Intermolecular C-h amination of complex molecules: insights into the factors governing the selectivity

Transition-metal-catalyzed C-H amination via nitrene insertion allows the direct transformation of a C-H into a C-N bond. Given the ubiquity of C-H bonds in organic compounds, such a process raises the problem of regio- and chemoselectivity, a challenging goal even more difficult to tackle as the complexity of the substrate increases. Whereas excellent regiocontrol can be achieved by the use of an appropriate tether securing intramolecular addition of the nitrene, the intermolecular C-H amination remains much less predictable. This study aims at addressing this issue by capitalizing on an efficient stereoselective nitrene transfer involving the combination of a chiral aminating agent 1 with a chiral rhodium catalyst 2. Allylic C-H amination of terpenes and enol ethers occurs with excellent yields as well as with high regio-, chemo-, and diastereoselectivity as a result of the combination of steric and electronic factors. Conjugation of allylic C-H bonds with the π-bond would explain the chemoselectivity observed for cyclic substrates. Alkanes used in stoichiometric amounts are also efficiently functionalized with a net preference for tertiary equatorial C-H bonds. The selectivity, in this case, can be rationalized by steric and hyperconjugative effects. This study, therefore, provides useful information to better predict the site of C-H amination of complex molecules.     

MALDI-MS/MS with Traveling Wave Ion Mobility for the Structural Analysis of N-Linked Glycans

The preference for singly charged ion formation by MALDI makes it a better choice than electrospray ionization for profiling mixtures of N-glycans. For structural analysis, fragmentation of negative ions often yields more informative spectra than fragmentation of positive ones but such ions are more difficult to produce from neutral glycans under MALDI conditions. This work investigates conditions for the formation of both positive and negative ions by MALDI from N-linked glycans released from glycoproteins and their subsequent MS/MS and ion mobility behaviour. 2,4,6-Trihydroxyacetophenone (THAP) doped with ammonium nitrate was found to give optimal ion yields in negative ion mode. Ammonium chloride or phosphate also yielded prominent adducts but anionic carbohydrates such as sulfated N-glycans tended to ionize preferentially. Carbohydrates adducted with all three adducts (phosphate, chloride, and nitrate) produced good negative ion CID spectra but those adducted with iodide and sulfate did not yield fragment ions although they gave stronger signals. Fragmentation paralleled that seen following electrospray ionization providing superior spectra than could be obtained by PSD on MALDI-TOF instruments or with ion traps. In addition, ion mobility drift times of the adducted glycans and the ability of this technique to separate isomers also mirrored those obtained following ESI sample introduction. Ion mobility also allowed profiles to be obtained from samples whose MALDI spectra showed no evidence of such ions allowing the technique to be used in conditions where sample amounts were limiting. The method was applied to N-glycans released from the recombinant human immunodeficiency virus glycoprotein, gp120.     

Excitation symmetry analysis method (ESAM) for calculation of higher order non-linearities

A non-linear system with 3rd order non-linearity is fully characterized using symmetry analysis (SA) applied to the excitation, as it is done in 2nd order non-linear systems using the pulse inverted method. Symmetry analysis is performed using irreductible representations and the character table of C₃ rotation point group, which leads to the construction of three eigen-excitations allowing extraction of the 3rd order non-linearity parameter without the perturbation of fundamental and 2nd order terms. Validation of this concept is based on excitation symmetry analysis method (ESAM) which was tested on simulated noisy signals and compared with classical spectral analysis.     

Thiourea-Catalyzed C−F Bond Activation: Amination of Benzylic Fluorides

We describe the first thiourea-catalyzed C−F bond activation. The use of a thiourea catalyst and Ti(OiPr)₄ as a fluoride scavenger allows the amination of benzylic fluorides to proceed in moderate to excellent yields. Preliminary results with S- and O-based nucleophiles are also presented. DFT calculations reveal the importance of hydrogen bonds between the catalyst and the fluorine atom of the substrate to lower the activation energy during the transition state.     

Fast and Efficient Postsynthetic DNA Labeling in Cells by Means of Strain-Promoted Sydnone-Alkyne Cycloadditions

Sydnones are highly stable mesoionic 1,3-dipoles that react with cyclooctynes through strain-promoted sydnone-alkyne cycloaddition (SPSAC). Although sydnones have been shown to be valuable bioorthogonal chemical reporters for the labeling of proteins and complex glycans, nucleic acids have not yet been tagged by SPSAC. Evaluation of SPSAC kinetics with model substrates showed fast reactions with cyclooctyne probes (up to k=0.59 M⁻¹ s⁻¹), and two different sydnones were effectively incorporated into both 2’-deoxyuridines at position 5, and 7-deaza-2’-deoxyadenosines at position 7. These modified nucleosides were synthetically incorporated into single-stranded DNAs, which were successfully postsynthetically labeled with cyclooctyne probes both in vitro and in cells. These results show that sydnones are versatile bioorthogonal tags and have the premise to become essential tools for tracking DNA and potentially RNA in living cells.     

Assembly of the Entire Carbon Backbone of a Stereoisomer of the Antitumor Marine Natural Product Hemicalide

A strategy for the assembly of the entire carbon backbone of a stereoisomer of the antitumor marine natural product hemicalide has been investigated. The devised convergent approach relies on Horner–Wadsworth–Emmons and Julia–Kocienski olefination reactions for the construction of the C6=C7 and C34=C35 double bonds, respectively, an aldol reaction to create the C27−C28 bond, and a Suzuki–Miyaura cross-coupling as the endgame to form the C15−C16 bond.     

The Adamantane Rearrangement of Tricyclo[4.2.2.01,5]decane to Tricyclo[5.3.0.04,8]decane

Regioselective generation of the C(2)-carbocation a of tricyclo[4.2.2.0^1,5]decane ( 1 ) by treatment of both corresponding epimeric alcohols 5 and 6 with BF₃ and trapping the rearranged tricyclo[5.3.0.0^4,8]decan-7-yl carbocation b with Et₃SiH as hydride-ion donor (ionic hydrogenation) gives the corresponding hydrocarbon 3 as sole product in almost quantitative yield. The latter is a known intermediate in the Lewis-acid-catalyzed rearrangement of 1 to adamantane ( 4 ).     

AGGREGATION OF CHLOROPHYLL a SPECIES ABSORBING NEAR 700nm–1. THE INFRARED CARBONYL BANDS

Abstract— Amorphous chlorophyll a obtained by electrodeposition(Chl–678) undergoes a bathoch-romic shift upon solvation with gaseous alcohol at ambient temperatures. The process is reversible when the alcohol is removed. With 1-propanol, the red band of Chi a is displaced from 678 nm to 701 nm and a new aggregate is formed,Chl–701. To determine the nature of the new aggregate, the IR carbonyl bands of Chi are monitored. The free ketone massive band ofChl–678, situated at 1691 cm^-1, is decreased upon solvation to the profit of the associated ketone carbonyl massive band which absorbs at 1656 cm^-1. The bandwidths of the massive bands are much greater than the typical value of a carbonyl band of a ketone in solution. This is an indication that the massive bands are composed of overlapping bands. In order to determine the number and the position of the bands, the Fourier self-deconvolution technique has been used to enhance the spectral characteristics of the infrared spectra. The band fitting technique is then used on the original spectra to determine the difference in intensity between the bands ofChl–678 and those ofChl–701. The interpretation of the resolved IR spectra shows that the amorphous sample is composed of open dimers linked together by the CO-Mg coordinate bonds. When the solvated species are formed, these coordinate bonds are not ruptured and one molecule of alcohol for two molecules of chlorophyll is linked to these molecules by an hydrogen bond between the hydrogen of the alcohol and the available ketone and by a coordinate bond between the available Mg and the oxygen of the alcohol. Closed dimers are thus formed.     

Spontaneous Isomerization of Peptide Cation Radicals Following Electron Transfer Dissociation Revealed by UV-Vis Photodissociation Action Spectroscopy

Peptide cation radicals of the z-type were produced by electron transfer dissociation (ETD) of peptide dications and studied by UV-Vis photodissociation (UVPD) action spectroscopy. Cation radicals containing the Asp (D), Asn (N), Glu (E), and Gln (Q) residues were found to spontaneously isomerize by hydrogen atom migrations upon ETD. Canonical N-terminal [z₄ + H]^+● fragment ion-radicals of the R-C^●H-CONH- type, initially formed by N?C_α bond cleavage, were found to be minor components of the stable ion fraction. Vibronically broadened UV-Vis absorption spectra were calculated by time-dependent density functional theory for several [^●DAAR + H]⁺ isomers and used to assign structures to the action spectra. The potential energy surface of [^●DAAR + H]⁺ isomers was mapped by ab initio and density functional theory calculations that revealed multiple isomerization pathways by hydrogen atom migrations. The transition-state energies for the isomerizations were found to be lower than the dissociation thresholds, accounting for the isomerization in non-dissociating ions. The facile isomerization in [^●XAAR + H]⁺ ions (X = D, N, E, and Q) was attributed to low-energy intermediates having the radical defect in the side chain that can promote hydrogen migration along backbone C_α positions. A similar side-chain mediated mechanism is suggested for the facile intermolecular hydrogen migration between the c- and [z + H]^●-ETD fragments containing Asp, Asn, Glu, and Gln residues.

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