Phosphinic Analogues Research Articles

Synthesis and Biological Activity of Homohypotaurine Obtained by the Enzyme-Based Conversion of Homocysteine Sulfinic Acid Using Recombinant Escherichia Coli Glutamate Decarboxylase.

l-Homocysteine, formed from S-adenosyl methionine following demethylation and adenosine release, accumulates when the methionine recycling pathway and other pathways become impaired, thus leading to hyperhomocysteinemia, a biomarker in cardiovascular diseases, neurological/psychiatric disorders, and cancer. The partial oxidation of the l-homocysteine thiol group and its decarboxylation on C-alpha lead to the formation of l-homocysteinesulfinic acid (l-HCSA) and homohypotaurine (HHT), respectively. Both compounds are not readily available from commercial suppliers, which hinders the investigation of their biological activities. Herein, the chemical synthesis of l-HCSA, from l-homocystine, was the starting point for establishing the bio-based synthesis of HHT using recombinant Escherichia coli glutamate decarboxylase (EcGadB), an enzyme already successfully employed for the bio-based synthesis of GABA and its phosphinic analog. Prior to HHT synthesis, kcat (33.92 ± 1.07) and KM (38.24 ± 3.45 mM) kinetic constants were determined for l-HCSA on EcGadB. The results of our study show that the EcGadB-mediated synthesis of HHT can be achieved with good yields (i.e., 40% following enzymatic synthesis and column chromatography). Purified HHT was tested in vitro on primary human umbilical vein endothelial cells and rat cardiomyoblasts and compared to the fully oxidized analog, homotaurine (OT, also known as tramiprosate), in widespread pharmaceutical use. The results show that both cell lines display statistically significant recovery from the cytotoxic effects induced by H2O2 in the presence of HHT.

Chemistry of ruthenium complexes with hexamethylbenzene and butadienesulfonyl ligands: Synthesis and reactivity toward phosphites and silver triflate

The addition reaction of (η6-C6Me6)Ru(Cl)(1-2,5-η-CH2CHCHCHSO2) (1) with one equivalent of P(OMe)3 or P(OPh)3 led to the formation of the corresponding compounds (η6-C6Me6)Ru(Cl)(5-η-SO2CHCHCHCH2)(P(OR)3) (R = Me, 4a; Ph, 4b). After 4a and 4b lose AgCl in presence of AgOTf, the immediate coordination of the terminal double bond of the butadienesulfonyl ligand affords the corresponding cationic complexes [(η6-C6Me6)Ru(1-2,5-η-CH2CHCHCHSO2)(P(OR)3]OTf (R = Me, 5a; Ph, 5b). The alternative metathesis reaction between dichlorido compounds (η6-C6Me6)Ru(Cl)2(P(OR)3) (R = Me, 2a, Ph, 2b) and the potassium butadiene sulfinate K(SO2CHCHCHCH2) (3) was only successful in the case of 4a. The 1H, 13C{1H} NMR data of 4a and 4b are consistent with a butadienesulfonyl ligand coordinated preferentially as an S conformer, while only traces of the thermodynamic W conformer have been seen in solution for 4a. The single crystal analysis of neutral 4a and cationic 5b reveals the presence of the butadienesulfonyl ligand binding to ruthenium exclusively through the sulfur atom in the case of 4a, while in 5b, the coordination of the terminal double bond to the metal center also occurs. A comparative study of the influence of the phosphite and phosphine ligands on analogue isoelectronic molecular structures with the η6-C6Me6 and η5-C5Me5 anchored ligands is analyzed. The high stability of 2a and 2b is corroborated and compared to the phosphine analogues. The single crystal of 2b is also discussed.

Electrosynthesis of iminophosphoranes and applications in nickel catalysis.

P(v) iminophosphorane compounds are accessed via electrochemical oxidation of commercially available P(iii) phosphines, including mono-, di- and tri-dentate phosphines, as well as chiral phosphines. The reaction uses inexpensive bis(trimethylsilyl)carbodiimide as an efficient and safe aminating reagent. DFT calculations, cyclic voltammetry, and NMR studies provide insight into the reaction mechanism. The proposed mechanism reveals a special case of sequential paired electrolysis. DFT calculations of the frontier orbitals of an iminophosphorane are compared with those of the analogous phosphines and phosphine oxides. X-ray crystallographic studies of the ligands as well as a Ni-coordination complex provide structural insight for these ligands. The utility of these iminophosphoranes as ligands is demonstrated in nickel-catalyzed cross-electrophile couplings including C(sp2)-C(sp3) and C(sp2)-C(sp2) couplings, an electrochemically driven C-N cross-coupling, and a photochemical arylative C(sp3)-H functionalization. In some cases, these new ligands provide improved performance over commonly used sp2-N-based ligands (e.g. 4,4'-di-tert-butyl-2,2'-bipyridine).

Theoretical Insight into the Effect of Phosphorus Oxygenation on Nonradiative Decays: Comparative Analysis of P-Bridged Stilbene Analogs.

Incorporation of the phosphorus element into a π-conjugated skeleton offers valuable prospects for adjusting the electronic structure of the resulting functional π-electron systems. Trivalent phosphorus has the potential to decrease the LUMO level through σ*-π* interaction, which is further enhanced by its oxygenation to the pentavalent P center. This study shows that utilizing our computational analysis to examine excited-state dynamics based on radiative/nonradiative rate constants and fluorescence quantum yield (ΦF) is effective for analyzing the photophysical properties of P-containing organic dyes. We theoretically investigate how the trivalent phosphanyl group and pentavalent phosphine oxide moieties affect radiative and nonradiative decay processes. We evaluate four variations of P-bridged stilbene analogs. Our analysis reveals that the primary decay pathway for photoexcited bis-phosphanyl-bridged stilbene is the intersystem crossing (ISC) to the triplet state and nonradiative. The oxidation of the phosphine moiety, however, suppresses the ISC due to the relative destabilization of the triplet states. The calculated rate constants match an increase in experimental ΦF from 0.07 to 0.98, as simulated from 0.23 to 0.94. The reduced HOMO-LUMO gap supports a red shift in the fluorescence spectra relative to the phosphine analog. The thiophene-fused variant with the nonoxidized trivalent P center exhibits intense emission with a high ΦF, 0.95. Our prediction indicates that the ISC transfer is obstructed owing to the relatively destabilized triplet state induced by the thiophene substitution. Conversely, the thiophene-fused analog with the phosphine oxide moieties triggers a high-rate internal conversion mediated by conical intersection, leading to a decreased ΦF.

Synthesis, characterization, computational studies, and reactivity of platinum(II) complexes of alkyl phosphite ligands

Air-stable phosphite-ligated platinum complexes of the form cis-Pt(P(OR)3)2Cl2 and cis-Pt(P(OR)3)2Me2 based on five small alkyl phosphite ligands have been synthesized and characterized. The crystal structures for several of these species are reported, allowing for comparison between spectroscopic and structural parameters. Michaelis-Arbuzov-type dealkylation during synthesis was observed for some of the phosphite ligands, and a dealkylated product was structurally characterized. Density Functional Theory (DFT) and Quantum Theory of Atoms in Molecules (QTAIM) was also used to examine the electronic structure of the phosphite compounds. The QTAIM results support the increased π-acidity of the phosphite ligands compared to analogous phosphines. Thermolysis experiments were performed to examine the stability and reactivity of Pt(P(OR)3)2X2 species. It was found that coordinated P(OiPr)3 ligands decompose via cyclometallation and propylene extrusion.

Determination of molecular hydration in solution via changes in magnetic anisotropy.

The hydration behaviour of coordination complexes is important for understanding their roles as bio-imaging agents. Determination of hydration is difficult, and various optical and NMR-based techniques have been used. Here we use EPR spectroscopy to unambiguously demonstrate that a t-butyl-pyridyl-functionalised ErIII DOTA derivative coordinates water, while its methylphosphinate analogue does not.

The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I

Processing of N-terminally elongated antigenic peptide precursors by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is a key step in antigen presentation and the adaptive immune response. Although ERAP1 can efficiently process long peptides in solution, it has been proposed that it can also process peptides bound onto Major Histocompatibility Complex I molecules (MHCI). In a previous study, we suggested that the occasionally observed “ontο MHCI” trimming by ERAP1 is likely due to fast peptide dissociation followed by solution trimming, rather than direct action of ERAP1 onto the MHCI complex. However, other groups have proposed that ERAP1 can trim peptides covalently bound onto MHCI, which would preclude peptide dissociation. To explore this interaction, we constructed disulfide-linked MHCI-peptide complexes using HLA-B*08 and a 12mer kinetically labile peptide, or a 16mer carrying a phosphinic transition-state analogue N-terminus with high-affinity for ERAP1. Kinetic and biochemical analyses suggested that while both peptides could access the ERAP1 active site when free in solution, they were unable to do so when tethered in the MHCI binding groove. Our results suggest that MHCI binding protects, rather than promotes, antigenic peptide precursor trimming by ERAP1 and thus solution trimming is the more likely model of antigenic peptide processing.

Selectivity of Rh⋅⋅⋅H-C Binding in a σ-Alkane Complex Controlled by the Secondary Microenvironment in the Solid State.

Single‐crystal to single‐crystal solid‐state molecular organometallic (SMOM) techniques are used for the synthesis and structural characterization of the σ‐alkane complex [Rh(tBu2PCH2CH2CH2PtBu2)(η2,η2‐C7H12)][BArF 4] (ArF=3,5‐(CF3)2C6H3), in which the alkane (norbornane) binds through two exo‐C−H⋅⋅⋅Rh interactions. In contrast, the bis‐cyclohexyl phosphine analogue shows endo‐alkane binding. A comparison of the two systems, supported by periodic DFT calculations, NCI plots and Hirshfeld surface analyses, traces this different regioselectivity to subtle changes in the local microenvironment surrounding the alkane ligand. A tertiary periodic structure supporting a secondary microenvironment that controls binding at the metal site has parallels with enzymes. The new σ‐alkane complex is also a catalyst for solid/gas 1‐butene isomerization, and catalyst resting states are identified for this.

Phosphine modification of proline-glycine-proline tripeptide and study of its neuroprotective properties

BackgroundTreatment of neurodegenerative diseases, such as Parkinson’s disease, Huntington’s chorea, Alzheimer’s disease, is one of the priority directions in modern medicine. Thus, search and production of new physiologically active substances for the treatment of neurodegenerative disorders is one of the most important tasks for organic chemistry. The approach based on the replacement of a peptide bond in a peptide molecule with a structural isostere, non-hydrolyzable methylene phosphoryl fragment makes it possible to increase the metabolic stability of peptide molecules to the destructive action of peptidases. MethodsThis work is devoted to the approbation of a new synthetic approach to the production of physiologically active substances in a series of peptide-type compounds with activity by replacing the peptide bond with isosteric methylene-phosphoryl fragment with the preservation of the original amino acid sequence. ResultsA phosphine analog of the known physiologically active tripeptide proline-glycine-proline was obtained, cytotoxicity and neuroprotective properties of the initial tripeptide and its phosphine analog were studied. ConclusionPreliminary biological tests have shown that the obtained phosphine analog of the proline-glycine-proline tripeptide is involved in modulating the formation of sediments in the cellular system of proteinopathy, which may indicate their potential antiaggregatory properties.

Enzymatic kinetic resolution of desmethylphosphinothricin indicates that phosphinic group is a bioisostere of carboxyl group

Escherichia coli glutamate decarboxylase (EcGadB), a pyridoxal 5’-phosphate (PLP)-dependent enzyme, is highly specific for L-glutamate and was demonstrated to be effectively immobilised for the production of γ-aminobutyric acid (GABA), its decarboxylation product. Herein we show that EcGadB quantitatively decarboxylates the L-isomer of D,L-2-amino-4-(hydroxyphosphinyl)butyric acid (D,L-Glu-γ-PH), a phosphinic analogue of glutamate containing C-P-H bonds. This yields 3-aminopropylphosphinic acid (GABA-PH), a known GABAB receptor agonist and provides previously unknown D-Glu-γ-PH, allowing us to demonstrate that L-Glu-γ-PH, but not D-Glu-γ-PH, is responsible for D,L-Glu-γ-PH antibacterial activity. Furthermore, using GABase, a preparation of GABA-transaminase and succinic semialdehyde dehydrogenase, we show that GABA-PH is converted to 3-(hydroxyphosphinyl)propionic acid (Succinate-PH). Hence, PLP-dependent and NADP+-dependent enzymes are herein shown to recognise and metabolise phosphinic compounds, leaving unaffected the P-H bond. We therefore suggest that the phosphinic group is a bioisostere of the carboxyl group and the metabolic transformations of phosphinic compounds may offer a ground for prodrug design.

Synthesis of Phosphinic Analogue of Alanylleucine

The amidoalkylation reactions of a phosphonous acid containing a structural isostere of leucine in acetyl chloride and(or) acetic anhydride were studied under conditions of acid catalysis. A two-component method for the synthesis of a phosphinic analogue of alanylleucine using ethylidenebis(benzylcarbamate) was proposed.

Divergent Reactivity of Phosphapalladacycles toward E–H (E = N, P, As) Bonds

Secondary arsines were observed to decomplex strongly chelating phosphapalladacycles rapidly under mild conditions. As–H bond migration led to ortho-protonation of the C,P ligand. On the other hand, N–H and P–H bonds in amine and phosphine analogues were acidified under the same conditions and no ligand decomplexation of the metallacycle was observed. Subsequently, secondary arsines bearing the As–H bond were applied in deuteration by directed ortho-metalation (DoM) and decomplexation strategies. In the former, HAsPh2 was a convenient deuterium shuttle which facilitated the ortho-deuteration of DoM-palladacycle intermediates under neutral conditions. High deuterium incorporation (>99%) was achieved without specialized preformed deuterating agents. In the latter, HAsPh2 afforded the preligands of monomeric, dimeric, bidentate, and tridentate complexes of Pd in excellent yields of 95–98% within 30 min at room temperature. Key reaction steps for the intramolecular insertion of As–H into the Pd–C bond were ou...

SUN-465 Thyrotropin-Releasing Hormone-Degrading Ectoenzyme Controls Thyrotropin Secretion and Body Weight in Male Rodents

Thyrotropin-releasing hormone (TRH) is expressed in the brain, and a few peripheral tissues. Apart from controlling TSH secretion from the pituitary, it has an anorexic effect. TRH is a short-lived intercellular signaling molecule, hydrolyzed by the TRH-degrading ectoenzyme (TRH-DE), a narrow specificity peptidase which only known biological substrate is TRH. TRH-DE activity is mainly detected in brain, with an uneven distribution among regions; at the base of the third ventricle, Trhde is expressed by β2 tanycytes whose end-feet form synaptoid contacts with TRH terminals in the external layer of the median eminence (ME). Tanycyte TRH-DE activity is sensitive to thyroid hormone feedback and energy balance clues and may contribute to adjust the thyroid axis to changing energy needs. To test whether this enzyme is relevant for energy balance, we used mice generated in the B6/129S background in which Trhde exon 2 was deleted and backcrossed to C57BL/6NJ background for 11 generations. TRH-DE activity was reduced in heterozygote (HT) and eliminated in homozygote (KO) compared to wild type (WT) animals. Male mice (70-75 days old) were switched from a standard diet to a high fat high fructose diet (HFFD) for 9 weeks. On HHFD, KO animals ingested less kcal and gained less body weight (BW) than WT animals. Bio-impedance data indicated a lower fat mass in KO mice, compared to WT or HT mice. Glucose tolerance was higher in KO mice than in WT or HT mice. To clarify the specific relevance of tanycyte TRH-DE, we used adeno-associated virus (AAV) vectors in male rats to either knock down (with TRH-DE*, a dominant negative isoform) or overexpress TRH-DE in ME tanycytes. Serum TSH concentration increased when TRH-DE activity decreased, and the converse occurred when TRH-DE activity increased. Thus, TRH-DE activity from β2-tanycytes controls the concentration of TSH in the circulation, probably because it regulates the turnover of TRH before entry into the hypothalamus-pituitary portal vessels. However, 2- or 3-weeks treatment with AAV-TRH-DE or AAV-TRH-DE* did not affect BW. To further test the role of peripheral TRH-DE activity, a phosphinic analogue of TRH (P-TRH) was administered to adult male HFFD mice during 28 days through osmotic pumps connected to an intraperitoneal catheter. P-TRH treatment reduced TRH-DE activity in serum, but not inside the blood brain barrier, compared with mice treated with vehicle; however, treatment with P-TRH did not change food consumption and BW. In conclusion, ablation of TRH-DE impedes diet-induced obesity in male mice, possibly through enhanced thyroid axis activity and amplification of the anorectic effect of TRH. Supported in part by grants from DGAPA-UNAM (PAPIIT IN206712, IN206416, IN212719), and CONACYT (CB154931, CB254960 and PN562).

Synthesis of a New Lopinavir Phosphinic Analog as HIV-1 Inhibitor

HIV/AIDS has been one of the most devastating global diseases. HIV-1 protease proteolytic action is responsible for the manufacture of grown, infectious species, consequently HIV-1 protease has become an attractive goal in the treatment and therapy of HIV. Several HIV-1 protease inhibitors based therapeutic agents are under investigation or currently in the market. Lopinavir (ABT-378) has a great value in this research field. Therefore, different methods have appeared aiming to develop efficient analogs by the utilization of variable techniques, since Lopinavir had showed low bioavailability when being prescribed alone, and various side effects after the combination of Lopinavir with another HIV-1 inhibitors such as Ritonavir, which is available in the markets nowadays under the brand name Kaletra. Replacement of the hydroxyethylene moiety in Lopinavir structure, which is responsible for the monohydroxylated metabolites with the stable to hydrolysis phosphinic group has been considered, since that hydroxyl group in the central core is responsible for the interaction with the carboxylic acid in the catalytic aspartyl residue of HIV-1 by hydrogen bonding and consequently supports the drug affinity to the protease. The small scale processes for the synthetic strategies for the new candidate phosphinic analog of Lopinavir protease inhibitor (PL1) is presented here in along with some preliminary pharmacological data.

Neutral and cationic phosphine and arsine complexes of tin(iv) halides: synthesis, properties, structures and anion influence.

The reaction of trans-[SnCl4(PR3)2] (R = Me or Et) with trimethylsilyltriflate (TMSOTf) in CH2Cl2 solution substitutes one chloride to form [SnCl3(PR3)2(OTf)]; addition of excess TMSOTf does not substitute further chlorides. The complexes have been fully characterised by microanalysis, IR and multinuclear NMR (1H, 13C{1H}, 19F{1H}, 31P{1H}, 119Sn) spectroscopy. The crystal structure of [SnCl3(PMe3)2(OTf)] revealed mer-chlorines and trans-phosphines. In contrast, trans-[SnBr4(PR3)2], [SnCl4{Et2P(CH2)2PEt2}], [SnCl4{o-C6H4(PMe2)2}] and [SnCl4{o-C6H4(AsMe2)2}] did not react with TMSOTf in CH2Cl2 solution even after 3 days. The arsine complexes, [SnX4(AsEt3)2] (X = Cl, Br), were confirmed as trans-isomers by similar spectroscopic and structural studies, while attempts to isolate [SnI4(AsEt3)2] were unsuccessful and reaction of SnX4 with SbR3 (R = Et, iPr) resulted in reduction to SnX2 and formation of R3SbX2. trans-[SnCl4(AsEt3)2] is converted by TMSOTf into [SnCl3(AsEt3)2(OTf)], whose X-ray structure reveals the same geometry found in the phosphine analogues, with the triflate coordinated. The salts, [SnCl3(PEt3)2][AlCl4] and [SnCl2(PEt3)2][AlCl4]2 were made by treatment of [SnCl4(PEt3)2] with one and two mol. equivalents, respectively, of AlCl3 in anhydrous CH2Cl2, whereas reaction of [SnCl4(AsEt3)2] with AlCl3 produced a mixture including Et3AsCl2 and [Et3AsCl][Sn(AsEt3)Cl5] (the latter identified crystallographically). In contrast, using Na[BArF] (BArF = [B{3,5-(CF3)2C6H3}4]-) produced [SnCl3(PEt3)2][BArF] and also allowed clean isolation of the arsine analogue, [SnCl3(AsEt3)2][BArF]. [SnCl4{o-C6H4(PMe2)2}] also reacts with AlCl3 in CH2Cl2 to form [SnCl3{o-C6H4(PMe2)2}][AlCl4] and [SnCl2{o-C6H4(PMe2)2}][AlCl4]2. Multinuclear NMR spectroscopy on the [AlCl4]- salts show that δ31P and δ119Sn move progressively to high frequency on conversion from the neutral complex to the mono- and the di-cations, whilst 1J(119Sn-31P) follow the trend: [SnCl3{o-C6H4(PMe2)2}]+ > [SnCl4{o-C6H4(PMe2)2}] > [SnCl2{o-C6H4(PMe2)2}]2+. DFT studies on selected complexes show only small changes in ligand geometries and bond lengths between the halide and triflate complexes, consistent with the X-ray crystallographic data reported and the HOMO and LUMO energies are relatively unperturbed upon the introduction of (coordinated) triflate, whereas the energies of both are ca. 4 eV lower in the cationic species and reveal significant hybridisation across the pnictine ligands.

Recent advance in sulfur ylide and sulfonium salts chemistry

Organosulfur compounds are ubiquitous in natural products and active pharmaceutical ingredients. They are also versatile scaffold that are widely applicable in material and food chemistry. The increasing demand indeed lead to a continuous progress in developing of new methodologies in organosulfur chemistry. Among them, sulfur ylides and sulfonium salts with unique reactivities have been employed to provide simple, effective, and often stereoselective methods to gain access to sulfur containing molecules. The essential goal of this review is to provide a comprehensive account of representative research progress on sulfonium salt and sulfur ylide chemistry in the past three years. Seminal reports on this topic are occasionally covered with the purpose of providing a brief research background. For the sake of convenience, this review is organized in three parts based on the role they played in organic reactions (synthetic intermediates, reagents and catalysts). In the first section, the development of new approaches for generate sulfur ylide or sulfonium salt intermediates were summarized. Electrophilic aryne species could be employed to react with sulfides or sulfoxides to form the desired sulfur intermediates, which could underwent a variety of interesting transformations. Moreover, recent progress in metal carbene-based sulfur ylide approaches have also been introduced. Both the progress in asymmetric catalysis variants and reactions in aqueous solution have been presented. The second section describes the transformations using stabilized sulfonium salts and sulfur ylides as bench-stable reactants. The extra stability of these species is accompanied by a compromise in the reactivity, which usually requires developing activation methods. With transition metal catalysts to activate sulfonium salts, they have been discovered as efficient coupling partners in carbon-carbon bond and carbon-heteroatom bond formation reactions. Stable sulfur ylides could also be utilized to install fluorine-containing groups in a large variety of transformations. The third section covers recent progress in employing sulfonium salts as catalysts in organic reactions. The acidity of the α C−H in sulfonium salt is relatively high than its nitrogen and phosphine analogues. Therefore, it could be easily removed to form the sulfur ylide, which have restricted its application as catalysts. On one hand, scientists took advantage of these properties and developed new cyclic sulfonium salts as hydrogen bonding catalysts. On the other hand, sulfonium salts could be used as stable phase transfer catalysts under base free conditions in order to avoid degradations. Finally, the review discussed the limitations of the known chemistry in this field as well as the future opportunities. Sulfur ylide and sulfonium salts have displayed many unique reactivities as summarized in this review. New reactivity will still be the central theme of research given the importance of organosulfur compounds. In addition, insights into the factors controlling the reactivity via mechanistic studies will be of great importance for further research and development. Moreover, the applications of sulfonium salts as organocatalysts are still limited to a relatively narrow range of transformations. Therefore, it remains to be an elusive task to unlock their full potential, and future research must include the development of scalable and cost-efficient methods, broadening of reaction scopes, and integration with other catalytic manifolds. We hope that this review will pique the interests of readers and deliver inspiration for future development in this interesting and promising field.

Variations on the Theme of JohnPhos Gold(I) Catalysts: Arsine and Carbene Complexes with Similar Architectures

Arsine and carbene gold(I) complexes with architectures closely related to those of 2-(di-tert-butylphosphino)biphenyl gold(I) complexes have been prepared and structurally characterized. As predicted, 2-(di-tert-butylarsine)biphenyl gold(I) complexes are more electrophilic catalysts in comparison to their phosphine analogues, whereas those based on 4-arylindazole behave similarly to NHC-gold(I) catalysts.

An efficient one-pot synthesis of bis(α-aminoalkyl)phosphinic acids, phosphorus-isosteric analogues of HIV protease inhibitors

An acid-catalyzed three-component reaction between hypophosphorous acid, aldehydes and alkyl carbamates under mild conditions afforded bis(α-aminoalkyl)phosphinic acids. The proposed facile single-stage protocol is prospective for expansion of a range of phosphinic analogues of HIV protease inhibitors.

Synthesis and Structure of Metal Complexes of P-Stereogenic Chiral Phosphiranes: An EDA-NOCV Analysis of the Donor–Acceptor Properties of Phosphirane Ligands

Reaction of the enantiomerically enriched P-stereogenic phosphiranes syn-(RP,SC)-Mes*PCH2CH(Ph) (syn-1) and anti-(SP,SC)-Mes*PCH2CH(Ph) (anti-2, Mes* = 2,4,6-(t-Bu)3C6H2) with metal complex precursors gave Au(L)(Cl) (L = 1 (3); L = 2 (4)), trans-ML2Cl2 (L = 1, M = Pd (5), Pt (6)), Pd(η3-C3H5)(L)(Cl) (L = 1 (7)), and trans-RhL2(CO)(Cl) (L = 1 (8); L = 2 (9)); 3, 4, 7, and 9 were crystallographically characterized. Phosphirane coordination resulted in shortening of the P–C bonds and increased bond angles at P, consistent with rehybridization at phosphorus. A comparison of complexes of phenylphosphirane and phenyldimethylphosphine using IR spectra, coupled with DFT studies using electronic decomposition analysis (EDA) and natural orbitals for chemical valence (NOCV), indicated that phosphiranes are slightly poorer σ-donors than the analogous phosphines and that the π-acceptor properties of these ligands are similar. Pauli repulsion, dispersion, and electrostatic attraction are also important factors in deter...

Synthesis, Application and Kinetic Studies of Chiral Phosphite‐Oxazoline Palladium Complexes as Active and Selective Catalysts in Intermolecular Heck Reactions

AbstractThis study identifies new phosphite‐oxazoline ligands that have been successfully applied in the palladium‐catalyzed intermolecular asymmetric Heck reaction. The design of the new phosphite‐oxazoline ligands derives from a previous successful generation of phosphine‐oxazoline ligands, by replacing the phosphine group with several π‐acceptor biaryl phosphite moieties. With these simple modifications, the new phosphite‐based ligands, unlike previous phosphine‐oxazoline, not only present a modular design with numerous potential phosphite groups available, but they are also air‐stable solids, which can be made in the same number of synthetic steps as the phosphine analogues. The substitution of the phosphine by a biaryl phosphite group extended the range of substrates and triflates sources that can be coupled with regio‐, enantioselectivities and activities comparable to the few best ones reported. In addition, the ligands that provided the best selectivities contained an isopropyl oxazoline moiety instead of the tert‐butyl group found in the related phosphine‐oxazoline ligands, which is made from a much more expensive precursor. In this paper we have also carried out kinetic studies and a Hammett plot analysis to determine the rate determining step of this system in the regime of interest. We suggest a likely explanation for the fast Heck reaction of the phosphite‐oxazoline catalysts.magnified image