Supported N-Terminal Prolyl Peptides

In 2009, Kudo and coworkers investigated the asymmetric Michael-type addition of N-methylated and unsubstituted indoles to a,(3-unsaturated aldehydes by resin-supported polypeptides. In an initial survey of several amphiphilic polyethyleneglycol-grafted crosslinked polystyrene-supported catalysts, organocatalyst 22, which adopts a p-turn conformation aided by the polyleucine moiety under aqueous conditions, was revealed as the ideal catalyst for the preparation of a series of Michael adducts that were, in a final 

The chiral indole-substituted alcohols were obtained in moderate to good yields and enantiomeric excesses of up to 94%. Conveniently, catalyst 22 could be used in five repetitive cycles without losing its catalytic power. 

As an improvement of prior studies on enantioselective Michael additions the already well-studied tripeptide 15b was immobilised on a TentaGel-resin by Wennemers and coworkers and applied in the organoea-talysed addition of aldehydes to nitro-olefins under the same conditions. The peptide catalyst can be easily recovered by filtration and be repetitively used in 30 cycles without any negative impact on yield or stereoselectivity.  

The application of resin-supported peptides for the asymmetric Michael addition was further investigated by the group of Kudo for the preparation of p-substituted y-lactones via addition of boronic acids to y-hydroxy-a,p-un-saturated aldehydes followed by an additional oxidation step. Intense screening of resin-supported peptide catalysts gave the desired intermediate lactols in moderate to excellent yield and enantioselectivity. ROESY and CD spectra of related peptides indicated that both the p-turn as well as a partial helicily of the peptide are important for the high enantioselectivity of the catalyst. 

Asymmetric 1,4-conjugate addition of nitromethane to a,p-unsatur-ated aldehydes catalysed by resin-supported polypeptide 23. 

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Scheme 13.23 Aldol reactions catalysed by supported N-terminal prolyl peptides 37-40.

Remarkable advances in the field of peptide organocatalysis have been made in recent years. Asymmetric synthesis employing IV-allqrl imidazole-based peptides, N-terminal prolyl peptides, N-terminal primary amino peptides, supported N-terminal prolyl peptides as well as oligopeptides have become a facile tool in organic chemistry. 

P-Melhyl substituted cinnamaldehydes have been reduced under aqueous media employing a resin-supported N-terminal prolyl peptide having a P-tum motif and a hydrophobic polyleucine chain [22]. The reaction, which is performed in a mixture of THF and water (1/2) at rt, allows the preparation of chiral aldehydes with high enantioselectivities (93-96%) employing a 20 mol% of catalyst 10 and 1.2 equivalents of ester 4 in aqueous media at rt (Scheme 2.4). 

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