Efficient Synthesis of (S)-4-Phthalimido-1,3,4,5- tetrahydro-8-(2,6-dichlorobenzyloxy)-3-oxo-2H-2-benzazepin-2-acetic Acid (Pht-Hba(2,6-Cl₂-Bn)-Gly-OH)¹

Abstract

4-Amino-2-benzazepin-3-ones have proven very useful for studying the biologically active conformations of peptides. The synthesis of Pht-Aba-Xaa-OH by reaction of the corresponding 1,3-oxazolidin-5-one with trifluoromethanesulfonic acid (TFMSA) has been reported in the literature. However, when this procedure was applied to the preparation of Pht-Hba(Bn)-Gly-OH 8, many byproducts were formed and the yield of the desired aminobenzazepinones 7 and 8 was very low. We report in this paper an efficient methodology for the synthesis of Pht-Hba(2,6-Cl2-Bn)-Gly-OH 17 starting from the commercially available tyrosine. In our procedure, the dipeptide Pht-Tyr(2,6-Cl2-Bn)-Gly-OH 15 is converted to the 1,3-oxazolidin-5-one 16 which then undergoes Friedel-Crafts cyclization in the presence of tin tetrachloride to afford the desired 4-phthalimido-1,3,4,5-tetrahydro-8-(2,6-dichlorobenzyloxy)-2-be nzazepin-3-one 17 in excellent yield.

Synthesis and biological evaluation of constrained analogues of the opioid peptide H‐Tyr‐d‐Ala‐Phe‐Gly‐NH2 using the 4‐amino‐2‐benzazepin‐3‐one scaffold

“…Starting from the protected residues phtaloyl (Pht)‐Phe‐OH 9a ( R 2 = H) and Pht‐Tyr(2,6‐Cl 2 Bn)‐OH 9b , dipeptides 11a (Pht‐Phe‐Gly‐OH) and 11b [Pht‐Tyr(2,6‐Cl 2 Bn)‐ d ‐Ala‐OH] could be obtained after hydrolysis of the corresponding esters 10a and 10b (11). The conversion to the corresponding oxazolidinones 12a,b (94% and 84% respectively) was realized by treatment with paraformaldehyde in acid catalysed conditions.…”

“…The conversion to the corresponding oxazolidinones 12a,b (94% and 84% respectively) was realized by treatment with paraformaldehyde in acid catalysed conditions. The N ‐acyliminium ion is subsequently generated by treatment with TiCl 4 for inducing the formation of the protected benzazepine Aba‐Gly 13a (100%) and with SnCl 4 for Hba‐ d ‐Ala 13b (84%) (11). The Lewis acids show specific reactivity, the tyrosine analogue could not be obtained using the titanium (IV) catalyst.…”

“…Synthesis of the 4-amino-2-benzazepin-3-one scaffolds Hba and Aba was performed using previously reported procedures (11)(12)(13)(14) which were slightly modified resulting in better yields and purities so that intermediates did not need purification (Fig. 2).…”

Copper(II) Sulfate

“…(Lewis acid catalyst for alcohol dehydration, 1,31 acetonide formation, 6 acetal exchange, 9 ketone, 33 alcohol, and phenol 34 protection, trans-esterification of β-ketoesters, 36 imine 37 and oxime 38 formation, diazo-transfer, 39 cleavage of N-O bonds, 42 hydrolysis of imines, 43 reductive amidation; 44 reagent for formation of copper carbenoids, 15 intramolecular and intermolecular cyclopropanations, 21,48 redox catalyst with potassium permanganate for oxidation of alcohols 25, 53 and alkenes; 28,53 reagent for reduction of alkenes, 59 oximes, 60 and azides 61 with sodium borohydride or hydrazine; reductive removal of diazo group, 64 reductive dehydrazination, 65 and amino acid complexation 66 ). and handled in the laboratory using normal laboratory methods; anhyd CuSO 4 is a powerful desiccant and must be stored out of contact with moisture, but can be weighed and transferred in the laboratory if atmospheric exposure is minimized; copper(II) sulfate is a strong irritant to the skin and mucous membranes.…”

Photocycloaddition of Phthalimide Anion to Alkenes − A Highly Efficient, Convergent Method for [2]Benzazepine Synthesis

“…[2] Galanthamine, the parent compound in the latter family, and its synthetic analogues are cholinesterase inhibitors and are currently undergoing testing in Alzheimer's disease therapy. [3] Other biologically prominent examples include fused pyrimido [5,4-d] [2]benzazepines, which exhibit promising antitumor activity, [4] the conformationally restricted amino acids derived from 4-amino-1,3,4,5-tetrahydro [2]benzazepine-3-one, used in the synthesis of peptides, [5] and 1-aryl [2]benzazepinones, which are active on the central nervous system. [6,7] Two major approaches to the synthesis of [2]benzazepine heterocycles have been employed.…”