Polyleucine

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]. 

Biomimetic reactions should also be considered for the preparation of optically active cyanohydrins (using a cyclic dipeptide as catalyst) and also for the epoxidation of a, (3-unsaturated ketones (using polyleucine or congener as a catalyst). 

The asymmetric epoxidation reaction with polyleucine as catalyst may be applied to a wide range of a, 3-unsaturated ketones. Table 4.1 shows different chalcone derivatives that can be epoxidized with poly-L-leucine. The substrate range included dienes and tctracncs151. Some other examples were reported in a previous edition161 and by M. Lastcrra-Sanchcz171. 

For epoxidation of chalcones using Ender s method, the results depend on the nature of the substrate. For the ( )-benzylideneacetophcnonc (R1, R2 = Ph), the enantiomeric excess was only 60 % using the same procedure as the one described above, whereas the polyleucine method furnished the epoxide with an enantiomeric excess > 95%. Table 4.3 gives some results of the epoxidation of some acyclic enones using Ender s method. 

Some of the practicals describe the use of similar catalysts and/or catalysts that accomplish the same task. This has been done purposely to try to get the best match between the substrate described and the one being considered by an interested reader. Moreover when catalysts can be compared, this has been done. Sometimes a guide is given as to what we found to be the most useful system in our hands. In this context, it is important to note that, except for polyleucine-catalysed oxidations and the use of a bicyclic bisphosphinite for asymmetric hydrogenation, the Liverpool group had no previous experience in... 

Their studies involved the partial polymerization of NCAs of mixtures of specific amino adds having known e.e.s, followed by determination of the e.e.s of the amino adds in both the resulting polypeptides and in the residual unreacted NCA monomers. [94] In a typical experiment it was found that when an optically impure leucine NCA monomer having an l > d e.e. of 31.2% was polymerized to the extent of 52 % to the helical polyleucine peptide, the e.e. of the polymer was enhanced to 45.4 %, an increase of 14.2 %. In the same experiment the e.e. of the unreacted leucine NCA monomer was depleted to a similar extent. Analogous experiments with valine NCAs of known e.e.s, however, led to a reverse effect, namely, the preferential incorporation of the racemate rather than one enantiomer into the growing polyvaline peptide. This finding was interpreted to be the result of the fact that polyvaline consists of (3-sheets rather than a-helices, emphasizing that the Wald mechanism applies only to a-helix polymers. At about the same time Brach and Spach [95] showed that, under proper conditions, (3-sheet polymers could also be implicated in the amplification of amino add e.e.s. 

In the above experiments with polyleucines it was also observed that the partial hydrolysis of mixtures of nonhomochiral leudne peptides led to the preferential hydrolysis of those components of the mixtures that were enantiomerically more random. This produced a corresponding e.e. enrichment in the unhydrolyzed polymer. [96] For example, when the above polyleudne sample having an i > d e.e. of 45.4% was 27% hydrolyzed, the residual unhydrolyzed polymer had an e.e. of 55.0%, representing an e.e. increase of 9.6%. 

This enhancement required just two steps from the initial leucine NCA monomer to the final polyleucine peptide. 

In determining the diversity of reactions which may be catalysed by polyleucine, it has been shown that the oxidation of sulfides to sulfoxides can be performed, achieving excellent levels of asymmetric induction. Thus, when polyleucine is coated onto a platinum electrode, oxidation of sulfides to optically active sulfoxides has been achieved in 77% e.e. and 56% yield, (Scheme 11) [22]... 

Since the polyleucine epoxidation conditions are only favourable for highly electron-deficient unsaturated systems (i. e. ketones), use of the Baeyer-Villiger oxidation subsequent to the epoxidation reaction allows access to the optically active epoxyesters. 

The use of a polyamino acid such as polyleucine as a catalyst for the asymmetric epoxidation of a,/l-unsaturated ketones is clearly established. The advantages and disadvantages of this methodology may be summarised as follows ... 

Polymerization of L-leucine in the presence of PVP with molecular weight 1x10" gives polyleucine with M=1,000, while use of PVP with molecular weight 3.6x10 , leads to daughter polymer with M almost 35,000. Polycondensation of various amino acids hy the synthesis with triphenyl phosphite in the presence of PVP is presented in Table 6.5. 

Figure 1.51 Diltiazem synthesis using polyleucine epoxidation.

ASYMMETRIC EPOXIDATION OF PHENYL-2-(3 -PYRlDYLVlNYL)SULFONE USING POLYLEUCINE HYDROGEN PEROXIDE GEL... 

Poly-(L)-leucine-l,3-diaminopropane (740mg, O.lOmmol, 1.0mol%) and tetrabutylammonium hydrogen sulfate (l.Og, 2.95 mmol, 30mol%) were placed in a flask with a stirrer bar. Toluene (2 ml), sodium hydroxide solution (5M, 30 ml, 10 eq.) and aq. hydrogen peroxide (30%, 15 ml, 10 eq.) were added and stirred for three hours. The aqueous layer was removed and sodium hydroxide solution (5M, 30 ml, 10 eq.) and aq. hydrogen peroxide (30%, 15 ml, 10 eq.) were added and the mixture was stirred overnight. The aqueous layer was removed to leave the activated polyleucine gel. 

A solution of phenyl(3-pyridyl) vinyl sulfone (2.50 g) in toluene (5 ml) was added to the stirred polyleucine-hydrogen peroxide gel suspension in toluene. The mixture was stirred at room temperature for six hours and the reaction followed by TLC (eluent 60% ethyl acetate in hexane, vis. CAN). The product was isolated by hltration through Celite washing with ethyl acetate, drying over magnesium sulfate and concentration in vacuo. 

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... 

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