Synthesis of chiral five‐membered carbocyclic ring amino acids with an acetal moiety and helical conformations of its homo‐chiral homopeptides

Abstract

Chiral five-membered carbocyclic ring amino acids bearing various diol acetal moieties were synthesized starting from l-malic acid, and homo-chiral homopeptides composed of cyclic amino acid (S)-Ac5 c(3EG) bearing an ethylene glycol acetal, up to an octapeptide, were prepared. A conformational analysis revealed that (S)-Ac5 c(3EG) homopeptides formed helical structures. (S)-Ac5 c(3EG) homopeptides, up to hexapeptides, formed helical structures without controlling the helical screw direction, while (S)-Ac5 c(3EG) hepta- and octapeptides formed helical structures with a preference for the left-handed (M) helical-screw direction. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 555-562, 2016.

Helical l–Leu‐Based Peptides Having Chiral Five‐Membered Carbocyclic Ring Amino Acids with an Ethylene Acetal Moiety

“…The chiral centers of L-Leu residues may control the helical-screw sense of peptides into right-handedness because 66% content of L-Leu exists in heteropeptides 4 and 5, and the propensity of the helical-screw control of cyclic amino acid (S)-Ac 5 c 3EG is relatively weak. [20] The intensities of maxima in (S)-Ac 5 c 3EG hexapeptide 4a were stronger than those of (R)-Ac 5 c 3EG hexapeptide 4b. This may be attributed to the chiral centers of L-Leu matching that of (S)-Ac 5 c 3EG and mismatching that of (R)-Ac 5 c 3EG ; however, the (S)-Ac 5 c 3EG homopeptides preferentially formed left-handed (M)-helices.…”

“…Tripeptide Cbz-[L-Leu-L-Leu-{(S)-Ac 5 c 3EG }]-OMe (3a) was prepared by coupling between Cbz-(L-Leu-L-Leu)-OH (1) and (S)-Ac 5 c 3EG -OMe (2a) [20] using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBt) as coupling reagents in 94% yield. The hydrolysis of the C-terminal methyl ester in 3a under alkaline conditions (NaOH/H 2 O-THF) proceeded to give a tripeptide carboxylic acid, and the N-terminal-protecting group in 3a was removed by hydrogenolysis using H 2 /Pd(OH) 2 -C to produce a tripeptide amine.…”

“…[23] On the other hand, homopeptides (hepta-and octapeptides) composed of the five-membered carbocyclic ring amino acid (R)-Ac 5 c 3EG with an acetal moiety at the γ-position showed left-handed (M) helical structures in solution without the N(i)-H···-O-(i, acetal)-type intramolecular hydrogen bond. [20] The carbocyclic ring size difference of dAAs may affect the distance of N(i)-H and -O-(i, acetal), and the intramolecular hydrogen bond pattern may be different. …”

“…[16][17][18][19] We previously reported the synthesis of a chiral five-membered carbocyclic ring dAA: (R)-or (S)-amino-3,3-(ethylenedioxy)cyclopentanecarboxylic acid (Ac 5 c 3EG ) with an ethylene acetal moiety, in which the α-carbon atom was a chiral center, and the helical structures of its homo-chiral homopeptides. [20] In the present study, to reveal the influence of (S)-or (R)-Ac 5 [a]…”

Design and Synthesis of Helical N-Terminal l-Prolyl Oligopeptides Possessing Hydrocarbon Stapling

“…From this point of view, the introduction of allyl tethered cis -4-hydroxy- l -proline or ( R )-α-allyl-proline can be suitable for this purpose. Secondary structures, as well as helical screw directions, can be controlled by introducing 1-aminocycloalkane-1-carboxylic acid in homopeptides [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ] and heteropeptides [ 41 , 42 , 43 ], and these constrained peptides catalyze asymmetric 1,4-addition reactions [ 44 , 45 , 46 ]. Therefore, poly l -leucine-incorporating 1-aminocyclopentane-1-carboxylic acid was used as an α-helix-inducing motif.…”