Epoxidation Julia-Colonna

Nucleophilic epoxidation (Julia-Colonna epoxidation) of trans-chalcone and derivatives with hydrogen peroxide catalysed by Nagasawa-G (Scheme 23.1) was shown to proceed successfully with a biphasic system consisting of water and toluene. This is a highly atom economical reaction (92% for chalcone). 

The asymmetric epoxidation of enones with polyleucine as catalyst is called the Julia-Colonna epoxidation [27]. Although the reaction was originally performed in a triphasic solvent system [27], phase-transfer catalysis [28] or nonaqueous conditions [29] were found to increase the reaction rates considerably. The reaction can be applied to dienones, thus affording vinylepoxides with high regio- and enantio-selectivity (Scheme 9.7a) [29]. 

The improved Julia-Colonna epoxidation conditions have been successfully employed for poly-(D)-leucine. 

TABLE 14. Epoxidation results obtained under Julia-Colonna and Roberts conditions... 

Gerlach, A. and Geller, T. Scale-up Studies for the Asymmetric Julia-Colonna Epoxidation Reaction. Adv. Synth. Catal. 2004, 346, 1247-1249. 

Adger, B.M., Barkley, J V. Bergeron, S., Cappi, M.W., Elowerdew, B.E., Jackson, M. R, McCague, R., Nugent, T.C. and Roberts, S.M. Improved Procedure for Julia-Colonna Asymmetric Epoxidation of a,/l-Unsaturated Ketones Total Synthesis of Diltiazem and Taxol Side-chain. J. Chem. Soc., Perkin Trans. 1 1997, 23, 3501-3507. 

The Julia - Colonna asymmetric epoxidation of electron-deficient unsaturated ketones to the corresponding epoxides with high yields and high ee is well known. This technique produces chiral chemical entities from the clean oxidant, hydrogen peroxide, without the use of a toxic or water sensitive transition metal additive. 

The Julia-Colonna epoxidation uses poly-L-leucine and hydrogen peroxide to effect enantioselective epoxidation of chalconc derivatives such as 12. In a pair of back-to-back papers (Tetrahedron Lett. 2004,45, 5065 and 5069), H.-Christian Militzer of Bayer Healthcare AG, Wuppertal, reports a detailed optimization of this procedure. In the following paper (Tetrahedron Lett. 2004,45,5073), Stanley Roberts of the University of Liverpool reports the extension of this procedure to unsaturated sulfones such as 14. 

J. Skidmore, and J. A. Smith, beta-Peptides as catalysts poly-beta-leudne as a catalyst for the Julia-Colonna asymmetric epoxidation of enones, Chem. Commun. 2001, (22), 2330-2331. 

D. Reichert, A. Kuhnle, H.-P. Krimmer and K. Drauz, Julia-Colonna asymmetric epoxidation in a continuously operated chemzyme membrane reactor, Synlett 2002, (5), 707-710. 

Also striking was the discovery, by Julia, Colonna et al. in the early 1980s, of the poly-amino acid (15)-catalyzed epoxidation of chalcones by alkaline hydrogen peroxide [19, 20]. In this experimentally most convenient reaction, enantiomeric excesses > 90% are readily achieved (Scheme 1.6). 

Because the catalyst is usually prepared by the polymerization of amino acid N-carboxy anhydrides, induced by water or amines [66, 67], the Julia-Colonna epox-idation was soon recognized as a reaction of great practical value. In the course of exploration of the scope of the Julia-Colonna procedure many enone substrates were successfully epoxidized by use of the original three-phase conditions (Table 10.8). 

An example of catalysts which are themselves heterogeneous are the poly-amino acids used for the asymmetric Julia-Colonna-type epoxidation of chalcones using alkaline hydrogen peroxide (Section 10.2) [8]. Because of the highly efficient synthesis of epoxides, this process also has attracted industrial interest (Section 14.3). Since recent work by the Berkessel group revealed that as few as five L-Leu residues are sufficient for epoxidation of chalcone, several solid-phase-bound short-chain peptides have been used, leading to enantioselectivity up to 98% ee [14], For example, (L-Leu)5 immobilized on TentaGel S NH2 , 8, was found to be a suitable solid-supported short-chain peptide catalyst for epoxidations. 

Case Study 1 Julia-Colonna-type epoxidation... 

Researchers at Bayer AG addressed these critical issues and developed successful solutions enabling commercial application of Julia-Colonna-type epoxidation [35-40]. Starting with optimization of catalyst preparation, a straightforward synthesis based on inexpensive reagents and requiring a shorter reaction time was developed for the poly-Leu-catalyst [35], In particular, the reaction time for the new polymerization process was only 3 h when the process was conducted at 80 °C in toluene, compared with 5 days under classic reaction conditions (THF, room temperature). Furthermore, the catalyst prepared by the Bayer route is much more active and does not require preactivation [35-40],... 

Researchers at Degussa AG focused on an alternative means towards commercial application of the Julia-Colonna epoxidation [41]. Successful development was based on design of a continuous process in a chemzyme membrane reactor (CMR reactor). In this the epoxide and unconverted chalcone and oxidation reagent pass through the membrane whereas the polymer-enlarged organocatalyst is retained in the reactor by means of a nanofiltration membrane. The equipment used for this type of continuous epoxidation reaction is shown in Scheme 14.5 [41]. The chemzyme membrane reactor is based on the same continuous process concept as the efficient enzyme membrane reactor, which is already used for enzymatic a-amino acid resolution on an industrial scale at a production level of hundreds of tons per year [42]. 

It should be mentioned here that in addition to the Julia-Colonna epoxidation, the Shi epoxidation is also attracting commercial interest. In a recent presentation DSM reported current activity on the application of the Shi technology on a commercial scale [43],... 

The Julia-Colonna method, which uses polyleucine, can form an epoxide from a chalcone (Scheme 9.17).126-132 However, the method is limited to aryl-substituted enones and closely related systems, and even then scale up of the procedure has been found to be problematic.133 The product of the epoxidation 14 has been used in a synthesis of (+)-clausenamide (15).134... 

Preparation and activation of silica-supported poly-L-leucine[150] has been studied under a variety of reaction conditions leading to an efficient procedure for the preparation of material suitable for use in the Julia-Colonna asymmetric epoxidation reaction. Poly-L-leucine, can be added to the list of natural11511 and non-natural[152] oxidation catalysts that benefit from being supported on commercially available silica gel. 

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