Backbone Modification of β-Hairpin-Forming Tetrapeptides in Asymmetric Acyl Transfer Reactions

Abstract

Synthetic oligopeptides as mimics of enzymes have been increasingly exploited as catalysts for asymmetric reactions, but highly effective oligopeptide catalysts with relatively low molecular weight are still in great demand. In this paper, we showed the conformational engineering of the β-hairpin-forming tetrapeptide 4 which was first reported by Miller's group as the catalyst for the asymmetric acyl transfer reaction of trans-2-(N-acetylamino)cyclohexan-1-ol (k(rel)=28). Through our backbone modification strategy, thioamide and sulfonamide as the isosteres of amide were introduced in the β-hairpin secondary structure. The thioxo peptides also adopt β-hairpin conformations as the oxopeptide supported by the combined use of NMR, IR, and X-ray techniques. Thioxo tetrapeptide 14 formed a more constrained β-hairpin conformation and therefore delivered much higher enantioselectivity (k(rel)=109) in the same reaction. Moreover, the examination of the conformational changes of tetrapeptide 8 upon the protonation of the N(π)-methylhistidine moiety provided evidence to explain the variation of its catalytic efficiency in the asymmetric acyl-transfer reaction.

Endothioxopeptides: A conformational overview

“…The most relevant results are: (i) In the chemotactic formyl‐Met‐Leu‐Phe‐OMe tripeptide analog containing a central β‐Ala residue replacing Leu and a β‐Alaψ[CSNH]Phe thionamide bond, the IR absorption bands at 3351 and 3290 cm −1 were assigned to NH…SC intraresidue, extended C 6 and CO…HN intramolecular, folded C 8 species, respectively . (ii) In a β‐hairpin forming catalyst tetrapeptide the ‐Aibψ[CSNH]Phe‐ thionamide NH is the donor of the β‐turn intramolecular H‐bond which shows a band at 3287 cm −1 . (iii) The IR absorption spectra of a series of mono‐thionamide analogs of the helical lipopeptaibiotic trichogin A were interpreted as arising almost exclusively from intramolecular CO(S)…HN H‐bonding .…”

“…(ii) In the type-II 0 b-turn forming, fully protected linear tripeptide the thionamide plane of the thionated Pro 1 residue is almost perpendicular to the plane of the b-turn. [92] (iii) The ABCD ring system of the w[CSNH] analog at position 4 of the glycopeptide antibiotic vancomycin overlaps nearly precisely with that of vancomycin itself with the obvious exception that the C@S bond length (1.66 Å) of the thionamide largely exceeds the C@O bond length (1.23 Å) of the natural compound. [93] Interestingly, this analog is totally unable to bind the classical D-Ala-D-Ala model ligand and was found to be antimicrobial inactive.…”

“…Other research groups utilized this spectroscopy to obtain information on linear peptide conformation. [92,[105][106][107][108][109][110][111][112][113] The most relevant results are: (i) In the chemotactic formyl-Met-Leu-Phe-OMe tripeptide analog containing a central b-Ala residue replacing Leu and a b-Alaw[CSNH]Phe thionamide bond, the IR absorption bands at 3351 and 3290 cm 21 were assigned to NAH. .…”

“…[106] (ii) In a b-hairpin forming catalyst tetrapeptide the -Aibw[CSNH]Phe-thionamide NH is the donor of the b-turn intramolecular H-bond which shows a band at 3287 cm 21 . [92] (iii) The IR absorption spectra of a series of mono-thionamide analogs of the helical lipopeptaibiotic trichogin A were interpreted as arising almost exclusively from intramolecular C@O(S). .…”

6.08 Acylation-Type Reactions: Synthesis of Esters via Acyl Transfer

“…80 A possible explanation might be the formation of a more constrained β-hairpin structure. Qu succeeded in the synthesis of a smaller, highly efficient catalyst for the KR of 196, but the substrate scope is still limited to trans-1,2-acetamidocycloalkanols.…”