Cycle-Specific Organocascade Catalysis: Application to Olefin Hydroamination, Hydro-oxidation, and Amino-oxidation, and to Natural Product SynthesisFinancial support was provided by the NIHGMS (R01 GM078201-01-01), Merck, and Amgen. B.S. is grateful for a Merck predoctoral fellowship

The discovery of new strategies that emulate nature!s capacity to rapidly construct architectural complexity continues to be a central focus for research and development in the chemical sciences. Recently, our laboratory disclosed the concept of organocascade catalysis, a new chemical paradigm that combines two modes of catalyst activation (iminium and enamine catalysis) into one mechanism, thereby allowing the rapid conversion of simple achiral starting materials into stereochemically complex, single-enantiomer products (! 99% ee, Scheme 1a). As a critical design feature, we revealed that the merger of these two activation modes can render a variety of transformations that are not yet possible using monocyclic catalysis pathways (e.g. enantioselective HCl, HF, and aryl–Cl addition across olefins). Moreover, we realized the ideal of cycle-specific catalysis, wherein each cycle in the cascade sequence is moderated by a different chiral amine catalyst, a scenario that enables selective access to any product enantiomer or diastereomer by judicious catalyst selection. Our initial studies on cycle-specific catalysis employed a combination of two chiral imidazolidinone catalysts, a system that was particularly effective for olefin hydrohalogenation. Herein we describe the use of imidazolidinone 1 and proline (2) as a dual-catalyst system that allows access to a greatly expanded array of valuable transformations including olefin hydroamination, hydro-oxidation, and amino-oxidation. As a further milestone, we report the first use of this organocascade catalysis as a strategy for natural product synthesis by the enantioselective construction of the sesquiterpene (")-aromadendranediol. Over the last 10 years, imidazolidinones (such as 1) have been established as LUMO-lowering iminium catalysts that can be employed in a wide variety of enantioselective transformations including conjugate additions, Friedel– Crafts alkylations, hydrido reductions, and cycloadditions. While imidazolidinones can also serve as enamine catalysts, they do not contain the necessary structural features to participate in bifunctional enamine catalysis (wherein activation of the electrophilic reaction partner is also performed by the amine catalyst). In contrast, proline (2) has been shown to be an enamine catalyst for which bifunctional activation is a standard mode of operation across a variety of transformation types; yet, remarkably, this amino acid is generally ineffective as an iminium catalyst with enals or enones. Given these mutually orthogonal reactivity profiles, we hypothesized that the combination of imidazolidinone 1 and proline should provide a dual-catalyst system that fully satisfies the chemoselectivity requirements for cycle-specific catalysis (i.e. 1 is Scheme 1. a) Absolute and relative stereocontrol in cycle-specific cascade catalysis. b) Imidazolidinone 1 and proline (2) as catalysts. LUMO= lowest unoccupied molecular orbital, HOMO=highest occupied molecular orbital.