Tetrahydroisoquinoline-Based Spirocyclic Lactam as a Type II′ β-Turn Inducing Peptide Mimetic

Abstract

We present here spirocyclic lactam derivatives, embodying D-Phe and L-Ala amino acids as the central core and acting as tetrapeptide and hexapeptide mimetics. An efficient route for their synthesis is demonstrated by using the strategic combination of Seebach's self-reproduction of chirality chemistry and the Pictet-Spengler condensation as key steps. The conformational behavior of peptide mimetics was investigated by molecular modeling, X-ray crystallography, NMR (solvent and temperature dependence), IR spectroscopy, and circular dichroism. All data suggest very stable and highly predictable type II' beta-turn conformations.

The spiropiperidine-3,3′-oxindole scaffold: a type II β-turn peptide isostere

“…We recently developed the diastereoselective Grignard addition of imines derived from isatine. 6 Following the described protocol, amine 7 could be obtained in good yield as a 3S single enantiomer. Acetylation of 7 with acetic anhydride to give 8, followed by allylation of the amide nitrogen with allyl bromide, afforded diene 9 in good overall yields.…”

“…In the course of a program directed towards the search for new methodologies to access pharmaceutically relevant heterocyclic scaffolds, 5 we recently developed a new protocol for the asymmetric synthesis of quaternary 3-aminooxindoles. 6 3,3 0 -Disubstituted oxindoles are important targets in organic synthesis 7 due to their frequent occurrence in natural products 8 and biologically relevant molecules 9 (Fig. 1).…”

“…4.1.7. (S)-2-(1 0 -Acetyl-2-oxospiro[indoline-3,2 0 -piperidine]-1-yl)-Nmethylacetamide(6). To a solution of 13 (26 mg, 0.08 mmol, 1 equiv) in dry ethanol (3 mL), under nitrogen atmosphere and at 0 C, an 8 M solution of MeNH 2 in EtOH (3 mL) was added.…”

Enantioselective synthesis of tricyclic amino acid derivatives based on a rigid 4-azatricyclo[5.2.1.02,6]decane skeleton

“…Incorporated in peptides or proteins, they may increase the metabolic stability and allow the introduction of novel structural motifs [1–4]. ß-Turns, for example, result if conformationally constrained spiro- or bicyclic amino acids such as 1 [5], 2 [6], and 3 [7–8] are embedded in peptidomimetics (Fig. 1).…”

Rapid access to reverse-turn peptidomimetics by a three-component Ugi reaction of 3,4-dihydroisoquinoline

“…The Ugi reaction is a well-known and much exploited fourcomponent reaction involving the use of an amine, an aldehyde, a carboxylic acid, and an isocyanide to produce an amino acid derivative. 22,23 Following the above considerations and based on our experience in the preparation of peptidomimetics, [24][25][26][27][28][29][30][31][32] we have designed the synthesis of a reverse-turn mimetics, easily achievable applying this strategy, starting from tetrahydroisoquinoline scaffolds. Tetrahydroisoquinoline Chemistry of Heterocyclic Compounds 2017, 53 (11), 1214-1219…”