Cycle‐Specific Organocascade Catalysis: Application to Olefin Hydroamination, Hydro‐oxidation, and Amino‐oxidation, and to Natural Product Synthesis

Abstract

Keywordscascade reactions; enantioselectivity; natural products; organocatalysisThe 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.[1] Recently, our laboratory disclosed the concept of organocascade catalysis,[2-4] 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).[5] 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).[2] 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.[3a] Herein we describe the use of imidazolidinone 1[6] and proline (2) [7] as a dual-catalyst system that allows access to a greatly expanded array of valuable transformations including olefin hydroamination, hydro-oxidation, and aminooxidation. 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 LUMOlowering iminium catalysts that can be employed in a wide variety of enantioselective transformations including conjugate additions, Friedel-Crafts alkylations, hydrido reductions, and cycloadditions.[8] While imidazolidinones can also serve as enamine catalysts,[9] they do not contain the necessary structural features to participate in bifunctional enamine catalysis (wherein activation of the electrophilic reaction partner is

Multi-Bond Forming Processes in Efficient Synthesis

“…[127] The MacMillan group has demonstrated the successive use of a metal catalyst and two organocatalysts in a one-pot transformation, in the enantioselective synthesis of (À)-aromadendranediol. [128] Specifically, consecutive use of the Grubbs II catalyst, imidazolidinone 36b, and proline brought about a three component union through olefin metathesis and iminium and enamine catalysis (Scheme 20). [128,129] In the search for a library of potentially bioactive compounds, Waldmann and coworkers recently developed a three-component, one pot sequence that proceeds by a striking 12-step mechanism (Scheme 21).…”

“…[128] Specifically, consecutive use of the Grubbs II catalyst, imidazolidinone 36b, and proline brought about a three component union through olefin metathesis and iminium and enamine catalysis (Scheme 20). [128,129] In the search for a library of potentially bioactive compounds, Waldmann and coworkers recently developed a three-component, one pot sequence that proceeds by a striking 12-step mechanism (Scheme 21). [130] The sequence involves two intermolecular Michael additions and various ring-closing and ring-opening steps.…”

Evolution of asymmetric organocatalysis: multi- and retrocatalysis

“…50 While imidazolidinones are principally able to serve as iminium and enamine catalysts, they are not capable of participating in bifunctional enamine catalysis (in which activation of the electrophile is performed by the same amine catalyst). In contrast, bifunctional activation is a standard mode of activation for proline 8 (due to its acid functionality; compare Fig.…”

“…50 With 1-methylindole (29) as π-nucleophile, the corresponding arylamination products were obtained (25: 14 : 1 syn/anti, 99% ee with catalyst combination G; epi-25: 7 : 1 anti/syn, 99% ee with catalyst combination H). An alkylamination reaction cascade with silyloxyoxazole 30 (TIPS = triisopropylsilyl) as nucleophile afforded the desired product 26 with three contiguous stereogenic centers (5 : 1 d.r.…”

Organocatalysis in Total Synthesis

“…One is the synthesis of (-)-aromadendranediol via a Mukaiyama-Michael-aldol condensation, through a triple-catalysis-cycle-specific mechanism involving cross-metathesis, iminium and enamine catalysis [58]. And others more recent are the total syntheses of six well-known alkaloids (strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine) based on the combination of collective synthesis of natural products and organocascade catalysis [59].…”