Synthesis of C-terminal glycopeptides from resin-bound glycosyl azides via a modified Staudinger reaction

The solid-phase synthesis of glycopeptides containing the sugar at the C-terminus is reported. The method is demonstrated on a model, the endogenous antinociceptive peptide Leu-enkephalin. 2,3,4-Tri-O-acetyl-1-azido-1-deoxy-beta-D-glucopyranuronic acid was synthesized and immobilized onto a variety of derivatized resins. Conjugation of the first amino acid was accomplished by reaction of the resin-bound glycosyl azide with an activated amino acid, in one step, via a modified Staudinger reaction. Standard solid-phase peptide synthesis then resulted in the desired amide-linked glycopeptide. Reaction conditions and reagents for the glycosylation were varied to optimize the yield and purity of the product. The optimum conditions were found to be the use of a 4-fold molar excess of activated amino acid and 3-fold excess of tri-n-butylphosphine in tetrahydrofuran. This methodology is generally applicable to most peptide sequences and is compatible with both Boc- and Fmoc- synthetic strategies on a variety of resins.     

Enantioselective Staudinger synthesis of beta-lactams catalyzed by a planar-chiral nucleophile

The development of efficient methods for the stereoselective generation of beta-lactams is an important goal, due to their biological activity and their utility as synthetic intermediates. The Staudinger reaction, an overall [2 + 2] cycloaddition of a ketene with an imine, provides a nicely convergent route to this family of compounds. Nearly all studies to date of asymmetric variants of the Staudinger reaction have focused on the use of chiral auxiliaries to control the stereochemistry of the beta-lactam. In this report, we establish that a planar-chiral derivative of 4-(pyrrolidino)pyridine serves as a very effective enantioselective catalyst for the Staudinger beta-lactam synthesis, coupling a range of symmetrical and unsymmetrical ketenes with an array of imines with very good stereoselection and yield.     

Synthesis of a triphenylphosphine reagent on non-cross-linked polystyrene support: application to the Staudinger/Aza-wittig reaction

A new triphenylphosphine reagent linked to a linear polystyrene was synthesized. The reactivity of this phosphine-bound polymer is superior to that of the phosphine bound to cross-linked polystyrene. The polymer reacted very rapidly with azides to generate iminophosphoranes which could then react with aldehydes to generate imines in good yields and high purities.     

Synthesis of a new chiral oxazolidinone auxiliary based on d-xylose and its application to the Staudinger reaction

The synthesis of a new chiral oxazolidinone auxiliary based on d-xylose is described which is employed in diastereoselective Staudinger-type β-lactam syntheses. Using 2-chloro-1-methylpyridinium iodide as the dehydrating reagent, the reaction of auxiliary tethered acetic acid with acyclic or cyclic imines gave the desired β-lactams in good yields with excellent cis- or trans-selectivity depending on the geometry of the imine. X-Ray structure determination of one of the obtained compounds corroborated the absolute configuration for all cis products.     

Remarkable ketene substituent dependent effect of photo irradiation on the diastereoselectivity in the Staudinger reaction

Controlling diastereoselectivity is a challenging issue in the Staudinger reaction. The influence of ultraviolet irradiation on the stereoselectivity in the Staudinger reaction has been investigated. The results indicate that ultraviolet irradiation is one of the most important means to regulate the diastereoselectivity of the products in the Staudinger reaction, whatever ketenes were generated from diazomethyl ketones or from substituted acetyl chlorides in the presence of triethylamine. However, the regulation is dependent on the ketene substituents obviously. Ultraviolet irradiation can even reverse the diastereoselectivity for the reactions involving ketenes without strong electron-donating substituents.     

Notable and obvious ketene substituent-dependent effect of temperature on the stereoselectivity in the Staudinger reaction

A notable and obvious ketene substituent-dependent effect of temperature on the stereoselectivity in the Staudinger reaction was observed. Most Staudinger reactions show concave Eyring plots characterized by two lines with an inversion point, following the principle of isoinversion. Their cis-selectivities decrease with increasing temperature. Reactions involving intramolecular p-pi and pi-pi interactions between the ketene substituents and imine C-substituents reveal protruding, S-shaped or straight-line Eyring plots. Their cis-selectivities increase with increasing temperature in a certain temperature region because such interactions enhance the cis-selectivity. Staudinger reactions involving cyclic imines with different ketenes clearly indicate that the temperature-dependent stereoselectivity is caused by the different rate increases of the direct ring closure, which are affected by the p-pi and pi-pi interactions between ketene substituents and imine C-substituents if they exist, and the isomerization of the zwitterionic intermediates generated from ketenes and imines during the change in the reaction temperature, not by the competition of the imine exo and endo attacks to the ketenes. Our results also indicate that nonlinear Eyring plots do not always reveal a change of the stereoselectivity-determining step. Thus, one should use them carefully to determine any changes in the stereoselectivity-determining step during the change in the reaction temperature.     

Synthesis of fluorinated geminal diisocyanides stabilized on a transition metal

Chromium complexes of the geminal diisocyanides bis(pentacarbonyl)-μ-2,2-diisocyano-1,1,1,3,3,3-hexafluoropropane)dichromium 1a and bis(pentacarbonyl)-μ-2,2-diisocyano-1,1,1,3,3-pentafluorobutane)dichromium 1b were obtained by radical alkylation of pentacarbonylcyanochromate besides pentacarbonyl(2-isocyano-1,1,1,3,3,3-hexafluoropropane)chromium 2a and pentacarbonyl(2-isocyano-1,1,1,3,3-pentafluorobutane)chromium 2b, respectively. Pentacarbonyl(2-isocyano-1,1,1,2,3,3,3-heptafluoropropane)chromium 2c was prepared analogously. The crystal and molecular structures of 1a and b were determined by X-ray diffraction.     

Catalytic asymmetric Staudinger reactions to form beta-lactams: an unanticipated dependence of diastereoselectivity on the choice of the nitrogen substituent

There are relatively few methods for the catalytic asymmetric synthesis of beta-lactams, and those that have been reported are generally cis selective. This communication describes the first catalytic enantioselective Staudinger reactions that preferentially furnish trans beta-lactams (trans = relationship of Ph to R1). The key to this method is the use of an N-triflyl protecting group for the imine. Along with serving as interesting targets in their own right, N-triflyl beta-lactams readily react with nucleophiles to generate useful families of compounds, such as gamma-amino alcohols and beta-amino acids.     

Rapid synthesis of 1,3,4,4-tetrasubstituted beta-lactams from methyleneaziridines using a four-component reaction

2-Methyleneaziridines can be transformed into a variety of 1,3,4,4-tetrasubstituted beta-lactams in moderate to good yields (46-63%) via a "one-pot" process that brings together four components with the formation of three new intermolecular carbon-carbon bonds.     

Synthesis and properties of undecatungstozirconates with a transition metal

Summary K _n [ZrW₁₁O₃₉M(H₂O)]·xH₂O complexes were prepared and characterized by elemental analysis, u.v.-vis., i.r. spectroscopy and electrochemistry. The title heteropolyanions catalyse olefin epoxidation by iodosylbenzene.     

Studies on the synergetic effect of group viii transition metal carbonyls on homogeneous catalysis of the water-gas shift reaction

Homogeneous catalysis of the water-gas shift reaction by Group VIII mixed metal carbonyls and by mixtures of Group VIII metal carbonyls in pyridine solution was examined under mild conditions (T= 100°C, P_co = 0.42–0.60 atm).A weak synergetic effect of Group VIII metals was observed between iron and iridium carbonyls. A stronger synergetic behaviour of mixed metal Fe/Ru catalyst precursors (Fe₂Ru(CO)₁₂ and FeRu₂(CO)₁₂) was noted. The effect of phosphine and phosphite substitution on Fe₂Ru(CO)₁₂ and FeRu₂(CO)₁₂ was examined. Only monosubstitution on Fe₂Ru(CO)₁₂ was found to have an enhancing effect on catalytic activity.Rhodium carbonyls, which were found to produce the most active catalyst solution under homogeneous water-gas shift conditions, did not show a synergetic behaviour with other Group VIII metals.     

2,2′-Bipyrimidine transition metal complexes: Synthesis, reaction chemistry and solid state structures

2,2′-Bipyrimidine metal complexes with Ti, Mo, Fe, Ru, Pt, Ag, and Cu transition metal atoms have been synthesized and structurally characterized. These molecules were prepared by following synthesis methodologies. The reaction of 2,2′-bipyrimidine (1; bipym) with {[Ti](μ-σ,π-CCSiMe₃)₂}AgOTf ([Ti] = (η⁵-C₅H₄SiMe₃)₂Ti, OTf = OSO₂CF₃) (2) in a 1:1 molar ratio gave [{[Ti](μ-σ,π-CCSiMe₃)₂}Ag(bipym)]OTf (3) which on further treatment with another equivalent of 2 produced [({[Ti](μ-σ,π-CCSiMe₃)₂}Ag)₂(μ-1,2,3,4-bipym)](OTf)₂ (4). As consequence thereof, the coordination number of Ag(I) was changed from 3 to 4. A platinum-bipym complex with two acetylide substituents was accessible by the gradual reaction of 1 with K₂[PtCl₄] (5) and two equivalents of HCCR (7a, R = SiMe₃; 7b, R = Fc; 7c, R = Rc; Fc = (η⁵-C₅H₄)(η⁵-C₅H₅)Fe; Rc = (η⁵-C₅H₄)(η⁵-C₅H₅)Ru) in di-iso-propylamine and in presence of [CuI]. Originating from cis-[(bipym)Pt(CCR)₂] (8a, R = SiMe₃; 8b, R = Fc; 8c, R = Rc) diverse multinuclear complexes with two, three or four different transition metals could be obtained. These are: [((CO)₄Mo)(μ-1,2,3,4-bipym)Pt(CCFc)₂] (10), [(AgClO₄)(μ-1,2,3,4-bipym){[Pt(μ-σ,π-CCFc)₂]AgOClO₃}] (12), [(McCC)₂Pt(μ-1,2,3,4-bipym)({[Ti](μ-σ,π-CCSiMe₃)₂}M)]X (15a, Mc = Fc, M = Cu, X = PF₆; 15b, Mc = Rc, M = Cu, X = PF₆; 15c, Mc = Fc, M = Ag, X = ClO₄), and [(McCC)₂Pt(μ-1,2,3,4-bipym)PtCl₂] (17). Like other organometallic Pt-Ag tweezer complexes, compound 12 decomposed to give FcCC-CCFc (13). During prolonged stirring of 15a and 15b, respectively, [(McCC)₂Pt(μ-1,2,3,4-bipym)({[Ti](μ-σ,π-CCSiMe₃)(μ-σ,π-CCH)}M)]X (15′a, M = Cu, X = PF₆; 15′b, M = Cu, X = PF₆) was formed.The structures of 8b, 8c, 15a′, and 15b′ in the solid state are reported. All complexes exhibit the anticipated planar dinuclear Pt-M structure (M = Pt, Cu, Ag) with the 2,2′-bipyrimidine unit in a μ-1,2,3,4-bridging mode.Electrochemical investigations were carried out with 8a, 8b, and 8c and show that no significant influence of R on the bipym redox potentials exists. The typical redox behavior for the bipym, ferrocene, ruthenocene units and platinum were observed.     

Synthesis of beta-lactams from diazoketones and imines: the use of microwave irradiation

[see reaction]. The transformation of diazoketones derived from alpha-amino acids to ketenes that, in turn, react further with imines to afford beta-lactams, can be realized not only by utilizing photochemical reaction conditions but also under the action of microwave irradiation. Under the latter reaction conditions 4-alkenyl-substituted beta-lactams derived from amino acids, substrates that were not previously accessible, have been prepared. beta-Lactams possessing a trans-substitution pattern at the ring were obtained exclusively.     

Nucleophilic metal complexes as acylation catalysts: solvent-dependent "switch" mechanisms leading to the first catalyzed Staudinger reaction

[formula: see text] Catalytic acylation using complex transition metal salts MCo(CO)4 is demonstrated. Surprisingly, a solvent-dependent mechanistic "switch" results in a Lewis acid-based acylation mechanism in nonpolar media and a nucleophilic mechanism in polar organic media. These observations lead to the first example of a catalyzed Staudinger reaction to form beta-lactams.     

Heteroatom effect on potential energy topology. A novel reaction mechanism of stereospecific Staudinger synthesis

The Staudinger synthesis of various β-carbolines and thienopyridines with acetyl chloride derivatives led to novel β-lactam-type fused heterocyclic compounds. The reaction was stereospecific, giving exclusively the cis cycloadducts as racemates. The enthalpy profile and the driving force for the cis-selectivity of this cycloaddition was studied by high level quantum chemical calculations and was assigned to a new effect of the neighbouring heteroatom of the acyl group. In the course of the reaction a new side product was formed supporting the mechanistic results.     

Synthesis of beta-lactams bearing functionalized side chains from a readily available precursor

The reaction of chlorosulfonyl isocyanate (CSI) with alkenes provides beta-lactams in quantity, and the products have frequently been used for ring-opening polymerization to generate nylon-3 materials. Prior uses of this approach have focused almost entirely on beta-lactams with purely hydrocarbon substitutents. We show how a variety of beta-lactams bearing protected polar substituents can be generated from CSI-derived building blocks.     

Diastereoselectivity in the Staudinger reaction: a useful probe for investigation of nonthermal microwave effects

The effect of microwave irradiation on the selectivity, especially stereoselectivity, is one of the most important issues in microwave-assisted organic reactions. The diastereoselectivity in Staudinger reactions involving the representative ketenes and the corresponding matched imines has been used as a probe to investigate carefully the existence of the specific nonthermal microwave effects. The results indicate that the microwave irradiation-controlled stereoselectivity in the Staudinger reaction is in fact the contribution of temperature. No specific nonthermal microwave effect was found in the Staudinger reaction.     

Staudinger ligation: a peptide from a thioester and azide

[reaction: see text] The technique of native chemical ligation enables the total chemical synthesis of proteins. This method is limited, however, by an absolute requirement for a cysteine residue at the ligation juncture. Here, this restriction is overcome with a new chemical ligation method in which a phosphinobenzenethiol is used to link a thioester and azide. The product is an amide with no residual atoms.