Dorothy M. David

Binaphthyl‐Based Dicationic Peptoids with Therapeutic Potential

[Extract] While the cationic glycopeptide vancomycin has long been regarded as the gold standard for the treatment of recalcitrant Gram-positive bacterial infection, this position has been compromised by the emergence of resistant strains. The first report of such resistance emerged in 1988, and has subsequently widened amongst the enterococci and staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA); 1, 2 cross-resistance to linezolid is also a concern. Some recent chemical strategies for overcoming this resistance have centered on other high molecular weight cyclic peptides, elegantly crafted vancomycin11 or vancomycin aglycone analogues, potent dual-action vancomycin/β-lactam hybrid antibiotics,or large vancomycin dimers. An alternative strategy is to design smaller, simpler cationic peptoids with some related design features to vancomycin which could still interact with the altered peptide-glycan cell-wall moiety in both vancomycin-resistant and -sensitive strains and thus broaden the antibacterial spectrum. Svendsen et al. designed minimal cationic peptidomimetics, and a pharmacophore has been developed for dipeptides which includes the presence of two cationic charges and two hydrophobic units of steric bulk. Subsequently, cationic tripeptide analogues were developed that demonstrated good activity against both Gram-positive (including MRSA) and Gram-negative bacteria, but were not evaluated with respect to vancomycin-resistant strains.

The synthesis of a novel binaphthyl-based cyclic peptoid with anti-bacterial activity

The novel cyclic peptoid 1, based upon a 1,1′-binaphthyl scaffold and a bridging tripeptide moiety, was synthesised utilising a ring-closing metathesis reaction, and was shown to possess anti-bacterial properties.

Synthesis and antibacterial studies of binaphthyl-based tripeptoids. Part 1

An efficient synthesis of 29 new binaphthyl-based neutral, and mono- and di-cationic, peptoids is described. Some of these compounds had antibacterial activities with MIC values of 1.9-3.9microg/mL against Staphylococcus aureus. One peptoid had a MIC value of 6microg/mL against a methicillin-resistant strain of S. aureus (MRSA) and a MIC value of 2microg/mL against vancomycin-resistant strains of enterococci (VRE).

Palladium (0) catalysed rearrangements of allylic sulfoximines to allyl sulfinimidic acid esters and optically active N-Cbz protected γ-amino-enones

Abstract N -Tosyl allylic sulfoximines undergo rearrangement to allyl sulfinimidic acid esters in the presence of bidentate chiral ligands while N -Cbz allylic sulfoximines give optically active N -Cbz protected γ-amino-enones.

Palladium catalysed rearrangement of allylic sulfoximines: Synthesis of γ-amino α,β-unsaturated ketones and esters

Abstract The synthesis of γ-amino α,β-unsaturated ketones and esters from the palladium(0) catalysed rearrangement of ( E ) α-sulfonimidoyl β,γ-unsaturated ketones and esters is reported.

The 1,3-Dipolar Cycloaddition Reactions of C, N-Diphenyl Nitrone with Vinyl Sulfoximines

Abstract The reactions of vinyl sulfoximines ( 1a-e ) with C , N -diphenylnitrone ( 2 ) are highly regioselective and give only 4-sulfonimidoyl-isoxazolidine cycloadducts. These reactions proceed with modest π -facial diastereoselectivity with respect to the dipolarophile. The stereochemical outcome of these reactions is consistent with attack on the favoured ground state conformation of the vinyl sulfoximine through an ‘ endo ’ like transition state

PALLADIUM(0) CATALYSED ALLYLATION REACTIONS WITH RACEMIC AND ENANTIOMERICALLY PURE ALLYLIC SULFOXIMINES

Abstract Stabilised carbon and nitrogen nucleophiles can be efficiently allylated in a regioselective manner using allylic sulfoximines and palladium(0) catalysis.

FACILE DETECTION OF ORGANOMETALLIC DERIVATIVES OF PEPTIDES USING ELECTROSPRAY MASS SPECTROMETRY

Abstract Electrospray mass spectrometry (ESMS) is shown to provide a facile and versatile method for the rapid in situ characterisation of adducts between the organometallic electrophile [(η5−C6H7) Fe(CO)3]+ (Fed+) and a range of peptides.

Diastereoselective nucleophilic additions to imines attached to arene tricarbonylchromium moieties

Abstract Some highly diastereoselective 1,2-addition reactions of N-benzylidene-1-methylaniline tricarbonylchromium complex 1a and related imines are reported along with the X-ray structure assignment of the major diastereomeric adduct from the reaction of 1a with methyllithium.

Asymmetric synthesis of chiral amines via nucleophilic addition to ferrocenylalkyl substituted imines

The isomerically pure imine (Ia) formed from 1-ferrocenylethyl amine and benzaldehyde undergoes diastereoselective nucleophilic attack (Me−, D−) on the NC double bond to give ca. 6733 mixtures of diastereomeric amines. The stereochemical outcome can be rationalised in terms of nucleophilic attack on the conformation of Ia in which allylic 1,3-strain is minimised. The opposite stereochemistry is favoured in the reduction by hydride of the related imine (Ib) formed from 1-ferrocenylethyl amine and methylphenyl ketone. These processes provide a useful new method for the asymmetric synthesis of amines from which the chiral ferrocenyl auxiliary may be readily regenerated.