Synthesis and Conformational Analysis of a Cyclic Peptide Obtained via i to i+4 Intramolecular Side-Chain to Side-Chain Azide−Alkyne 1,3-Dipolar Cycloaddition

• Published in: Journal of organic chemistry Vol. 73; no. 15; pp. 5663 - 5674
• Main Authors: Cantel, Sonia, Le Chevalier Isaad, Alexandra, Scrima, Mario, Levy, Jay J, DiMarchi, Richard D, Rovero, Paolo, Halperin, Jose A, D’Ursi, Anna Maria, Papini, Anna Maria, Chorev, Michael
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.08.2008; Amer Chemical Soc
• Subjects: Alkynes - chemistry; Amino Acid Sequence; Azides - chemistry; Chemistry; Chemistry, Organic; Circular Dichroism; Cyclization; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Models, Molecular; Nuclear Magnetic Resonance, Biomolecular; Organic chemistry; Peptides; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Physical Sciences; Preparations and properties; Protein Structure, Tertiary; Science & Technology; REMARKABLE RESISTANCE; HORMONE-RELATED PROTEIN; RING-CLOSING METATHESIS; SOLID-PHASE SYNTHESIS; CLICK CHEMISTRY; AMINO-ACIDS; TERMINAL ALKYNES; SECONDARY STRUCTURE; BICYCLIC ANALOGS; COUPLING REAGENT; 1,3-Dipolar cycloaddition; Acetylenic compound; Norleucine; Nitrogen heterocycle; Cyclic peptides; Stabilization; Conformational analysis; Lactam; NMR spectrometry; Selectivity; Molecular assembly; Proteolysis; Circular dichroism spectrometry; Copper I; Helical structure; Antagonist; Chemical synthesis; Hormone; Intramolecular reaction; Catalytic reaction; Organic azide; Side chain; Cyclization; Analog; Triazole derivatives; Cadmium II Compounds; Diazo compound; Solid phase; Primary amine
• ISSN: 0022-3263; 1520-6904; 1520-6904
• DOI: 10.1021/jo800142s

Intramolecular side-chain to side-chain cyclization is an established approach to achieve stabilization of specific conformations and a recognized strategy to improve resistance toward proteolytic degradation. To this end, cyclizations, which are bioisosteric to the lactam-type side-chain to side-chain modification and do not require orthogonal protection schemes, are of great interest. Herein, we report the employment of CuI-catalyzed 1,3-dipolar cycloaddition of side chains modified with azido and alkynyl functions and explore alternative synthetic routes to efficiently generate 1,4-disubstituted  [1,2,3]triazolyl-containing cyclopeptides. The solid-phase assembly of the linear precursor including ϵ-azido norleucine and the propargylglycine (Pra) in positions i and i+4, respectively, was accomplished by either subjecting the resin-bound peptide to selective on-resin diazo transformation of a Lys into the Nle(ϵ-N3) or the incorporation of Fmoc-Nle(ϵ-N3)-OH during the stepwise build-up of the resin-bound peptide 1b. Solution-phase CuI-catalyzed 1,3-dipolar cycloaddition converts the linear precursor Ac-Lys-Gly-Nle(ϵ-N3)-Ser-Ile-Gln-Pra-Leu-Arg-NH2 (2) into the 1,4-disubstituted [1,2,3]triazolyl-containing cyclopeptide [Ac-Lys-Gly-Xaa(&1)-Ser-Ile-Gln-Yaa(&2)-Leu-Arg-NH2][(&1(CH2)4-1,4-[1,2,3]triazolyl-CH2&2)] (3). The conformational preferences of the model cyclopeptide 3 (III), which is derived from the sequence of a highly helical and potent i to i+4 side-chain to side-chain lactam-containing antagonist of parathyroid hormone-related peptide (PTHrP), are compared to the corresponding lactam analogue Ac[Lys13(&1),Asp17(&2)]hPTHrP(11−19)NH2 (II). CD and NMR studies of 3 and II in water/hexafluoroacetone (HFA) (50:50, v/v) revealed a high prevalence of turn-helical structures involving in particular the cyclic regions of the molecule. Despite a slight difference of the backbone arrangement, the side-chains of Ser, Gln, and Ile located at the i+1 to i+3 of the ring-forming sequences share the same spatial orientation. Both cyclopeptides differ regarding the location of the turn-helical segment, which in II involves noncyclized residues while in 3 it overlaps with residues involved in the cyclic structure. Therefore, the synthetic accessibility and conformational similarity of i to i+4 side-chain to side-chain cyclopeptide containing the 1,4-disubstituted [1,2,3]triazolyl moiety to the lactam-type one may result in similar bioactivities.