An efficient and simple method for synthesis of 2,2-disubstituted-2H-chromenes by condensation of a phenol with a 1,1-disubstituted propargyl alcohol using BF3·Et2O as the catalyst

An efficient and simple method for the synthesis of 2,2-disubstituted-2H-chromenes by one-step cyclocondensation of a phenol with a variety of 1,1-disubstituted propargyl alcohols using BF₃·Et₂O as the catalyst is described.     

On the influence of charged side chains on the folding-unfolding equilibrium of beta-peptides: a molecular dynamics simulation study

The influence of charged side chains on the folding-unfolding equilibrium of beta-peptides was investigated by means of molecular dynamics simulations. Four different peptides containing only negatively charged side chains, positively charged side chains, both types of charged side chains (with the ability to form stabilizing salt bridges) or no charged side chains were studied under various conditions (different simulation temperatures, starting structures and solvent environment). The NMR solution structure in methanol of one of the peptides (A) has already been published; the synthesis and NMR analysis of another peptide (B) is described here. The other peptides (C and D) studied herein have hitherto not been synthesized. All four peptides A-D are expected to adopt a left-handed 3(14)-helix in solution as well as in the simulations. The resulting ensembles of structures were analyzed in terms of conformational space sampled by the peptides, folding behavior, structural properties such as hydrogen bonding, side chain-side chain and side chain-backbone interactions and in terms of the level of agreement with the NMR data available for two of the peptides. It was found that the presence of charged side chains significantly slows down the folding process in methanol solution due to the stabilization of intermediate conformers with side chain-backbone interactions. In water, where the solvent competes with the solute-solute polar interactions, the folding process to the 3(14)-helix is faster in the simulations.     

A combination of flow and batch mode processes for the efficient preparation of mGlu2/3 receptor negative allosteric modulators (NAMs)

Benzodiazepinones are privileged scaffolds with activity against multiple therapeutically relevant biological targets. In support of our ongoing studies around allosteric modulators of metabotropic glutamate receptors (mGlus) we required the multigram synthesis of a β-ketoester key intermediate. We report the continuous flow synthesis of tert-butyl 3-(2-cyanopyridin-4-yl)-3-oxopropanoate and its transformation to potent mGlu_2/3 negative allosteric modulators (NAMs) in batch mode.     

Note: Helix or No Helix of β‐Peptides Containing β3hAla(αF) Residues?

A remote ⁴J(F,H) coupling (F? C(α)? C(O)? N? H) of up to 4.2 Hz in α‐fluoro amides with antiperiplanar arrangement of the C? F and the C?O bonds (dihedral angle F? C? C?O ca. 180°) confirms that previous NMR determinations, using the XPLOR‐NIH procedure, of the secondary structures of β‐peptides containing β³hAla(αF) and β³hAla(αF₂) residues were correct. In contrast, molecular‐dynamics (MD) simulations, using the GROMOS program with the 45A3 force field, led to an incorrect conclusion about the relative stability of secondary structures of these β‐peptides. The problems encountered in NMR analyses and computations of the structures of backbone‐F‐substituted peptides are briefly discussed.     

NMR‐Solution Structures of Fluoro‐Substituted β‐Peptides: A 314‐Helix and a Hairpin Turn. The First Case of a 90° OC?C?F Dihedral Angle in an α‐Fluoro‐Amide Group

To further study the preference of the antiperiplanar (ap) conformation in α‐fluoro‐amide groups, two β‐peptides, 1 and 2 , containing a (2‐F)‐β³hAla and a (2‐F)‐β²hPhe residue, have been synthesized. Their NMR‐solution structures in CD₃OH were determined and compared with those of non‐F‐substituted analogs, 3 and 4a . While we have found in a previous investigation (Helv. Chim. Acta 2005 , 88, 266) that a stereospecifically introduced F‐substituent in the central position of a β‐heptapeptide is capable of ‘breaking’ the 3₁₄‐helical structure by enforcing the F? C? C?O ap‐conformation, we could now demonstrate that the same procedure leads to a structure with the unfavorable ca. 90° F? C? C?O dihedral angle, enforced by the 3₁₄‐helical folding in a β‐tridecapeptide (cf. 1 ; Fig. 4). This is interpreted as a consequence of cooperative folding in the longer β‐peptide. A F‐substituent placed in the turn section of a β‐peptidic hairpin turn was shown to be in an ap‐arrangement with respect to the neighboring C?O bond (cf. 2 ; Fig. 7). Analysis of the non‐F‐substituted β‐tetrapeptides (with helix‐preventing configurations of the two central β²/β³‐amino acid residues) provides unusually tight hairpin structural clusters (cf. 3 and 4a ; Figs. 8 and 9). The skeleton of the β‐tetrapeptide H‐(R)β³hVal‐(R)β²hVal‐(R)β³hAla‐(S)β³hPhe‐OH ( 4a ) is proposed as a novel, very simple backbone structure for mimicking α‐peptidic hairpin turns.