Synthesis of unnatural amino acids containing the 3,7-diazabicyclo-[3,3,1]nonane unit

Abstract

A. N. Lobov, L. V. Spirikhin, and V. A. DokichevUnnatural amino acids containing the 3,7-diazabicyclo [3,3,1]nonane unit were synthesized in one step by the reaction of diethyl 3-oxoglutarate, bis(methoxycarbonylmethyl) sulfone, with formaldehyde and primary amino acids under conditions of the Mannich reaction.Keywords: bis(methoxycarbonylmethyl) sulfone, 3,7-diazabicyclo[3,3,1]nonan-9-ones, diethyl 3-oxoglutarate, unnatural amino acids, 9-thia-3,7-diazabicyclo[3,3,1]nonane 9,9-dioxide, Mannich reaction.An important direction at present in the area of organic and pharmaceutical chemistry is the synthesis of new confomationally rigid analogs of natural amino acids [1]. Showing similarities in a number of parameters with natural analogs, the twenty classical amino acids, these compounds possess a high potential for physiological activity. The limited conformational mobility of the molecules may bring about high activity and selectivity in reactions with receptors.Many conformationally hindered and rigid amino acids, and peptide-mimics and synthetic peptides based on them, have been synthesized [1]. However there are few data on conformationally rigid cyclic amino acids containing the 3,7-diazabicyclo[3,3,1]nonane unit. Most of the publications are concerned with the synthesis of amino acids by functionalization of the natural alkaloid cytisine at the N-12 atom [2-4]. The paper [5] must also be noted in which two examples of unnatural amino acids of the 3,7-diazabicyclo[3,3,1]nonane series were synthesized by the reaction of glycine and L-alanine with paraformaldehyde and dibenzyl ketone.The high physiological activity (anticancer [6], antiarrhythmic [7], insecticidal [8], etc.) of derivatives of 3,7-diazabicyclo[3,3,1]nonane predetermines the development of new methods and principles for the preparation of amino acids of unnatural origin, containing the 3,7-diazabicyclo[3.3.1]nonane unit which are of interest from the point of view of developing pharmaceutical preparations. One of the possible methods for the synthesis of nitrogenous heterocycles is the reaction of CH-acids with aldehydes and primary amines, on the basis of which we developed methods for the preparation of derivatives of 1,5-dihydro-3,7-diaza-bicyclo[3,3,1]nonane [9, 10] and 9-thia-3,7-diazabicylo[3,3,1]nonane 9,9-dioxide [11].

The Synthesis of (2R)-Aziridine-2-carboxylic Acid Containing Dipeptides

“…1 H NMR spectra was found to be identical to the ones described in ref. 19 Benzyl (R)-1-((tert-butoxycarbonyl)-D-alanyl)aziridine -2-carboxylate (11) The compound was synthesized according to the general procedure A. The product was purified via flash column chromatography (hexane:EtOAc = 3:1), yielding 0.471 g (25.7%) of 11 as viscous oil.…”

“…In addition, this heterocyclic fragment has also been incorporated in numerous synthetic peptides as reactive electrophilic warheads to obtain promising irreversible inhibitors of different proteases, such as cathepsins, 13,14 papain, 15 aspartate proteases, 16 HIV proteases 17 and SARS-CoV main protease. 18 Their unusual reactivity due to ring strain renders aziridine-2-carboxylic acid derivatives important for the preparation of amino acids, [19][20][21] amino alcohols, 22,23 peptides and other peptide-like compounds. 17,[24][25][26][27][28][29][30][31][32][33] In addition, they have also been used for labelling biomolecules with fluorine-18.…”

Effect of aliphatic alcohols on the reaction of acetoacetic ester with formaldehyde and primary amines

“…Formaldehyde and primary amines are widely used in organic synthesis for preparation of tetrahydro-1,3oxazines [1,2], hexahydropyrimidines [1][2][3][4][5][6], 3-azaand 3,7-diazabicyclo[3.3.1]nonanes [7][8][9][10][11][12], as well as 1,3,5-hexahydrotriazines [13]. Specimens of compounds of this series possess a wide spectrum of biological activity [14][15][16][17] (antimicrobial, antiviral, antitumor, etc.)…”