Robert M. Adlington

The reaction cycle of isopenicillin N synthase observed by X-ray diffraction

Isopenicillin N synthase (IPNS), a non-haem iron-dependent oxidase, catalyses the biosynthesis of isopenicillin N (IPN), the precursor of all penicillins and cephalosporins. The key steps in this reaction are the two iron-dioxygen-mediated ring closures of the tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV). It has been proposed that the four-membered β-lactam ring forms initially, associated with a highly oxidized iron(IV)-oxo (ferryl) moiety, which subsequently mediates closure of the five-membered thiazolidine ring. Here we describe observation of the IPNS reaction in crystals by X-ray crystallography. IPNS·Fe2+·substrate crystals were grown anaerobically, exposed to high pressures of oxygen to promote reaction and frozen, and their structures were elucidated by X-ray diffraction. Using the natural substrate ACV, this resulted in the IPNS·Fe2+·IPN product complex. With the substrate analogue, δ-(L-α-aminoadipoyl)-L-cysteinyl-L-S-methylcysteine (ACmC) in the crystal, the reaction cycle was interrupted at the monocyclic stage. These mono- and bicyclic structures support our hypothesis of a two-stage reaction sequence leading to penicillin. Furthermore, the formation of a monocyclic sulphoxide product from ACmC is most simply explained by the interception of a high-valency iron-oxo species.

Trifluoromethyl alcohol and ketone inhibitors of metallo-β-lactamases

Abstract α-Amido trifluoromethyl alcohols and ketones were synthesised via two independent routes using Rupperts Reagent (TMS-CF3) and shown to be the first reported synthetic inhibitors of metallo-β-lactamases.

Stereospecific synthesis of dealanylalahopcin

Abstract The first synthesis of the novel α-amino acid dealanylalahopcin starting from (L) -aspartic acid is described.

Design and synthesis of novel monocyclic β-lactam inhibitors of prostate specific antigen

Abstract A novel series of monocyclic β-lactam analogues was designed using a homology derived model of prostate specific antigen (PSA) and by application of a multiple copy simultaneous search technique. Syntheses were conducted by assembly of the β-lactam core via a Staudinger reaction with elaboration at the 1, 3 and 4 positions to probe active site binding. Inhibition against PSA was evaluated.

Enantiospecific, biosynthetically inspired formal total synthesis of (+)-liphagal.

A biosynthetically inspired synthesis of (+)-liphagal has been achieved from (+)-sclareolide in 13 steps (9% overall yield). The key step is a biomimetic ring expansion of a highly stabilized benzylic carbocation, which generates the seven-membered ring and the benzofuran of the natural product in a single cascade reaction.

Carbocyclic ring expansion reactiuon VIA radical chain processes

Abstract A free radical mediated ring expansion of cis - and trans - α-alkylated-β-stannylcyclohexanones to provide efficient routes to cis - and trans -cyclononenones and cyclodecenones is described. The cis-/trans - relationship in the precursor was found to have significant bearing on the alkene geometry of the ring expanded product.

A Short Biomimetic Synthesis of the Meroterpenoids Guajadial and Psidial A

The biosynthesis of the meroterpenoid guajadial was previously hypothesized to occur via a hetero-Diels-Alder reaction between caryophyllene and an o-quinone methide. This hypothesis has been verified via the biomimetic synthesis of guajadial and psidial A in an aqueous three-component coupling reaction, between caryophyllene, benzaldehyde, and diformylphloroglucinol.

Biomimetic Synthesis of Polycyclic Polyprenylated Acylphloroglucinol Natural Products Isolated from Hypericum papuanum

Biomimetic syntheses of three polycylic polyprenylated acylphloroglucinol natural products isolated from Hypericum papuanum, ialibinone A, ialibinone B, and hyperguinone B, have been accomplished by selective oxidative cyclizations of the proposed biosynthetic precursor 5, which was synthesized from phloroglucinol in three steps.

Isolation of dihydroclavaminic acid, an intermediate in the biosynthesis of clavulanic acid

Abstract A primary isotope effect was utilised in an in vitro study to allow the isolation and characterisation of an intermediate between proclavaminic acid and clavaminic acid, in clavulanic acid biosynthesis. 1

Biomimetic studies on polyenes

The crispatenes and SNF4435 C&D are complex polypropionate derived natural products. The core structures of these compounds along with a complex unnatural structure can be easily prepared from a common polyene precursor simply by variation of the reaction conditions. The reaction pathways provide insight into the biosynthesis of these complex natural products.