Staudinger Reaction Research Articles

Synthesis of Chlorinated, Heteroatom‐Rich and Differently Fused Tricyclic β‐Lactams by Cu(I)‐Catalyzed Halogen Atom Transfer Radical Cyclization

AbstractThe application of Cu (I)‐catalyzed halogen atom transfer radical cyclization (ATRC) for the synthesis of two different series of chlorinated, heteroatom rich and differently fused tricyclic β‐lactams has been demonstrated. N‐substituted‐3,4‐dihydropyrimidine‐2(1H)‐thiones synthesized by Biginelli reaction were used as starting materials for this synthetic pathway which upon S‐allylation/alkylation furnished 2‐allylthio/alkylthio‐1,4‐dihydropyrimidines (cyclic imines). Staudinger reaction of these cyclic imines with dichloroketene was employed to obtain the bicyclic dichloro‐S‐allyl/N‐allyl‐β‐lactams, which upon subsequent Cu(I)‐catalyzed ATRC produced two different series of tricyclic β‐lactams. The difference in the relative behavior of N‐allyl bicyclic dichloro‐β‐lactams and S‐allyl bicyclic dichloro‐β‐lactams towards ATRC was also introspected in terms of their relative rates of cyclization, the amount of catalyst loading needed and the stabilities of tricyclic‐β‐lactams obtained after cyclization. To study the relative reactivity of N‐allyl group and S‐allyl group towards ATRC, the bicyclic dichloro‐β‐lactams having both S‐allyl and N‐allyl groups were synthesized. The intramolecular competitive experiments revealed the high reactivity of S‐allyl group towards ATRC than the N‐allyl group.

Mono‐Phosphazenyl Phosphines (R2N)3P=N–P(NR2)2 – Strong P‐Bases, P‐Donors, and P‐Nucleophiles for the Construction of Chelates

We present a convenient three‐step synthesis of amino substituted phosphazenyl phosphines of the general formula (R2N)3P=N–P(NR2)2 [NR2 = N(CH2)4, N(CH2)5, N(CH2)6]. These easily accessible mixed valent compounds display a surprisingly high proton affinity and basicity in the same range as the corresponding Schwesinger diphosphazene (Me2N)3P=N–P=NEt(NMe2)2 (Et‐P2) and Verkade's proazaphosphatrane superbases. Within the central [PIII–N=PV] scaffold, the phosphine PIII and not the phosphazene NIII atom is the center of highest proton affinity, basicity and donor strength. As P‐bases, the title compounds display calculated proton affinities between 265.8 (NR2 = NMe2) and 274.7 kcal·mol–1 [NR2 = N(CH2)4] and pKBH+ values between 26.4 (NR2 = NMe2) and 31.5 [NR2 = N(CH2)4] on the acetonitrile scale. As P‐nucleophiles, they are key intermediates in the synthesis of hyperbasic bis(diphosphazene) proton sponges, chiral bis(diphosphazene) proton pincers, bisphosphazides, and superbasic P2‐bisylides. Their Staudinger reactions as nucleophile towards 1,8‐diazidonaphthalene leading to 1,8‐naphthalene‐bisphosphazides is described in detail. The donor strength of the title compounds towards fragments [Se] and [Ni(CO)3] is in the same range as that of N‐heterocyclic carbenes.

Synthesis of novel bisphosphorylimides based on Staudinger reaction

A series of bisphosphorylimides based on the reaction sequence of Atherton-Todd and Staudinger reaction were synthesized. These bisphosphorylimides containing phosphorus in different chemical environments, while the reaction sequence is using mild conditions and moreover can be synthesized in an one-pot procedure. The molecular structures were revealed by nuclear magnetic resonance spectroscopy and x-ray crystallography. The stability of the bisphosphorylimides against hydrolysis and thermal influences was tested which allows an initial estimation about the usage as flame retardant.

Synthesis of novel bisphosphorylimides based on Staudinger reaction

Synthesis of novel bisphosphorylimides based on Staudinger reaction

The Staudinger Ligation.

While the Staudinger reaction has first been described a hundred years ago in 1919, the ligation reaction became one of the most important and efficient bioconjugation techniques in the 1990s and this century. It holds the crucial characteristics for bioorthogonal chemistry: biocompatibility, selectivity, and a rapid and high-yielding turnover for a wide variety of applications. In the past years, it has been used especially in chemical biology for peptide/protein synthesis, posttranslational modifications, and DNA labeling. Furthermore, it can be used for cell-surface engineering, development of microarrays, and drug delivery systems. However, it is also possible to use the reaction in synthetic chemistry for general formation of amide bonds. In this review, the three major types, traceless and nontraceless Staudinger Ligation as well as the Staudinger phosphite reaction, are described in detail. We will further illustrate each reaction mechanism and describe characteristic substrates, intermediates, and products. In addition, not only its advantages but also stereochemical aspects, scope, and limitations, in particular side reactions, are discussed. Finally, the method is compared to other bioorthogonal labeling methods.

Electrophilic Azides for Materials Synthesis and Chemical Biology.

Organic azides are involved in a variety of useful transformations, including nitrene chemistry, reactions with nucleophiles and electrophiles, and cycloadditions. The 1,3-dipolar cycloadditions of azides constitute a major class of highly reliable and versatile reactions, as shown by the development and rapid adoption of click chemistry and bioorthogonal chemistry. Metal-catalyzed azide-alkyne cycloaddition (Cu/RuAAC), the prototypical click reaction, has found wide utility in pharmaceutical, biomedical, and materials sciences. The strain-promoted, or distortion-accelerated, azide-alkyne cycloaddition eliminates the need for a metal catalyst.In the azide-mediated 1,3-dipolar cycloaddition reactions, azides are ambiphilic, i.e., HOMO-LUMO-controlled dipoles where both the HOMO and LUMO interact strongly with the dipolarophile. Azide-alkyne cycloaddition proceeds primarily through the HOMOazide-LUMOdipolarophile interaction, and electron-deficient dipolarophiles react more readily. The inverse-electron-demand reaction, involving the LUMOazide-HOMOdipolarophile interaction, is less common because of the low stability of electron-deficient azides such as acyl, sulfonyl, and phosphoryl azides. Nevertheless, there have been reports since the 1960s showing enhanced reaction kinetics between electron-poor azides and electron-rich dipolarophiles. Our laboratory has developed the use of perfluoroaryl azides (PFAAs), a class of stable electron-deficient azides, as nitrene precursors and for reactions with nucleophiles and electron-rich dipolarophiles. Perfluorination on the aryl ring also facilitates the synthesis of PFAAs and quantitative analysis of the products by 19F NMR spectroscopy.In this Account, we summarize key reactions involving electrophilic azides and applications of these reactions in materials synthesis and chemical biology. These electron-deficient azides exhibit unique reactivity toward nucleophiles and electron-rich or strained dipolarophiles, in some cases leading to new transformations that do not require any catalysts or products that are impossible to obtain from the nonelectrophilic azides. We highlight work from our laboratories on reactions of PFAAs with enamines, enolates, thioacids, and phosphines. In the reactions of PFAAs with enamines or enolates, the triazole or triazoline cycloaddition products undergo further rearrangement to give amidines or amides as the final products at rates of up to 105 times faster than their non-fluorinated anlogues. Computational investigations by the distortion/interaction activation strain model reveal that perfluorination lowers the LUMO of the aryl azide as well as the overall activation energy of the reaction by decreasing the distortion energies of the reactants to reach the transition states. The PFAA-enamine reaction can be carried out in a one-pot fashion using readily available starting materials of aldehyde and amine, making the reaction especially attractive, for example, in the functionalization of nanomaterials and derivatization of antibiotics for the preparation of theranostic nanodrugs. Similar fast kinetics was also observed for the PPAA-mediated Staudinger reaction, which proceeds at 104 times higher rate than the classic Staudinger ligation, giving stable phosphoimines in high yields. The reaction is biorthogonal, allowing cell-surface labeling with minimal background noise.

Multifluorinated Aryl Azides for the Development of Improved H2 S Probes, and Fast Strain-promoted Azide-Alkyne Cycloaddition and Staudinger Reactions.

The development of advanced bioorthogonal reactions for detection and labeling of biomolecules is significant in chemical biology. Recently, researchers have found that multifluorinated aryl azides hold great potential for the development of improved bioorthogonal reactions. The fluorine atom can be a perfect substituent group because of its properties of excellent electronegativity and small steric hindrance. In this Minireview, we discuss recent developments of improved hydrogen sulfide (H2 S) fluorescence probes, fast strain-promoted azide-alkyne cycloaddition (SPAAC) and nonhydrolysis Staudinger reactions based on the use of multifluorinated aryl azides. Additionally, kinetic studies and biological applications of these reactions are also presented.

Reactive & Efficient: Organic Azides as Cross-Linkers in Material Sciences.

The exceptional reactivity of the azide group makes organic azides a highly versatile family of compounds in chemistry and the material sciences. One of the most prominent reactions employing organic azides is the regioselective copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition with alkynes yielding 1,2,3-triazoles. Other named reactions include the Staudinger reduction, the aza-Wittig reaction, and the Curtius rearrangement. The popularity of organic azides in material sciences is mostly based on their propensity to release nitrogen by thermal activation or photolysis. On the one hand, this scission reaction is accompanied with a considerable output of energy, making them interesting as highly energetic materials. On the other hand, it produces highly reactive nitrenes that show extraordinary efficiency in polymer crosslinking, a process used to alter the physical properties of polymers and to boost efficiencies of polymer-based devices such as membrane fuel cells, organic solar cells (OSCs), light-emitting diodes (LEDs), and organic field-effect transistors (OFETs). Thermosets are also suitable application areas. In most cases, organic azides with multiple azide functions are employed which can either be small molecules or oligo- and polymers. This review focuses on nitrene-based applications of multivalent organic azides in the material and life sciences.

Regioselective and Stereodivergent Synthesis of Enantiomerically Pure Vic-Diamines from Chiral β-Amino Alcohols with 2-Pyridyl and 6-(2,2'-Bipyridyl) Moieties.

In this report, we describe the synthetic elaboration of the easily available enantiomerically pure β-amino alcohols. Attempted direct substitution of the hydroxyl group by azido-functionality in the Mitsunobu reaction with hydrazoic acid was inefficient or led to a diastereomeric mixture. These outcomes resulted from the participation of aziridines. Intentionally performed internal Mitsunobu reaction of β-amino alcohols gave eight chiral aziridines in 45–82% yield. The structural and configuration identity of products was confirmed by NMR data compared to the DFT calculated GIAO values. For 1,2,3-trisubstituted aziridines slow configurational inversion at the endocyclic nitrogen atom was observed by NMR at room temperature. Moreover, when aziridine was titrated with Zn(OAc)2 under NMR control, only one of two N-epimers directly participated in complexation. The aziridines underwent ring opening with HN3 to form the corresponding azido amines as single regio- and diastereomers in 90–97% yield. Different results were obtained for 1,2-disubstituted and 1,2,3-trisubstituted aziridines. For the later aziridines ring closure and ring opening occurred at different carbon stereocenters, thus yielding products with two inverted configurations, compared to the starting amino alcohol. The 1,2-disubstituted aziridines produced azido amines of the same configuration as the starting β-amino alcohols. To obtain a complete series of diastereomeric vic-diamines, we converted the amino alcohols into cyclic sulfamidates, which reacted with sodium azide in SN2 reaction (25–58% overall yield). The azides obtained either way underwent the Staudinger reduction, giving a series of six new chiral vic-diamines of defined stereochemistries.

Solid‐Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation

AbstractWe report a solid‐phase strategy for total synthesis of the peptidic natural product yaku'amide B (1), which exhibits antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β‐dialkylated α,β‐dehydroamino acid residues and is capped with an N‐terminal acyl group (NTA) and a C‐terminal amine (CTA). To realize the Fmoc‐based solid‐phase synthesis of this complex structure, we developed new methods for enamide formation, enamide deprotection, and C‐terminal modification. First, traceless Staudinger ligation enabled enamide formation between sterically encumbered alkenyl azides and newly designed phosphinophenol esters. Second, application of Eu(OTf)3 led to chemoselective removal of the enamide Boc groups without detaching the resin linker. Finally, resin‐cleavage and C‐terminus modification were simultaneously achieved with an ester–amide exchange reaction using CTA and AlMe3 to deliver 1 in 9.1 % overall yield (24 steps from the resin).

Solid-Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation.

We report a solid-phase strategy for total synthesis of the peptidic natural product yaku'amide B (1), which exhibits antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β-dialkylated α,β-dehydroamino acid residues and is capped with an N-terminal acyl group (NTA) and a C-terminal amine (CTA). To realize the Fmoc-based solid-phase synthesis of this complex structure, we developed new methods for enamide formation, enamide deprotection, and C-terminal modification. First, traceless Staudinger ligation enabled enamide formation between sterically encumbered alkenyl azides and newly designed phosphinophenol esters. Second, application of Eu(OTf)3 led to chemoselective removal of the enamide Boc groups without detaching the resin linker. Finally, resin-cleavage and C-terminus modification were simultaneously achieved with an ester-amide exchange reaction using CTA and AlMe3 to deliver 1 in 9.1 % overall yield (24 steps from the resin).

Me CAAC=N- : A Cyclic (Alkyl)(Amino)Carbene Imino Ligand.

A cyclic (alkyl)(amino)carbene (CAAC) has been shown to react with a covalent azide similar to the Staudinger reaction. The reaction of MeCAAC with trimethylsilyl azide afforded the N‐silylated 2‐iminopyrrolidine (MeCAAC=NSiMe3), which was fully characterized. This compound undergoes hydrolysis to afford the 2‐iminopyrrolidine and trimethylsiloxane which co‐crystallize as a hydrogen‐bonded adduct. The N‐silylated 2‐iminopyrrolidine was used to transfer the novel pyrrolidine‐2‐iminato ligand onto both main‐group and transition‐metal centers. The reaction of the tetrabromodiborane bis(dimethyl sulfide) adduct with two equivalents of MeCAAC=NSiMe3 afforded the disubstituted diborane. The reaction of MeCAAC=NSiMe3 with TiCl4 and CpTiCl3 afforded MeCAAC=NTiCl3 and MeCAAC=NTiCl2Cp, respectively.

Triazole formation of phosphinyl alkynes with azides through transient protection of phosphine by copper.

An efficient preparation method of functionalized phosphines by copper-catalyzed azide-alkyne cycloaddition (CuAAC) through the transient protection of phosphine from the Staudinger reaction is disclosed. Diverse phosphines were prepared from phosphinyl alkynes and azides by the click reaction at the ethynyl group without damaging the phosphinyl group. Double- and triple-click assemblies of azides were accomplished by triazole formations and robust azaylide formation.

Synthesis of 1,3-diaryl-spiro[azetidine-2,3'-indoline]-2',4-diones via the Staudinger reaction: cis- or trans-diastereoselectivity with different addition modes.

A new synthetic approach for realizing biologically relevant bis-aryl spiro[azetidine-2,3′-indoline]-2′,4-diones was developed based on Staudinger ketene–imine cycloaddition through the one-pot reaction of substituted acetic acids and Schiff bases in the presence of oxalyl chloride and an organic base. A series of [azetidine-2,3′-indoline]-2′,4-diones were synthesized using this method. For comparison, the same compounds were obtained using a known technique, where ketene is generated from pre-synthesized acyl chloride. It was shown that the use of oxalyl chloride for ketene generation in the one-pot reaction at room temperature allows for the reversal of the diastereoselectivity of spiro-lactam formation, unlike previously described procedures.

Fast phosphine-activated control of protein function using unnatural lysine analogues.

Effective, general methods for conditionally activating proteins in their native biological environments are highly useful for biological studies. Since phosphines and azides are not found in pro- and eukaryotic cells, the Staudinger reduction can function as an excellent small molecule-controlled switch for protein activation. This methodology involves site-specifically incorporating azidobenyl-lysine analogues into proteins in live cells. When placed at a crucial position, these unnatural side chains block protein function until a phosphine trigger is added. We discuss methods for expressing caged proteins in bacterial and mammalian cells in high yields, and activating the proteins with an optimized phosphine trigger. We also discuss important considerations for safe and effective synthesis of these molecules. This methodology was used to translocate proteins to the nucleus and to turn-on a protein post-translational modification (SUMOylation) in living cells.

Anionic Polymerization of Azidoalkyl Glycidyl Ethers and Post-Polymerization Modification

Polyethers like poly(ethylene glycol) have been widely used for a variety of valuable applications, although their functionalization still poses challenges due to the absence of functional handles along the polymer backbone. Herein, a series of novel azide-functionalized glycidyl ether monomers are presented as a universal approach to synthesize functional polyethers by post-polymerization modification. Three azide-functionalized glycidyl ether monomers possessing different alkyl spacers (ethyl, butyl, and hexyl) were designed and synthesized by a simple two-step substitution reaction. Organic superbase-catalyzed anionic ring-opening polymerization can proceed under mild conditions compatible with an azide pendant group, affording well-controlled azide-functionalized polyethers with low dispersity (Đ < 1.2). The azide pendant groups on the resulting polymers were readily modified to a variety of functional groups via copper-catalyzed azide–alkyne cycloaddition reactions and Staudinger reduction. Furthermore, copolymerization of azidohexyl glycidyl ether with allyl glycidyl ether was demonstrated to provide an additional orthogonal functional handle. We anticipate that this work provides a new platform for the preparation of diverse functional polyethers.

Synthesis, in vitro biological evaluation and in silico molecular docking studies of novel β-lactam-anthraquinone hybrids

Schiff bases from 2-aminoanthraquinone have been prepared by reaction with aldehydes and used to prepare novel β-lactam-anthraquinone hybrids via [2+2] ketene-imine cycloaddition (Staudinger reaction) reaction. In vitro antibacterial studies of all synthesized compound were carried out against three gram-positive strains Staphylococcus aureus (Methicillin-resistant strain), Enterococcus faecium (Vancomycin-resistant strain) and Bacillus subtilis, and two gram-negative strains Escherichia coli and Pseudomonas aeruginosa. These compounds were further evaluated for their in vitro antifungal activity against Candida albicans, Aspergillus niger and Trichophyton mentagrophytes. Hybrid compounds showed moderate to excellent antibacterial and antifungal activities. Surprisingly, among the tested compounds, some of them revealed equal antibacterial and antifungal properties and even better than standards. In addition, results demonstrated that the new hybrids are very promising antibacterial agents against resistant strains. Also molecular docking studies were carried out by Autodoc software. Penicillin-binding protein 2a (PDB ID: 1VQQ) from methicillin-resistant Staphylococcus aureus strain used as a target which good binding interactions were observed.

New phosphazine and phosphazide derivatives as multifunctional ligands targeting acetylcholinesterase and β-Amyloid aggregation for treatment of Alzheimer's disease.

Phosphazine and phosphazide derivatives are described herein as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and β-amyloid aggregation inhibitors. Phosphazines (5-7) were synthesized smoothly via a redox-condensation reaction of 1,2-bis(diphenylphosphino)ethane with different amines derivatives in the presence of dialkyl azodicarboxylate (Staudinger reaction) while phosphazides (8) via electrophilic attack of azido derivatives. Structures of the synthesized compounds were justified on the basis of compatible elementary and spectroscopic analyses. All the compounds were evaluated for their acetylcholinesterase inhibitory activity. The most three potent compounds (5b-c and 8b) showing AChE IC50 values (29.85-34.96nM) comparable to that of donepezil (34.42nM) were subjected to further investigation by testing their butyrylcholinesterase, MMP-2 and self-induced Aβ aggregation inhibition activity. Especially, the coumarin phosphazide derivative (8b) presented the best AChE inhibition selectivity index (IC50=34.96nM, AChE/BuChE; 3.81) together with good inhibition ability against MMP-2 (IC50=441.33nM) and self-induced Aβ1-42 aggregation (IC50=337.77nM). In addition, the inhibition of metal-induced Aβ aggregation by 8b was confirmed by thioflavine T fluorescence. The most potent effect of 8b was observed on the Zn2+-induced Aβ42 aggregation. Kinetic study of compound 8b suggested it to be a competitive AChE inhibitor. Also, it specifically chelates metal and is predicted to be permeable to BBB. It also possesses low toxicity on SH-SY5Y neuroblastoma cells with a safety index of 15.37. In addition, it was demonstrated that compound 8b can improve the cognitive impairment of scopolamine-induced model in mice with % alternations and transfer latency time comparable to that of donepezil. Also, a docking study was carried out and it was in accordance with the in vitro results. These promising in vitro and in vivo findings highlight compound 8b as a possible drug candidate in searching for new multifunctional AD drugs.

MicroRNA Detection with Turnover Amplification via Hybridization-Mediated Staudinger Reduction for Pancreatic Cancer Diagnosis.

The occurrence of and development in the early pathological stage of pancreatic cancer has proved to be associated with microRNAs. However, it remains a great challenge to directly monitor low-expression, and downregulation of, microRNA among living cells, tissues, and serum samples. In this work, Staudinger reduction is first applied in intracellular microRNA detection, establishing a set of smart hybridization-mediated Staudinger reduction probes (HMSR-probe) which contain designed oligonucleotide sequences. Meanwhile, 40 serum samples (healthy people (6), patients with pancreatitis (22), and pancreatic cancer patients (12)) are tested for exploring the potential clinical application. Of note, the molecules bound to nucleic acid confine the reactive site to close proximity in a compact space, and nonconnected product from Staudinger reaction facilitates turnover amplification to an ameliorative detection limit (1.3 × 10-15 M). Moreover, compared with qRT-PCR, a low false positive signal and an excellent specificity makes the probe more suitable and convenient for pancreatic cancer diagnosis in blood samples. For practical applications, HMSR-probe enable accurate differentiation in cell and tissue samples under both 488 and 785 nm and have good coherence to known research. As a proof of concept, the reliable results in distinguishing pancreatic cancer patients from different morbid stages might supply a feasible method for endogenous microRNA detection in fundamental research and clinical diagnostics.

Promoting Dendrimer Self-Assembly Enhances Covalent Layer-by-Layer Encapsulation of Pancreatic Islets.

For type 1 diabetics, islet transplantation can induce beneficial outcomes, including insulin independence and improved glycemic control. The long-term function of the grafted tissue, however, is challenged by host inflammatory and immune responses. Cell encapsulation can decrease detrimental host responses to the foreign implant, but standard microencapsulation imparts large transplant volumes and impaired metabolite and nutrient diffusion. To mitigate these effects, we developed an efficient covalent Layer-by-Layer (cLbL) approach for live-cell nanoencapsulation, based on oppositely charged hyperbranched polymers functionalized with complementary Staudinger ligation groups. Reliance on cationic polymers for cLbL, however, is problematic due to their poor biocompatibility. Herein, we incorporated the additional feature of supramolecular self-assembly of the dendritic polymers to enhance layer uniformity and decrease net polymer charge. Functionalization of poly (amino amide) (PAMAM) with triethoxysilane decreased polymer charge without compromising the uniformity and stability of resulting nanoscale islet coatings. Encapsulated pancreatic rat islets were viable and functional. The implantation of cLbL islets into diabetic mice resulted in stable normoglycemia, at equivalent dosage and efficiency as uncoated islets, with no observable alterations in cellular engraftment or foreign body responses. By balancing multi-functionality and self-assembly, nano-scale and stable covalent layer-by-layer polymeric coatings could be efficiently generated onto cellular organoids, presenting a highly adaptable platform for broad use in cellular transplantation.