Spiro β-Lactams as β-Turn Mimetics. Design, Synthesis, and NMR Conformational Analysis

Abstract

Molecular modeling calculations using high-level ab initio methods (MP2/6-31+G) of a new type of spiro beta-lactams predict that these systems could adopt a beta-turn secondary structure in solution. Strong intramolecular hydrogen bonds stabilize the beta-turn conformation with a geometry that is very close to the ideal type II beta-turns. The synthesis of the spiro beta-lactams is achieved by Staudinger reaction of a cyclic ketene derived from N-bencyloxycarbonyl-L-proline acid chloride with an imine. This reaction allows the formation of the spiranic backbone in a single-step with high diastereoselectivity and good yields. The new spiro beta-lactams obtained are the core for the preparation of different types of peptidomimetics using well-established peptide chemistry. The NMR conformational analysis shows that these compounds adopt beta-turn conformation as predicted by the theoretical studies.

Synthesis of Novel 4-Halomethyl-1,3-oxaselenolane Substituted Spirocyclic Azetidin-2-ones from cis-3-Allyloxy-3-benzylselenoazetidin-2-ones

“…Over recent years, there has been a surge of attention towards synthesizing spirocyclic β-lactams in view of their inimitable biological properties such as antiviral [6], antibacterial [7], antimalarial (A,B) [8], antidiabetic [9], acyl-CoA cholesterol O-acyl transferase (ACAT) inhibitors (C) [10,11], β-turn mimetics [12] and β-lactamase inhibitors (D) [13]. The spiro-β-lactam (E) serves as a precursor for the synthesis of glutamine synthetase inhibitor [14] (Fig.…”

Synthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostere

“…The most interesting feature displayed by d-amino acids is their structural analogy with dipeptides, and many d-amino acids as peptidomimetics have been constructed to mimic dipeptide sequences with added structural constraints . Relevant examples of d-amino acids include linear (Wipf et al, 1998;Gardner et al, 1999;Shankaramma et al, 1999;Casimir et al, 2000), cyclic (Poitout et al, 1995;Graf von Roedern et al, 1996;Suhara et al, 1996;Wattersom et al, 2003;Durrat et al, 2004), bicyclic (Hanessian et al, 1997;Van Well et al, 2003), and spiro (Genin and Johnson, 1992;Khalil et al, 1999;Alonso et al, 2001) compounds, and different templates have been applied for the generation of such amino acids. Moreover, since the b-turn is a common structural feature of proteins associated with the dipeptide unit, much research about d-amino acids has been concentrated on the creation of reverse turn mimetics, where the central amide bond is replaced by a rigid moiety (Kim and Germanas, 1997a, b;Belvisi et al, 1999;Estiarte et al, 2000;Trabocchi et al, 2002).…”

Synthesis of novel spiro fused polycyclic β-lactam derivatives

“…1,4,5 Recently, spiro-β-lactams became particularly interesting compounds because their antiviral 7 and antibacterial properties 8 as well as their inhibition of cholesterol absorption 9 make them potentially useful candidates for drug development. They can also be used as β-turn mimetics in peptide chemistry [10][11][12] and, particularly 4-spiro-β-lactams, are synthetic precursors for cyclic α,α-disubstituted β-amino acids and peptide derivatives. 13,14 Thus, the synthesis of spiro-β-lactam derivatives has recently received much attention.…”

“…Several synthetic methods for spiro-β-lactams have been developed. [7][8][9][10][11] Among these, the cyclic ketene-participating Staudinger reaction is one of important strategies. derivatives of benzothiazepines, benzodiazepines, and dibenzo[b,f]oxazepines because of their potential biological and pharmaceutical importance.…”

“…Herein, we report the synthesis of fused seven-membered heterocycle-β-lactam derivatives from 2,3-dihydro-1,5-benzothiazepines and dibenzo[b,f]oxazepines with pentamethyleneketene. Cyclic ketenes with electron-rich substituents generated from prolines, 10 20,21 have been widely used in the synthesis of spiro-β-lactam derivatives. In this report a disubstituted cyclic ketene with weak electron-donating substituents is employed in the Staudinger reaction with heterocyclic imines.…”