Synthesis of Phosphinic Isosteres of Leucyl- and Isoleucylglycines
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hesis of Phosphinic Isosteres of Leucyl- and Isoleucylglycines S. R. Golovasha, M. E. Dmitrieva, V. I. Shestova, and V. V. Ragulina,* a Institute
of Physiologically Active Compounds of the Russian Academy of Sciences, Chernogolovka, 142432 Russia *e-mail: [email protected] Received March 26, 2020; revised March 26, 2020; accepted April 8, 2020
Abstract—Phosphinic isosteres of leucylglycine and isoleucylglycine were obtained by amidoalkylation of (3-benzyloxy-3-oxopropyl)phosphonous acid bearing the structural isostere fragment of glycine benzyl ester in acetyl chloride. A three-component amide version of the Kabachnik–Fields reaction involving methyl (benzyl) carbamates and 2(3)-methylbutanals was studied. The reaction proceeded under the conditions of acylation of the starting (3-benzyloxy-3-oxopropyl)phosphonous acid and in situ generation of a bisacetyl derivative of the threecoordinated phosphorus, the formation of which was detected using NMR 31Р. Keywords: pseudo-leucylglycine, pseudo-isolecylglycine, acetyl chloride, amidoalkylation, bisacetyl(3-benzyloxy3-oxopropyl)phosphonite
DOI: 10.1134/S107036322009008X Phosphinic peptides are isosteres of natural peptides, in the molecule of which the NHC(O) peptide bond is replaced by a zinc chelating methylenephosphorylic fragment CH2P(O)(OH), which mimics the natural peptide bond in the transition state of peptide hydrolysis with a tetracoordinated carbon atom [1–3]. Phosphinic peptides, including a non-hydrolyzable phosphinic fragment that binds two amino acid components of the dipeptide, are effective inhibitors of Zn-metalloproteinases [3, 4]. The currently prevailing NP+C strategy for the synthesis of phosphinic dipeptides is based on the CibaGeigy company developed methods [5, 6] for obtaining N,P-protected building blocks, which are a phosphonous isostere of a natural amino acids. The Michael‒Pudovik reaction of these compounds with the corresponding α-substituted acrylates leads to the formation of phosphinic peptides [3, 4]. A shorter promising N+PC strategy for the synthesis of phosphinic peptides with the reverse order of construction of the molecules 1 or 2 (Scheme 1) [7–9] consists in the amidoalkylation of phosphonous acids 3 (PC components), including the structural isostere of amino acids (glycine isostere in Scheme 1), using alkyl carbamates 4 and aldehydes 5. In this case, N-protected aminophosphinic acids 6a, 6b and 7a, 7b are formed, the hydrolysis of which leads to the target phosphinic pseudopeptides 1 and 2 (Scheme 1).
Developing the previously proposed strategy for the synthesis of peptide phosphoisosteres from hypophosphites [7–12], we obtained pseudo-leucylψ[P(O)(OH)CH 2]-glycine 1 and pseudo-isoleucylψ[P(O)(OH)CH2]-glycine 2 (Scheme 1), promising inhibitors of matrix metalloproteinases, which are a family of Zn-endoproteases involved into various biological processes [2–4, 13, 14]. The approach proposed earlier [7–10] to the synthesis of PC-component 3 is based on the ability of hypophosphites to efficiently form one or two symmetric and non
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