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.

A study towards the natural product tetrodecamycin is reported. A modified Schlosser–Wittig reaction was utilized to prepare the precursor for the subsequent intramolecular Diels–Alder reaction, which delivered the trans-decalin ring of the natural product. The tetronic­ acid moiety of the molecule was prepared by a Dieckmann cyclization­. The cyclization of the tetronic acid to the trans-decalin double­ bond to form a seven-membered ring was examined.

Abstract 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. Substrate binding ablates the interaction between Gln330 and the metal, triggering rearrangement of seven C‐terminal residues, which move to take up a conformation that extends the final α‐helix and encloses ACV in the active site. Mutagenesis studies are reported, which probe the role of the C‐terminal and other aspects of the substrate binding pocket in IPNS. The hydrophobic nature of amino acid side‐chains around the ACV binding pocket is important in catalysis. Deletion of seven C‐terminal residues exposes the active site and leads to formation of a new type of thiol oxidation product. The isolated product is shown by LC‐MS and NMR analyses to be the ene‐thiol tautomer of a dithioester, made up from two molecules of ACV linked between the thiol sulfur of one tripeptide and the oxidised cysteinyl β‐carbon of the other. A mechanism for its formation is proposed, supported by an X‐ray crystal structure, which shows the substrate ACV bound at the active site, its cysteinyl β‐carbon exposed to attack by a second molecule of substrate, adjacent. Formation of this product constitutes a new mode of reaction for IPNS and non‐heme iron oxidases in general.

ADVERTISEMENT RETURN TO ISSUEPREVRetractionRetraction of "Biomimetic Total Synthesis of Himbacine"Kirill Tchabanenko, Robert M. Adlington, Andrew R. Cowley, and Jack E. Baldwin*Cite this: Org. Lett. 2015, 17, 12, 3190Publication Date (Web):June 19, 2015Publication History Received1 June 2015Published online19 June 2015Published inissue 19 June 2015https://pubs.acs.org/doi/10.1021/acs.orglett.5b01596https://doi.org/10.1021/acs.orglett.5b01596retractionACS PublicationsCopyright © 2015 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views2496Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (112 KB) Get e-Alertsclose Get e-Alerts

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. Epimeric δ‐( l ‐α‐aminoadipoyl)‐ l ‐cysteinyl‐ O ‐methyl‐ d ‐ allo ‐threonine (ACm a T) is converted to a bioactive penam product. ACmT and ACm a T differ from each other only in the stereochemistry at the β‐carbon atom of their third residue. These substrates both contain a methyl ether in place of the isopropyl group of ACV. We report an X‐ray crystal structure for the anaerobic IPNS:Fe(II):ACmT complex. This structure reveals an additional water molecule bound to the active site metal, held by hydrogen‐bonding to the ether oxygen atom of the substrate analogue.

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. To investigate this and solution‐phase results with other tripeptides δ‐( L ‐α‐aminoadipoyl)‐ L ‐homocysteinyl‐ D ‐Xaa, we have crystallised AhCV and δ‐( L ‐α‐aminoadipoyl)‐ L ‐homocysteinyl‐ D ‐ S ‐methylcysteine (AhCmC) with IPNS and solved crystal structures for the resulting complexes. The IPNS:Fe II :AhCV complex shows diffuse electron density for several regions of the substrate, revealing considerable conformational freedom within the active site. The substrate is more clearly resolved in the IPNS:Fe II :AhCmC complex, by virtue of thioether coordination to iron. AhCmC occupies two distinct conformations, both distorted relative to the natural substrate ACV, in order to accommodate the extra methylene group in the second residue. Attempts to turn these substrates over within crystalline IPNS using hyperbaric oxygenation give rise to product mixtures.

The combined effects of an asymmetric (square or V-shaped) notch and uniaxial strain are studied in a zigzag graphene nanoribbon (ZGNR) device using a generalized tight-binding model. The spin-polarization and conductance-gap properties, calculated within the Landauer–B¨uttiker formalism, were found to be tunable for uniaxial strain along the ribbon-length and ribbon-width for an ideal ZGNR and square (V-shaped) notched ZGNR systems. Uniaxial strain along the ribbon-width for strains 10% initiated significant notch-dependent reductions to the conduction-gap. For the V-shaped notch, such strains also induced spin-dependent changes that result, at 20% strain, in a semi-conductive state and metallic state for each respective spin-type, thus demonstrating possible quantum mechanisms for spin-filtration.

Isopenicillin N synthase (IPNS) converts its linear tripeptide substrate δ-l-α-aminoadipoyl-l-cysteinyl-d-valine (ACV) to bicyclic isopenicillin N (IPN), the key step in penicillin biosynthesis. Solution-phase incubation experiments have shown that IPNS will accept and oxidise a diverse array of substrate analogues, including tripeptides that incorporate l-homocysteine as their second residue, and tripeptides with truncated side-chains at the third amino acid such as δ-l-α-aminoadipoyl-l-cysteinyl-d-α-aminobutyrate (ACAb), δ-l-α-aminoadipoyl-l-cysteinyl-d-alanine (ACA) and δ-l-α-aminoadipoyl-l-cysteinyl-glycine (ACG). However IPNS does not react with dipeptide substrates. To probe this selectivity we have crystallised the enzyme with the dipeptide δ-l-α-aminoadipoyl-l-homocysteine (AhC) and solved a crystal structure for the IPNS:Fe(II):AhC complex to 1.40 Å resolution. This structure reveals an unexpected mode of peptide binding at the IPNS active site, in which the homocysteinyl thiolate does not bind to iron. Instead the primary mode of binding sees the homocysteinyl carboxylate coordinated to the metal, while its side-chain is oriented into the region of the active site normally occupied by the benzyl group of protein residue Phe211.

Three new sterically demanding ligands based on the bispyrazolylacetic acid motif have been prepared and complexes with Fe(II), Fe(III), Ni(II) and Mn(II) have been synthesised and characterised. Single crystal X-ray structures are included for two of the ligands in the protonated form and ten other complexes. Additionally, a new general route to amide derivatives has been established, a range of amide derivatives synthesised and their coordination chemistry investigated. Only one metal complex was synthesised from the amide ligands, and was bound via the hydroxylamine groups in preference to the pyrazole and carboxylate donor set.

Isopenicillin N synthase (IPNS) catalyses cyclization of δ-(l-α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) to isopenicillin N (IPN), the central step in penicillin biosynthesis. Previous studies have shown that IPNS turns over a wide range of substrate analogues in which the valine residue of its natural substrate is replaced with other amino acids. IPNS accepts and oxidizes numerous substrates that bear hydrocarbon sidechains in this position, however the enzyme is less tolerant of analogues presenting polar functionality in place of the valinyl isopropyl group. We report a new ACV analogue δ-(l-α-aminoadipoyl)-l-cysteinyl-d-methionine (ACM), which incorporates a thioether in place of the valinyl sidechain. ACM has been synthesized using solution phase methods and crystallized with IPNS. A crystal structure has been elucidated for the IPNS:Fe(II):ACM complex at 1.40Å resolution. This structure reveals that ACM binds in the IPNS active site such that the sulfur atom of the methionine thioether binds to iron in the oxygen binding site at a distance of 2.57Å. The sulfur of the cysteinyl thiolate sits 2.36Å from the metal.

Isopenicillin N synthase (IPNS) catalyses the synthesis of isopenicillin N (IPN), the biosynthetic precursor to penicillin and cephalosporin antibiotics. IPNS is a non‐heme iron(II) oxidase that mediates the oxidative cyclisation of the tripeptide δ‐L‐α‐aminoadipoyl‐L‐cysteinyl‐D‐valine (ACV) to IPN with a concomitant reduction of molecular oxygen to water. Solution‐phase incubation experiments have shown that, although IPNS can turn over analogues with a diverse range of hydrocarbon side chains in the third (valinyl) position of its substrate, the enzyme is much less tolerant of polar residues in this position. Thus, although IPNS converts δ‐L‐α‐aminoadipoyl‐L‐cysteinyl‐D‐isoleucine (ACI) and AC‐D‐allo‐isoleucine (ACaI) to penam products, the isosteric sulfur‐containing peptides AC‐D‐thiaisoleucine (ACtI) and AC‐D‐thia‐allo‐isoleucine (ACtaI) are not turned over. To determine why these peptides are not substrates, we crystallized ACtaI with IPNS. We report the synthesis of ACtaI and the crystal structure of the IPNS:FeII:ACtaI complex to 1.79 Å resolution. This structure reveals direct ligation of the thioether side chain to iron: the sulfide sulfur sits 2.66 Å from the metal, squarely in the oxygen binding site. This result articulates a structural basis for the failure of IPNS to turn over these substrates.

Three new palladium(II) complexes incorporating the bispyrazolylmethane core have been synthesised and fully characterised in the solution and solid state. Single crystal X-ray studies revealed almost complete blocking of the upper face of the palladium ion by the substituents at the 3- and 5-positions of the pyrazole rings.

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.

Simplified ethyl-substituted labdane diterpenoids 14 and 19 have been synthesised from (+)-sclareolide (18). Biomimetic rearrangements of these compounds, involving stereospecific 1,2-alkyl and hydride shifts, have been carried out by treatment with a variety of Lewis and protic acids. Halimane compounds, such as 34 and simple dehydration products such as 3, 32 and 33 have been formed either selectively or as mixtures depending on the reaction conditions. However, further rearrangement to clerodane products such as 1 and 2 was not observed, indicating a high degree of enzymatic control for the in vivo formation of these natural products.

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.

Key feature of the title synthesis is a ring expansion of a fused 6,6-ring system via stereoselective epoxide ring opening and combined recyclization—furan ring closure to build the tetracyclic framework (VI).