A critical objective for the continued advancement of the field of asymmetric catalysis is the design and implementation of novel activation modes that allow the invention of unprecedented transformations. 1 Recently, our laboratory introduced a new mode of organocatalytic activation, termed (singly occupied molecular orbital) SOMO catalysis, 2 that is founded upon the transient production of a 3π-electron radical-cation 3 species that can function as a generic platform of induction and reactivity. As part of these studies, we documented the first direct and enantioselective allylic alkylation, 2 enolation, 4 and vinylation 5 of aldehydes, three protocols that were not previously known in a chiral or achiral format. Continuing this theme, we recently questioned whether feedstock olefins, such as styrenes, might be exploited in this SOMO pathway to allow the enantioselective α-homobenzylation of aldehydes, a new C-C bond-forming reaction between functional groups that are generally inert to chemical combination. In this context, we disclose the first asymmetric SOMO-catalyzed carbooxidation of styrenes to provide γ-nitrate-α-alkyl aldehydes, a valuable synthon for the production of enantioenriched butyrolactones, pyrrolidines, and α-formyl homobenzylation adducts. Most important, this new organo-SOMO reaction allows simple styrenes to function as α-alkylation partners for aldehydes, a transformation that to our knowledge is without precedent. 6
Design PlanIn our previous SOMO catalysis studies, we exploited the capacity of the aldehyde-derived radical cation DFT-2 7 to rapidly engage electron-rich olefins that incorporate traceless activation handles (e.g., enolsilanes, allylsilanes, vinyl trifluoroborate salts). 2,4,5 A common mechanistic feature of these coupling reactions is the transient production of a β-silyl or β-borato cation intermediate that can regioselectively collapse to render an olefinic or carbonyl containing product. With this in mind, we questioned whether a simple, nonactivated olefin, such as styrene,might also undergo addition to the radical cation DFT-2 to form a benzylic
NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript radical 3 that upon further oxidation will generate a similar carbocation 4 (eq 1). As a key design element, the benzylic cation 4 cannot readily participate in an E1 elimination mechanism (the salient pathway of our previous studies) as the styrene precursor does not incorporate a β-activation/leaving group. Instead we hoped to capture the value of this high energy intermediate via intermolecular addition of an anionic or neutral heteroatom addend (e.g., NO 3 − , Cl − , H 2 O), a step that would create a second stereogenic center while increasing the relative molecular complexity of the alkylation product. In accord with our previous studies, we expected high levels of enantiocontrol on the basis that catalyst 1 should selectively form a SOMO-activated cation 2 (DFT-2) that projects the 3π-electron system away from the bulky tert-butyl group, while ...