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PubMed1986

Interaction of the aziridine moiety of RSU-1069 with nucleotides and inorganic phosphate. Implications for alkylation of DNA.

The aziridine moiety of RSU-1069 (1-(2-nitro-1-imidazolyl)-3-(1-aziridino-2-propanol] alkylates inorganic phosphate and a range of nucleotides in aqueous solutions of pH 7.0. From the rate constants obtained and a study of the adducts formed it is demonstrated that phosphate is a major target on nucleotides at neutral pH, although additional sites may exist particularly on dGMP and dAMP. From the dependence of reactivity on pH and the influence of ionic strength, it is established that the protonated aziridine is the reactive species and that hydrolysis is insignificant when compared to the rate of phosphorylation. The reaction kinetics detailed in this study are discussed in terms of DNA alkylation and strand breakage effected by the aziridine moiety of RSU-1069.

Adamantane↗
PubMed1993

Interaction of hepatic microsomal epoxide hydrolase derived from a recombinant baculovirus expression system with an azarene oxide and an aziridine substrate analogue.

A recombinant baculovirus (vEHX) encoding rat hepatic microsomal epoxide hydrolase has been constructed. Infection of Spodoptera frugiperda (Sf9) cells with the recombinant virus results in the expression of the enzyme at a level estimated to be between 5% and 10% of the cellular protein. The enzyme, which can be purified in 15% yield by a simple three-step procedure involving detergent extraction, DEAE-cellulose chromatography, and removal of the detergent on hydroxylapatite, has physical and kinetic properties very close to those of the enzyme obtained from rat liver microsomes. The interaction of the enzyme with two nitrogen-containing analogues of the substrate phenanthrene 9,10-oxide (1) was investigated in order to delineate the contributions of the oxirane group and the hydrophobic surface of the substrate to substrate recognition. The enzyme exhibits altered kinetic properties toward 1,10-phenanthroline 5,6-oxide (2) in which the biphenyl group of 1 is replaced with a bipyridyl group, suggesting that hydrophobic interaction between the complementary surfaces of the substrate and active site has an influence on catalysis. The conjugate acid of the aziridine analogue of 1, phenanthrene 9,10-imine (3), in which the oxirane oxygen is replaced with NH, has a pKa of 6.1, which allows the characterization of both the neutral and protonated aziridine (3H+) as substrate analogues for the enzyme. The pH dependence of the solvolysis reveals that 3H+ rearranges to a 65/35 mixture of 9-aminophenanthrene and 9-amino-10-hydroxy-9,10-dihydrophenanthrene 10(3)-fold faster than does 3. The neutral aziridine is a competitive inhibitor (Ki = 26 microM) of the enzyme at pH 8.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Stereoselective recognition of an aziridine with a Co(III) complex: a potential transition-state analogue for catalytic epoxidation.

Reversible and stereoselective coordination of 1-(R)-phenyl-2-(S)-methylaziridine to (S,S)L-Co(III) and (R,R)L-Co(III) (where L represents a salen ligand obtained from diamino cyclohexane and 2,4-di-tert-butyl salicylaldehyde) has been investigated. 1H NMR data indicate that the aziridine binds about three times more tightly to (S,S)L-Co(III) than to (R,R)L-Co(III). Crystal structures of two molecules of the aziridine coordinated to the Co(III) complexes have been determined. These structures together with molecular mechanics computation provide insight into the origin of stereoselective recognition of the aziridine to the Co(III) complexes.

Journal Article↗
PubMed2002

A unique and highly efficient method for catalytic olefin aziridination.

A facile, high yielding, and stereospecific method for olefin aziridination is described. This process capitalizes on the unique reactivity of sulfamate esters in combination with 1-2 mol % Rh2(tfacam)4 and PhI(OAc)2 as the terminal oxidant to promote N-atom transfer reactions. A range of structurally and electronically disparate alkenes are found to react under conditions that employ substrate as the limiting reagent and only a slight excess of H2NSO3CH2CCl3 as the nitrogen source. The product alkoxysulfonyl aziridines are useful intermediates that react smoothly with nucleophiles to generate 1,2-amine derivatives. Following aziridine ring-opening, the N-trichloroethoxysulfonyl group can be removed under mild reductive conditions (Zn(Cu)/AcOH-MeOH) to give the corresponding 1 degrees amine. The efficient and convenient performance of this chemistry should establish it as a useful tool for synthesis.

Journal Article↗
PubMed2003

Oxidative cycloamination of olefins with aziridines as a versatile route to saturated nitrogen-containing heterocycles.

Highly reactive [5,3] and [6,3] bicyclic aziridines can be readily prepared from the corresponding NH aziridines and N-bromosuccinimide by intramolecular oxidative cycloamination of olefins. These compounds, including surprisingly stable exo-methylene bicyclic aziridines, provide versatile synthetic entries into a wide range of pyrrolidine- and piperidine-containing heterocycles.

Journal Article↗
PubMed2005

Bronsted acid-promoted olefin aziridination and formal anti-aminohydroxylation.

A straightforward synthesis of aziridines is reported from an electron-rich azide (alkyl or aryl azide), electron-deficient olefin, and triflic acid in cold acetonitrile. The only coproduct of the reaction is dinitrogen (N2). Active ester substrates bearing a nucleophilic carbonyl engage the putative protonated aziridine intermediate to produce the product of olefin aminohydroxylation in which the nitrogen is benzyl protected and the oxygen is acylated. The possibility that a triazoline need not be an intermediate in aziridine production is advanced.

Journal Article↗
PubMed2001

Synthesis of optically active 2-alkyl-3,4-iminobutanoic acids. Beta-amino acids containing an aziridine heterocycle.

All four stereoisomers of 2-alkyl-3,4-iminobutanoic acid, a novel class of beta-amino acids bearing a chemically versatile aziridine ring, were synthesized starting with aspartic acid. The synthetic strategy involves the introduction of an alkyl group at the beta-position of fully protected optically active aspartic acid followed by the construction of an aziridine ring making use of the alpha-carboxylate and alpha-amino groups. The alpha-carboxylate was reduced to the corresponding alcohol, which was then subjected to cyclization to form an aziridine ring with the N-protected amino group. Removal of the protection groups yielded the target compounds.

Journal Article↗
PubMed2003

Regio- and stereoselective C-2 and C-3 cleavage of 2-(1-aminoalkyl)aziridines with alcohols, carboxylic acids, and sodium iodide.

Ring opening of nonactivated aziridines 1 using several nucleophiles, such as alcohols, carboxylic acids, and sodium iodide, is described. Depending on the nucleophile used, aziridines 1 are cleaved at C-3 or C-2 with total regio- and stereoselectivity, affording chiral 2-alkoxy-1,3-diamines 2 with alcohols, or O-acylated-1-hydroxy-2,3-diamines 6 with carboxylic acids in moderate or high yield. In the case of the aziridines derived from phenylalanine, treatment with NaI afford trans-4-phenylbut-3-en-1,2-diamines 9, generating the alkene with total diastereoselectivity. Mechanisms have been proposed to explain these reactions.

Journal Article↗
PubMed2005

A novel entry toward 2-imino-1,3-thiazolidines and 2-imino-1,3-thiazolines by ring transformation of 2-(thiocyanomethyl)aziridines.

A new, efficient, and straightforward synthesis of 3-arylmethyl-4-chloromethyl-2-imino-1,3-thiazolidines and 2-(N-acylimino)-3-arylmethyl-4-chloromethyl-1,3-thiazolidines has been developed by ring transformation of 1-arylmethyl-2-(thiocyanomethyl)aziridines upon treatment with a catalytic amount of titanium(IV) chloride in dichloromethane. The latter 2-(thiocyanomethyl)aziridines were prepared in high yields from 1-arylmethyl-2-(bromomethyl)aziridines by reaction with potassium thiocyanate in DMF. The 2-imino-1,3-thiazolidines and 2-(N-acylimino)-1,3-thiazolidines thus obtained can be easily interconverted, either by treatment with an acid chloride and a base in ether toward 2-(N-acylimino)thiazolidines or by treatment with potassium carbonate in methanol toward N-deprotected 2-iminothiazolidines. Dehydrohalogenation of 2-(N-acylimino)-3-arylmethyl-4-chloromethyl-1,3-thiazolidines by means of potassium tert-butoxide in DMSO afforded 2-(N-acylimino)-4-methyl-2,3-dihydro-1,3-thiazolines in good yields.

Journal Article↗
PubMed2005

A practical, fast, and high-yielding aziridination procedure using simple Cu(II) complexes containing N-donor pyridine-based ligands.

Four-coordinate dichlorocopper(II) complexes derived from di(2-pyridyl)methanes or pyridine itself exhibit high catalytic activity in aziridination of regular olefins with PhINTs in weakly coordinating chloroform in the presence of 1-2 equiv of NaBArF4 (BArF4- = tetra[3,5-di(trifluoromethyl)phenyl]borate). High yields of aziridines exceeding 90% can be obtained with a 1:1 olefin/PhINTs ratio and 1-5 mol % catalyst loading for such reactive olefins as styrene, tri- and tetramethylethylene. For cis-cyclooctene, indene, methyl acrylate, methyl methacrylate, vinyl methyl ketone, tert-butylethylene, and neopentylethylene, as well as for 1-hexene and cyclopentene, yields of corresponding aziridines vary from 44% to 83%. The catalytic activity and efficiency of the reported copper complexes decrease moderately in the absence of NaBArF4.

Journal Article↗
PubMed2006

The profound effect of fluorine substitution on the reactivity and regioselectivity of nucleophilic substitution reactions of strained heterocycles. A study of aziridine and its derivatives.

Unlike the synthetically exploited oxiranes and thiiranes, aziridines that lack electron-withdrawing substituents, such as acyl or sulfonyl functionalities at nitrogen, are rather unreactive. As expected, three-membered aziridine 6 was calculated to be significantly more reactive than azetidine 7 in nucleophilic cleavage by ammonia, a typical nucleophile. The reactivity of 7 was about the same as that of an acyclic model compound, 8, when release of ring strain in the transition state was taken into account. Fluorine due to its similar size but vastly different electronegativity has been substituted for hydrogen as a means of modifying chemical properties for varied applications. In the present investigation, the effect of fluorine substitution at aziridine positions other than nitrogen was studied. Computations at the MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level found a vast preference for attack by ammonia at the 3-position of 2-fluoroaziridine in the gas phase at 298 K. When release of ring strain was taken into account, this compound reacted more than 10(11) times faster than 6. The reaction rate with trans-2,3-difluoroaziridine was about twice that of 2-fluoroaziridine, while its diastereomer reacted with ammonia considerably slower. Acyclic fluorinated amine model compounds were employed to assess the generality of the effects produced by fluorine substitution. The results were rationalized by the energy contributions of strain energy releases, stabilization of the leaving group, and the relative electrostatic energies of the heterocycles in the transition states. The more reactive fluoroaziridines underwent nucleophilic attack at rates comparable to those of N-acetylaziridine.

Fluorine↗
PubMed1996

Exploratory Investigations Probing a Preparatively Versatile, Pyridinium Salt Photoelectrocyclization-Solvolytic Aziridine Ring Opening Sequence.

A novel pyridinium salt photoelectrocyclization-nucleophilic bicyclic aziridine ring opening reaction sequence has been investigated in order to determine its preparative potential. N-Alkylpyridinium perchlorates were found to undergo photoinduced electrocyclization upon irradiation in nucleophilic solvents, such as H(2)O and MeOH, to efficiently produce 6-alkyl-6-azabicyclo[3.1.0]hex-2-en-4-yl alcohols and ethers. The bicyclic aziridine photoproducts react with a number of different nucleophiles (e.g., H(2)O, MeOH, AcOH, AcSH) under acid-catalyzed conditions to produce 5-(nucleophile-substituted)-4-(alkylamino)cyclopenten-3-yl alcohols and ethers. The aziridine ring opening processes are both regioselective and stereoselective, yielding trans,trans-trisubstituted cyclopentenes exclusively, apparently as a consequence of the operation of an SN(2) mechanism. The effects of C-alkyl substitution on the regiochemistry of the pyridinium cation photocyclization reaction were briefly probed, and a method was developed to produce trans,cis-trisubstituted cyclopentenes by use of this tandem preparative sequence.

Journal Article↗
PubMed1997

2,3-Aziridino-2,3-dideoxy-D-ribono-gamma-lactone 5-Phosphonate: Stereocontrolled Synthesis from D-Lyxose and Unusual Aziridine Ring Opening.

The synthesis of (1R,4S,5S)-N-(benzyloxycarbonyl)-4-[(diethoxyphosphinyl)methyl]-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (23), a new member of the 2,3-aziridino gamma-lactone family of compounds, was achieved in 15 steps from D-lyxose. Like all aziridino gamma-lactones known so far, 23 reacted with a soft nucleophile (ethanethiol) to give exclusively the product of aziridine ring opening at C-2 (24). On the other hand, hard nucleophiles (alcohols) did not react directly with the aziridine ring of 23 but appeared to promote intramolecular attack of the aziridine ring at C-3 by the C-5 phosphonate group, resulting, after hydrolytic workup, in formation of the 2-amino-3-hydroxy-D-ribono-1,4-lactone derivatives 25 and 26, instead of the expected 2-amino-3-alkoxy-D-xylono-1,4-lactone derivatives.

Journal Article↗
PubMed1999

Aziridination of Activated Imines with Monocarbonyl Iodonium Ylides Generated from (Z)-(2-Acetoxyvinyl)iodonium Salts via Ester Exchange: Stereoselective Synthesis of 2-Acylaziridines.

Monocarbonyl iodonium ylides, generated in situ from (Z)-(2-acetoxyvinyl)iodonium salts via an ester exchange reaction with EtOLi, undergo alkylidene transfer reactions to activated imines yielding 2-acylaziridines in good yields. The stereochemical outcome of this aziridination was shown to be dependent on both the activating groups of the imines and the reaction solvents: that is, the aziridination of N-(2,4,6-trimethylbenzenesulfonyl)imines in THF affords cis-aziridines as a major product while that of N-benzoylimines in THF-DMSO or THF gives the trans isomer stereoselectively.

Journal Article↗
PubMed2004

Synthesis of silyl aziridines and alpha-amino acylsilanes with silyldibromomethyllithium.

The reaction of silyldibromomethyllithium with aromatic imines provides alpha-amino acylsilanes via a bromo aziridine intermediate upon quenching the reaction with water. Alternatively, treatment of the bromo aziridine intermediate with various Grignard reagents or lithium aluminum hydride permits the nucleophilic displacement of the halogen to furnish substituted silyl aziridines.

Journal Article↗
PubMed2005

Cobalt-catalyzed efficient aziridination of alkenes.

[reaction: see text]. Cobalt porphyrins are capable of catalyzing the aziridination of alkenes with bromamine-T as the nitrene source. Among cobalt complexes of different porphyrins, Co(TDClPP) is an effective catalyst that can aziridinate a wide variety of alkenes. The catalytic system can operate at room temperature in a one-pot fashion with alkenes as limiting reagents, forming the desired N-sulfonylated aziridine derivatives in high to excellent yields with NaBr as the byproduct.

Journal Article↗
PubMed2006

Reduction of 4-(haloalkyl)azetidin-2-ones with LiAlH4 as a powerful method for the synthesis of stereodefined aziridines and azetidines.

[reaction: see text] A new synthesis of stereodefined aziridines and azetidines, starting from 4-(1- or 2-haloalkyl)azetidin-2-ones, is described. Treatment of the latter compounds with LiAlH(4) gave 1,2-fission of the beta-lactam, followed by an intramolecular nucleophilic substitution of the halogen, giving rise to the formation of 2-(1-alkoxy-2-hydroxyethyl)aziridines in the case of 4-(1-haloalkyl)azetidin-2-ones and of 2-(1-alkoxy-2-hydroxyethyl)azetidines in the case of 4-(2-haloalkyl)azetidin-2-ones. The resulting 2-(1-alkoxy-2-hydroxyethyl)aziridines were transformed into the corresponding trans-3,4-substituted oxolanes via an intramolecular nucleophilic ring opening, triggered by AlCl(3).

Journal Article↗
PubMed1983

Contact allergy to trimethylolpropane triacrylate (TMPTA) in an aziridine plastic hardener.

4 workers developed hand and face dermatitis when exposed to a floor top coat. This contained a polyurethane and a polyfunctional aziridine hardener and additives. The aziridine hardener was made by reacting propyleneimine with a polyfunctional acrylate, trimethylolpropane triacrylate (TMPTA). All 4 reacted to the hardener and to TMPTA, which is present in excess. 2 of them also reacted to pentaerythritol triacrylate (PETA), which can be used in the production of aziridine hardeners. TMPTA and PETA cross-react, and are known sensitizers in UV-hardening acrylates. The present finding shows that well-known sensitizers can be found in hidden sources when used in a quite different chemical process.

Acrylates↗