Edward W. Huber

Stereospecific synthesis of 1-fluoro olefins via (fluorovinyl)stannanes and an unequivocal NMR method for the assignment of fluoro olefin geometry

Abstract (E)- and (Z)-Fluorovinyl sulfones (II) form (fluorovinyl)stannanes (III) on treatment with two equivalents of tributyltin hydride and a catalytic amount of AIBN; the free radical catalyzed reaction proceeds with retention of configuration for 2,2-disubstituted fluorovinyl sulfones (IIa and IIb). Conversion of III to 1-fluoro olefins (IV) is a stereospecific reaction and provides a general method to (E) and (Z) fluoro olefins. The utility of this method is exemplified by the synthesis of the deutero fluoro olefin 27, nucleosides 32 and 34, and the amino acids 43 and 47. Proton observe, 19F irradiated (1H-19F) NOE difference specroscopy was used for the first time as an unequivocal method for the assignment of olefin geometry for fluorovinyl sulfones, (fluorovinyl)stannanes and fluoro olefins.

Constrained amino acids. An approach to the synthesis of 3-substituted prolines

Abstract The synthesis of diastereomeric substituted proline peptidomimetics as conformationally restricted tyrosine derivatives 1a,b has been accomplished utilizing the intramolecular hydroboration-cycloalkylation of azido-olefins 7a,b as the key step.

Pyrrolidine and hexahydro-1 H-azepine mimics of the ‘flap up’ mannosyl cation

Abstract The pyrrolidine 4, 6-amino-1,4,6-trideoxy-1,4-imino–D-mannitol dihydrochloride, and the hexahydro-1 H–azepine 5, 4-amino-1,4,6-trideoxy-1,6-imino-D-mannitol dihydrochloride, were synthesized as potential inhibitors of α-mannosidase.

An acyliminium ion route to and “Anti” phe-gly dipeptide mimetics

The synthesis of two series of constrained mimetics of the dipeptide phenylalanylglycine oriented in the “anti” conformation (X1 = 180°) are described. These benzolactams differ about the geometry of the internal amide bond (ω1=0° or 180°). Solution NMR studies support specific conformational assignments for these mimetics. The synthesis of two series of constrained mimetics of the dipeptide Phenylalanyl-glycine oriented in the “anti” conformation (κ1=180°) are described. These benzolactams differ about the geometry of the internal amide bond (ω1=0° or 180°). Solution NMR studies support specific conformational assignments for these mimetics.

A convenient synthetic access to β,β-difluoro-γ-keto-α-amino acids. Application to the synthesis of a potential inhibitor of kynureninase

Abstract A convenient synthesis of a novel class of kynureninase inhibitors, difluoroketoamino acid ( 11 ) is described.

Synthesis of 6-amino-5-oxo-7-phenyl-1,4-oxazepines as conformationally constrained gauche (−) dipeptide mimetics

Abstract 6-Amino-5-oxo-7-pheynl-1,4-oxazepines were synthesized from β-phenylserine by a versatile route to provide gauche (−) phenylalanyl-X dipeptide mimetics ( 1a-h ). NMR was utilized to elucidate the solution conformation of the protected mimetics. The seven membered ring was found to be in a chair conformation with the phtalimide moiety and the phenyl ring pseudo-equatorial, consistent with the gauche (−) conformation (dihedral angle X1 = −60°). Dipeptide mimetic 2 was synthesized from 1 a to probe the effect of the gauche (−) conformation on the inhibition of metalloproteinases. These gauche (−) dipeptide mimetics may be useful tools for the investigation of conformational preferences of enzyme substrates and receptor ligands.

Diastereoselectivity in the intramolecular nitrone, oxime, and nitrile oxide cycloaddition reactions. Synthesis of amino inositol derivatives as α-glucosidase inhibitors

Abstract The diastereoselectivity in the intramolecular 1,3-dipolar cycloaddition reactions of 4 and 5 (RBn, 4-MeOBn) was examined.

INVESTIGATION INTO THE YELLOWING ON AGING OF SABRIL@ TABLET CORES

AbstractUncoated Sabril® tablet cores under long term storage become slightly discolored from the initial white to a yellowish off-white color. In order to ensure the aesthetics of the product, Sabril tablet cores are film coated with an opaque white coating. The nature of this yellowing reaction was of interest even though discolored tablets showed no significant loss of potency on assay. Excipient compatibility studies showed that the vigabatrin active in Sabril mixed with Avicel (microcrystalline cellulose) in the presence of moisture also became off-colored when stressed at elevated temperatures.The nature of the discoloration in aged Sabril core tablets was investigated. Chromatographic and spectroscopic data indicate that the source of this color comes from the Maillard Reaction between vigabatrin and Avicel which results in a multitude of products analogous to “browning reactions” of food products. A gravimetric determination of the leached colored products from 7 year old Sabril core tablets gave ...

Constrained amino acids. The synthesis of glutamine mimetics

Abstract The preparation and utility of conformationally constrained homoserines trans- 8 a and cis- 8b as intermediates for the synthesis of constrained glutamine mimetics trans- 1 a and cis- 1 b is presented.

The conversion of a diazolactam to an α-methylenelactam: An entrance to new conformationally restricted inhibitors of angiotensin-converting enzyme

Abstract Methodology for the conversion of an α-aminolactam dipeptide mimic to an α-methylenelactam derivative was developed utilizing the decomposition of an α-diazolactam intermediate in the presence of triphenylphosphine as the key step. Conjugate addition of thiolbenzoic acid to the derived unsaturated lactam and deesterification gave two new potent sulfhydryl containing inhibitors of angiotensin-converting enzyme.