Paul Lloyd-Williams

Atropisomerism, biphenyls and the Suzuki coupling: peptide antibiotics

The formidable synthetic challenge posed by the vancomycin class of glycopeptide antibiotics has only recently been met. Foremost among the difficulties associated with the synthesis of these molecules is the control of non-conventional stereochemical issues. These are a consequence of the molecules possessing biphenyl and biaryl ether linkages between amino acid residues situated within the constituent macrocycles. Among the keys to success is the availability of methods that allow the efficient formation of biaryl linkages between amino acid derivatives under mild conditions. Recent progress in the chemistry of the Suzuki coupling suggests that this constitutes a very powerful and general method for the synthesis of peptide biphenyls.

Solid-phase synthesis of peptides using allylic anchoring groups. An investigation of their palladium-catalysed cleavage

Abstract The use of two different allylic “handles” has been investigated in the solid-phase synthesis of protected peptides. Very high yields for the cleavage of peptides from the resin, under mild conditions which preserve side-chain protecting groups can be achieved by carrying out the cleavage reaction in 2:2:1 THF/DMSO/0.5 M HCl, using morpholine as nucleophile and Pd(Ph 3 P) 4 as catalyst.

Use of BOP reagent for the suppression of diketopiperazine formation in Boc/Bzl solid-phase peptide synthesis

Abstract BOP coupling reagent suppresses the formation of diketopiperazines in the solid-phase coupling of the third amino acid to dipeptides when a nitro-benzylic “handle” is used to link the peptide to the resin. The amino function of the second amino acid may be deprotected with TFA and the coupling carried out without a prior neutralisation step.

Solid-phase synthesis of peptides using allylic anchoring groups 2. Palladium-catalysed cleavage of Fmoc-protected peptides

Abstract High yields for the cleavage reaction of Fmoc-protected peptide segments from an allylic handle may be obtained using tributyltin hydride in the presence of (Ph3P)PdCl2 in a 1:1 mixture of DMF/DCM. Alternatively the cleavage reaction may be carried out using NMA as nucleophile in a 2:2:1 mixture of DMSO/THF/0.5M HCl in the presence of (Ph3P)4Pd. The Fmoc group is completely stable to both these cleavage methods.

Convergent solid-phase peptide synthesis. X. Synthesis and purification of protected peptide fragments using the photolabile Nbb-resin☆☆☆

Abstract Protected peptide fragments corresponding to the 12–18, 31–38 and 59–67 segments of the Uteroglobin monomer have been synthesised on a solid support using the photolabile ortho -nitrobenzyl unit as a handle. Attachment of the first amino acid of the sequence has been carried out in three different ways and a new procedure for avoiding the formation of DKPs in the coupling of the third amino acid with this resin-handle is described. Photolytic detachment of the peptides from the solid support occurs in good yields. In spite of their low solubility in the normal solvents used in reverse-phase MPLC and HPLC techniques, protected peptide fragments can be purified by MPLC utilising solvents containing a high proportion of DMF.

Use of the SPhos Ligand to Suppress Racemization in Arylpinacolboronate Ester Suzuki Couplings Involving α-Amino Acids. Synthesis of Biaryl Derivatives of 4-Hydroxyphenylglycine, Tyrosine, and Tryptophan

Alpha-amino acid derivatives, particularly those of phenylglycine, can suffer significant racemization in Suzuki couplings. When arylpinacolboronate esters are used as coupling partners this unwanted side reaction can be suppressed by the use of Pd(OAc)(2) as Pd(0) source, in the presence of Buchwalds SPhos ligand. The syntheses of biaryl amino acids of tyrosine, phenylglycine, and tryptophan, including Phg-Trp units similar to those found in the chloropeptin family of natural products, are reported.

CONVERGENT SOLID-PHASE PEPTIDE SYNTHESIS

Publisher Summary This chapter discusses solid-phase synthesis and coupling of protected peptides. There are two main strategies for the chemical synthesis of peptides: (1) chain elongation in linear synthesis is carried out by repetitive N α amino group deprotection and protected amino acid coupling steps, (2) convergent synthesis involves the synthesis and coupling of protected peptide segments. Both strategies can be carried out in solution or on a solid support, although solution and solid-phase methodologies can coexist in convergent synthesis. Protected peptide segments can be elaborated on solid supports and coupled in solution or vice versa. Convergent solid-phase peptide synthesis (CSPPS) involves (1) solidphase synthesis of protected peptides (these must retain the protecting groups of the N α -amino and the side-chain functions after cleavage from the resin), (2) purification and characterization of the protected peptides, and (3) their solid-phase coupling.

[8] Voltammetric measurements of quinones

Publisher Summary This chapter describes electrochemical methods of obtaining thermodynamic data from quinones. Quinones are cyclic conjugated carbonyl compounds, which may be formally derived from benzene, fused polycyclic aromatics, or certain heterocycles. Quinones play vital roles in many biological systems. The majority of those which occur naturally belong to the para series, although oquinones are well represented. Oxidized catecholamines may be considered as substituted nascent 1,2-benzoquinones. Quinones are involved in membrane electron transfer systems, 3 some soluble dehydrogenases, 4 blood coagulation, defensive chemistry, and pigmentation. Some are important antineoplastic agents. In many of these roles, the quinine undergoes consecutive reduction-oxidation (redox) processes which can involve a variety of pathways and redox couples. This chapter illustrates that two related techniques have proven most useful for routine electrochemical measurements, cyclic voltammetry and dc polarography, conceptually, both techniques scan the potential at the working electrode and monitor the current required.

Convergent solid-phase peptide synthesis. VIII. Synthesis, using a photolabile resin, and purification of a methionine-containing protected peptide.

The solid-phase synthesis, photolytic detachment from the solid support and purification in solution, of a fully-protected octapeptide containing a methionine residue (protected as the sulphoxide) is described. Protection of methionine in this manner avoids problems associated with the oxidation of this residue during the photolysis. The peptide has been purified by medium pressure liquid chromatography using solvent mixtures containing a high proportion of dimethylformamide in order to avoid precipitation of the peptide on the column.

Convergent solid-phase peptide synthesis. XI. Synthesis and purification of protected peptide segments spanning the entire sequence of the uteroglobin monomer using the photolabile nbb-resin.

Abstract Protected peptide segments corresponding to the 1–4, 5–11, 19–30, 39–49 and 50–58 segments of the Uteroglobin monomer have been synthesised on a solid support using the photolabile ortho -nitrobenzyl unit as a handle. Photolytic detachment of the peptides from the solid support occurred in good yields. The 50–58 protected peptide segment has also been synthesised using the base-labile NPE handle, and detached from the solid support in excellent yield by treatment with a 20% solution of piperidine in DMF. The protected peptide segments were purified by MPLC and/or preparative HPLC, using solvents containing DMF.