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

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.