4-hydroxymethylphenol Research Articles

Efficient generation of peptide hydrazides via direct hydrazinolysis of Peptidyl-Wang-TentaGel resins.

Peptide hydrazides are valuable building blocks in peptide and protein chemistry, e.g. as precursors of peptide thioesters that allow the preparation of these important intermediates under mild conditions. Additional robust and versatile methods for the generation of peptide hydrazides from standard solid supports are therefore highly desired in order to facilitate access to peptide thioester via Fmoc-based SPPS. Here, the efficient generation of peptide hydrazides from conventional 4-hydroxymethyl phenol Wang-TentalGel peptidyl resins is described. Direct hydrazinolysis of a 19mer mucin1 peptide gives the protected peptide hydrazide in excellent yields. Testing a series of octapeptides carrying the 20 common proteinogenic amino acids at their C-terminus led to preparation of all corresponding peptide hydrazides in very good to excellent yields and purities. The available set of octapeptides allowed analyzing the influence of the nature of the C-terminal amino acid and of the solvent on the hydrazinolysis reaction. Furthermore, the compatibility of the method with posttranslational modifications (here glycosylation) and with potentially sensitive functional groups in amino acid side chains makes this approach a viable alternative for obtaining peptide hydrazides. It combines the advantages of a straightforward synthesis with stereochemical stability and flexibility, as it provides easy access to the peptide acid and the peptide thioester (via the hydrazide) from the same solid support.

Silver Cation Affinities of Monomeric Building Blocks of Polyethers and Polyphenols Determined by Guided Ion Beam Tandem Mass Spectrometry

Energy-resolved collision-induced dissociation (CID) of seven silver cation-ligand complexes, Ag(+)(L), with Xe is studied using guided ion beam tandem mass spectrometry techniques. The ligands, L, investigated are monomeric building blocks of polyethers and polyphenols including phenol, 2-hydroxyphenol, 3-hydroxyphenol, 4-hydroxyphenol, 2-hydroxymethyl phenol, 3-hydroxymethyl phenol, and 4-hydroxymethyl phenol. In all cases, Ag(+) is observed as the primary CID product, corresponding to endothermic loss of the intact neutral ligand. The kinetic-energy-dependent cross sections for CID of these Ag(+)(L) complexes are analyzed using an empirical threshold law to extract absolute 0 and 298 K Ag(+)-L bond dissociation energies (BDEs). Density functional theory calculations at the B3LYP/6-31G* level of theory are used to determine the structures of the neutral ligands and their complexes to Ag(+) using either the Stuttgart RSC 1997 valence basis set and effective core potential (SRSC ECP) or DZVP-DFT to describe Ag(+). Theoretical BDEs are determined at the B3LYP/6-311+G(2d,2p) level of theory again using the SRSC ECP or DZVP-DFT for Ag(+). For all systems, the most stable binding conformations found involve cation-π interactions when the SRSC ECP is used to describe Ag(+). When DZVP-DFT is employed, the most stable binding geometries remain cation-π complexes except for the complex to 2HP, where the ground-state conformer involves bidentate binding of Ag(+) to the hydroxyl oxygen atoms of both substituents. The agreement between the measured and calculated BDEs is excellent with a MAD of 2.9 ± 1.7 kJ/mol when the SRSC ECP is used to describe Ag(+) and less satisfactory for DZVP-DFT, which underestimates the strength of binding in these systems by ~14% or 26.0 ± 6.7 kJ/mol.

The Lactol Route to Fesoterodine: An Amine-Promoted Friedel–Crafts Alkylation on Commercial Scale

We report the discovery and optimization of an amine-promoted Friedel–Crafts alkylation of cinnamaldehyde with 4-hydroxymethyl phenol. This reaction has been used successfully on commercial scale (200 kg) in the context of the manufacture of fesoterodine, a muscarinic antagonist used for the treatment of overactive bladder. Reductive aminations of diisopropylamine and lactol 4 are also discussed, as well as the resolution of the racemic amine rac-2 into its enantiomerically pure form.