phospha-Michael Addition Research Articles

Horner–Wadsworth–Emmons olefination of proteins and glycoproteins

Chemo-selective modifications of proteins are fundamental to the advancement of biological and pharmaceutical sciences. The search for biocompatible chemical reactions has prompted us to investigate Horner–Wadsworth–Emmons (HWE) olefinations, iconic reactions in organic synthesis that would give rise to new selective protein olefinations. Our choice of HWE olefinations was inspired by the growing number of methods for generating aldehydes as transient reactive groups in proteins and the potential for mild and simple reaction conditions. Here we show that HWE olefination reactions on aldehydes, produced by both chemical and enzymatic methods, are compatible with physiological conditions and highly selective in small and large proteins, including therapeutic antibodies and stable recombinant proteins exemplified by green fluorescent protein. Reaction kinetics can be fine-tuned over orders of magnitude both by judicious use of substituents and pH regulation. The electrophilic nature of the HWE olefination products can be tuned to allow for subsequent nucleophilic additions, including thiol- and phospha-Michael additions. Our results demonstrate that HWE olefination of aldehydes in proteins provides efficient and selective bioconjugation chemistries that are orthogonal to existing methods.

Coumarin-DPPO a new bio-based phosphorus additive for poly(lactic acid): Processing and flame retardant application

This study addresses very important aspects of the sustainable development of new flame retardant materials: (i) the preparation of a novel flame retardant (FR) additive from bio-resource, (ii) its use as FR additive in poly(lactic acid) (PLA) based composites and, (iii) the in vitro toxicity assessment of the FR. The synthesis of this bio-based FR additive was achieved through a phospha-Michael addition of diphenylphosphine oxide (DPPO) and the naturally occurring compound coumarin, yielding 4-(diphenylphosphoryl)chroman-2-one (CU-DPPO). The flame-retarded CU-DPPO PLA composites were prepared either via conventional melt blending of commercially available PLA or through reactive extrusion (REX) of L-lactide. Characterization of the composites was performed through nuclear magnetic resonance (NMR), size exclusion chromatography (SEC) and thermogravimetric analysis (TGA). TGA analysis of the FR-PLA composites showed an increase in thermal stability, confirming the beneficial effect of the CU-DPPO additive. Direct insertion probe mass spectrometry (DIP-MS) analysis was used to gain insight on the mechanism of action of the FR additive, suggesting gas-phase activity. Rheological measurements exhibited the thermo-oxidative stabilizing effect in the modified PLA. The flame retardancy of the melt-blended PLA composites with CU-DPPO was investigated by limited oxygen index (LOI), cone calorimetry and vertical burning tests (UL 94 and BKZ-VB). Samples containing 10 wt.% of CU-DPPO showed improved fire performance with a limiting oxygen index (LOI) of 29%, passing Swiss vertical burning test (BKZ-VB) and obtaining a V-0 rating in the UL 94 test. Moreover, a preliminary toxicity assessment of the CU-DPPO, carried out using an established in vitro platform, showing no adverse effects on cell viability.

Reactivities of tertiary phosphines towards allenic, acetylenic, and vinylic Michael acceptors.

The addition of phosphines (PR3) to Michael acceptors is a key step in many Lewis-base catalysed reactions. The kinetics of the reactions of ten phosphines with ethyl acrylate, ethyl allenoate, ethyl propiolate, ethenesulfonyl fluoride, and ethyl 2-butynoate in dichloromethane at 20 °C was followed by photometric and NMR spectroscopic methods. The experimentally determined second-order rate constants k 2 show that electronic effects in sterically unencumbered phosphines affect their nucleophilicity towards different classes of Michael acceptors in the same ordering. Michael acceptors with sp-hybridised electrophilic centres, however, are less susceptible to changes in the PR3 nucleophilicity than those with sp2-hybridised reactive sites. Linear correlations of lg k 2 from this work with published rate constants for SN2 and SN1 reactions as well as with Brønsted basicities and fugalities for PR3 demonstrate the generality of the detected reactivity trends. Computed reaction barriers (ΔG ‡ calc) as well as reaction energies (ΔG add) for Michael adduct formations show excellent correlations with experimentally obtained reaction barriers (ΔG ‡ exp) corroborating the interpretation of the kinetic data and revealing the philicity/fugality features of the reactants in phospha-Michael additions.

Novel Macromolecular and Biobased Flame Retardants Based on Cellulose Esters and Phosphorylated Sugar Alcohols.

The increasing demand to provide sustainably produced plastic materials requires, a.o., the development of biobased flame retardants (FRs) for applications where flame retardancy is essential. To meet those challenging new sustainability requirements, a set of novel phosphorus-containing cellulose esters were synthesized by an efficient two-step procedure. In the first step, cellulose was treated with acrylic anhydride to synthesize acrylate-functionalized cellulose esters-more specifically, cellulose acrylate butyrate (CeAcBu) and propionate (CeAcPr). Subsequently, phosphorylated anhydro erythritol (PAHE), synthesized from the sugar alcohol erythritol, was added to the acrylate-functionalized cellulose esters via Phospha-Michael addition. For comparison a cellulose ester based on 6H-Dibenzo[c,e][1,2]oxaphosphorin-6-on (DOPO) was prepared analogously. The acrylate-functionalized cellulose esters and novel FRs were characterized by NMR spectroscopy. TGA investigations of PAHE-functionalized CeAcBu revealed an onset temperature of decomposition (2% mass loss) of approx. 290 °C. The novel PAHE-based FR was incorporated into a polypropylene-polyethylene copolymer (PP-co-PE) together with poly-tert-butylphenol disulfide (PBDS) (8 wt.%/2 wt.%) as a synergist. The PP-PE samples achieved V2 classification in the UL 94 V test. In addition, specimens of a rapeseed oil-based polyamide containing PAHE-functionalized CeAcBu at 20 wt.% loading yielded a V2 rating with short burning times.

ACTIVE-BAPO - A Versatile Transfer Agent for Photoactive Bis(acyl)phosphane Oxide Units.

A N-hydroxy succinimide (NHS) ester substituted bis(acyl)phosphane oxide (ACTIVE-BAPO) was prepared by phospha-Michael addition and used for an easy one-step BAPO ligation with substrates containing primary amino groups, such as amino acids, proteins, and poly(amidoamine) (PAMAM) dendrimers. Thereby, a range of new molecular and polymeric photoinitators was obtained. Real-time photo-rheology experiments demonstrated the outstanding efficiency of the PAMAM BAPOs as photoinitiators for free radical polymerization. Remarkably, it is found that PAMAM BAPOs also act as crosslinking agents to convert monofunctional methacrylate monomers into thermosetting networks without any further additives. Depending on the number of the attached BAPOs, thermosets with a different degree of crosslinking and swelling capability in water were obtained.

Organocatalyzed Phospha-Michael Addition: A Highly Efficient Synthesis of Customized Bis(acyl)phosphane Oxide Photoinitiators.

Addition of the P-H bond in bis(mesitoyl)phosphine, HP(COMes)2 (BAPH), to a wide variety of activated carbon-carbon double bonds as acceptors was investigated. While this phospha-Michael addition does not proceed in the absence of an additive or catalyst, excellent results were obtained with stoichiometric basic potassium or caesium salts. Simple amine bases can be employed in catalytic amounts, and tetramethylguanidine (TMG) in particular is an outstanding catalyst that allows the preparation of bis(acyl)phosphines, R-P(COMes)2 , under very mild conditions in excellent yields after only a short time. All phosphines RP(COMes)2 can subsequently be oxidized to the corresponding bis(acyl)phosphane oxides, RPO(COMes)2 , a substance class belonging to the most potent photoinitiators for radical polymerizations known to date. Thus, a simple and highly atom economic method has been found that allows the preparation of a broad range of photoinitiators adapted to their specific field of application even on a large scale.

Lipase-Catalyzed Phospha-Michael Addition Reactions under Mild Conditions.

Organophosphorus compounds are the core structure of many active natural products. The synthesis of these compounds is generally achieved by metal catalysis requiring specifically functionalized substrates or harsh conditions. Herein, we disclose the phospha-Michael addition reaction of biphenyphosphine oxide with various substituted β-nitrostyrenes or benzylidene malononitriles. This biocatalytic strategy provides a direct route for the synthesis of C-P bonds with good functional group compatibility and simple and practical operation. Under the optimal conditions (styrene (0.5 mmol), biphenyphosphine oxide (0.5 mmol), Novozym 435 (300 U), and EtOH (1 mL)), lipase leads to the formation of organophosphorus compounds in yields up to 94% at room temperature. Furthermore, we confirm the role of the catalytic triad of lipase in this phospha-Michael addition reaction. This new biocatalytic system will have broad applications in organic synthesis.

Recent Advances in Base-assisted Michael Addition Reactions

Abstract: The Michael addition is an important, highly efficient, and atom-economical method for the diastereoselective and enantioselective C-C bond formation. MA used in the synthesis of natural products and drugs is tandem sequenced reactions. An important tandem sequence of Michael and Aldol additions is the Robinson annulation. MA is a versatile reaction employed for efficient bond formation between electron-poor olefins as Michael acceptors with varied nucleophiles as Michael donors. Apart from being involved in C-C bond formation, MA is also employed in the formation of C-X bond (X=O, N, S, P etc.) giving rise oxa-, aza-, thia-, phospha-Michael addition products. In recent years many articles have been published on MA. The mechanism of MA gives an insight into the reaction is initiated by the base. The present review provides comprehensive information on recent advancements in base-assisted Michael addition reactions including varied organic and inorganic bases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-Diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP), triethylamine (Et3N), tributylamine (Bu3N), N,N-diisopropylethylamine (DIEPA), diethylamine (NHEt2), guanidine derivatives, and bifunctional thiourea. A variety of inorganic bases including metal alkoxides, metal acetates, metal hydroxides, metal hydrides, metal carbonates, metal halides, and triphenylphosphine (TPP) can also be successfully used in Michael reactions.

Phospha-Michael Addition on α-Fluorinated Acrylates: A Straightforward Access to Polyfunctionalized Fine Chemicals.

α-Fluorinated acrylates could act as Michael acceptors and become a platform toward the synthesis of relevant complex molecules. Very few conjugate additions have been developed in the literature with these specific substrates, and herein, we reported the first phospha-Michael addition (PMA) on α-trifluoromethylacrylates and α-fluoromethylacrylates. The reaction proved to be highly tolerant and gave original products containing contiguous C-P and C-CFY2 (Y = F or H) bonds in good to excellent yields and diastereoselectivities.

Transition metal-free domino aryl-aryl coupling/phospha-Michael addition of diarylphosphinite to α,β-unsaturated ketones triggered by alkaline hydrolysis of (4-(2-alkenoyl)phenyl)triarylphosphonium salts

Alkaline hydrolysis of a variety of (4-(2-alkenoyl)phenyl)triarylphosphonium bromides is reported. This hydrolysis triggers coupling of 4-(2-alkenoyl)phenyl with one aryl via phosphorus(V). Both diarylphosphinite and an α,β-unsaturated ketone are in situ generated and then undergo phospha-Michael addition to provide β-diarylphosphoryl ketones bearing a biaryl moiety in 27–70% yields in the absence of a transition metal.

Synthesis of α-chiral phosphine sulfides via non-covalent organocatalysis

Despite rapid advances in phosphine-containing compound as a privileged ligand for transition metal catalysis, synthesis and coordination chemistry are underexplored for the phosphine sulfide analogs. In this article, we report the enantioselective phospha-Michael addition reaction that leads to α-chiral phosphine sulfide. An independent hydrogen-bonding co-catalyst is found essential to high enantioselectivity (up to 98% yield and 95% enantiomeric excess [ee]). Divergent derivatizations under mild conditions are also attempted for the generic phosphine and phosphine oxide compounds, further emphasizing the bridge role of phosphine sulfide. An X-ray diffraction structure of κ 3 -NNS palladium complex also authenticates the coordination ability of p = S moiety. Combination of NHC and hydrogen bonding donor catalysis α-Chiral phosphine sulfides Downstream derivatizations κ 3 -NNS palladium complex In an effort to diversify the family of phosphine ligands, Li et al. report the orchestration of NHC catalysis and an H-bond donor as a straightforward synthetic strategy to yield α-chiral phosphine sulfides. Preliminary results for downstream derivatization and metal chelation further demonstrate the applications for p = S ligands.

Phospha-Michael Addition to Access β-Phosphorus-Containing α-Amino Acids

Key words phospha-Michael addition - phosphono amino acids - chiral Ni(II) complexes - asymmetric synthesis - Schiff bases

Phosphine-Catalyzed Chemoselective Reduction/Elimination/Wittig Sequence for Synthesis of Functionalized 3-Alkenyl Benzofurans.

An efficient protocol for the construction of functionalized 3-alkenyl benzofurans is demonstrated under metal-free conditions using catalytic amount of phosphine proceeding an intramolecular Wittig reaction. This one-pot reaction initiated by the phospha-Michael addition of phosphine to O-acylated nitrostyrene, in which phosphine was in-situ-generated from the chemoselective reduction of phosphine oxide with PhSiH3, would provide the phosphorus ylide to result in the aforementioned multifunctionalized benzofuran via O-acylation/nitrous acid elimination/Wittig reaction.

Recoverable Phospha-Michael Additions Catalyzed by a 4-N,N-Dimethylaminopyridinium Saccharinate Salt or a Fluorous Long-Chained Pyridine: Two Types of Reusable Base Catalysts.

Phospha-Michael addition, which is the addition reaction of a phosphorus-based nucleophile to an acceptor-substituted unsaturated bond, certainly represents one of the most versatile and powerful tools for the formation of P-C bonds, since many different electrophiles and P nucleophiles can be combined with each other. This offers the possibility to access many diversely functionalized products. In this work, two kinds of basic pyridine-based organo-catalysts were used to efficiently catalyze phospha-Michael addition reactions, the 4-N,N-dimethylaminopyridinium saccharinate (DMAP·Hsac) salt and a fluorous long-chained pyridine (4-Rf-CH2OCH2-py, where Rf = C11F23). These catalysts have been synthesized and characterized by Lu’s group. The phospha-Michael addition of diisopropyl, dimethyl or triethyl phosphites to α, β-unsaturated malonates in the presence of those catalysts showed very good reactivity with high yield at 80–100 °C in 1–4.5 h with high catalytic recovery and reusability. With regard to significant catalytic recovery, sometimes more than eight cycles were observed for DMAP·Hsac adduct by using non-polar solvents (e.g., ether) to precipitate out the catalyst. In the case of the fluorous long-chained pyridine, the thermomorphic method was used to efficiently recover the catalyst for eight cycles in all the reactions. Thus, the easy separation of the catalysts from the products revealed the outstanding efficacy of our systems. To our knowledge, these are good examples of the application of recoverable organo-catalysts to the DMAP·Hsac adduct by using non-polar solvent and a fluorous long-chained pyridine under the thermomorphic mode in phospha-Michael addition reactions.

Microwave-assisted Phospha-Michael addition reactions in the 13α-oestrone series and in vitro antiproliferative properties

Microwave-assisted phospha-Michael addition reactions were carried out in the 13α-oestrone series. The exocyclic 16-methylene-17-ketones as α,β-unsaturated ketones were reacted with secondary phosphine oxides as nucleophilic partners. The addition reactions furnished the two tertiary phosphine oxide diastereomers in high yields. The main product was the 16α-isomer. The antiproliferative activities of the newly synthesised organophosphorus compounds against a panel of nine human cancer cell lines were investigated by means of MTT assays. The most potent compound, the diphenylphosphine oxide derivative in the 3-O-methyl-13α-oestrone series (9), exerted selective cell growth-inhibitory activity against UPCI-SCC-131 and T47D cell lines with low micromolar IC50 values. Moreover, it displayed good tumour selectivity property determined against non-cancerous mouse fibroblast cells.

1,1-Diaminoazines as organocatalysts in phospha-Michael addition reactions.

1,1-Diaminoazines can act as effective organocatalysts for the formation of phosphorus-carbon bonds between biphenylphosphine oxide and an activated alkene (Michael acceptor). These catalysts provide the P-C adducts at a faster rate and with relatively better yields in comparison to the organocatalysts employed earlier. The notable advantage is that 1,1-diaminoazines catalyse the reaction even in an aqueous medium with very good yields. Organocatalysis using 1,1-diaminoazines was also successfully carried out between dimethylphosphite and benzylidenemalononitrile under multicomponent conditions.

Mesoporous titania–ceria mixed oxide (MTCMO): a highly efficient and reusable heterogeneous nanocatalyst for one-pot synthesis of β-phosphonomalonates via a cascade Knoevenagel–phospha-Michael addition reaction

Mesoporous titania–ceria mixed oxide (MTCMO) was synthesised in a sol–gel method using cerium chloride and titanium isopropoxide (TTIP) as CeO2 as well as TiO2 precursors and sodium dodecyl sulphate (SDS) as a structure-directing agent and its application was evaluated in the synthesis of aromatic β-phosphonomalonate derivatives via cascade Knoevenagel–phospha-Michael addition reaction. The catalyst characterised by various techniques like FT-IR spectroscopy, XRD, SEM, EDS, TEM and N2 adsorption-desorption. Partial substitution of Ti4+ cations with Ce4+ improved the BET surface area because TiO2 crystallites were suppressed to be grown. Furthermore, as a consequence of charge imbalance in the obtained Ti-O-Ce solid solution, some oxygen vacancies have generated that act as Lewis base sites while cations (Ti and Ce) around the oxygen vacancies act as Lewis acid sites. Reusability up to eight consecutive runs without significant decrease in reactivity, Mild reaction conditions, environmentally benign and compatibility with various functional groups are some of the advantages of this work.

Late-stage peptide and protein modifications through phospha-Michael addition reaction.

We developed a late-stage modification strategy by a phospha-Michael addition reaction between various functional phosphines and unprotected dehydroalanine (Dha) peptides and proteins under mild conditions. This strategy was applied to generate a staple peptide to enhance its cell membrane penetrability, and it was also able to regulate α-synuclein aggregation properties and morphological characteristics with the addition of different charges.

Synthesis of the H-phosphonate dibenzo[d,f][1,3,2]dioxaphosphepine 6-oxide and the phospha-Michael addition to unsaturated compounds

A series of phosphonate-containing compounds based on dibenzo[d,f][1,3,2]dioxaphosphepine 6-oxide (BPPO) is presented. BPPO is synthesized by a three–component condensation and is added to activated alkenes with systematically varied structure via phospha-Michael addition. Acrylates, α,β-unsaturated carboxylic acid diesters and benzoquinone are used as activated alkenes. The new compounds are characterized by 1H, 13C and 31P NMR spectroscopy. The as-prepared phosphonates are envisioned to have flame retardant properties.

Direct Synthesis of Phosphonates and α-Amino-phosphonates from 1,3-Benzoxazines.

A straightforward and novel method for transformation of readily available 1,3-benzoxazines to secondary phosphonates and α-aminophosphonates using boron trifluoride etherate as catalyst is developed. The formation of phosphonates proceeds through ortho-quinone methide (o-QM) generated in situ, followed by a phospha-Michael addition reaction. On the other hand, the α-aminophosphonates were obtained by iminium ion formation and the subsequence nucleophilic substitution of alkylphosphites. This method can be also used for the preparation of o-hydroxybenzyl ethers through oxa-Michael addition.