Steen Ingemann

Enantioselective BINOL-Phosphoric Acid Catalyzed Pictet-Spengler Reactions of N-Benzyltryptamine

Optically active tetrahydro-beta-carbolines were synthesized via an ( R)-BINOL-phosphoric acid-catalyzed asymmetric Pictet-Spengler reaction of N-benzyltryptamine with a series of aromatic and aliphatic aldehydes. The tetrahydro-beta-carbolines were obtained in yields ranging from 77% to 97% and with ee values up to 87%. The triphenylsilyl-substituted BINOL-phosphoric acid proved to be the catalyst of choice for the reaction with aromatic aldehydes. For the aliphatic aldehydes, 3,5-bistrifluoromethylphenyl-substituted BINOL-phosphoric acid was identified as the best catalyst.

Formation and chemistry of radical anions in the gas phase

The research concerned with the ion/molecule chemistry of radical anions is reviewed together with the thermochemical properties of these ions and the related neutral species. Attention has been given to the formation of radical anions in the gas phase by various pathways, such as (dissociative) electron attachment and bimolecular reactions. A brief discussion of the electron affinity of the neutral species related to a given radical anion has been included, because this parameter is important for the discussion of the finding that an HA˙ radical is often more acidic than the related H2A molecule. In addition, the thermochemical properties form the basis for a discussion of the various processes that may occur in reactions of radical anions with organic molecules. In particular, electron transfer, proton transfer, and hydrogen atom abstraction reactions have been described for selected radical anions. Other processes that have been reviewed include SN2 substitution and an attack on a carbonyl function in an organic molecule. The interplay between these latter two processes has been described for the reactions of some halogen-substituted carbene radical anions with the methyl ester of trifluoroacetic acid and dimethyl carbonate. The structural characterization of radical anions, distonic radical anions in particular, is summarized with an emphasis on methods such as isomer-specific ion/molecule reactions and collision-induced dissociation or charge-reversal processes.

Electron capture and collisionally activated dissociation mass spectrometry of doubly charged hyperbranched polyesteramides

Electron capture dissociation (ECD) of doubly protonated hyperbranched polyesteramide oligomers (1100–1900 Da) was examined and compared with the structural information obtained by low energy collisionally activated dissociation (CAD). Both the ester and amide bonds of the protonated species were cleaved easily upon ECD with the formation of odd electron (OE·+) or even electron (EE+) fragment ions. Several mechanistic schemes are proposed that describe the complex ECD fragmentation behavior of the multiply charged oligomers. In contrast to studies of biomolecules, the present results indicate that consecutive cleavages induced by intramolecular H-shifts are significant for ECD and of less importance for low energy CAD. The capture of an electron by the ionized species results in fragmentation associated with a redistribution of the excess internal energy over the products and the subsequent bond cleavage. Low energy, multiple collision CAD is found to be a more selective dissociation method than ECD in view of the observation that only amide bonds are cleaved for most of the hyperbranched polymers examined with CAD in this study. ECD appears not to provide complementary structural information compared to CAD in the study of hyperbranched polymers, even though a significantly more complex ECD fragmentation behavior is observed. ECD is shown to be of use for the structural characterization of large oligomers that may not dissociate upon low energy CAD. This is a direct result of the fact that ECD produces ionized hyperbranched oligomers with a relatively high internal energy.

Proton affinities and heats of formation of the imines CH2NH, CH2NMe and PhCHNH

The proton affinities of the imines CH2NH, CH2NMe and PhCHNH have been determined by Fourier transform ion cyclotron resonance (FT-ICR) mass Spectrometry to be 854 ± 8 kJ mol–1, 880 ± 8 kJ mol–1 and 908 ± 8 kJ mol–1, respectively. These results lead, in conjunction with known ΔHf0 values for the protonated species, to ΔHf0(CH2NH)= 69 ± 8 kJ mol–1, which is significantly lower than previously reported in the literature, and to ΔHf0(CH2NMe)= 44 ± 8 kJ mol–1. The proton affinities of the small imines are between the values for the corresponding amines and nitriles. The decrease in proton affinity with the change in hybridization of the nitrogen atom from sp3 to sp2 to sp is discussed together with the increase in proton affinity upon introduction of a methyl group on either the carbon atom or the nitrogen atom in CH2NH.

Organocatalytic Enantioselective Pictet–Spengler Reactions for the Syntheses of 1-Substituted 1,2,3,4-Tetrahydroisoquinolines

A series of 1-substituted 1,2,3,4-tetrahydroisoquinolines was prepared from N-(o-nitrophenylsulfenyl)phenylethylamines through BINOL-phosphoric acid [(R)-TRIP]-catalyzed asymmetric Pictet-Spengler reactions. The sulfenamide moiety is crucial for the rate and enantioselectivity of the iminium ion cyclization and the products are readily recrystallized to high enantiomeric purity. Using this methodology we synthesized the natural products (R)-crispine A, (R)-calycotomine and (R)-colchietine, the synthetic drug (R)-almorexant and the (S)-enantiomer of a biologically active (R)-AMPA-antagonist.

Non-equilibrium isomer distribution of the gas-phase photoactive yellow protein chromophore

The conjugate base of para-coumaric acid, which can be conveniently generated in the gas phase by electrospray ionization (ESI), is a commonly used model system for the chromophore of the photoactive yellow protein. Here we report its gas-phase IR spectrum, which shows that the anion easily adopts a carboxylate structure lying 60 kJ/mol higher in energy than the global minimum phenoxide structure. Generation of the biologically more relevant phenoxide isomer by ESI can be achieved using dry acetonitrile as solvent.

Thermochemical properties of halogen-substituted methanes, methyl radicals, and carbenes in the gas phase.

The thermochemical properties of a series of chlorine- and bromine-substituted methanes, methyl radicals, and carbenes have been (re)examined on the basis of ion–molecule reactions as performed with the use of Fourier transform ion cyclotron resonance mass spectrometry. In particular, the occurrence of reversible proton transfer in the reactions of the CHClBr−, CHBr2−, and CBr3− anions with selected reference acids has been used to obtain the following gas-phase acidities: ΔH°acid(CH2ClBr) = 1560 ± 8 kJ mol−1, ΔH°acid(CH2Br2) = 1544 ± 8 kJ mol−1, and ΔH°acid(CHBr3) = 1463 ± 8 kJ mol−1. In addition, the gas-phase acidities of the ·CHCl2, ·CHClBr, and ·CHBr2 radicals have been placed at 1524 ± 10, ∼1509, and ∼1494 kJ mol−1, respectively. The values for the ·CHClBr and ·CHBr2 radicals have been derived on the basis of the occurrence/nonoccurrence of proton transfer in the reactions of the CClBr−· and CBr2−· carbene radical anions with various reference acids in combination with the trend in the gas-phase acidities of bromine containing methanes and methyl radicals. The present gas-phase acidities together with experimentally determined electron affinities of the dihalogen-substituted carbenes have been used to estimate the enthalpies of formation of the CCl2, CClBr, and CBr2 carbenes [ΔH°f(CCl2) = 226 ± 25 kJ mol, ΔH°f(CClBr) ∼ 267 kJ mol, and ΔH°f(CBr2) ∼ 324 kJ mol−1).

Organocatalytic Enantioselective Pictet-Spengler Approach to Biologically Relevant 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline Alkaloids

A general procedure for the synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines was developed, based on organocatalytic, regio- and enantioselective Pictet-Spengler reactions (86-92% ee) of N-(o-nitrophenylsulfenyl)-2-arylethylamines with arylacetaldehydes. The presence of the o-nitrophenylsulfenyl group, together with the MOM-protection in the catechol part of the tetrahydroisoquinoline ring system, appeared to be a productive combination. To demonstrate the versatility of this approach, 10 biologically and pharmaceutically relevant alkaloids were prepared using (R)-TRIP as the chiral catalyst: (R)-norcoclaurine, (R)-coclaurine, (R)-norreticuline, (R)-reticuline, (R)-trimemetoquinol, (R)-armepavine, (R)-norprotosinomenine, (R)-protosinomenine, (R)-laudanosine, and (R)-5-methoxylaudanosine.

Total syntheses of mitragynine, paynantheine and speciogynine via an enantioselective thiourea-catalysed Pictet–Spengler reaction

The pharmacologically interesting indole alkaloids (-)-mitragynine, (+)-paynantheine and (+)-speciogynine were synthesised in nine steps from 4-methoxytryptamine by a route featuring (i) an enantioselective thiourea-catalysed Pictet-Spengler reaction, providing the tetrahydro-β-carboline ring and (ii) a Pd-catalysed Tsuji-Trost allylic alkylation, closing the D-ring.

Gas-phase ion-molecule reactions of the CH3O+ cation

The methoxy cation, CH30+, formed by collision-induced charge reversal of methoxr anions with a kinetic energy of 8 keY, has been differentiated from the isomenric CH2OH+ ion by performing low kinetic energy ion-molecule reactions In the radiofrequency-only quadrupole of a reverse-geometry double-focusing quadrupole hybrid mass spectrometer. The methoxy cation reacts with CH3SH, CH3−CH=CH2, (CH3)2O, and CH3CH2Cl by electron transfer, whereas the CH2OH+ ion reacts by proton transfer with these substrates