Stereoselective Synthesis of 3-Substituted 2-Aminocyclopentanecarboxylic Acid Derivatives and Their Incorporation into Short 12-Helical β-Peptides That Fold in Water

Abstract

A stereoselective synthetic route is reported for the introduction of side chains at the 3-position of trans-2-aminocyclopentanecarboxylic acid (ACPC). Ring opening of the aziridine 2-benzyloxymethyl-6-azabicyclo[3.1.0]hexane with selected nucleophiles occurs in a regioselective manner and provides ACPC precursors with functional groups at the 3-position, trans to the 2-amino group. Oligomers composed of the 3-substituted ACPC residues maintain the 12-helical conformation displayed by the nonsubstituted analogues, as shown by their similar circular dichroism signatures. The added diversity of the new residues provides good dispersion of NMR signals, allowing the assignment of nearly all the NOE signals of a selected hexamer in aqueous solution. The NOEs between protons on nonadjacent residues are characteristic of the 12-helix. 3-Substituted ACPC residues allow one to arrange specific functional groups in a geometrically defined fashion, which should facilitate the design of beta-peptides for biological applications.

A Novel Strategy Towards the Asymmetric Synthesis of Orthogonally Funtionalised 2-N-Benzyl-N-α-methylbenzylamino- 5-carboxymethyl-cyclopentane-1-carboxylic acid.

“…The oxidative coupling of the dianion derived from crotonic acid (8), as shown in Scheme 3, afforded a 70% yield of a 2:1 mixture of (E,E)-octa-2,6-diendioic and (E)-5-vinyl-hex-2-endioic acids (9 and 10) that could be easily separated by crystallization of 9 [13]. Methylation of these diacids using diazomethane or methanol in acid media is quantitative.…”

“…Furthermore, Gellman et al have demonstrated that short chain β-peptides derived from trans-pentacin adopt 12-membered helical structures [2][3][4][5] and when a pyrrolidine-base β-amino acid is incorporated into the hexa-β-peptide 3, it confers water solubility when the ring nitrogen is protonated [6][7]. In addition, oligomers composed of the 3-substituted transpentacin residues 4, 5 and 6 fold in water, which should facilitate the design of β-peptides for biological applications (Figure 1) [8]. We have recently demonstrated the asymmetric synthesis of the eight stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylate (I) using (E,E)-octa-2,6-diendioate as the only prochiral precursor [9], as shown in the retrosynthesis in Scheme 1.…”

Syntheses of Hydroxylated Cyclic β-Amino Acid Derivatives

“…NMR studies on the resulting -hydroxylated -hexapeptide gave strong indications that in pyridine no helical structure was formed [21]. In contrast, in 2002 Gellman et al reported that oligomers composed of 3-methoxy-or 3-phenoxysubstituted trans-2-aminocyclopentanecarboxylic acid (ACPC) residues maintain the 12-helical conformation displayed by the nonsubstituted analogs [22]. Thus, the presence of unprotected -hydroxy groups exerts a great influence on the formation of the secondary structure.…”

Efficient synthesis of multifunctional furanoid C-glycoamino acid precursors

“…2,3 In particular, Fleet et al 4,5 have reported a number of peptidomimetics and unnatural biopolymers adopting interesting secondary structures because of the carbohydrate-derived tetrahydrofuran systems they contain. On their hand, the SeebachÕs 6,7 and GellmanÕs [8][9][10][11] groups have found that b-peptides are able to adopt defined three-dimensional structures similar to those of natural peptides. The unnatural b-peptide backbone is resistant to proteolysis, 2 in contrast to a-amino acid backbone.…”