Maris Turks

Discovery and structure-activity relationship studies of irreversible benzisothiazolinone-based inhibitors against Staphylococcus aureus sortase A transpeptidase.

Gram-positive bacteria, in general, and staphylococci, in particular, are the widespread cause of nosocomial and community-acquired infections. The rapid evolvement of strains resistant to antibiotics currently in use is a serious challenge. Novel antimicrobial compounds have to be developed to fight these resistant bacteria, and sortase A, a bacterial cell wall enzyme, is a promising target for novel therapies. As a transpeptidase that covalently attaches various virulence factors to the cell surface, this enzyme plays a crucial role in the ability of bacteria to invade the hosts tissues and to escape the immune response. In this study we have screened a small molecule library against recombinant Staphylococcus aureus sortase A using an in vitro FRET-based assay. The selected hits were validated by NMR methods in order to exclude false positives and to analyze the reversibility of inhibition. Further structural and functional analysis of the best hit allowed the identification of a novel class of benzisothiazolinone-based compounds as potent and promising sortase inhibitors.

Use of sultines in the asymmetric synthesis of polypropionate antibiotics

At low temperature and in the presence of an acid catalyst, SO2 adds to 1,3-dienes equilibrating with the corresponding 3,6-dihydro-1,2-oxathiin-2-oxides (sultines). These compounds are unstable above -60 °C and equilibrate with the more stable 2,5-dihydrothiophene 1,1-dioxides (sulfolenes). The hetero-Diels-Alder additions of SO2 are suprafacial and follow the Alder endo rule. The sultines derived from 1-oxy-substituted and 1,3-dioxy-disubstituted 1,3-dienes cannot be observed at -100 °C but are believed to be formed faster than the corresponding sulfolenes. In the presence of acid catalysts, the 6-oxy-substituted sultines equilibrate with zwitterionic species that react with electron-rich alkenes such as enoxysilanes and allylsilanes, generating β,γ-unsaturated silyl sulfinates that can be desilylated and desulfinylated to generate polypropionate fragments containing up to three contiguous stereogenic centers and an (E)-alkene unit. Alternatively, the silyl sulfinates can be reacted with electrophiles to generate polyfunctional sulfones (one-pot, four-component synthesis of sulfones), or oxidized into sulfonyl chlorides and reacted with amines, then realizing a one-pot, four-component synthesis of polyfunctional sulfonamides. Using enantiomerically enriched dienes such as 1-[(R)- or 1-(S)-phenylethyloxy]-2-methyl-(E,E)-penta-1,3-dien-3-yl isobutyrate, derived from inexpensive (R)- or (S)-1-phenylethanol, enantiomerically enriched stereotriads are obtained in one-pot operations. The latter are ready for further chain elongation. This has permitted the development of expeditious total asymmetric syntheses of important natural products of biological interest such as the baconipyrones, rifamycin S, and apoptolidin A.

Total Synthesis and Determination of the Absolute Configuration of (−)‐Dolabriferol

Keywords: asymmetric synthesis ; natural products ; polypropionates ; SO2 umpolung ; stereotriads ; Enantioselective Synthesis ; Asymmetric-Synthesis ; Sulfur-Dioxide ; Polypropionate ; Dolabriferol ; Esterification ; Macrolactonization ; Fragments ; Moiety Reference EPFL-ARTICLE-172197doi:10.1002/anie.201003735View record in Web of Science Record created on 2011-12-16, modified on 2017-05-12

Synthesis of (E,Z)-1-Alkoxy-3-acyloxy-2-methylpenta-1,3-dienes via Danishefsky-Type Dienes or O-Acylation of Enones

1-Alkoxy-2-methyl-3-acyloxy-(E,E)-penta-1,3-dienes have been prepared applying among others a modified Danishefskys general method, including chiral, racemic, and achiral derivatives.

Concise Synthesis of Complicated Polypropionates through One‐Pot Dissymmetrical Two‐Directional Chain Elongation

Herein, a major breakthrough in a sulfur dioxide-mediated oxyallylation cascade reaction is reported that allows the preparation of complex long-chain polyketide fragments with more than ten stereogenic centers through a carefully designed desymmetrization process. An allylbissilane is combined, under the appropriate reaction conditions, with two different 1,3-dioxy-1,3-dienes permitting the construction of a 13-membered polypropionate precursor in one pot. Four stereocenters are selectively created during this process. The so-obtained pseudo-C(2)- or -C(S)-symmetric products are desymmetrized through selective deprotection and can be selectively elongated in both directions using aldol chemistry.

Total asymmetric syntheses of β-hydroxy-δ-lactones via Umpolung with sulfur dioxide.

Cyclic stereotriads and stereotetrads of the β-hydroxy-δ-lactone type, e.g. prelactones B and E, common in polyketides and polypropionates, are prepared via SO(2)-induced oxyallylations of enoxysilanes with (1E,3Z)-1-(1-phenylethoxy)penta-1,3-dien-3-yl carboxylates. Using (Z)- or (E)-enoxysilanes both 4,5-cis- or 4,5-trans-δ-lactones are obtained. Depending on the reduction method applied to the obtained aldol intermediates 5,6-trans or 5,6-cis-derivatives are formed. The δ-lactones can be prepared in both their enantiomeric forms depending on the (1R)- or (1S)-configuration of the starting 1-(1-phenylethoxy)penta-1,3-dienes.

Discovery of aziridine-triazole conjugates as selective MMP-2 inhibitors

A series of (aryltriazolyl)methylaziridines was synthesized and evaluated as selective inhibitors of matrix metalloproteinase-2. They constitute a novel class of hydroxamic acid-free matrix metalloproteinase inhibitors. The triazole fragment serves as a linker between the hydrophilic aziridine and the lipophilic part of the molecule. The best inhibition was observed with 1-(aziridin-2-ylmethyl)-4-(4-butylphenyl)-1H-1,2,3-triazole and 1-(aziridin-2-ylmethyl)-4-phenyl-1H-1,2,3-triazole that selecti-vely inhibited metalloproteinase-2 at 73% in 20 μM concentration and at 75% in 10 μM concentration, respectively.

Structural Proof of Tetrazolo[1,5-a]quinazoline Derivatives and Their Application in the Synthesis of 4-Amino-2-(1,2,3-triazol-1-yl)quinazolines

5-Azidotetrazolo[1,5-a]quinazoline (formally known as 2,4-diazidoquinazoline) undergoes regio-selective nucleophilic aromatic substitution with amines at the C-5 atom and provides corresponding 5-amino derivatives of tetrazolo[1,5-a]quinazoline. For the first time, the molecular structure of the latter tricyclic system is unambiguously proved by X-ray structural analysis. Tautomeric equilibrium between tetrazolo[1,5-a]quinazolines and 2-azidoquinazolines permits their use in the copper- catalyzed azide–alkyne 1,3-dipolar cycloaddition reaction. In this way a series of 4-(R-amino)-2-(1,2,3-triazol-1-yl)quinazolines were obtained.

Synthesis and antioxidant activity of new analogs of Quin-C1

New derivatives of 4-oxo-1,2,3,4-tetrahydroquinazoline, analogs of Quin-C1, have been synthesized by the condensation of aroyl- and heteroaroylhydrazides of anthranilic acid with cinnamic, crotonic, and 4-hydroxy-3-methoxybenzoic aldehydes. The antioxidant activity of the obtained compounds has been determined.

Total Synthesis of Polypropionate Natural Products: Application of New Sulfur Dioxide Chemistry

Abstract In the presence of a Lewis or protic acid at low temperature, electron-rich dienes add to sulfur dioxide and carbon nucleophiles generating silyl sulfinates. The latter can be transformed into valuable polyketide precursors.