John S. Davies

Protection of hydroxy groups by silylation: use in peptide synthesis and as lipophilicity modifiers for peptides

A survey of a series of organosilyl derivatives of serine and tyrosine has shown that they have a satisfactory stability profile for use in peptide synthesis. Only when alkaline conditions were used did side-reactions appear. A range of stability profiles have been determined from a study of organosilyl derivatised dipeptides under different conditions, giving t½-values for hydrolysis ranging from 41 to 465 min in acid conditions, yet giving long-term stability at pH-values near to neutrality.

Assessment of racemisation in N-alkylated amino-acid derivatives during peptide coupling in a model dipeptide system

N.m.r. analysis of diastereoisomeric benzoyl dipeptide esters has been used to monitor racemisation during the coupling of benzoyl-N-alkylated amino-acids to alanine and valine methyl esters. Results confirm the greater susceptibility of these amino-acids to racemisation, but conditions have been found which eliminate racemisation. The additives HONSu and HOBt vary in their capability as ‘chiral stabilisers’. N.m.r. techniques provide a facile means for monitoring the involvement of oxazolonium ions during coupling. A possible mechanism for racemisation is proposed.

Cyclic, modified and conjugated peptides

The subject matter for this Chapter has again been allocated sub-headings that reflect main subject areas under which a reasonable number of publications have been cited. In the absence of a detailed keyword index, the sub-headings also provide continuity from previous volumes, so that searching the...

Novel heterocyclic systems. Part 3. The first dipyrido-oxathiin, and new routes to a dipyridodioxin and a dipyridodithiin

Abstract The first example of a dipyrido-oxathiin has been prepared, and a dipyridodithiin and a dipyridodioxin have been obtained by improved methods. Their spectroscopic properties are compared.

Synthesis and applications of cyclopeptides and depsipeptides

A solid phase protocol has been devised for the synthesis of linear precursors to cyclic depsipeptide analogues of dolastatin D.t-Butyldimethylsilyl groups were used for hydroxy group protection, with deprotection being carried out byt-butyl ammonium fluoride. HATU and PyBrop were successful in coupling highly hindered residues and in depside bond formation. Cyclic peptide analogues, cyclo[Arg-Gly-Asp-d-Phe-Lys(or Tyr)] have been synthesised and modified for use as carrier molecules for the transport of radio isotopes (111In and125I) into blood platelets as prototypes for medical imaging.

Novel heterocyclic systems, Part 4: A simple, convenient synthesis of 3-hydroxypyridine-2-thione, and the preparation of two novel tricyclic betaines

Abstract Fusion of P4S10 with 3-hydroxy-2-pyridone gives 3-hydroxypyridine-2-thione as the major product, along with significant amounts of two isomeric tricyclic betaines - the first examples of their class.

Application of 1,2,4-triazoline-3,5-diones in the synthesis of the piperazic acids (hexahydropyridazine-3-carboxylic acids)

Diels–Alder reactions between penta-2,4-dienoic acid (and substituted analogues) and 4-phenyl-1,2,4-triazoline-3,5-dione (or 1,2,4-triazoline-3,5-dione) give adducts which, after hydrogenation and hydrolysis, yield the piperazic acid residues identified in the hydrolysates of the monamycin series of cyclohexadepsipeptide antibiotics.

Synthesis and cell-adhesion properties of cyclo(-Arg-Gly-Asp-Ser-Lys-), a constrained analogue of the active domain of fibronectin

Details of the synthesis of the protected pentapeptide linear precursor on a resin with an acid-labile linker, and its subsequent cyclisation to cyclo(-Arg-Gly-Asp-Ser-Lys-) are presented. The cyclopentapeptide, which is known to exist in solution in a β- and γ-turn conformation, shows specific differences in its effect on adhesion and cell spreading for fibroblast 3T3 and macrophage Bac 1 cells.

1H NMR studies on cyclo[-Arg(Mtr)-Gly-Asp(But)-Ser(But)-Lys(Boc)-] and cyclo(-Arg-Gly-Asp-Ser-Lys-), cyclic analogues of the ‘adhesion’ domain of fibronectin

High-field 1H NMR techniques in DMSO solution, augmented by a comparison with calculated conformations based on cyclo(-Ala-Gly-Ala-Ala-Ala-), and restrained molecular dynamics calculations have revealed preferred conformations for both of the conformationally constrained-Arg-Gly-Asp-Ser-analogues studied. A type II′β-turn spanning Gly-Asp and a slightly less stable γ-turn at the Lys residue were revealed for both peptides.

A 1H, 13C, and 19F nuclear magnetic resonance study of rotational isomerism and long-range coupling in methyl (1S,5R,7R)-1-ethyl-3-oxo-6-trifluoroacetyl-2,8-dioxa-6-azabicyclo[3.2.1]octane-7-carboxylate

The 1H, 13C, and 19F n.m.r. spectra of the title compound show that it exists in solution as a mixture of rotamers about the amide bond. Each rotamer possesses a distinct pattern of long-range 1H, 19F, 13C and 19F couplings. Proton spin–lattice relaxation time experiments have been used to assign the n.m.r. spectra of each rotamer. These assignments show that large values of the long-range couplings are associated with a close spatial approach of the nuclei involved. The title compound was obtained via degradation of methyl clavulanate with acid followed by hydrogenation.