Phosphinic Acid Derivatives Research Articles

Palladium catalyzed cross-coupling reactions for phosphorus-carbon bond formation.

Underappreciated in the realm of palladium catalyzed cross-coupling chemistry is the formation of phosphorous-carbon bonds. This tutorial review summarises a collection of important contributions in the area, providing a flavour of the many types of phosphorus species that are participants in palladium catalyzed phosphorus-carbon bond formation. Recent developments include the usage of the cross-coupling reaction for preparation of phosphine ligands and the involvement of low molecular weight phosphinic acid derivatives for the synthesis of unsaturated phosphinic and phosphonic acid derivatives. Mechanistic cycles are offered in some instances. Stereochemical issues are addressed where applicable. The literature is covered to mid 2003.

Synthesis and structural studies (1H,13C,31P NMR and X-ray) of new C-bonded cyclotriphosphazenes with heterocyclic substituents from novel phosphinic acid derivatives

Three new C-bonded cyclotriphosphazenes, [N3P3(2-thienyl)6], 2, [N3P3(3-thienyl)6], 4, and [N3P3(3,3′-bithienyl-2,2′-ylene)3], 6, have been prepared by two new synthetic procedures and are the first examples of non-spiro and trispirocyclotriphosphazene derivatives composed of thiophene and 3,3′-dithiophene substituents, respectively. Their 1H, 13C and 31P NMR parameters are given. The solid state structures of 2, 4 and 6 have been determined by X-ray crystallography.

Structure and function of the Mur enzymes: development of novel inhibitors.

One of the biggest challenges for recent medical research is the continuous development of new antibiotics interacting with bacterial essential mechanisms. The machinery for peptidoglycan biosynthesis is a rich source of crucial targets for antibacterial chemotherapy. The cytoplasmic steps of the biosynthesis of peptidoglycan precursor, catalysed by a series of Mur enzymes, are excellent candidates for drug development. There has been growing interest in these bacterial enzymes over the last decade. Many studies attempted to understand the detailed mechanisms and structural features of the key enzymes MurA to MurF. Only MurA is inhibited by a known antibiotic, fosfomycin. Several attempts made to develop novel inhibitors of this pathway are discussed in this review. Three novel inhibitors of MurA were identified recently. 4-Thiazolidinone compounds were designed as MurB inhibitors. Many phosphinic acid derivatives and substrate analogues were identified as inhibitors of the MurC to MurF amino acid ligases.

Reactions of 3′-C-Halomethyl and 3′-C-Sulfonylmethyl Uridines with Phosphinic Acid Derivatives − Synthesis of Building Blocks for Oligonucleotides Containing 3′-C-Methylenephosphonate Linkages

An efficient method for the synthesis of nucleoside 3′-C-methylenephosphinates, building blocks for oligo(ribonucleoside methylenephosphonate)s, has been developed. Treatment of bis(trimethylsilyl)hypophosphite (BTSP) with a 3′-deoxy-3-C-(iodomethyl)uridine resulted both in substitution to give the corresponding 3′-C-methylenephosphinate and in reduction of the iodomethyl group to afford the uridine 3′-deoxy-3′-C-methyl derivative. Optimisation of solvent and temperature gave a substitution/reduction ratio of 5:4 at best. Through the use of a trifluoromethanesulfonyl leaving group and further optimisation of reaction conditions, however, the triethylammonium 2′-O-(tert-butyldimethylsilyl)-3′-deoxy-5′-O-(4-methoxytriphenylmethyl)uridine-3′-C-methylenephosphinate was obtained in 93% isolated yield. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis of a novel diarylphosphinic acid: a distorted ground state mimic and transition state analogue for amide hydrolysis

We describe herein the synthesis of a new unsymmetrical diarylphosphinic acid, a hapten aimed to produce catalytic antibodies for the hydrolysis of heterocyclic amides. The phosphinate functionality was selected as a mimic both of the tetrahedral intermediate and the transition state of higher energy along the reaction profile. The phenyl and 2,4,6-(trimethyl)-phenyl groups flanking the phosphinate were chosen in order to impose rotation around the P–C bond, a choice supported by ab initio calculations. This new hapten should elicit catalytic antibodies whose binding site could affect the distortion at nitrogen as well as the twist along the N–C(O) bond for heterocyclic amides. This hapten along with a series of new sterically hindered unsymmetrical phosphinic acid derivatives was prepared by a key palladium-catalysed step.

Triethylborane-initiated room temperature radical addition of hypophosphites to olefins: synthesis of monosubstituted phosphinic acids and esters.

A novel and practical approach to monosubstituted phosphinic acid (alkylphosphonous acid) derivatives from hypophosphite salts or esters is described. Phosphorus-centered radical formation is initiated with Et(3)B/O(2), and the reaction is conveniently conducted at room temperature in an open flask. In contrast to previously reported conditions for the radical reaction of hypophosphorous acid and sodium hypophosphite (peroxide initiators, acid catalysis, heat), the method proceeds under neutral conditions and therefore tolerates a wide range of functional groups. Previously inaccessible phosphinic acids can be prepared in a single step from cheap starting materials. Excellent selectivity is observed for monoaddition, and symmetrical dialkyl phosphinates do not form in significant amounts. Monosubstituted phosphinic acids are usually obtained in better than 90% purity by a simple extractive workup; however, isolated yields are diminished if the substituent is polar. Because radicals derived from hypophosphites are electrophilic, the reaction is limited to the use of electron-rich olefins. The reaction conditions can also be employed in the room temperature radical reduction of alkyl halides and provide an exceptionally mild and environmentally friendly alternative to the use of tributyltin hydride. The remarkable mild nature of the reaction conditions allows for the radical reaction of sensitive alkyl hypophosphites to occur, in which case, a catalytic amount of Et(3)B suffices to deliver alkyl phosphinate esters in reasonable yield.

Spontaneous Self-Ionization in the Gas Phase: A Theoretical Prediction

Proton transfer between dimers is associated with strong bases and very good hydrogen bond donors, namely, between very different chemical species. A spontaneous self-ionization and concomitant proton transfer can occur in dimers involving phosphinic acid derivatives (see picture), even when they present the same functional group. It is also possible, by choosing the appropriate substituents, to modulate the degree of the interaction, from a hydrogen bonded complex to an ion pair, without changing the nature of the functional groups involved.

Synthesis, Crystal Structures, and Solution Properties ofN-Methylene(phenyl)phosphinic Acid Derivatives of Cyclen and Cyclam

Synthesis, Crystal Structures, and Solution Properties ofN-Methylene(phenyl)phosphinic Acid Derivatives of Cyclen and Cyclam

ChemInform Abstract: Synthesis of Novel α‐Functionalized Phosphinic Acid Derivatives of Thiophene and the First Crystal Structure of an α‐Hydroxyalkylphosphinate.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of novel α-functionalized phosphinic acid derivatives of thiophene and the first crystal structure of an α-hydroxyalkylphosphinate

Reaction of 2,5-diformylthiophene with Ph2CHNH2 and hypophosphorus acid yields novel α-hydroxy- or α-amino-methylphosphinic acid derivatives depending on reaction conditions; the X-ray structure analysis of diphenylmethylammonium 5-formyl-2-thienyl(hydroxy)methylphosphinate provides the first direct structural information on the α-hydroxyalkylphosphinate class of compounds.

Highly potent and selective inhibitors of endothelin converting enzyme

Phosphinic acid derivatives, represented by structure 1, have been synthesized and evaluated as endothelin converting enzyme (ECE) inhibitors. Several of these compounds (for example, 1b, 1c, and 1f) were found to be potent inhibitors of ECE with a high degree of selectivity against neutral endopeptidase (NEP).

Patent Evaluation Cardiovascular & Renal: Phosphinic acid derivatives as endothelin converting enzyme inhibitors

Patent Evaluation Cardiovascular & Renal: Phosphinic acid derivatives as endothelin converting enzyme inhibitors

Fosinopril: a reappraisal of its pharmacology and therapeutic efficacy in essential hypertension.

Fosinopril is a phosphinic acid derivative which undergoes rapid hydrolysis after oral administration to the active diacid ACE inhibitor fosinoprilat. Cardiotropic effects have been associated with the drug, and the compensatory dual elimination route of fosinopril via renal and hepatic systems offers an opportunity for ACE inhibitor treatment of hypertension in patients with renal or hepatic impairment. Comparative trials of monotherapy with fosinopril 10 to 40 mg/day have demonstrated antihypertensive efficacy equivalent to that of sustained release nifedipine 40 mg/day, hydrochlorothiazide 25 to 50 mg/day, enalapril 5 to 10 mg/day amlodipine 5 to 10 mg/day and sustained release verapamil 240 to 480 mg/day, and superior to that of isradipine 5 mg/day. The efficacy of combination therapy with fosinopril 10 to 20 mg/day and hydrochlorothiazide 12.5 mg/day was significantly superior to that of hydrochlorothiazide alone, tended to be superior to that of fosinopril 20 mg/day alone and was similar to that of sustained release nifedipine 40 mg/day alone. The combination of fosinopril/chlorthalidone 20 to 40/25 mg/day was as effective as propranolol/chlorthalidone 80 to 160/25 mg/day. The incidence of adverse effects associated with fosinopril is low, and cough may possibly occur less often with this drug than with other ACE inhibitors. Fosinopril thus offers an effective and well tolerated option for the treatment of hypertension in adult and elderly patients, including those with renal or hepatic impairment.

Phosphonic acid and phosphinic acid tripeptides as inhibitors of glutathionylspermidine synthetase

A series of phosphonic and phosphinic acid derivatives of glutathione were synthesized as potential inhibitors of glutathionylspermidine synthetase, an essential enzyme in the biosynthesis of trypanothione in trypanosomatids. The compounds showed moderate activity.

C-fluorinated phosphate analogues

C-fluorinated phosphinic acid derivatives RP(O)(OEt)CF 2Br (R=Ph, Me) 2a, b and [RP(O)(OR 1)] 2CF 2 (R =Ph, R 1= Et, H) 3, 4 have been prepared via a Michaelis-Arbuzov reaction. The signs of the scalar coupling constants in the AMX spin system of (EtO) 2P(O)CHFCOOEt (5) formed by the P, F and H of the P-C(H)F unit were determined using spin-tickling techniques.

Recent advances in the stereoselective synthesis of L‐phosphinothricin

AbstractL‐Phosphinothricin, the parent α‐amino acid of the herbicide glufosinate‐ammonium, has been obtained in high enantiomeric purity by three different methods. The stereoselective alkylation of a D‐valine‐derived bis‐lactim ether, followed by the hydrolysis of the heterocyclic intermediate, represents an attractive approach for gram‐scale quantities in the laboratory. Another very efficient access to L‐phosphinothricin consists of the asymmetric hydrogenation of a prochiral α‐acylamido acrylate with a chiral bis‐phosphine‐rhodium catalyst, while the reaction of chiral pre‐built C‐4‐fragments, like L‐vinylglycine or L‐2‐amino‐4‐halobutyric acid, which can be obtained from the inexpensive starting materials L‐aspartic acid and L‐glutamic acid, with (methyl)phosphinic acid derivatives represents a third route which allows the production of nearly enantiomerically pure L‐phosphinothricin.

Phosphinic acid derivatives as baclofen agonists and antagonists in the mammalian spinal cord: an in vivo study

The actions of a series of derivatives of 3-aminopropyl-phosphinic acid as baclofen agonists and antagonists have been examined on the synaptic excitation of neurones by impulses in primary afferent fibres in the lumbar spinal cords of pentobarbitone-anaesthetised cats and rats. Both the pre- and postsynaptic inhibitory actions of microelectrophoretic (-)-baclofen were reduced by similarly administered CGP 35,348, 36,742, 46,381, 52,432, 54,626 and 55,845, the latter being the most potent antagonist. None of these antagonists either decreased or increased the excitability of spinal neurones, and the inhibitory action of GABA was reduced only by local concentrations of antagonists which also reduced the action of piperidine-4-sulphonic acid, a GABAA agonist. Although the weak inhibitory effect of 3-aminopropylphosphinic acid in both the rat and the cat was not reduced by these baclofen antagonists, the pre- and postsynaptic inhibitory effects of 3-aminopropyl-methyl-phosphinic acid (CGP 35,024), which was more potent than (-)-baclofen, were reduced by the antagonists. Like (-)-baclofen, CGP 35,024 was relatively ineffective in reducing transmitter release in the cord from the terminals of excitatory spinal interneurones, the terminals of excitatory tracts in the dorsolateral funiculus and the cholinergic terminals of motor axon collaterals. In both rat and cat cords, receptors for (-)-baclofen could not be demonstrated to be activated by microelectrophoretic GABA, possibly because of the predominantly dendritic location of GABAB receptors. Spinal pre- and postsynaptic baclofen receptors appeared to be pharmacologically similar but differed from those in the higher central nervous system of the rat, where 3-aminopropylphosphinic acid has been reported to be an effective baclofen agonist. The compounds tested, particularly CGP 55,845 and 46,381, will be of use in further investigations of the physiological relevance of baclofen receptors at central synapses where GABA may be the transmitter.

Living cationic polymerization of vinyl ethers by electrophile/lewis acid initiating systems. XII. Phosphoric and phosphinic acids/zinc chloride initiating systems for isobutyl vinyl ether

AbstractPhosphoric and phosphinic acid derivatives (R1R2PO2H; R1, R2 = OPh, OPh; OnBu, OnBu; Ph, Ph; Ph, H) in conjunction with zinc chloride (ZnCl2) led to living cationic polymerization of isobutyl vinyl ether (IBVE) in toluene below 0°C. The number‐average molecular weights (M̄n) of the polymers (M̄n > 2 × 104) were directly proportional to monomer conversion and in excellent agreement with the calculated values assuming that one polymer chain forms per R1R2PO2H molecule. Throughout the reaction, the molecular weight distributions (MWDs) stayed narrow (M̄w/M̄n ⩽ 1.1). A dibasic acid, PhOP (O) (OH)2, coupled with ZnCl2, also induced living cationic polymerization of IBVE where one molecule of the acid generated two living polymer chains. The polymerization by (PhO)2PO2H/ZnCl2 and its model reactions were directly analyzed by 31P and 1H‐NMR spectroscopy. The analysis showed that the acid initially forms the adduct [CH3CH(OiBu)OP(O)(OPh)2], the phosphate linkage of which is in turn activated by ZnCl2 so as to initiate living propagation. The finding thus indicates that (PhO)2PO2H indeed acts as an initiator in the living polymerization. The NMR analysis also suggested that an exchange reaction occurs between the phosphate group at the polymer terminal and the chlorine in ZnCl2. The occurrence of living IBVE polymerization with these various R1R2PO2H/ZnCl2 systems shows that phosphoric and phosphinic acids are another general class of protonic acids which are effective initiators for the living cationic polymerization assisted by Lewis acids. © 1993 John Wiley & Sons, Inc.

Hepato-biliary and renal excretion in mice of charged and neutral gadolinium complexes of cyclic tetra-aza-phosphinic and carboxylic acids

Tissue distribution of 21 new 157 153 Gd complexes was measured at 5 min and 24 hr after an intravenous injection into mice. A complex was judged to be stable in vivo when the percentage of 153Gd retained in the liver and skeleton at 24 hr was comparable with that of 153Gd(DOTA) −. Complexes varied in net charge and lipophilicity and 20 were phosphinic or carboxylic acid derivatives of tetra-aza-cyclo-dodecane. Three anionic, lipophilic complexes were cleared predominantly by the hepato-biliary pathway and were stable in vivo. The remaining 18 complexes were cleared mainly by the kidneys. Of these 18, 1 anionic, 8 neutral, and 3 cationic complexes were stable in vivo. These findings augur well for the future of hepato-biliary and general purpose Gd contrast enhancing agents for MRI.

Biosynthetic Mechanisms of C-P Bond Formation of Bialaphos.

Bialaphos (BA) is a tripeptide produced by Streptomyces hygroscopicus SF-1293 and is characterized by the presence of a unique C-P-C bond. Through the biosynthetic studies on BA we have revealed the involvement of three enzymes catalyzing different C-P bond formation mechanisms. Two of them, phosphoenolpyruvate phosphomutase (PEP phosphomutase) and carboxyphosphonoenolpyruvate phosphonomutase (CPEP phosphonomutase), have been purified and characterized to catalyze the reactions of a similar type, i.e., intramolecular rearrangements of phosphate esters to form a C-P bond. On the other hand, the remaining one catalyzes P-methylation of phosphinic acid derivatives. In order to reveal these enzymatic properties in more detail, the corresponding genes were identified in the biosynthetic cluster of BA and then expressed in S. lividans. Introduction of PEP phosphomutase or CPEP phosphonomutase gene into S. lividans using pIJ680 resulted in efficient expression of the corresponding enzymes. On the other hand, the P-methylation enzyme was only expressed in S. lividans when the gene was under control of a thiostrepton-inducible strong promoter of pAK114.