Cascade Reaction

What we can do in Asymmetric Organocatalysis except to design catalysts based on the enamine, iminium mechanism or explore the potential of chiral phosphoric acid? The answer might be Cascade Reactions. That is an unexplored field in organocatalysis except some recent papers published by List, Terada and Wang.

Early this year, List reported an amazing reaction which combined enamine catalysis, iminium catalysis and Bronsted acid catalysis to form cyclohexylamine.1 The amine substrate and the catalytic amount of chiral phosphoric acid both act as catalysts. The first step of the reaction is the intramolecular Aldol reaction catalyzed by the substrate amine. The Aldol product is then dehydrated to form a C-C double bond which is then reduced by Hanztsch ester through an iminium catalysis. During the reduction, the chiral phosphoric acid form an " ion pair" with the iminium to provide stereo-control. Then the C-N double bond is reduced by Hanztsch ester catalyzed by the chiral phosphoric acid.

Later, Terada using their chiral phophoric acid catalyzed a tandem aza-ene/cascade cyclization reaction.2 The chiral phosphoric acid can catalyze two aza-ene reaction sequencely to generate two chiral center. Then the intramolecular cyclyzation can produce the third chiral center induced by the substrate chirality. Though not so elegant as List's work, the efficiency of the reaction is very satisfactory, with only 2 mol % of catalyst loading the reaction can finish in 30 mins.

Very recently, Wang reported their very comprehensive work on the asymmetric cascade Michael-Alkylation reaction.3 This is another well designed cascade reaction. The key for the reaction is the selection of a suitable substrate which can act both as a nucleophile for the Michael Addition step and electrophile for the subsequent Alkylation step. Bromo-malonate seems to be the best of the choice. The reaction starts with a iminium catalyzed Michael Addition and followed by a enamine catalyzed alpha-alkylation, affording the cyclopropane, a very important and yet difficult to generate product, in very high yield, diastereoselectivity and enantioselectivity. Fantastic, isn't it?

After posting this post, I found an article in Chemistrys wrold titled " At the top of the cascade". It's really a good article on organocatalysis and as you can see in the article, MacMillan used the term " Organocascade". I believe in the near future there will be a pile of papers on the so called "Organocascade" reactions. Organocatalysis is beginning to change from improving the exsiting reactions to create something new. Though I have quit this hot field, I just feel relieved. The competition in this field might drive you crazy.

Hydrogen-Mediated C-C Bond Formation

In the last group meeting I presented Krische's work on the hydrogen-mediated C-C bond formation. Krische winned the 2007 Presidential Green Chemistry Challenge Awards for their development of this methodology. In his 2007 JOC perspective he introduced the orgin of this kind of reaction and reviewed their work on this reaction. Although they are not the first to do this kind of reaction(Molander and Miura have reported this kind of in 1992(JACS 114, 3121) and 1995 (O.M. 14, 4521) independently), they extended the scope of this reaction and provided some mechanistic insight into the reaction. They say they were inspired by the hydroformylation reaction. It's easy to get the idea but difficult to realize it.

From a mechanistic point of view, the key for the reductive aldol 1 2 3 4 and mannich reaction 5 they reported is how to tune the properties of the metal hydride to just coordinate to the alkene and form the metal-enolate which then undergo an aldol reaction with the aldehyde and not to reduce the aldehyde and C-C double bond. The catalyst chosen and the base they added is crucial, which can help form a monohydride species and disable the dihydride cycle which will reduce the C-C double bond.

For the Alkyne-Carbonyl 6 7 and Alkyne-Imine 8 9 coupling reaction, however, an acid additive is necessary. Based on a computational study by Musashi and Sakaki and their experimental evidence they believe that the acid can help form a six member ring intermediate which require lower energy than the four member ring hence accelerate the reaction

Interestingly, in order to probe the role of acid they used a chiral bronsted acid together with a achiral ligand to do the reaction and found that for the pyridinealdehyde 82% enantioselectivity could be obtained. It's pity that they did not explore this kind of strategy which might leading to some new chemistry. They should be the first to combine the chiral phosphoric acid with achiral metal (If Reuping's paper adopt the same kind of idea, it will be not original).

For the substrate bearing a pyridine ring, they proposed another mechanism in which the acid interact with the basic pyridine nitrogen and lower the LUMO of the substrate to facilitate oxidative coupling.

What I learned from this chemistry is that the mechanism is vital to catalysis. Novel ideas could be obtained only when you have a very good command of all kinds of mechanisms. Also you should have the ability, courage and perseverance to realize the ideas.

Combination of Organometallic Catalysis with Organocatalysis

Toste published a paper in the current issue of Science. Utilizing the chiral phosphate anion as a couterion of metal with achiral ligand to induce chirality in organometallic catalysis. The structure of the phosphate anion they used was extensively studied in organocatalysis. The chiral BINOL based phophoric acid was first applied to the asymmetric Mannich type Reaction by Akiyama 1 2 and Terada 3 4 5. Then Magus Rueping( in Rueping's homepage there is also a similar paper which they say published on Angew. Chem. Int. Ed., but I cannot find it online) and Benjamin List used them in asymmetric imine reduction 6 7. Later they were employed by MacMillan and List to do the asymmetric reductive amination of ketone and DKR of alfa-branched aldehyde respectively 8 9. Recently, Rueping used this kind of catalysts to realize some amazing reduction. The BINOL based chiral phosphoric acid become a star molecule today in organocatalysis like Proline. Now their usage as a bridge between organocatalysis and organometallic catalysis will make them more popular.

Since I did organocatalysis as a Master student and am currently doing organometallic chemistry, when I begin my project here, one of my idea is to combine the organocatalysis with the organometallic catalysis, that is to use a achiral metal catalyst together with a chiral organocatalyst to do asymmetric reaction. That's very spotaneous based on my background and seems not novel at all. However, after the knowledge this paper, I think sometimes I should not undervalue my ideas.

Note: Reuping's paper could be found now titled "Dual Catalysis: A Combined Enantioselective Brønsted Acid and Metal-Catalyzed Reaction - Metal Catalysis with Chiral Counterions". In fact, Reuping's concept is different from the science paper. Though they said their reaction may involve a chiral counter ion catalyst, their reaction may most likely go through a mechanism in which the chiral phosphoric acid activate the imine substrate to provide stereo-control while the silver salt just act as an achiral catalyst to activate the alkyne.

The essence of chemistry is to create

The objective of this blog is to practice my English, keep me learning and share my ideas of chemistry with you. I feel lucky to major in chemistry because chemsitry is the only science subject which create new things. Chemists can have the experience of both Scientists and artists. Chemistry is the art of science. And that is where the name of my blog originated. Hope you will love chemistry too.