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PubMed2005

The first total synthesis of the peptaibol hypomurocin A1 and its conformation analysis: an application of the 'azirine/oxazolone method'.

The first total synthesis of Hypomurocin A1 (HM A1) in solution phase is described. As members of the peptaibol family, hypomurocins are constituted by two groups of peptides: six undecapeptides (undecamers) in the HM A group and six octadecapeptides (18-mers) in the HM B group. The synthesis presented has been successfully achieved by the 'azirine/oxazolone method' to introduce the two Aib-Pro sequences included in this undecapeptaibol in one step with methyl 2,2-dimethyl-2H-azirine-3-prolinate as the building block. The coupling reactions of the Z-protected amino acids or peptide acids involved the use of N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt), and led to the peptides in good-to-very-good yields. The peptides were purified by reverse-phase HPLC and characterized by NMR spectroscopy (1H, 13C, COSY, TOCSY, HSQC, HMBC, ROESY), ESI-MS, IR, elemental analysis, optical rotation, and X-ray crystallography. An NMR analysis of HM A1 was also carried out in deuterated micelles to perform a structural comparison of the helix in solution and in membranes.

Amino Acid Sequence↗
PubMed2003

Mass spectral fragmentation of (S,S)-2-substituted 4,4-diphenyl-3,1-oxazabicyclo[3.3.0]octanes: ring contraction of pyrrolidine and 1,3-oxazolidine in mass spectrometry.

The mass spectral behaviour of (S,S)-2-substituted 4,4-diphenyl-3,1-oxazabicyclo[3.3.0]octanes has been studied with the aid of mass-analyzed ion kinetic energy spectrometry and accurate mass measurements under fast atom bombardment (FAB) and electron impact (EI) ionization conditions. Under FAB ionization, all compounds show a tendency to form protonated aldehyde or benzophenone ions and to form protonated 1-azabicyclo[3.1.0]hexane ions, which can further lose an ethylene or cyclopropane from the pyrrolidine ring to produce protonated 1-azabicyclo[1.1.0]butane ions and 3H-azirine ions, respectively. Under EI ionization, a similar fragmentation to that under FAB ionization was observed. The title compounds also show a tendency to yield oxirane ions and oxirenium ions by loss of pyrrolidine and pyrrolidine plus H. Ring contractions of 1,3-oxazolidine by loss of an aldehyde or ketone and of pyrrolidine by loss of an ethylene or cyclopropane were observed under both FAB and EI ionization conditions.

Journal Article↗
PubMed1999

The synthesis of (R)- and (S)-[N-methyl-11C]beta, beta-difluoromethamphetamine for the investigation of the binding mechanism of biogenic amines in vivo.

In an attempt to elucidate the contribution of the extent of nitrogen protonation on the in vivo binding of methamphetamine in the brain, the enantiomers of [N-methyl-11C]beta, beta-difluoroamphetamine (4) were prepared for use in positron emission tomography (PET) studies. Thus, the enantiomers of beta, beta-difluoroamphetamine were prepared from trans-beta-methylstyrene, via bromination, conversion into the azirine, fluorination and resolution as the tartrate salts. (R)- and (S)-beta, beta-difluoroamphetamine (3) were then each labelled with carbon-11 (tt/2 = 20.4 min) by N-methylation of the corresponding homochiral beta, beta-difluoroamphetamine with [11C]methyl iodide. The labelled products were each synthesised, purified and formulated in 35 min, starting from [11C]carbon dioxide in 15-16% decay-corrected radiochemical yield, with a radiochemical purity of > 99% and specific radioactivity of 50-150 GBq mumol-1 at end of synthesis.

Binding Sites↗
PubMed2001

A laser flash photolysis and quantum chemical study of the fluorinated derivatives of singlet phenylnitrene.

Laser flash photolysis (LFP, Nd:YAG laser, 35 ps, 266 nm, 10 mJ or KrF excimer laser, 10 ns, 249 nm, 50 mJ) of 2-fluoro, 4-fluoro, 3,5-difluoro, 2,6-difluoro, and 2,3,4,5,6-pentafluorophenyl azides produces the corresponding singlet nitrenes. The singlet nitrenes were detected by transient absorption spectroscopy, and their spectra are characterized by sharp absorption bands with maxima in the range of 300-365 nm. The kinetics of their decay were analyzed as a function of temperature to yield observed decay rate constants, k(OBS). The observed rate constant in inert solvents is the sum of k(R) + k(ISC) where k(R) is the absolute rate constant of rearrangement of singlet nitrene to an azirine and k(ISC) is the absolute rate constant of nitrene intersystem crossing (ISC). Values of k(R) and k(ISC) were deduced after assuming that k(ISC) is independent of temperature. Barriers to cyclization of 4-fluoro-, 3,5-difluoro-, 2-fluoro-, 2,6-difluoro-, and 2,3,4,5,6-pentafluorophenylnitrene in inert solvents are 5.3 +/- 0.3, 5.5 +/- 0.3, 6.7 +/- 0.3, 8.0 +/- 1.5, and 8.8 +/- 0.4 kcal/mol, respectively. The barrier to cyclization of parent singlet phenylnitrene is 5.6 +/- 0.3 kcal/mol. All of these values are in good quantitative agreement with CASPT2 calculations of the relative barrier heights for the conversion of fluoro-substituted singlet aryl nitrenes to benzazirines (Karney, W. L. and Borden, W. T. J. Am. Chem. Soc. 1997, 119, 3347). A single ortho-fluorine substituent exerts a small but significant bystander effect on remote cyclization that is not steric in origin. The influence of two ortho-fluorine substituents on the cyclization is pronounced. In the case of the singlet 2-fluorophenylnitrene system, evidence is presented that the benzazirine is an intermediate and that the corresponding singlet nitrene and benzazirine interconvert. Ab initio calculations at different levels of theory on a series of benzazirines, their isomeric ketenimines, and the transition states converting the benzazirines to ketenimines were performed. The computational results are in good qualitative and quantitative agreement with the experimental findings.

Journal Article↗
PubMed1986

Synthesis and antineoplastic activity of bis[[[(alkylamino)carbonyl]oxy]methyl]-substituted 3-pyrrolines as prodrugs of tumor inhibitory pyrrole bis(carbamates).

A series of bis[(carbamoyloxy)methyl]pyrrolines 2-4 were synthesized from either the appropriate alpha-silylated iminium salt, or an aziridine, or a 2H-azirine in a sequence involving 1,3-dipolar cycloaddition reactions. The antineoplastic activities of the pyrrolines were compared to the corresponding pyrroles. The C-2 gem-dimethyl-substituted pyrroline, 4, which cannot be converted to the pyrrole in vivo, was inactive. The activity of the 2-phenyl-substituted pyrrolines 3 was markedly dependent on the nature of the phenyl substituent, although the corresponding phenylpyrroles all showed comparable activity. The differences in the activities of the pyrrolines 3 may be due to the rate of metabolic conversion of the pyrroline to the pyrrole. Electron-withdrawing substituents on the phenyl ring appear to retard this process.

Animals↗
PubMed2000

On the aromaticity and Meisenheimer rearrangement of strained heterocyclic amine, phosphine, and arsine oxides.

A theoretical investigation (AIM and ELF analyses together with NMR chemical shifts) has been conducted for three-membered heterocycle (N, P, and As) oxides. An aromatic stabilization was found for the P and As rings. However, the N derivatives displayed a net negative hyperconjugation in the N-O bond formation, without ring aromaticity observed for their electronic properties. The calculated delta(C) and delta(H) shifts also supported the ring delocalization for the P and As unsaturated heterocycle oxides (delta(C) approximately 165 and delta(H) approximately 9 ppm). In addition, these values for 1H-azirine oxide resembled standard C=C double bond values (delta(C) approximately 130 and delta(H) approximately 7 ppm). The different behavior for the N oxides was also observed in their Meisenheimer rearrangement (MR). All the reaction paths, yielding the corresponding hydroxyl structures, were exothermic (G2 method). However, the N derivatives showed the lowest values for activation enthalpy, DeltaH(). The C=C bond influence in the MR was slight, with the same DeltaH values for the saturated and unsaturated paths. This rearrangement for the P and As oxides yielded TSs closer to the reactives; however, the corresponding TSs resembled the products for the N-derivatives. The different reaction paths have been examined by their corresponding AIM and ELF analyses at the B3LYP/6-311G level.

Journal Article↗
PubMed2002

Linear ketenimines. Variable structures of C,C-dicyanoketenimines and C,C-bis-sulfonylketenimines.

C,C-dicyanoketenimines 10a-c were generated by flash vacuum thermolysis of ketene N,S-acetals 9a-c or by thermal or photochemical decomposition of alpha-azido-beta-cyanocinnamonitrile 11. In the latter reaction, 3,3-dicyano-2-phenyl-1-azirine 12 is also formed. IR spectroscopy of the keteniminines isolated in Ar matrixes or as neat films, NMR spectroscopy of 10c, and theoretical calculations (B3LYP/6-31G) demonstrate that these ketenimines have variable geometry, being essentially linear along the CCN-R framework in polar media (neat films and solution), but in the gas phase or Ar matrix they are bent, as is usual for ketenimines. Experiments and calculations agree that a single CN substituent as in 13 is not enough to enforce linearity, and sulfonyl groups are less effective that cyano groups in causing linearity. C,C-bis(methylsulfonyl)ketenimines 4-5 and a C-cyano-C-(methylsulfonyl)ketenimine 15 are not linear. The compound p-O2NC6H4N=C=C(COOMe)2 previously reported in the literature is probably somewhat linearized along the CCNR moiety. A computational survey (B3LYP/6-31G) of the inversion barrier at nitrogen indicates that electronegative C-substituents dramatically lower the barrier; this is also true of N-acyl substituents. Increasing polarity causes lower barriers. Although N-alkylbis(methylsulfonyl)ketenimines are not calculated to be linear, the barriers are so low that crystal lattice forces can induce planarity in N-methylbis(methylsulfonyl)ketenimine 3.

Journal Article↗
PubMed2002

Highly diastereoselective aziridination of imines with trimethylsilyldiazomethane. Subsequent silyl substitution with electrophiles, ring opening, and metalation of C-silylaziridines--a cornucopia of highly selective transformations.

Treatment of a range of N-sulfonyl (Ts and SES) imines derived from aromatic, heteroaromatic, aliphatic, and unsaturated aldehydes with trimethylsilydiazomethane gave C-silylaziridines in good yield (32-83%) and with high diastereoselectivity in favor of the cis product (80:20-100:0). In contrast, an alpha-imino ester gave predominantly the trans-aziridine (89:11) in high yield (91%). The synthetic potential of C-silylaziridines was investigated. Treatment with F(-) (tetrabutylammonium triphenyldifluorosilicate was used) in the presence of aldehydes gave the alpha-hydroxyaziridines in high yield and high diastereoselectivity (86:14-98:2) for the newly created stereogenic center. Complete retention of configuration was observed in the substitution of the silyl group with electrophiles in all cases. Trapping with deuterium (using CDCl(3) as electrophile) was also successful, but trapping with phosphate [using ClP(O)(OPh)(2)] and acetate (using Ac(2)O) was unsuccessful. In these latter cases ring opening by chloride and acetate, respectively, was observed. Further ring-opening reactions were effected using azide and thiolate nucleophiles and in all cases complete regioselectivity in favor of attack at the silyl-bearing carbon occurred. Complete regioselectivity was also observed in the carbonylative ring expansion using Co(2)(CO)(8) to give a beta-lactam. Treatment of cis-1-tosyl-2-phenyl/butyl-3-trimethylsilylaziridines with n-BuLi and subsequent quenching with MeI followed completely different pathways, depending on the 2-substituent. In the case of the 2-phenylaziridine, metalation was initiated alpha to the phenyl group and led finally to a fused tricyclic adduct with four stereogenic centers as a single diastereoisomer. In the case of the 2-butylaziridine, metalation occurred alpha to the silyl group and led to a trisubstituted silylaziridine, probably via an azirine intermediate.

Journal Article↗
PubMed2006

Adventures in sulfur-nitrogen chemistry.

This account reviews our efforts over the past 37 years to understand the chemistry of a select group of sulfur-nitrogen compounds including sulfinimines (N-sulfinyl imines) and N-sulfonyloxaziridines. Our early exploration of the thermal properties of sulfenamides, a class of sulfur-nitrogen compounds about which little was known, resulted in a new procedure, the silver-assisted method, for the construction of sulfenimines (N-sulfenyl imines). Selective oxidations of these compounds resulted in the production of N-sulfinyl imines (sulfinimines) and N-sulfonyloxaziridines. N-Sulfonyloxaziridines turned out to be a new class of aprotic neutral oxidizing reagents. Enantiomerically pure examples afford high ee values in the oxidation of enolates to alpha-hydroxy carbonyl compounds and in the oxidation of sulfides and selenides to sulfoxides and selenoxides. Additions of organometallic reagents to enantiomerically pure sulfinimines provide the best and most versatile method for the asymmetric construction of the carbon-nitrogen stereocenters found in many biologically active compounds. Sulfinimine-derived chiral building blocks provide efficient access to many classes of nitrogen heterocycles including aziridines, 2H-azirines, pyrrolidines, and piperidines.

Nitrogen↗
PubMed2005

Pyrazolo[1,5-a]pyridines as p38 kinase inhibitors.

[reaction: see text] A convergent synthesis of substituted pyrazolo[1,5-a]pyridines has been achieved either via a regioselective [3 + 2] cycloaddition of N-aminopyridines with alkynes or by thermal cyclization of disubstituted azirines. Subsequent palladium-catalyzed introduction of pyridines or de novo synthesis of pyrimidines affords inhibitors of p38 kinase.

Crystallography, X-Ray↗
PubMed2001

The reactions of methanimine and cyanogen with carbon monoxide in prebiotic molecular evolution on earth.

A primeval atmosphere is proposed containing simple molecules such as formaldehyde, ammonia, carbon monoxide, cyanogen and hydrogen cyanide, which have been detected in space. Chemical reactions are described for the formation of aziridine-2-one and di-azirine-3-one derivatives as potential precursors for the original synthesis of amino-acids, proteins, pyrimidines, purines, nicotinamide and flavin. The reactions have been shown to be kinetically feasible from the overall enthalpy changes in the ZKE approximation at the MP2/6-31G* level.

Carbon Monoxide↗