja9b12239_si_003.cif (7.01 MB)

Enantioselective C–H Lactonization of Unactivated Methylenes Directed by Carboxylic Acids

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posted on 2020-01-09, 14:38 authored by Marco Cianfanelli, Giorgio Olivo, Michela Milan, Robertus J. M. Klein Gebbink, Xavi Ribas, Massimo Bietti, Miquel Costas
The formidable challenges of controlling site-selectivity, enantioselectivity, and product chemoselectivity make asymmetric C–H oxidation a generally unsolved problem for nonenzymatic systems. Discrimination between the two enantiotopic C–H bonds of an unactivated methylenic group is particularly demanding and so far unprecedented, given the similarity between their environments and the facile overoxidation of the initially formed hydroxylation product. Here we show that a Mn-catalyzed C–H oxidation directed by carboxylic acids can overcome these challenges to yield γ-lactones in high enantiomeric excess (up to 99%) using hydrogen peroxide as oxidant and a Brønsted acid additive under mild conditions and short reaction times. Coordination of the carboxylic acid group to the bulky Mn complex ensures the rigidity needed for high enantioselectivity and dictates the outstanding γ site-selectivity. When the substrate contains nonequivalent γ-methylenes, the site-selectivity for lactonization can be rationally predicted on the basis of simple C–H activation/deactivation effects exerted by proximal substituents. In addition, discrimination of diastereotopic C–H bonds can be modulated by catalyst design, with no erosion of enantiomeric excess. The potential of this reaction is illustrated in the concise synthesis of a tetrahydroxylated bicyclo[3.3.1]­nonane enabled by two key, sequential γ-C–H lactonizations, with the latter that fixes the chirality of five stereogenic centers in one step with 96% ee.