McLafferty-type rearrangement in the collision-induced dissociation of Li+, Na+ and Ag+ cationized esters of N-acetylated peptides

In this study we investigated the multi-stage collision-induced dissociation (CID) of N-terminally acetylated di-, tri- and tetrapeptides in the form of C-terminal ethyl, n-propyl, isopropyl, n-butyl and tert-butyl esters and cationized by the attachment of Li(+), Na(+) and Ag(+). While methyl ester versions of the metal cationized peptides primarily eliminate H(2)O following collisional activation and dissociation, the ethyl, propyl and butyl ester versions of the peptides exhibit a dissociation pathway consistent with gamma-hydrogen transfer to the C-terminal carbonyl group, with associated elimination of an alkene, in a McLafferty-type rearrangement. The rearrangement leaves a metal cationized, free-acid form of the peptide, as confirmed by comparing the multi-stage CID of rearrangement products generated from peptide esters with the CID of corresponding metal cationized free-acid peptides. The transfer of a gamma-hydrogen in the rearrangement reaction was confirmed by investigating the CID of ethyl esters for which the terminal methyl group was labeled with deuterium. We found that the rearrangement product was significantly more abundant, relative to other product ions, when derived from isopropyl and tert-butyl esters than from ethyl, n-propyl or n-butyl ester analogues.     

Synthesis of Highly Substituted γ‐Butyrolactones by a Gold‐Catalyzed Cascade Reaction of Benzyl Esters

Easily accessible benzylic esters of 3‐butynoic acids in a gold‐catalyzed cyclization/rearrangement cascade reaction provided 3‐propargyl γ‐butyrolactones with the alkene and the carbonyl group not being conjugated. Crossover experiments showed that the formation of the new C?C bond is an intermolecular process. Initially propargylic–benzylic esters were used, but alkyl‐substituted benzylic esters worked equally well. In the case of the propargylic–benzylic products, a simple treatment of the products with aluminum oxide initiated a twofold tautomerization to the allenyl‐substituted γ‐butyrolactones with conjugation of the carbonyl group, the olefin, and the allene. The synthetic sequence can be conducted stepwise or as a one‐pot cascade reaction with similar yields. Even in the presence of the gold catalyst the new allene remains intact.     

Use of odorless thiols: formal asymmetric Michael addition of hydrogen sulfide to alpha-substituted alpha,beta-unsaturated carbonyl compounds

[reaction: see text] The Michael addition to alpha-substituted alpha,beta-unsaturated esters and amides using complex A containing a chiral odorless thiol proceeded diastereoselectively. The Michael adducts were converted to beta-mercapto esters and amides via a Wagner-Meerwein rearrangement with boron trifluoride etherate and a thiol exchange reaction using odorless 1-dodecanethiol. This conversion constitutes a formal asymmetric Michael addition of hydrogen sulfide to alpha,beta-unsaturated carbonyl compounds using odorless thiols instead of the toxic hydrogen sulfide.     

The carbanions of S-alkanoate-O,O-dialkyl phosphates: new synthons for reaching α, β-ethylenic esters

The stabilization of phosphorothiolate carbanions has been achieved. Condensation of these carbanions with carbonyl derivatives lead to the corresponding α,β-unsaturated esters; a mechanism, via a β-hydroxyphosphorothiolate-β-mercaptophosphate rearrangement, is described. These new synthons are compared with the phosphonate analogs (Wittig-Horner's reagent).     

Gas-phase ozonolysis of alkenes: formation of OH from anti carbonyl oxides

Gas-phase ozone-alkene reactions are known to produce the hydroxyl radical (OH) in high yields. Most mechanistic studies to date have focused on the role of syn carbonyl oxides; however, OH production from ethene ozonolysis indicates a second, poorly understood OH-forming channel, which may contribute to OH production in the ozonolysis of substituted alkenes as well. Using laser-induced fluorescence, we have measured OH and OD yields from the ozonolysis of two partially deuterated alkenes, cis- and trans-3-hexene-3,4-d2. OD is formed from both alkenes, indicating a pathway of hydroxyl-radical formation involving vinylic hydrogens, accounting for one-third of total OH formation from cis-3-hexene. The lack of a significant kinetic isotope effect suggests this pathway is the "hot acid" channel, arising from rearrangement of anti carbonyl oxides. Measured yields also allow for the estimation of syn:anti carbonyl oxide ratios, approximately 50:50 for trans-3-hexene and approximately 20:80 for cis-3-hexene, qualitatively consistent with our understanding of ozonide decomposition pathways.     

Synthesis of Secondary and Tertiary Alkyl Boronic Esters by gem‐Carboborylation: Carbonyl Compounds as Bis(electrophile) Equivalents

An unprecedent gem‐carboborylation of aldehydes and ketones provides access to various secondary and tertiary alkyl boronic esters. The addition of B₂pin₂ to a carbonyl compound generates α‐oxyl‐substituted alkyl boron species. Organolithium and Grignard reagents are then applied as C nucleophiles for the 1,2‐metalate rearrangement process. The organolithium reagents can also be generated by C?H lithiation or halogen/lithium exchange. The use of chiral ligands led to the generation of chiral alkyl boronic esters in enantioenriched form, demonstrating that the enantioselectivity of this transformation is catalyst‐controlled.     

Study on [(4-substituted benzoylamino)phenylmethyl]phosphonic acid diisopropyl esters under electrospray ionization tandem mass spectrometric conditions

Phosphonate esters were synthesized and investigated by positive ion electrospray ionization mass spectrometry (ESI-MS) in conjunction with tandem mass spectrometry (MS/MS). It was found that for the sodiated adduct there were two novel rearrangement reactions, in which the phosphoryl oxygen atom migrated to the carbonyl carbon and a cleavage occurred at the amide bond, or a benzylamine fragment was lost and the phosphorus was reduced. However, when the methyl group substituted for the isopropyl group, these migrations were inhibited. A possible mechanism was proposed, and high-resolution mass spectrometry was applied to identify the formula of these novel ions. These results showed that ESI-MS is a useful tool for the structural determination of phosphonate esters.     

Thermal Rearrangement of Nitrone and Nitrile Oxide Cycloadducts to Bicyclopropylidene.(1) Synthesis of 3-Spirocyclopropane-4-pyridone and Furo[2,3-c]pyridine Derivatives

Bicyclopropylidene smoothly undergoes 1,3-dipolar cycloadditions to nitrones or nitrile oxides under different reaction conditions. The strained bisspirocyclopropanated isoxazolidines obtained from nitrones easily rearrange upon heating with selective opening of one of the two spirofused cyclopropane rings. This process produces 4-pyridone, 7-indolizinone, and 2-quinolizinone derivatives containing a spirocyclopropane moiety in the alpha-position to the carbonyl group in good yields. The same sequence of cycloaddition and rearrangement can be achieved in a "one-pot" operation with considerable benefit for the reaction yield. Bisspirocyclopropaneisoxazolines obtained from nitrile oxides are more stable than their saturated counterparts and rearrange only at higher temperature less chemoselectively. Opening of both spiro-fused cyclopropyl rings followed by aromatization produces interesting 2-substituted dihydrofuro[2,3-c]pyridine derivatives.     

α-Alkenyl analogs of phosphorylcholines

The new type of α-alkenyl esters of phosphorus acids containing ammonium or phosphonium groups in unsaturated radicals as well as carbonyl or other complexes of Mo, Cr, W, Mn, or Pt with such organophosphorus ligands have been described. The alkenyl phosphates undergo dealkylation upon heating to give betaines. This conversion results in a substantial decrease of an anticholinesterase activity of the compounds and in a sharp rise of their hydrolytic stability. The prototropic rearrangement is observed for the phosphonium betaines.     

Effects of the substituents on the reactivity of carbonyl oxides. A theoretical study on the reaction of substituted carbonyl oxides with water

The reactions between fifteen carbonyl oxides and water have been investigated with the aim of contributing to a better understanding of the effects of the substituents in the reactivity of carbonyl oxides. We have employed density functional theory and large scale ab initio methods (CCSD(T), CASSCF, and CASPT2), combined with transition state theory, to investigate the addition of water to carbonyl oxide and, for those carbonyl oxides having a methyl substituent in syn, the hydrogen transfer from the methyl group to the terminal oxygen of carbonyl oxide. In this case, the water acts as a catalyst and this reaction can contribute to the atmospheric formation of a hydroxyl radical. Carbonyl oxides with electron withdrawing substituents and zwitterionic character have low energy barriers and react fast, whereas carbonyl oxides with electron releasing substituents have high energy barriers and react slowly. The position of the substituents plays also an important role and carbonyl oxides having a hydrogen atom substituent in syn react faster than carbonyl oxides having a hydrogen atom substituent in anti. The differences in the reactivity of different substituted carbonyl oxides raise up to ten orders of magnitude and the branching ratios for the two different reactions investigated are also reported.     

High stereocontrol in aldol reaction with ketones: enantioselective synthesis of beta-hydroxy gamma-ketoesters by ester enolate aldol reactions with 2-acyl-2-alkyl-1,3-dithiane 1-oxides

The asymmetric aldol reaction of 1,2-diketones, masked as nonracemic 2-acyl dithiane oxides, with lithium enolates derived from several esters and lactones, proceeds with a high degree of stereocontrol at both carbonyl and enolate prochiral centers, the stereocontrol mainly determined by the configuration of the sulfoxide sulfur atom. The sense of induced stereochemistry observed for ester enolates is different from that seen for lactone enolates. Hydrolysis of the dithiane oxide units of the major diastereoisomerically pure aldol products affords enantiomerically pure tertiary alpha-substituted beta-hydroxy-gamma-ketoesters.     

Wolff Rearrangement of Oxidatively Generated α‐Oxo Gold Carbenes: An Effective Approach to Silylketenes

Gold‐catalyzed oxidations of alkynes by N‐oxides offer direct access to reactive α‐oxo gold carbene intermediates from benign and readily available alkynes instead of hazardous diazo carbonyl compounds. Despite various versatile synthetic methods developed based on this strategy, one of the hallmarks of α‐oxo carbene/carbenoid chemistry, that is, the Wolff rearrangement, has not been realized in this context. This study discloses the first examples that show the Wolff rearrangement can be readily realized by α‐oxo gold carbenes oxidatively generated from TBS‐terminated alkynes (TBS=tert‐butyldimethylsilyl). The thus‐generated silylketenes can be either isolated pure or subsequently trapped by various internal or external nucleophiles in one pot to afford α‐silylated carboxylic acids, their derivatives, or TBS‐substituted allenes.     

Further Report on A Novel Scission of Alkyl Carbonyl C-C Bond by Substituted 4-Hydroxyacetophenones

Continuedfromourpreviousletter',wereporthereinourfurtherstudiesonthescissionofsomemono-anddisubstituted4-hydroxyacetophenonesla-g.3-Nitro-la,3,5-dinitrolb,and3,5-dibromo-4-hydroxyacetophenones1cbehavednormalIyandyieIdedrespectiveethylenebetalsZa-cingoodyields.Thesubstituted4-hydroxyacetophenonesid-funderwentfissionoftheC-Cbondtoyieldtheirrespectivesubstituted4hydroxybenzoateesters6d-fand2-indanols10d-f(Scheme1).Theformationofindanols10d-fwasrationalized(Scheme2)byaninitialdimerizationviaana…     

Alkenylation of C(sp3)−H Bonds by Zincation/Copper‐Catalyzed Cross‐Coupling with Iodonium Salts

α‐Vinylation of phosphonates, phosphine oxides, sulfones, sulfonamides, and sulfoxides has been achieved by selective C?H zincation and copper‐catalyzed C(sp³)?C(sp²) cross‐coupling reaction using vinylphenyliodonium salts. The vinylation transformation proceeds in high efficiency and stereospecificity under mild reaction conditions. This zincative cross‐coupling reaction represents a general alkenylation strategy, which is also applicable for α‐alkenylation of esters, amides, and nitriles in the synthesis of β,γ‐unsaturated carbonyl compounds.     

Mechanistic and kinetic study on the ozonolysis of 2,4-hexadienedial

The formation and unimolecular reactions of primary ozonides and carbonyl oxides arising from the O₃-initiated reactions of 2,4-hexadienedial (HDE) have been investigated using the density functional theory and ab initio method. The activation energies of O₃ cycloaddition to the >C=C< and >C=O bonds of HDE for the formation primary ozonides (POZ1 and POZ2) are 4.79 and 21.37 kcal mol^?1, respectively, implying that the initial O₃ to the >C=C< bond is favorable pathway. Cleavage of POZ1 to form carbonyl oxides occurs with a barrier of 12.19–21.35 kcal mol^?1, and the decomposition energies range from ?1.09 to ?15.75 kcal mol^?1. The CHOCHOO radical, the hydroxyl radical (OH) formation via H-migration is more favorable than the dioxirane formation via rearrangement. However, the CHOCH=CHCHOO radical, the dioxirane formation via rearrangement is more favorable than OH formation. Using the transition state theory, the rate constants of formation of POZ1 and POZ2 are 1.49 × 10^?19 and 6.03 × 10^?25 cm³ molecule^?1 s^?1 at 300 K, respectively. This study shows that the hyperconjugative effect makes O₃ addition to >C=C< and >C=O bonds of HDE more difficult than to >C=C< bond of ethylene and isoprene and to >C=O bond of formaldehyde. The largest rate constants of OH formation and dioxirane formation in the unimolecular reactions of carbonyl oxides are 6.13 × 10^?4 and 7.93 × 10^?1 s^?1 at 300 K, respectively. The dioxirane is main product in the unimolecular reaction of the carbonyl oxides arising from the O₃-initiated reaction of HDE.     

Recent Results in Carbanion Chemistry

The Wittig rearrangement of ethers metalated in the alpha position with alkali metals is a 1,2-shift to an atom with a lone pair of electrons. The alkyl shift proceeds with racemization (and partial retention) at the migrating carbon atom. The experimental observations suggest a cleavage-recombination mechanism involving a radical pair, as must also be assumed for the ylide rearrangements. In the allyl migration, the double bond is displaced within the migrating residue (allyl inversion). This is readily explained by a one-step S′ mechanism, the transition state of which is allowed on symmetry grounds. In the case of benzyl 2-butynyl ether metalated on the butynyl residue, the ortho isomerization (corresponding to the Sommelet rearrangement) predominates. – α-Metalated alkyl isocyanides can react with carbonyl compounds to form olefins and metal cyanate (carbonyl olefination). Isocyanoacetic esters occupy a special place; they react with aldehydes and ketones to form β-substituted α-formylaminoacrylates (formylaminoalkoxycarbonylmethylenation), which can enter into a wide range of reactions. β-Hydroxyalkyl isocyanides or 2-oxazolines can be isolated as intermediates in the carbonyl olefination. α-Metalated isocyanides react with acylating agents to form β-ketoalkyl isocyanides, which cyclize to give oxazoles.     

Quinazolines et benzodiazépines-1, 4. LVI. Oxadiazolo-1, 2, 4[4, 5-d] benzodiazépines-1, 4: synthése et passage aux oxazolo [3, 2-d] benzodiazépines-1, 4

The tricyclic derivatives 4–14 can be prepared by 1, 3-dipolarcycloaddition of the appropriate nitrile oxides on the corresponding 1, 4-benzodiazepines. NaBH⁴ reduction of the esters 12–14 was found to proceed very readily; starting from 13 it is possible, by proper reaction conditions, to get in good yield either the monoalcohol 19 or the aminodiol 20 . The alcohols 19 and 23 undergo an acid-catalysed rearrangement which produces the amidoximes 24 and 26 . The determination of the structure of 24 by X-ray diffraction analysis is also presented.     

Electron ionisation induced fragmentation of ethyl 5(1H)-oxo- and 7(1H)-oxo-1-aryl-2,3-dihydroimidazo[1,2-a]-pyrimidine-6-carboxylates: evidence for an unusually regioselective rearrangement of M(+*) ions.

The 70-eV electron ionisation (EI) mass spectra of the title compounds show clear differences between the 5-oxo and 7-oxo isomers due to regioselective fragmentations involving the ester function. Exceptionally abundant metastable peaks due to molecular ions fragmenting to [M -CO2](+.) were observed exclusively for the 7-oxo isomers, suggesting that the sufficiently long-lived molecular ions undergo a slow rearrangement preceding this fragmentation reaction. The results are contrasted to the available literature data on the ester group fragmentations involving the loss of CO2 and the EI mass spectrometry of pyrimidone beta-oxo esters. A reaction mechanism is proposed for the elimination of CO2 following ethyl group migration to the pyrimidone carbonyl oxygen.     

Ozonolysis of alpha-pinene and beta-pinene: kinetics and mechanism

A combined quantum-chemical and RRKM/ME (ME--master equation) approach is employed to investigate the structures, energetics, and kinetics of intermediate and stable species, and the yields of stabilized carbonyl oxides and OH radicals from the alpha-pinene and beta-pinene ozonolysis reactions. The cycloaddition of O(3) is highly exothermic, with the reaction energies of 55.1 and 51.1 kcal mol(-1) for alpha- and beta-pinenes, respectively. Cleavage of primary ozonides yields carbonyl oxides with the barrier height of 12.2-17.5 kcal mol(-1). For the prompt reactions of carbonyl oxides from alpha- and beta-pinene ozonolysis, H migration to hydroperoxides represents the dominant pathway over ring closure to dioxiranes. The kinetic calculations indicate a significant portion of stabilization for alpha- and beta-carbonyl oxides. The yields of stabilized carbonyl oxides are estimated to be 0.34 for alpha-pinene and 0.22 for beta-pinene. The applicability of theoretical methods for investigation of oxidation reactions of large hydrocarbon molecules is demonstrated.     

Intramolecular catalysis in the mass spectrometer: Mechanisms for loss of methanol from methyl esters upon electron-impact

A review of the literature indicates compelling evidence that: (1) loss of ROH from esters requires protonation of the alkoxy oxygen; (2) the (symmetry forbidden) [1,3] hydrogen migration from protonated carbonyl to alkoxy oxygen does not occur in the mass spectra of esters; (3) hydrogen abstraction in esters occurs almost exclusively to the carbonyl oxygen. Mechanisms are proposed which account for all examples of ROH loss from esters. Alkanol loss from molecular ions in esters requires the presence of a second functional group to act as an intramolecular catalyst, either as a general acid in transferring a proton to the alkoxy oxygen, or as a general base in assisting the [1,3] carbonyl oxygen to alkoxy oxygen proton transfer. Loss of ROH from fragment ions requires proton transfer from an atom α to the positive charge to the alkoxy oxygen. These mechanisms are generalized to include a wide class of bifunctional esters and a selection of natural products.