Mechanism and Origin of Stereoselectivity in Chiral Phosphoric Acid-Catalyzed Aldol-Type Reactions of Azlactones with Vinyl Ethers

The precise mechanism of the chiral phosphoric acid-catalyzed aldol-type reaction of azlactones with vinyl ethers was investigated. DFT calculations suggested that the reaction proceeds through a Conia-ene-type transition state consisting of the vinyl ether and the enol tautomer of the azlactone, in which the catalyst protonates the nitrogen atom of the azlactone to promote enol tautomerization. In addition, the phosphoryl oxygen of the catalyst interacts with the vinyl proton of the vinyl ether. The favorable transition structure features dicoordinating hydrogen bonds. However, these hydrogen bonds are not involved in the bond recombination sequence and hence the catalyst functions as a template for binding substrates. From the results of theoretical studies and experimental supports, the high enantioselectivity is induced by the steric repulsion between the azlactone substituent and the binaphthyl backbone of the catalyst under the catalyst template effect.     

A new route to 2-styrylbenzimidazoles

An attempt was made to prepare 2-benzylquinoxalin-3-one by hydrolyzing the azlactone, 2-phenyl-4-benzylidene-5-oxazolone to β-phenylpyruvic acid and then treating this in situ with o-phenylenediamine (OPDA). The initial hydrolysis apparantly proceeded only as far as opening the azlactone ring forming 2-benzamidocinnamic acid which condensed with OPDA to form a substituted styrylbenzimidazole.     

Design and synthesis of 2,4-difluorophenylpyruvic acid and of its azlactone precursor for macrophage migration inhibitory factor (MIF) tautomerase activity

The macrophage migration inhibitory factor (MIF) is an important cytokine implicated in several diseases and currently a target for drug development. This study aimed to synthesize phenylpyruvic acid like structures that fit the molecular requirements of MIF with respect to keto/enol tautomerism and E/Z isomerism of the enol forms. The synthesis of 2,4-difluorophenylpyruvic acid and its azlactone precursor as potential ligands to interact with the active site of MIF is reported here. Both the E and Z isomers of the azlactone of 2,4-difluorobenzaldehyde were synthesized using different synthetic methods. Hydrolysis of these isomeric azlactones yielded similar enol/keto tautomeric mixtures of 2,4-difluorophenylpyruvic acid, with the enol form predominating. NMR spectroscopy was used to confirm the structures of these compounds, while an X-ray crystallographic study also confirmed the configuration of the E isomer of the azlactone.     

Synthesis and Antioxidative Properties of Conjugates of Dextran with 4-(4-Hydroxy-3,5-di-<Emphasis Type="Italic">tert</Emphasis>-butylbenzylidene)-2-phenyl-4, 5-dihydrooxazol-5-one

The possibility of synthesis of conjugates differing in molecular weight, degree of substitution of the dextran glycoside units, and, accordingly, in the solubility in water from a hydrophilic polymer (dextran) and an azlactone derivative of a sterically hindered phenol, 4-(4-hydroxy-3,5-di-tert-butylbenzylidene)-2-phenyl-4,5-dihydrooxazol-5-one, was analyzed, and their antiradical and antioxidative activity was studied.__________Translated from Zhurnal Prikladnoi Khimii, Vol. 78, No. 6, 2005, pp. 962–965.Original Russian Text Copyright © 2005 by Sergeeva, Aref’ev, Domnina, Komarova.     

Palladium(O)-catalyzed allylic alkylation and amination of allylic phosphates

Allyl diethyl phosphates (1) can be easily substituted with malonates and amines in the presence of palladium(O) catalyst. Synthetic utility of the reaction is demonstrated by the sequential amination-amination and alkylation-amination of (Z)-4-acetoxybut-2-enyl diethyl phosphate (1b) with high regio- and stereoselectivity.     

Sequential catalytic isomerization and allylic substitution. Conversion of racemic branched allylic carbonates to enantioenriched allylic substitution products

A catalytic protocol for the conversion of readily accessible racemic, branched aromatic allylic esters to branched allylic amines, ethers, and alkyls has been developed. Palladium-catalyzed isomerization of branched allylic esters to terminal allylic esters, followed by sequential iridium-catalyzed allylic substitution, gave the branched allylic products in good yield with high regioisomeric and enantiomeric selectivity. Both electron-rich and electron-poor branched allylic esters gave products in >90% ee. High enantiomeric excesses were also observed for the products from the reactions of 2-thienyl acetates and dienyl carbonates.     

Palladium-catalyzed alpha-arylation of azlactones to form quaternary amino acid derivatives

[reaction: see text] The synthesis of alpha-aryl-alpha-alkyl amino acid derivatives from alpha-amino acids by the arylation of azlactone derivatives is reported. Arylation of azlactones derived from alanine, valine, phenalanine, phenyl glycine, and leucine all provided good yields of the arylated product. Mechanistic studies of this reaction revealed that a stable complex containing a ligand formed by reaction of dba with the azlactone accounts for a new inhibiting effect of dba when reactions are initiated with Pd(dba)(2).     

Luminophores of the azlactone series with a difluoromethylsulfonyl group

Organic luminophores of the azlactone series that contain a strong electronacceptor substituent, viz., a difluoromethylsulfonyl group, were synthesized. The significant effect of the electronic nature of the substituents on the frequencies of the stretching vibrations of the CO and C=N groups was demonstrated, and the trans configuration of the investigated compounds was confirmed. The introduction of a difluoromethylsulfonyl group in the azlactone molecule promotes the development of intense fluorescence in solutions at room temperature. The character of the substituents and their mutual orientation have a substantial effect on the optical characteristics.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1600–1603, December, 1981.     

Acylaminoacetyl derivatives of active methylene compounds. 3 . C-Acylation Reactions via the Hippuric Acid Azlactone

The C-acylation reactions of the active methylene compounds, methyl cyanoacetate and Meldrum's acid, with hippuric acid, using the DCC activation and the mixed anhydride conditions, are shown to proceed through initial formation of 2-phenyl-5(4H)-oxazolone, the hippuric acid azlactone. The conditions of these reactions using the azlactone as the acylating agent were investigated and discussed.     

Catalytic Asymmetric Synthesis of Spirocyclic Azlactones by a Double Michael‐Addition Approach

Spirocyclic azlactones are shown to be useful precursors of cyclic quaternary amino acids, such as the constrained cyclohexane analogues of phenylalanine. These compounds are of interest as building blocks for the synthesis of artificial peptide analogues with controlled folds in the peptide backbone. They were prepared in the present study by a step‐ and atom‐economic catalytic asymmetric tandem approach, requiring two steps starting from N‐benzoyl glycine and divinylketones. The key of this protocol is the enantioselective formation of the azlactone spirocycles, which involves a Pd^II‐catalyzed double 1,4‐addition of an in situ generated azlactone intermediate to the dienone (a formal [5+1] cycloaddition). As the catalyst, a planar chiral ferrocene bispalladacycle was used. Mechanistic studies suggest a monometallic reaction pathway. Although the diastereoselectivity was found to be moderate, the enantioselectivity is usually high for the formation of the azlactone spirocycles, which contain up to three contiguous stereocenters. Spectroscopic studies have shown that the spirocycles often prefer a twist over a chair conformation of the cyclohexanone moiety.     

Surface-anchored poly(2-vinyl-4,4-dimethyl azlactone) brushes as templates for enzyme immobilization

We explored surface-anchored poly(2-vinyl-4,4-dimethyl azlactone) (PVDMA) brushes as potential templates for protein immobilization. The brushes were grown using atom transfer radical polymerization from surface-anchored initiators and characterized by a combination of ellipsometry, atomic force microscopy, and X-ray photoelectron spectroscopy. RNase A was immobilized as a model enzyme through the nucleophilic attack of azlactone by the amine groups in the lysines located in the protein. The surface density of RNase A increased linearly from 5 to 50 nm. For 50 nm thick poly(2-vinyl-4,4-dimethyl azlactone) brushes, 7.5 microg/cm2 of RNase A was bound. The kinetics and thermodynamics of RNase A immobilization, the activity relative to surface density, and the pH and temperature dependence were examined. A Langmuir-like model for binding kinetics indicates that the kinetics are controlled by the rate of adsorption of RNase A and has an adsorption rate constant, k(ads), of 2.8 x 10(-8) microg(-1) s(-1) cm3. A maximum relative activity of approximately 0.95, which is near the activity of free RNase A, was reached at 1.2 microg/cm2 (approximately 3.0 monolayers) of immobilized RNase A. The immobilized RNase A had a similar temperature and pH dependence as free RNase A, indicating no significant change in conformation. The PVDMA template was extended to other biotechnologically relevant enzymes, such as deoxyribonuclease I, glucose oxidase, glucoamylase, and trypsin, with relative activities higher than or comparable to those of enzymes immobilized by other means. PVDMA brushes offer an efficient route to immobilize proteins via the ring opening of azlactone without the need for activation or pretreatment while retaining high relative activities of the bound enzymes.     

Chemistry of alkenyl azlactones. VII. Preparation and properties of multiazlactones derived from mercaptan-functional compounds and oligomers

The reaction of polymercaptans and 2-alkenyl azlactones has been further investigated, and several new multiazlactones which are liquids at room temperature have been prepared and characterized. Michael addition yielding the multiazlactones was found to take place slowly in the absence of and rapidly in the presence of acid catalysts. If basic impurities capable of forming mercaptide ion were present, however, the reaction underwent a substantially different course producing primarily ring-opened products. A source of these basic impurities was determined to be the method of preparation of the alkenyl azlactone itself. When the azlactone was prepared from its acyclic N-substituted aminoacid precursor by cyclodehydration by use of ethyl chloroformate and triethylamine, a small amount of triethylamine remained that dramatically altered the course of reaction. Nonbasic cyclodehydration agents such as dicyclohexylcarbodiimide were effective at eliminating this side reaction, as well as was the practice of adding excess acid to the reaction system to neutralize the basic impurities.     

Low-valent titanium-mediated stereoselective alkylation of allylic alcohols

We have developed low-valent titanium-mediated 1,3-transpositive cross-coupling reactions of acyclic and cyclic allylic alcohols for the stereoselective introduction of ethyl, 2-silylethyl, 2-phenethyl, and alkenyl groups. Cross-coupling of an allylic alcohol with a vinylsilane or styrene derivative is particularly noteworthy, as an efficient cross-selective coupling of two alkenes has been elusive. The stereochemistry of the cross-coupling alkylation is consistent with syn addition/beta-elimination.     

Stereodivergent synthesis via iridium-catalyzed asymmetric double allylic alkylation of cyanoacetate

Methods that enable the rapid construction of multiple C–C bonds using a single catalyst with high diastereo- and enantio-control are particularly valuable in organic synthesis. Here, we report an Ir-catalyzed double allylic alkylation reaction in which bisnucleophilic cyanoacetate reacted successionally with electrophilic π-allyl-Ir species, producing various pseudo-C₂-symmetrical cyanoacetate derivatives in high yield with excellent stereocontrol. More challenging sequential allylic alkylation/allylic alkylation with two distinct allylic carbonates that can deliver the corresponding products bearing three contiguous tertiary–quaternary–tertiary stereocenters was also developed by using a modified catalytic system, which is revealed to be associated with the quasi-dynamic kinetic resolution of the initially formed diastereomeric monoallylation intermediates. Notably, stereodivergence for this sequential process depending on a single iridium catalyst was successfully realized, and up to six stereoisomers could be predictably prepared by combining the appropriate enantiomer of the chiral ligand for the iridium catalyst and adjusting the adding sequence of two distinct allylic precursors.

Ir-catalyzed asymmetric double AAA reaction of cyanoacetate was developed, affording cyanoacetate derivatives in high yield with excellent stereocontrol. Notably, quasi-DKR is involved in the sequential protocol with two distinct allylic carbonates.     

Chemistry and technology of 2‐alkenyl azlactones

The chronology of 2‐alkenyl azlactone research at 3M is discussed in terms of its origination; consideration of economics, overall safety, and opportunities for patent protection; elaboration of the chemistry; and, finally, applying lessons learned toward the development of commercial technologies. The chemistry is dominated by the presence of three electrophilic reaction centers and a readily polymerizable 2‐alkenyl group. Technological development has been focused in four general areas: acrylamide monomers, acrylamide materials, azlactone materials, and polymer modification. Application areas disinclude lithographic printing plates, contact lens materials, adhesives, dispersants for printing inks, and supports for immobilizing enzymes. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 3655–3677, 2001     

Total synthesis of the dolabellane marine diterpenoids, claenone, palominol and dolabellatrienone

The synthesis of marine dolabellane diterpenoids claenone, palominol and dolabellatrienone was conducted from d-mannitol. In each case, formation of the bicyclo[2.2.1]heptane derivative by sequential Michael reaction, preparation of the tetrasubstituted cyclopentane derivative by retro-aldol reaction and cyclization of sulfone were involved as key steps.     

Synthesis of 2,5-diaryloxazoles through friedel-crafts reaction of azlactones with aromatic hydrocarbons

2-Phenyl-5-oxazolone (hippuric acid azlactone, I) gives good yields of benzoylamino-ketones(II) in the Friedel-Crafts benzoylaminoacetylation of aromatic hydrocarbons. On this basis a new synthesis of 2,5-diaryloxazoles was devised, resulting in the simplest preparation of several 2-phenyl-5-aryl-oxazoles (III), which are good scintillator solutes. Ultra-violet absorption spectra are described and discussed.     

Total synthesis of marine diterpenoid stolonidiol

Marine dolabellane diterpenoid stolonidiol was synthesized from l-ascorbic acid. The method for this total synthesis involves formation of the bicyclo[2.2.1]heptane derivative using a diastereoselective sequential Michael reaction, formation of cyclopentane derivative by the retro-aldol reaction and construction of an 11-membered carbocyclic ring through the intramolecular Horner–Wadsworth–Emmons reaction.     

Preparation of stable,camphor-derived,optically active allylic sulfoxides

(+)-Camphor has been stereospecifically converted in three steps into a single isoborneol allyl sulfoxide derivative, which upon heating to 145° is quantitatively converted into its sulfoxide epimer; the anions of these compounds undergo stereospecific conjugate addition to cyclopent-2-en-1-one.     

Dendritic oxazoline ligands in enantioselective palladium-catalyzed allylic alkylations

First to fourth generation dendritic substituents based on 2,2-bis(hydroxymethyl)propionic acid and (1R,2S,5R)-menthoxyacetic acid were attached to 2-(hydroxymethyl)pyridinooxazoline and bis[4-(hydroxymethyl)oxazoline] compounds. The new ligands obtained were assessed in palladium-catalyzed allylic alkylations. The first type of ligands exhibited enantioselectivity similar to that of a benzoyl ester derivative, whereas the latter type of ligands afforded products with higher selectivity than the analogous benzoyl ester. The activity of the dendritic catalysts decreased with increasing generation.