Steven Coulton

1,3-Biarylureas as Selective Non-peptide Antagonists of the Orexin-1 Receptor

This communication reports SARs for the first orexin-1 receptor antagonist series of 1-aryl-3-quinolin-4-yl and 1-aryl-3-naphthyridin-4-yl ureas. One of these compounds, 31 (SB-334867), has excellent selectivity for the orexin-1 receptor, blood-brain barrier permeability and shows in vivo activity following ip dosing.

Intramolecular radical additions to quinolines

The paper is concerned with intramolecular radical additions to quinolines. Radical additions to C-2, C-3 and C-4 of a quinoline have all been shown to proceed under neutral conditions. In each case formation of heteroaromatic products, rather than dihydroquinolines, was observed (implicating the so called oxidative tin hydride pathway).

Penem inhibitors of bacterial signal peptidase

Abstract C(3)-Penem esters and amides having the (5S)-configuration at the bridgehead are inhibitors of Escherichia coli leader peptidase, the best activity being seen with a 6-(1-acetoxyethyl) derivative having the (5S, 6S, 8R)-stereochemistry. These compounds represent the first examples of potent inhibitors of bacterial signal peptidase.

Intramolecular radical additions to pyridines

Intramolecular 6-exolendo-trig and 5-exo-trig cyclisations of aryl radical intermediates to the alpha-, beta- and gamma-carbons of pyridine have been shown to be facile processes at neutral pH. The tether conjoining the radical donor to the pyridine plays an important role in determining the outcome of the reaction. When a Z-alkene is used as a tether, ortho-cyclisation proceeds in good yield. A more complex course is followed when a saturated two carbon tether is employed, leading to products derived from hydrogen atom abstraction, ipso-cyclisation and ortho-cyclisation pathways. All attempts to effect 5-exolendo-trig cyclisations failed. Tributyltin hydride, tris(trimethylsilyl)silane, tris(trimethylsilyl)germane and, in part, samarium(II) iodide can each be employed as mediators of the reaction.

Intramolecular radical cyclisations to pyridines

Abstract Intramolecular radical additions to the α-, β- and γ-carbons of a pyridine have each been shown to be facile processes. When a cis -alkene conjoins an ortho -iodoarene and a pyridine, radical cyclisation induced by homolysis of the carbon to iodine bond favours a 6- exo / endo -trig course. With a two carbon alkane conjoining the ortho -iodoarene and the pyridine, intermolecular hydrogen atom abstraction, 6- exo / endo -trig cyclisation and 5- exo -trig cyclisation modes compete. That the spirocyclic intermediates formed in the 5- exo -trig cyclisation rearrange with migration of the alkyl chain is noteworthy.

The chemistry of pseudomonic acid: Part 9. Reduction, inversion and replacement of the c-13 hydroxyl group

Abstract The preparations of methyl 13-deoxypseudomonate (2c) and methyl (13R)-monate (4f) via mesylate derivatives are described. Introduction of an amino function by nucleophilic displacement at the C-13 position was unsuccessful but the 13-amine (2f) was prepared via the o -methyloxime (7b) and lithium borohydrlde reduction.

CATALYTIC HYDROGENATION OF N-T-BUTOXYCARBONYLINDOLES

Abstract The rhodium catalysed hydrogenation of a range of N-t-butoxycarbonylindoles has been investigated. In most cases the hydrogenation proceeded smoothly at 200 psi in the presence of acetic acid to give the corresonding N-t-butoxycarbonyl-cis-2,3-dihydroindoles in high yield. Some indoles, in particular those bearing an acyl substituent at C2 or C3, were not selectively reduced at the C2–C3 bond.

Benzocarbapenems from ethyl indole-2-acetate

Abstract The benzocarbapenem 1 has been prepared trom ethyl indole-2-acetate by reduction, hydrolysis ol the ester and cyclisation. The methyl substituted carbapenems 12, 13 and 14 have also been prepared. The hydrogenation of ethyl N-BOC-indole-2-proparioate 5 is diastereoselective.

Synthesis of γ-lactam analogues of 1-acetoxy carbapenem derivatives

Abstract The syntheses of γ-lactam analogues of the 1-acetoxy carbapenem esters, from dl-pyroglutamic acid are described. Attempted deprotection to provide the free carboxylic acids resulted in degradation. Whilst the free acid of the 1-hydroxy carbapenem analogue was chemically stable, it lacked antibacterial activity.

Synthesis of (5R)-(Z)-6-(1-methyl-1,2,3-triazol-4-ylmethylene)penem-3-carboxylic acid, a potent broad spectrum β-lactamase inhibitor, from 6-aminopenicillanic acid

(5R)-(Z)-6-(1-Methyl-1,2,3-triazol-4-ylmethylene)penem-3-carboxylic acid 34(BRL 42715) has been prepared from 6-aminopenicillanic acid 4(6-APA) by a short, stereoselective and efficient route via the novel intermediate, p-methoxybenzyl (5R, 6S)-6-bromopenem-3-carboxylate 17.Elaboration of 6-APA 4 to the azetidinone disulfide 10 by established methodology, followed by reductive formylation provided the crystalline C-4 formylthio-azetidinone derivative 29. Cyclization of the oxalimide 28, obtained by ozonolysis of the formylthio derivative 29, to the crystalline 6α-bromopenem ester 17 was effected by way of the phosphite-mediated carbonyl–carbonyl coupling reaction.Sequential treatment of bromopenem 17 with lithium diphenylamide, 1-methyl-1,2,3-triazole-4-carbaldehyde, and acetic anhydride gave a diastereoisomeric mixture of acylated bromohydrins 32; reductive elimination of this mixture afforded a separable mixture of (Z)- and (E)-triazolylmethylene penem esters, 33 and 35 respectively. Lewis acid-mediated deprotection of ester 33 provided (5R)(Z)-6-(1-methyl-1,2,3-triazol-4-ylmethylene)penem-3-carboxylic acid 34(BRL 42715) as a crystalline sodium salt monohydrate.The 6-heterocyclylmethylene penems, represented by BRL 42715, are potent inhibitors of bacterial β-lactamases and their combination with an appropriate penicillin or cephalosporin results in good synergistic activity against a broad range of β-lactamase-producing bacteria.