Organocascade Catalysis
Ξ August 1st, 2009 | → 0 Comments | ∇ Cascade reactions |
Cycle-Specific Organocascade Catalysis: Application to Olefin Hydroamination, Hydro oxidation, and Amino-oxidation, and to Natural Product Synthesis
Bryon Simmons, Abbas M. Walji, and David W. C. MacMillan
Angew. Chem. Int. Ed. 2009, 48, 1 – 6
Recently MacMillan’s group disclosed the concept of organocascade catalysis, a strategy that combines two modes of catalyst activation into one mechanism, allowing the rapid conversion of simple achiral starting materials into stereochemically complex, single-enantiomer products. This strategy can also 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).
In this paper they describe the use of imidazolidinone 1 and proline 2 as a dual-catalyst system that allows access to a lot of valuable transformations, such as olefin hydroamination, hydro-oxidation, and amino-oxidation. They also report the first use of this organocascade catalysis as a strategy for natural product synthesis by the enantioselective construction of the sesquiterpene (-)-aromadendranediol.
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Imidazolidinones such as 1 have been estabilished as LUMO-lowering iminium catalyst; while they can also serve as enamine catalyst, they do not contain the necessary structural features to partecipare in bifunctional enamine catalysis. In contrast, proline 2 has been shown to be an enamine catalyst, but this amino acid is generally ineffective as an iminiumm catalst with enals or enone. The combination of imidazolidinone 1 and proline should provide a dual-catalyst system that satisfies the chemoselectivity requirements fos cycle-specific catalysis.
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The initial studies were directed on cycle-specific catalysis towards the enantioselective olefin hydroamination, olefin hydro-oxidation and reductive Mannich reaction. The experiments were performed using methylcinnamaldehyde, Hantzsch ester, two separate combinations of proline and imidazolidinone and one of the three electrophiles that are known to be susceptible to bifunctional enamine activation.
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| Reaction | Catalys Combination | Yield | ee | Syn/Anti |
|
Olefin Hydroamination |
A | 75% | 99% | 1 : 6 |
|
Olefin Hydroamination |
B | 82% | 99% | 8 : 1 |
|
Olefin hydro-oxidation |
A | 73% | 99% | 1 : 11 |
|
Olefin hydro-oxidation |
B | 62% | 99% | 10 : 1 |
| Reductive Mannich | A | 86% | 99% | 14 : 1 (dr) |
| Reductive Mannich | B | 80% | 99% | 12 : 1 (dr) |
The synthetic methodologies has been applied to the synthesis of (-)-aromadendranediol, a widely distributed sesquiterpene, by means of a triple-cascade catalysis (metathesis, iminium catalysis and enamine catalysis).