The world of organocatalysis

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.

 

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.

 

 

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.  

 

 

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).

 

 

Cascade Organocatalysis

Ξ December 27th, 2008 | → 2 Comments | ∇ Cascade reactions, Thiourea catalysis |

A New entry to Cascade Organocatalysis: Reaction of Stable Sulfur Ylides and Nitroolefines Sequentially Catalyzed by Thiourea and DMAP

Liang-Qiu Lu, Yi-Ju Cao, Xiao-Peng Liu, Jing An, Chang-Jiang Yao, Zhi-Hui Ming, and Wen-Jing Xiao

J. AM. CHEM. SOC. 2008, 130, 6946–6948

 

The development of new synthetic methods that would rapidly transform readily accessible starting materials into complex molecules is of considerable current interest. Recently, significant efforts have been made to develop organocatalytic cascade reactions with the objective to mimicking the biosynthetic strategy.

Sulfur ylides and nitroolefines have proven to be extremely useful reagents in organic synthesis; their reactivities and synthetic diversities provide an important platform for the development of novel cascade strategies. In this paper, the authors describe a new cascade protocol: an unprecedent reaction of stable sulfor ylides and nitroolefines sequentially catalyzed by thiourea and DMAP to afford diverse structurally complex oxazoldin-2-ones

They initially studied the reaction of sulfori ylide 1 with trans-nitrostyrene 2 in the presence of 10% mol of Takemoto’s catalyst  3: the reaction afforded anti-5-benzoyl-4-pheyloxazolidin-2-one 4 as a major isolable product (35%) with great diastereoselectivity (> 95:5) and low enantioselectivity (ee 6%). Encouraged by this result, we wxaminedthe reaction in detail under a variety of conditions. Below are shown the general reaction and catalysts used to find the best reaction conditions.

 

Among the catalyst examinated in dichloromethane, the combination of catalyst 6 and DMAP showed the highest activity for this cascade organocatalysis, while the reaction gave a complicated mixture in the absence of catalysis; with the use of 6 or DMAP alone, the reaction gave 3 in poor yields. Other catalyst combinations such as 7/DMAP, 4-5/DMAP, 6/DBU, 6/DABCO, 6/NEt ₃, were less effective.

The reaction is really general and a lot of different nitroolefines and sufur ylides can be used; in any case the oxazolidin-2-one can be obtained in high yields and dr. 

What about the mechanism? Below is shown the catalytic cycle of the reaction.

 

The cascade sequence is initiated by the addition of sulfur ylide A to nitroolefin D in the presence of thiourea catalyst C, which results in the formation of diuble H-bonding nitronate E.  Subsequent oxygen alkylation affords isoxazoline N-oxide F and regenerates the thiourea catalyst. F can be converted into oxaziridine intermediate G under the reaction condition, which then generates intermediate H, upon deprotonation of the deuterium by DMAP. The ring opening is driven by a release in ring strain that would yield nitrene L via intermediate I. Finally Hofmann rearrangement of nitrene L to form isocyanate M: this would allow for intramolecular ring closing to provide N, which then reacts with DMAP-D^₊ to afford oxazolidin-2-one and regenerates DMAP. 

A demonstration of the synthetic manipulation of the products is presented in the scheme below: the oxazolidin-2-ones can be readly converted into 1,2-aminoalcohols and hydroxyl-aminoacid.