Synthesis of Phosphonic Acids Related to the Antibiotic Fosmidomycin from Allylic α- and γ-Hydroxyphosphonates

Abstract

Fosmidomycin is the most active compound of a group of natural phosphonic acid antibiotics bearing a unique hydroxamic acid functionality in the γ-position¹. We present here two efficient and novel routes to precursors and analogues of these compounds.     

Phosphonic analogues of morphactines

Abstract

Derivatives of 9-aminofluorene-9-phosphonic acid and 9-aminofluorene-9-phosphinoxides, the phosphonic analogues of morphactines, were synthesized. All the obtained compounds showed marked morphactin-like activity against test plants: Spirodela oligorrhiza and Lepidium sativum.     

Herbicidal Activity of Phosphonic,Phosphinic and Phosphinous Acid Analogues of Aromatic Amino Acids

Abstract

Over 40 phosphonic, phosphinic and phosphinous acid analogues of phenylglycine and phenylalanine were synthesized and screened for their herbicidal activity on Lepidium sativum (crest) and Cucumis sativus (cucumber). The most active appeared to be 2-amino-1-hydroxy-3-phenylpropylphosphonic acid which was equipotent with popular herbicide glyphosate. Also aminobenzylphosphonic acids, analogues of phenylglycine, exhibited notable herbicidal activity and thus represent a group of the most active herbicides found among simple aminophosphonic acids. Other compounds showed moderate herbicidal activity. Preliminary results indicate that analogues of aromatic amino acids display their activity as effectors of biosynthesis of aromatic amino acids.     

New Synthesis of Substituted Cyclopropanephosphonic Acid Esters

Abstract

Aminocyclopropane phosphonic acids are considered to be “transition state analogues” of aminocyclopropanecarboxylic acids and they may serve as enzyme inhibitors¹. We attempted to synthesise aminocyclopropane derivatives by a new route². Phosphonoacetic acid allylic esters were subjected to an intramolecular, radical cyclisation in the presence of iodine, solid potassium carbonate and phase transfer catalyst.     

Synthesis of Novel 2‐Vinylcyclopropane Phosphonic Acids

2‐Vinylcyclopropane‐1‐phosphonic acid diesters 1a–d were synthesized by the reaction of trans‐1,4‐dibromo‐2‐butene with α‐substituted phosphonic acid diesters. Esterification of 1‐ethoxycarbonyl‐2‐vinylcyclopropane‐1‐carboxylic acid with dimethyl 2‐hydroxyethyl‐phosphonate gave the 2‐vinylcyclopropane phosphonic acid dimethylester 1e. The silylation of phosphonic acid diesters 1a–e by halotrimethylsilanes followed by solvolysis with methanol or water resulted in the formation of phosphonic acids 2a–e. In the case of steric hinderance of the phosphoryl group, monoesters 3c,d were also formed. Furthermore, ethyl carboxylate 1b could be chemoselectively cleaved by aqueous potassium hydroxide to carboxylic acid 4.     

Isosteres of Natural Phosphates. Methylene and Hydroxyrnethylene Analogues of Tyrosine O-Phosphate

Abstract

The ability of phosphonic acid analogues isosteric with natural phosphate esters to Serve as inhibitors of enzymatic phosphate hydrolysis has been documented in a wide variety of systems.¹ The use of such an analogue in place of the natural phosphate ester provides a functionality which the enzyme may not be able to distinguish from the natural ester, but which is incapable of being hydrolyzed. In some instances the use of hydroxymethylene analogues has resulted in a greater degree of recognition, and resultant inhibition of hydrolytic activity, than the simple methylene analogues.² On this basis, the methylene and hydroxymethylene analogues of tyrosine O-phosphate appear to be reasonable candidates to Serve as inhibitors for phosphoprotein phosphatases and alkaline phosphatase, and as probes for biological mechanisms.     

Synthesis of Phosphonoindoprofen

Two synthetic routes to phosphonic analogues of indoprofen, a nonsteroidal anti-inflammatory drug, were developed by the cyclization of aniline 2 (method A) and by the Arbuzov reaction of corresponding alkylchloride 3 with triethylphosphite (method B).     

New crystal structures of fluorinated α-aminophosphonic acid analogues of phenylglycine

The four novel phosphonic acid analogues of phenylglycine with various substituents in phenyl ring (mostly fluorine atoms) have been synthesized by using procedure of amidoalkylation of phosphorus trichloride with aromatic aldehydes and acetamide. The NMR, ESI-MS spectroscopy, and single-crystal X-Ray diffraction methods were used to characterize unusual structures: the amino-(4-trifluoromethylbenzyl)-(1), amino-(3,4-difluorobenzyl)-(2), amino-(2,4,6-trifluorobenzyl)-(3), and amino-(2-fluoro-4-hydroxybenzyl)-(4) phosphonic acids. Since the α-aminophosphonates have a potential for biological activity and could be used as building blocks in medicinal chemistry, it is important to know their detail crystal structures and properties which, in turn, may extend the knowledge on their interaction with physiologic receptors.

     

A Straightforward Synthesis of Six‐Membered‐Ring Heterocyclic α‐Aminophosphonic Acids from N‐Acyliminium Ions

A convenient synthesis of phosphonic analogues of pipecolic acid and its heterocyclic analogues is reported. The major step of the elaborated procedure is the introduction of the phosphonate group into the skeleton of the appropriate cyclic amide through N‐acyliminium ions. The former ones were obtained by preparation of the hemiaminals or their methyl ethers from the N‐protected cyclic amides. Finally, the reaction with trimethyl phosphite in the presence of BF₃·OEt₂ afforded the desired phosphonates, which were converted into phosphonic acids by the hydrolysis of phosphonate moiety with simultaneous cleavage of the nitrogen protecting groups.     

Comparison of Phosphonic and Pyrophosphonic Acids as Collectors for the Cassiterite Flotation

Abstract

Styryl phosphonic acid (SPA) is a collector used in the industrial flotation of cassiterite, During its production from styrene and PCl₅ by-products are formed in different amounts. One of these is condensed SPA caused by uncomplete hydrolysis of the intermediary phosphonic acid chloride. Attempts were made to synthesize definite forms of condensed SPA in order to study their influence on the results of flotation. Conventional methods-partial hydrolysis of phosphonic acid chlorides or reaction of acid chlorides with the free acid-did not lead to the desired result. Diammonium salt of the pyro-SPA was obtained by the method of (1) using dehydration of phosphonic acid by heating with urea. A series of analogous aromatic pyro-phosphonic acids was synthesized. The hydrophobization effect on Sn0₂ surfaces was studied by microflotation tests in a modified Hallimond tube. Pyrophosphonic acids are more hydrophobic than the corresponding phosphonic acids. The results of the microflotation experiments were confirmed by batch flotation tests with a natural tin ore in a 2–1 cell. The Sn recovery was higher with the pyro compounds.     

Synthesis of a Novel Bisphosphonic Acid Alkene Monomer

The convenient, scaleable synthesis of a novel ?-fluorinated bisphosphonic acid, incorporating a tethered acrylamide monomer, [1-fluoro-1-phosphono-7-(prop-2-enamido)heptyl]phosphonic acid (1), is described. The α–fluorine substituent offers the advantage (compared to an α–hydroxy) of compatibility with basic conditions in tetraester intermediates (avoiding phosphonate-phosphate rearrangement) while maintaining a phosphonic acidity that mimics that of pyrophosphoric acid. Sodio tetraisopropyl methylenebis(phosphonate) was monoalkylated with 1,6-dibromohexane and fluorinated with Selectfluor. An ω-nitrogen atom was introduced into the tether via incorporation of a phthalimide group, which as a UV-visible chromophore facilitated purification. Subsequent removal of the ester (HCl) and phthalimide (hydrazine) groups yielded ?–F, ω-aminohexyl methylenebis(phosphonic acid), which was reacted with acryloyl chloride at pH 8-9, then treated with HCl to give 1.     

Phospha-Pharmaca - Antibacterial and Virucidic Compounds

Abstract

Synthetic, antibacterial, and antiviral aspects of the P-glutamic acid type compounds, of phosphonic acids, phospha -peptides, and of phosphorus derivatives of the formic acid are considered.     

Alkylester und N,N-Dimethylaminoethylester unsymmetrischer Phosphinsäuren

Summary The phosphinic acid chlorides6 and9 react in good yields with N,N-dimethylaminoethanol to the corresponding esters3 and10. Reaction of the phenylphosphonous acid esters1 and2 with arylbromides, heteroarylbromides and carboxylic acid chlorides give esters of unsymmetrical phosphinic acids. Similarly, cyanphenylphosphinic acid ethylester reacts with aliphatic amines to phosphonic acid esterchlorides.

     

Sodium and Onium Persorate Salts as Decontaminants of Neutotoxic Organophosphorus Compounds

Abstract

We compare the Sodium Perborate and various Phosphonium and Ammonium Perborates in their abilities to hydrolyse a series of phosphoric and phosphonic acid esters [OP].     

Synthesen der Phosphono- bzw. Phosphino-Analoga des Pantothensäure-ethylesters und des Phosphono-Analogons des Pantetheins

Syntheses of Phosphonic- and Phosphinic Analogues of Pantothenic Acid Ethyl Ester and of the Phosphonic Analogue of Pantetheine The replacement of amino acids in peptides by phosphono-analogous (aminoalkyl)phosphonic acids 1 , (2-aminoethyl)phosphonic acid ( 2 ) and substituted derivatives has been an important aspect of peptides research in the last years. In pantothenic acid ( 3 ), there is a peptide linkage between (2R)-2,4-dihydroxy-3,3-dimethylbutyric acid and the amino group of β-alanine, and in pantetheine ( 4 ), there is a second peptide linkage between the β-alanine and cysteamine. The synthesis of phosphono and phosphino analogues of pantothenic acid ethyl ester, where the β-alanine is replaced by the diethyl ester of (2-aminoethyl)phosphonic acid and the ethyl ester of (2-aminoethyl)methylphosphonic acid, respectively, and the syntheses of the phosphono analogue of pantetheine, where the β-alanine is replaced by (2-aminoethyl)phosphonic acid, are described.     

Crown Ethers with Three- and Four-Coordinated Phosphorus Atom in the Cycle

Abstract

Starting from phosphonic, phosphorous, phosphonous and phosphoric acid chlorides new crown ethers with three- and four-coordinated phosphorus atom in the cycle were formed.     

Über eine Reaktion von o-Hydroxybenzylalkoholen mit Estern von Säuren des Phosphors mit der Koordinationszahl 3

Abstract

o-Hydroxybenzyl alcohol reacts with trimethyl phosphite under smooth conditions to o-hydroxyphenylmethane phosphonic acid dimethyl ester. This unusual reaction is of widest applicability. Derivatives of o-hydroxybenzyl alcohol independent of type, number or position of substituents in the ring, react with alkyl esters of phosphorous, phosphonous or phosphinous acids in an analogous process, forming the corresponding o-hydroxyphenylmethane phosphonic or phosphinic esters or phosphine oxides.     

Asymmetric Synthesis of α-Amino Phosphonic Acids Employing the Condensation of Nitrones with Phosphite Derivatives

Abstract

Chiral α-amino phosphonic acid derivatives were synthesized by condensing an enantiomerically homogeneous diazasilyl phosphite with a series of prochiral nitrones. The reactions proceed under mild conditions with moderate to high enantioselectivities and good yields.     

Preparation of Novel Piperidine Phosphinic Acid Analogues of the Inhibitory Neurotransmitter γ-Aminobutyric Acid (GABA)

Abstract

Novel pipendine phosphinic, methylphosphinic and phosphonic acids were synthesized (5a-5c and 6 in the figure). The acids are bioisosteres of the corresponding carboxylic acid isonipecotic, which is a GABAA agonist.     

SIMPLE AND IMPROVED PREPARATION OF α-OXOPHOSPHONATE MONOLITHIUM SALTS

Some α-OxoPhosphonate monolithium salts were synthesized by a facile one-step procedure. In this way, α-(2,4-dichlorophenoxyacetoxy)alkyl phosphonic acid dimethyl esters 5 can be transformed into the corresponding phosophonate monolithium salts 6 without influence on the carboxylic ester group under mild conditions.