Synthesis of 1-aminoalkylphosphinic acids. Part 2. An alkylation approach

Abstract

Aminomethylphosphinic acid ( 7 ) , protected at nitrogen as the imine derived from benzophenone and at phosphorus as the diethylacetal and ethyl ester [i.e. (6)], undergoes facile LDA-induced alkylation. Treatment with primary alkyl halides affords, on product hydrolysis, a versatile route to phosphinic analogues of or-amino carboxylic acids. Analogues of alanine, valine, leucine, phenylalanine, tyrosine, histidine, and aspartic and glutamic acids are thus prepared; the phosphonic histidine analogue (23b) can be prepared similarly from the imine phosphonate diester (21 ). Intra-and inter-molecular dialkylation reactions provide analogues of 1 -aminocyclopropanecarboxylic acid (1 4) and 2,6diaminoheptanedioic acid (1 6). Benzyl bromide alkylation of (25a) and (30a), where the nitrogen is protected as the imine of the 2-hydroxypinan-3-one chiral auxiliary (24) or (29), is diastereospecific leading to asymmetric synthesis of either (+)-or (-)-phenylalanine analogues; this selectivity is compared to that shown by the corresponding chiral imine phosphonate (25b) and imine carboxylate (25c).In a previous paper from these laboratories,' the synthesis of a-amino phosphinic acids (1)$ was described by addition of phosphinic acid to the imine derived from an aldehyde and benzhydrylamine followed by hydrolysis (Scheme 1). It was rationalised that this class of compound would be the closest phosphorus analogue to the a-amino carboxylic acids.The previous method depends upon the availability of a suitable precursor aldehyde, and these compounds are not always readily prepared. An alternative synthetic strategy can be envisaged by alkylation of a suitably protected aminomethylphosphinic acid. This method is well known for synthesis of a-amino carboxylic acids and or-amino phosphonic and we now demonstrate that it can also be applied to synthesizing a-amino phosphinic acids (1).

Phosphinic Peptide Matrix Metalloproteinase-9 Inhibitors by Solid-Phase Synthesis Using a Building Block Approach

“…Neither the method by Baylis et al [57] nor the most recently described preparation [58] were successful in our hands. Therefore, a third procedure [59,60] was attempted and proved to be successful. Thus, reaction of ethyl (diethoxymethyl)phosphinate [61,62] with 1,3,5-(diphenylmethyl)-hexahydro-s-triazine [57] followed by complete deprotection with concentrated aqueous HBr gave the desired compound 2 a.…”

Rapid and Efficient Synthesis of Unsymmetrical Phosphinic Acids R′P(O)OHR″

“…[5] Of the many phosphorus compounds, phosphinic acids are increasingly being used in peptidomimetic design. [6,7] It has been shown that these pseudopeptides are transition-state analogue inhibitors of peptidases and in this role they are typically tightly binding and specific. [8][9][10] From the simplest starting materials, hypophosphorous acid (H 3 PO 2 ), the synthesis of phosphinic-containing molecules requires the formation of two P-C bonds.…”

“…New reactions are continuously being developed for the efficient synthesis of such compounds. [11,12] However, most of the methods reported for their preparation are not general and suffer from severe limitations: [7,13] A large excess of reagents, the direct formation of symmetrical dialkylphosphinate or the instability and handling difficulties of the starting materials. Thus, new methods using more general and milder conditions are required to allow the preparation of functionalized dialkylphosphinates.…”

Synthesis of phosphinic acids on the basis of hypophosphites: IV. Synthesis of pseudo-γ-glutamylglycine and its enantiomers

“…In this connection elaboration of convenient synthetic approaches to phosphine analogs of peptides is a prospective route to potentially physiologically active compounds [335]. The synthesis of the aminoalkylphosphonous component, that forms the first phosphorus3carbon bond, has been satisfactorily developed [9,10]. In this case, the synthesis of component B requires introduction of protective groups both to the nitrogen and phosphorus ÄÄÄÄÄÄÄÄÄÄÄÄ 1 For communication III, see [1].…”

“…In this case, the synthesis of component B requires introduction of protective groups both to the nitrogen and phosphorus ÄÄÄÄÄÄÄÄÄÄÄÄ 1 For communication III, see [1]. atoms and consists of three or four steps [9,10]. The synthesis of the pseudopeptide fragment, that forms the second phosphorus3carbon bond, most commonly involves the addition of silyl esters of aminoalkylphosphonous acids to acrylates by the procedure in [11].…”