Chemical Conversion of Cyclic .ALPHA.-Amino Acids to Cyclic .ALPHA.-Aminophosphonic Acids.

Abstract

a-Aminophosphonic acids are believed to be phosphorus analogs of naturally occurring a-amino acids and have found applications as potent active compounds with a wide range of biological activities as antibiotics, 1) enzyme inhibitors,2) pharmacological agents, 2b,3) antiviral agents, 4) and herbicides.5) Their negligible mammalian toxicity, and the fact that they bear a very close chemical resemblance to their amino carboxylic counterparts, make them remarkably important structural units of phosphonopeptides and peptidomimetics.6) During the last two decades, considerable efforts toward the synthesis of a-aminophosphonic acids have been made. 7) However, a simple and general synthetic method for cyclic amino-type of compounds, such as phosphonic acid analogs of 2-pyrrolidinecarboxylic acid (proline) and 2-piperidinecarboxylic acid, is not relatively known, and most of the reported methods are about acyclic compounds. The cyclic analogues can be viewed as useful tools for the elucidation of conformational requirements of a receptor, since the conformation is easily fixed. Many synthetic routes to a-aminophosphonic acids and their derivatives include a key step of nucleophilic phosphonylation to either performed or in situ generated imines (Schiff bases) or iminium ions. 8)Shono 9) and co-workers reported the phosphonylation of Nprotected 2-methoxyamines using trialkyl phosphites in the presence of Lewis acids. Similar transformation of 2-benzotriazolylpyrrolidine derivatives into pyrrolidine-2-phosphonic acid esters was reported by Katritzky 10) and co-workers. We wish to report herein the convenient conversion of cyclic aamino acids to cyclic a-aminophosphonic acids through the corresponding N-protected 2-hydroxyamines, with which easy generation of acyliminium ions in the presence of Lewis acids would be expected. To our knowledge, only a few studies concerning the chemical conversion of naturally occurring cyclic a-amino acid (proline or proline-containing dipeptide) into the corresponding phosphonic acid analogues have been published, 11,12) and these are not systematic or detailed studies. In this paper, we describe a systematic study on a simple route to a series of phosphonic acid analogues from proline and 2-piperidinecarboxylic acid, as illustrated in Chart 1.Initially, we examined the transformation of commercially available cyclic a-amino acids (1, 2) into the key intermediates of cyclic N-protected 2-hydroxyamines (5, 6). Displacement of the carboxylic acid moiety by hydroxy group or its equivalents such as acetoxy group had been realized by using two methods of oxidative decarboxylation: lead tetraacetate [Pb(OAc) 4 ] oxidation 13) of carboxylic acids and m-chloroperbenzoic acid (m-CPBA) oxidation 14) of active esters. We applied these methods to N-protected amino acids (3a-e, 4a-c) and their active esters (3f, g), as summarized in Table1. L-Proline derivatives (3a-e) having various N-protecting groups were oxidized with Pb(OAc) 4 to the desired 2-hydroxy compounds (5a-e) in good yields. N-Benzoyl (B...

Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity

“…The obtained 2-hydroxypyrrolidines 215 are then converted to the corresponding phosphonates 217 by a reaction with trialkyl phosphite in the presence of trimethylsilyl triflate as a Lewis acid. As mentioned before, an intermediate iminium ion is formed, to which the phosphite adds (Scheme ) 51 …”

“…Using Lewis acids, it is also possible to substitute a methoxy or hydroxy function by trialkyl phosphite (see section 4.3). − , …”

The Synthesis of α-Aminophosphonates via Enantioselective Organocatalytic Reaction of 1-(N-Acylamino)alkylphosphonium Salts with Dimethyl Phosphite

“…It seems natural that α-amino acids should be the most frequently used substrates for the synthesis of α-aminophosphonic acids. However, to the best of our knowledge, only a few methods for the transformation of α-amino acids into their phosphonic analogues have been reported so far [12][13][14][15][16][17][18][19][20][21][22][23][24]. Furthermore, only five of them can be classified as stereoselective processes.…”

Practical and Efficient Synthesis of α-Aminophosphonic Acids Containing 1,2,3,4-Tetrahydroquinoline or 1,2,3,4-Tetrahydroisoquinoline Heterocycles

“…This class of compounds is currently attracting interest in organic and medicinal chemistry, due to their important biological and pharmacological properties [9,10,11,12]. The great importance of this type of compound has prompted organic chemists to report numerous procedures for their racemic or stereoselective synthesis [13,14,15,16,17,18], principally using the diastereoselective and enantioselective Pudovik [19,20] and Kabachnik–Fields [21,22,23,24,25] reactions for acyclic α-aminoalkylphosphonates, and through N -acyl iminium ions for the synthesis of cyclic derivatives [26,27,28,29,30,31,32,33,34]. However, to the best of our knowledge, the synthesis of 1,2,3,4-tetrahydroquinoline-2-phosphonic acid 4 and 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid 5 analogues [35,36,37,38] has not yet been described in the literature, whereas the synthesis of 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid 6 has been recently described by our research group [39,40] (Figure 1).…”