Preparation of Sugar Amino Acids by Claisen‐Johnson Rearrangement: Synthesis and Incorporation into Enkephalin Analogues

Abstract

We have developed a convenient route for the synthesis of an unsaturated branched sugar bearing a carboxylic acid and an amino group (masked as an azide group) by employing a totally stereoselective Claisen−Johnson rearrangement as the key step. Several Met-and Leu-enkephalin analogues with different substitution patterns at the N-and C-termini

Classification of conformation for sugar amino acid systems using chiroptical spectroscopy

“…11 SAAs have been used as dipeptide isosteres and scaffolds for the preparation of mimetics, such as enkephalins, 12 somatostatin, 13 integrin antagonists (RGD mimics), 14,15 farnesyltransferase inhibitors, 16 mammalian ribonucleotide reductase inhibitors, 17 and ion channels. 18 As a result of the presence of amine and acid moieties, SAAs are suitable for conventional library synthesis in both solid and solution phase.…”

The Orthoester Johnson–Claisen Rearrangement in the Synthesis of Bioactive Molecules, Natural Products, and Synthetic Intermediates – Recent Advances

“…[57] The Johnson-Claisen rearrangement of allyl alcohol 82 with triethyl orthoacetate and catalytic quantities of propionic acid at 140°C cleanly delivered the desired ester 83, which was conveniently elaborated to 84, representing the C18-C34 fragment of the natural product 85. In this context, Herradón and co-workers [59] synthesized several Met-and Leu-enkephalin analogues with various substitution patterns at the C and N termini by incorporating a sugar amino acid (SAA) as a replacement for the original Gly-Gly fragment of the parent pentapeptides. [58] Their pharmacological utility is limited, however, which has resulted in a search for analogues in order to increase their enzymatic stability and to restrict their conformational flexibility.…”

“…[58] Their pharmacological utility is limited, however, which has resulted in a search for analogues in order to increase their enzymatic stability and to restrict their conformational flexibility. In this context, Herradón and co-workers [59] synthesized several Met-and Leu-enkephalin analogues with various substitution patterns at the C and N termini by incorporating a sugar amino acid (SAA) as a replacement for the original Gly-Gly fragment of the parent pentapeptides. The SAA, with its amino group masked as an azide moiety, was synthesized by use of the Johnson-Claisen rearrangement as key step.…”

Pentafluorophenyl (3R,4R,5R)-5-{[(3R,4R,5R)-5-azidomethyl-3,4-dimethoxy-2,3,4,5-tetrahydrofuran-3-carbonylamino]methyl}-3,4-dimethoxy-2,3,4,5-tetrahydrofuran-3-carboxylate

“…-Tetrahydrofuran (THF) SAAs such as (1) (Smith et al, 2003;Chakraborty et al, 2004) have become well established as dipeptide isosteres (Grotenberg et al, 2004). Such systems continue to provide an increased understanding of the factors inducing secondary structure and insight into the complex nature of protein folding (Billing & Nilsson, 2005;Claridge et al, 2005;Long et al, 1999) with potential chemotherapeutic activities as integrin antagonists (van Well et al, 2004), enkephalin analogues (Montero et al, 2004) and somatastatin mimics (Gruner et al, 2002). In the past, almost all THF SAAs have contained linear carbon chains, since the only carbohydrate building blocks from which they can be derived have unbranched chains (Bols, 1996).…”