Biomimetic synthetic studies on meroterpenoids from the marine sponge Aka coralliphaga: Divergent total syntheses of siphonodictyal B, liphagal and corallidictyals A-D.

The marine sponge Aka coralliphaga is a rich source of biologically active and structurally interesting meroterpenoids. Inspired by these natural products, we have used biosynthetic speculation to devise biomimetic syntheses of siphonodictyal B, liphagal and corallidictyals A-D from sclareolide. This work resulted in the development of new cascade reactions in the synthesis of liphagal, the reassignment of the structure of siphonodictyal B, and the realisation that corallidictyals A and B are possibly isolation artefacts.

Terminally Truncated Isopenicillin N Synthase Generates a Dithioester Product: Evidence for a Thioaldehyde Intermediate during Catalysis and a New Mode of Reaction for Non-Heme Iron Oxidases.

Isopenicillin N synthase (IPNS) catalyses the four-electron oxidation of a tripeptide, l-δ-(α-aminoadipoyl)-l-cysteinyl-d-valine (ACV), to give isopenicillin N (IPN), the first-formed β-lactam in penicillin and cephalosporin biosynthesis. IPNS catalysis is dependent upon an iron(II) cofactor and oxygen as a co-substrate. In the absence of substrate, the carbonyl oxygen of the side-chain amide of the penultimate residue, Gln330, co-ordinates to the active-site metal iron.

Synthesis of rac-Lindenene via a thermally induced cyclopropanation reaction.

The first synthesis of the sesquiterpene Lindenene is described. A novel non-catalysed intramolecular cyclopropanation reaction between a diazoketone and an unactivated alkene was utilised to construct the relatively labile ketone precursor with complete stereocontrol. This ketone was transformed in three steps into Lindenene.

The crystal structure of an isopenicillin N synthase complex with an ethereal substrate analogue reveals water in the oxygen binding site.

Isopenicillin N synthase (IPNS) is a non-heme iron oxidase central to the biosynthesis of β-lactam antibiotics. IPNS converts the tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N while reducing molecular oxygen to water. The substrate analogue δ-(L-α-aminoadipoyl)-L-cysteinyl-O-methyl-D-threonine (ACmT) is not turned over by IPNS.

The interaction of isopenicillin N synthase with homologated substrate analogues δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-Xaa characterised by protein crystallography.

Isopenicillin N synthase (IPNS) converts the linear tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) into bicyclic isopenicillin N (IPN) in the central step in the biosynthesis of penicillin and cephalosporin antibiotics. Solution-phase incubation experiments have shown that IPNS turns over analogues with a diverse range of side chains in the third (valinyl) position of the substrate, but copes less well with changes in the second (cysteinyl) residue. IPNS thus converts the homologated tripeptides δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-valine (AhCV) and δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-allylglycine (AhCaG) into monocyclic hydroxy-lactam products; this suggests that the additional methylene unit in these substrates induces conformational changes that preclude second ring closure after initial lactam formation.