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The neurotransmitter metabolite 3,4-dihydroxy-phenylglycolaldehyde (dopegal) damages neurons and the myocardium by protein cross-linking, resulting in conglomerations and cell death. We investigated this process on a synthetic scale, leading to the discovery of an Amadori-type rearrangement of dopegal in the reaction with several amino acids and neuropeptides. This alkylation also occurs with neurotransmitters, suggesting an influence of dopegal on neurochemical processes. The rearrangement occurs readily under physiological conditions.

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-arylethyl-amines 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.

We report on experimental high-resolution spectroscopic studies in combination with ab initio computational studies that investigate the excited-state dynamics of methyl-4-hydroxycinnamate thioester and (5-hydroxyindan-(1E)-ylidene)acetic acid, derivatives of the photoactive yellow protein (PYP) chromophore. These studies aim to elucidate (a) how the thioester moiety influences the photophysics and photochemistry of the p-coumaric acid chromophore and (b) to what extent rotation of the single bond adjacent to the phenyl ring is involved in the decay dynamics of the electronically excited states. The experimental studies show that sulfur substitution leads to broad, unstructured excitation spectra that contrast sharply with the well-resolved spectra of compounds with an oxygen-based ester. Furthermore, internal conversion to the lower-lying nπ* state is absent. The absence of this decay channel is rationalized by quantum-chemical calculations that reveal that in the nπ* state of the thio compounds the molecule exhibits a large out-of-plane "kink" at the sulfur atom. Franck-Condon simulations of the excitation spectra of the V(ππ*) state highlight the activity of various vibrational modes in the neutral chromophore and indicate that upon sulfur substitution internal conversion to the ground state occurs at a significantly higher rate. The similarities observed in the excitation spectra and decay dynamics of the locked and unlocked compounds suggest that in the present experiments single-bond torsion does not show up prominently. The conclusion that for the isolated molecule double-bond torsion is dominating the excited-state dynamics is tentatively confirmed by the quantum-chemical calculations.

Trp-cage is a synthetic 20-residue miniprotein which folds rapidly and spontaneously to a well-defined globular structure more typical of larger proteins. Due to its small size and fast folding, it is an ideal model system for experimental and theoretical investigations of protein folding mechanisms. However, Trp-cage's exact folding mechanism is still a matter of debate.,Here we investigate Trp-cage's relaxation dynamics in the amide I' spectral region (1530- 1700 cm(-1)) using time-resolved infrared spectroscopy. Residue-specific information was obtained by incorporating an isotopic label (C-13=O-18) into the amide carbonyl group of residue Gly11, thereby spectrally isolating an individual 3(10)-helical residue. The folding unfolding equilibrium is perturbed using a nanosecond temperature jump (T jump), and the subsequent re-equilibration is probed by observing the time dependent vibrational response in the amide I' region. We observe bimodal relaxation kinetics with time constants of 100 +/- 10 and 770 +/- 40 ns at 322 K, suggesting that the folding involves an intermediate state, the character of which can be determined from the time and frequency resolved data We find that the relaxation dynamics close to the melting temperature involve fast fluctuations in the polyproline II region, whereas the slower process can be attributed to conformational rearrangements due to the global (un)folding transition of the protein. Combined analysis of our T-jump data and molecular dynamics simulations indicates that the formation of a well-defined alpha-helix precedes the rapid formation of the hydrophobic cage structure, implying a native like folding intermediate, that Mainly differs from the folded conformation in the orientation of the C-terminal polyproline II helix relative to the N-terminal part of the backbone., We find that the main free energy barrier is positioned between the folding intermediate and the unfolded state ensemble, and that it involves the formation of the alpha-helix, the 3(10)-helix, and the Asp9- Arg16 salt bridge. Our results suggest that at low temperature (T << T-m) a folding path via formation of alpha-helical contacts followed by hydrophobic clustering becomes more important.

Item does not contain fulltext A novel P,N-type ligand family (ClickPhine) is disclosed that is easily accessible using the Cu(I)-catalyzed azide-alkyne "click" cycloaddition. A diverse set of ligands was made in just three steps from readily available starting materials to give several homogeneous and a heterogeneous catalyst. Preliminary experiments show the efficacy of these ligands in the Pd-catalyzed allylic alkylation reaction.

Several 2-substituted and 2,5-disubstituted piperazine-3,6-diones were synthesized starting from readily available alpha-amino acids. After activation of a lactam carbonyl via introduction of a methoxycarbonyl group onto nitrogen, this carbonyl was selectively reduced. Treatment of the resulting urethane with protic acid generated the corresponding N-acyliminium ion, which was trapped by a nucleophilic C2-side chain to provide 2,6-bridged piperazine-3-ones. Several aromatic, heteroaromatic, and nonaromatic side chains were used as pi-nucleophiles. In addition, the effect of the presence of a C5-methyl group on the stereochemical outcome of the cyclization was examined.

Treatment of a variety of N-acyliminium ion precursors with 2,3-butadienyl(trimethyl)silane and related allenes in the presence of BF(3).OEt(2) provides good yields of N-protected 2-(aminomethyl)-substituted 1,3-dienes, which prove to be useful substrates for subsequent Diels-Alder and alkene metathesis reactions. [reaction: see text]

Conversion de N-hydroxytryptamines en derives N-alkoxy par protections successives avec le [2-(trimethysilyl)ethyl]chloroformate, reaction avec des sulfures de chloromethyle fonctionnalises et deprotection avec un florure. Cyclisation intramoleculaire, reduction du methyle ester par le DIBAL et traitement par le TFA pour obtenir la paire de diastereoisomeres (eudistomine) avec une legere selectivite pour l'isomere trans (cis/trans∼35/65)

Corynanthe analogues in which the D ring is a tetrahydro-1,2-oxazine have been synthesized by an intramolecular Pictet-Spengler reaction in excellent yields (routes B and C). The cyclizations occur with high stereoselectivity of the product with a cis conformation of the C(6) and C(12b) substituents

In situ quantitative imaging of concentration profiles of reactants and products inside a microfluidic reactor is achieved, with submicron spatial resolution with similar to mM sensitivity and on similar to ms time scales, for a given position. The label-free approach relies on quantitative vibrational spectroscopy, using Coherent Anti-Stokes Raman scattering microscopy in a spectrally resolved fashion, and is demonstrated on an elementary acid-base reaction.