Poly-L-leucine

Chiral lactones were also formed by cyclocarbonylation [ 122] with chiral catalysts, such as Pd-poly-L-leucine catalytic system. For example, but-2-en-l-ol led to the corresponding cychc chiral lactone in the presence of Pd catalysts with chiral ligands (Scheme 33). About 10 mol% of Pd(II) chloride... 

Historically, after the development of oligopeptide-based vesicles, several groups developed and characterized vesicles using polypeptide hybrid systems consisting of polypeptide and synthetic polymer blocks [17-19]. Soon thereafter, vesicles formed entirely from polypeptides, such as poly(L-lysine)-h-poly(L-leucine) and poly(L-lysine)-h-poly(L-glutamate), were developed [20, 21]. This review will focus on recent developments in the formation of vesicles composed of polypeptide hybrid or polypeptide systems, as well as the potential promise of these systems as effective dmg delivery vehicles. A specific example of a polypeptide-based vesicle is shown in Fig. 1, where the hydrophobic segment is a-helical and the hydrophilic segment is a random coil. 

Fig. 1 Vesicle construct formed from poly(L-lysine)-i)-poly(L-leucme) polypeptides where the poly(L-leucine) block corresponds to the a-helical hydrophobic segments and the poly (L-lysine) block corresponds to the random coil hydrophilic segments. Note that this is one specific example and not all vesicle constructs have a-helical and random coil blocks. Moreover, the amphiphilic copolymer can be comprised of either a pure block copolypeptide or a macromolecule consisting of a polypeptide and another type of polymer. Adapted from [20] with permission. Copyright 2010 American Chemical Society...

The biomimetic protocol was invented by Julia and Colonna, and involves the use of polyamino acids (such as poly-(L)-leucine) as the catalysts for peroxide oxidation of chalcones, styryl alkyl ketones and conjugated alkenones. The substrate range is broad, especially when using immobilized catalysts and an organic solvent containing the substrate, urea-hydrogen peroxide and an organic base (Scheme 22)[101]. 

Scheme 22 Reagents and conditions i) poly-L-leucine, urea-hydrogen peroxide, THF, diazabicycloundecene.

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. 

Table 4.1 Epoxidation of enones using poly-L-leucine catalyst15 71.

Polyamino acids are easy to prepare by nucleophUe-initiated polymerisation of amino acid JV-carboxyanhydrides. Polymers such as poly-(L)-leucine act as robust catalysts for the epoxi-dation of a wide range of electron-poor alkenes, such as y-substituted a,Ji-unsaturated ketones. The optically active epoxides so formed may be transformed into heterocyclic compounds, polyhydroxylated materials and biologically active compounds such as dUtiazem and taxol side chain. 

Julid and Colonna showed that, as expected, poly-(L)-leucine and poly-(i)-isoleucine could be employed in place of poly-(L)-alanine, while poly-(L)-valine gave poorer results in terms of yields and stereoselectivity [13]. Some other eno-nes were tried without success and nucleophiles other than peroxide anion were... 

Scheme 2. Reagents and Conditions (i) NaOH, EDTA, n-hexane, poly-(L)-leucine, H2O, H2O2...

Methods A Immobilised poly-(L)-leucine, urea hydrogen peroxide, DBU, THE B Immobilised poly-(D)-leucine, urea hydrogen peroxide, DBU, THE... 

Attempts to use polyamino acids as catalysts in other reactions have proved successful, notably in the coupling of thiophenol with chalcones. Employing poly-(L)-leucine, the -phenylthioether was obtained in up to 45% e.e., (Scheme 10). Studies indicated that the best results were obtained by slow addition of the thiophenol to the reaction mixture. 

In a similar fashion to those results obtained for the oxidation process, on switching from poly-(L)-leucine to poly-(D)-leucine the opposite configuration of the polyether was observed (absolute configuration of products unknown). Unexpected, however, was the observation that poly-(L)-phenylalanine furnished the opposite enantiomer to that observed employing poly-(L)-leucine. Thus, it has been shown that addition of nucleophiles other than peroxide anion can be catalysed by polyamino acids with significant stereocontrol [22]. 

Scheme 18. Reagents and Conditions (i) Immobilised poly-(L)-leucine, urea hydrogen peroxide, DBU, THF, 12 h, 76%, 94% e.e. (ii) mCPBA, CH2CI2, 94%. (iii) HCl (g), CH2CI2, 66%. (iv) Amberlite IRA-420 ( OH), THF, 80%. (v) NaNj, MeOH, H20,94%. (vi) H2, Pd/C, EtOAc. (vii) NH3,MeOH. (viii) benzoyl chloride, (ix) trifluoroacetic acid, CH2CI2,74%...

Similarly, good results were obtained with poly-(i)-alanine, poly-(L)-leucine and poly-(i)-isoleucine, whereas with poly-(i)-vahne or random copolymers reduced chemical yields as weU as asymmetric induction were obtained. Chemical and optical yields are closely related in all cases. The enantiomeric excesses obtained increased as the average chain length of the catalyst increased varying from 10 to 30 amino acids (ee values between 50 to 99%). For high ee values it seems to be essential that the polymer chain is at least 10 units. The degree of asymmetric induction decreases as the temperature is raised. The amount of catalyst only influences the chemical yield, not the optical yield of... 

SCHEME 50. Poly-(L)-leucine catalyzed epoxidation of chalcones... 

The presence of poly(vinylpyrrolidone) in the system increases substantially molecular weight of poly(L-leucine) obtained. If the ratio of template to monomer is 1.35, the molecular weight is more then 10 times higher than for the blank reaction. The influence of molecular weight of PVP template on the molecular weight of the daughter polymer was very significant as seen from the Table 6.4. 

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. 

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