Catalytic asymmetric epoxidation α,β-Unsaturated Ketones: An Approach to Enantiopure Peroxyhemiketals, Epoxides, and Aldols.
Corinna M. Reisinger, Xingwang Wang, and Benjamin List
ACIE, ASAP 22/09/08
In this paper, List et al. report a highly enantioselective catalytic hydroperoxidation of simple aliphatic enones with hydrogen peroxide. The process delivers a enantiopure cyclic peroxyhemiketals, which are readly converted into either epoxides or aldols.
The authors have discovered a new highly efficient and enantioselective epoxidation of cyclic enones with hydrogne peroxide using cinchona alkaloid derived primary amine catalyst 1 and 2. These powerful and readily made catalysts have previously found utility in other selected transformations. In an effort to expand the scope of their epoxidation, the authours turned their attention to acyclic aliphatic α,β-unsaturated ketones.
When 2-decenone 3 was subjected to aqueous hydrogen peroxide and the primary amine salt catalyst 1 - Cl3CCO2H (10 mol%) at 30°C in dioxane for 20 h, peroxyhemiketal 4 was formed in 58% yield.
This this cyclic peroxide is an intermediate and a common byproduct in Weitz–Scheffer-type epoxidations; the expected epoxide 5 was also formed in roughly 30% yield. Since cyclic peroxyhemiketals are known to be transformed into the corresponding epoxides under basic conditions, basic workup of the product mixture will always enable quantitative epoxide formation independent of the initially observed ratio of peroxyhemiketal 4 to epoxide 5.Furthermore, reduction of peroxides such as 4 should provide 3-hydroxy ketones (6)
The factors influencing the peroxyhemiketal/epoxide ratio are reflected in the proposed catalytic cycle shown below which accounts for the formation of both peroxyhemiketal 4 and epoxide 5. The activation of enone 3 as iminium ion A is followed by the nucleophilic conjugate addition of hydrogen peroxide to give peroxyenamine intermediate B. Enamine intermediate B can either undergo ring closure to give epoxide 5 or hydrolysis to provide peroxyhemiketal 4. Additional water accelerates the hydrolysis step, whereas a stronger acid promotes the intramolecular nucleophilic ring closure by generating a suitable leaving group through protonation.
Functional Analysis of an Aspartate-Based Epoxidation Catalyst with Amide-to-alkene Peptidomimetic Catalyst Analogues
ACIE 2008, 47, 6707 - 6711
Here I report the work of Miller and coworkers, which in my opinion is one of the best recent paper about organocatalysis. Recently Miller has published the first enantioselective peptide-catalyzed epoxidation of olefines using an hydrogen peroxide as oxidant in combination with carbodiimide as activators (click here to see the post).
Figure 1
The conversion of 1 to 2 was originally undertaken with the hypothesis that substrate-catalyst hydrogen bonding might contribute to transition state organization. In order to evaluate which part of the peptide is the site of interaction with the substrate, the authors synthetize different peptide analogue (peptidomimetic) for studying their catalytic activity versus the epoxidation reaction.
To evaluate the importance of the NHBoc functionality, they synthesized catalyst analogue 4 in which the NHBoc is replaced with a methyl group; the X-ray cristallography of 4 shows that it adopts a Type-II β-turn conformation. When 4 is evaluated in the asymmetric epoxidation of 1 under a common set of conditions, 2 is produced with 88% ee: it means that NHBoc is not involved in an important H bonding with the substrates.
For the functional evaluation of the Pro-D-Val amide, they turned to the application of the alkene isosteric replacements of the amide bond; so, they synthesized catalyst 5
In this case, the conversion of 1 to 2 occurs with 16% ee, under the catalysis by peptide 5. Therefore peptidomimetic 5 exhibits conformational properties that are very different from catalyst 4; whereas dipeptide alkene isosteres have been found to be good steric mimics of amide bonds in peptide and proteins, it is also well-recognized that they provide a poor mimic of other properties intrinsic to amides.
In order to recapture amide-like character in an olefinic mimic, dipeptide fluoro-olefin isosteres have been introduced; so, they sinthesized catalyst 6. The hypothesis was that the fluoroalkene moiety would be a better mimic of the local properties contributing to faithful β-turn nucleation, and that this catalyst would therefore be a better probe of 3.
The asymmetric epoxidation reactions (Figure 1) catalyzed by 6 offer intriguing results, delivering the product with 52% ee—intermediate between the selectivity afforded by catalysts 3 (81%ee) and 5 (16%ee) under a common set of conditions.
In this way, with this report you can understand that not only peptides but also peptimimetics are able to catalyzed organic reactions.
Asymmetric Epoxidation of Olefin with Hydrogen Peroxide-Catalyst by an Aspartate-Containing Tripeptide
ACIE, 2008, 47, 3677 - 3679
The development of new methods for the asymmetric preparation of epoxide is an important goal in organic chemistry. There are a lot of methods for the synthesis of epoxide, which often involves the use of chiral metal complexes or the use of organocatalyst such as chiral ketones.
Miller and coworkers have demonstred that highly enantioselective organocatalyst can result from the combination of short oligopeptides with catalytically active functional groups. In one of the recent publications, Miller et al. presented the first enantioselective peptide-catalyst for the epoxidation of olefines by using an hydrogen peroxide as oxidant in combination with carbodiimide as activators.
Epoxidation catalyst is effected by the carboxylic acid function of L-aspartate and the incorporation of this catalytically active residue into tripeptide 1 show below provides the chiral enviroment necessary for the asymmetric epoxidation.
1
The sequence L-Pro-D-Val induces a turn that is stabilized by intramolecular hydrogen bond.
The epoxidation of 2 gives che corrispective epoxide with a very low ee (10%) while with 3 the ee is always upper than 90% also with different reaction condition. The substrate 3 infact is able to make a hidrogen bond with the catalyst; they demonstred in this way the importance of the hydrogen bond for the enantioselectivity of the reaction, Also the distance between the hydrogen-bonding moiety and the double bond to be epoxidiezed plays an important role in the reaction.
In this way the method is limited to olefin substrates with a pendant carbamate group that is important for hydrogen bonding to the peptide catalyst.
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