Novobiocin-related compounds: synthesis of 3-benzoylamino-2-oxo-2H-1-benzopyran-7-yl d-glycopyranosides by the trichloroacetimidate methodology (original) (raw)
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The synthesis of 7-carbonyl homologues of 1-deoxynojirimycin
Tetrahedron Letters, 1994
Inhibition of glycosidase~ may be useful for treatment of several diseases e.g. di&etes,t cancer,2 and some viral infaXion~.~ Important examples are the antiviral (including anti-HIV) and anWahctic actMi& found for the glucosiaase inhibitors l-deoxynojirimycin~ 1 and castand 2 (Figme 1). The pota~ti chemothcmpeutic applications of these natural polyhydroxylated alkaloids and their ana&ues have prompkd considerable synthetic interest towards squch& modification, such as the introduction of lipophik (e.g. fluoro.7 alkyl,' and acylq, amino,l"*ll and gluco~yl~~ groups at specific positions of compound 1. complete removal of the C-6 hydroxymethyl group of 1 has remarkably little effect on enzyme-substrate ~II~CXW&MW~~ This report deals with the conversion of 1-amino-ldeoxy-D-glucitol3 to the trihydroxypiperidh~ 4-7. These compounds rep-t a new class of ldeoxynojirimycin analogues where the C-6 hydroxyl has been replaced with a ketone, acid or amide carbonyl function. The synthesis started with the preparation of the 3,4;5,6di-Oisopropylidene w salt 9. The course of the reaction depicted in Scheme 1 was EWWAXI by t.1.c analysis of the N-acylvinyl [RNHCH=C(CO#t~ and N-Boc derivatives. l4 Under the acidic conditions, the iniIialIy formed diacetonide 8 rearranged to the regioisomer 9 which crystallized from the Won medium. Afta 24 heurs, pure compound 9 was collected by filtration (65% yield), whereas in the filtrate only c&&o&k 9 and triacdonide 1owucdebted.
Carbohydrate Research, 2000
Synthesis of the conveniently protected epimer at C-3% of the miharamycin sugar moiety was accomplished starting from the corresponding 3,3%-spiroepoxide. Reaction of the epoxide with lithium cyanide, followed by hydrolysis and spontaneous cyclization, afforded the intermediate deoxylactone methyl 4,6-O-benzylidene-3-C-(carboxymethyl)-a-Dglucopyranoside-3%,2-lactone (8). Stereoselective hydroxylation with MoO 5 ·py·HMPA, reduction with lithium aluminum hydride and cyclization with diethyl azodicarboxylate -triphenylphosphine gave the target molecule methyl 2,3¦-anhydro-4,6-O-benzylidene-3-C-[(R)-1,2-dihydroxyethyl]-a-D-glucopyranoside (5). Direct reduction of 8 gave other analogs having no C-3% hydroxyl group together with having a C-3¦ hydroxyl group (hemiacetal). In addition, C-3% epimers were also synthesized through C-3%, C-3¦ dihydroxy analogs. Wittig reaction of an appropriate ketosugar with [(ethoxycarbonyl)methylene]triphenylphosphorane leading to a 7:3 Z/E mixture, followed by hydroxylation with osmium tetroxide, reduction and cyclization afforded the target molecule 5 and the miharamycin sugar moiety methyl 2,3¦-anhydro-4,6-O-benzylidene-3-C-[(S)-1,2-dihydroxyethyl]-a-D-glucopyranoside. Examination of X-ray data for 5 and its NMR spectroscopy data allowed us to explain a contradiction reported in the literature.
The Journal of Organic Chemistry, 1996
A five-step synthesis from 3 leading to a partially protected amipurimycin sugar moiety 14 in an overall yield of 47% is described and includes deoxygenation at C-4 and regio-and stereoselective construction of the branched chain. Deoxygenation at C-4 of 3 was possible by three different methods. Radical reduction with tri-n-butyltin hydride of the appropriate phenoxythiocarbonyl derivative afforded the desired deoxysugar 5 in 47% overall yield together with the secondary products 6 and 7 due to depivaloylation at C-2 and elimination of methanol. The most adequate deoxygenation procedure used the system Ph 3 P/I 2 /imidazole which led to the preparation of 5 in one step in 61% yield. When the system Ph 3 PBr 2 /Ph 3 P was tried, only 8 was formed due to elimination of methanol. The synthesis of 5 was then accomplished by reaction of 8 with methanol in the presence of triphenylphosphine hydrobromide in 37% overall yield. Branched-chain construction was accomplished by Wittig reaction of 5 with [(ethoxycarbonyl)methylene]triphenylphosphorane, followed by osmilation and reduction with lithium aluminum hydride. Isopropylidenation of 14 afforded 16 with a free hydroxy group at C-6 for chain elongation and further synthesis of amipurimycin.
Archiv Der Pharmazie, 2008
In an attempt to find a new class of antibacterial agents, we have synthesized thirty new coumarin (2H-benzopyran-2-one) analogues. These derivatives include substituted azetidin-2-ones (β-lactam) 3a–f, pyrrolidin-2-ones 4a–f, 2H-1,3,4-oxadiazoles 5a–f, and thiazolidin-4-ones 6a–f attached to 4-phenyl-2H-benzopyran-2-one through an oxyacetamido or an oxymethyl bridge. The target compounds were synthesized starting from 2-oxo-4-phenyl-2H-benzo[b]pyran-7-yl-oxyacetic acid hydrazides 2a–f. The new compounds were evaluated as DNA gyrase-B inhibitors through molecular modeling and docking techniques using the Molsoft ICM 3.4-8C program. The synthesized compounds were also screened for antibacterial activity against four different species of Gram-positive and Gram-negative bacteria; as well as screening against C. albicans for antifungal activity. The molecular modeling data were in accordance with the antimicrobial screening results.
ChemBioChem, 2008
Mithramycin is an antitumor drug produced by Streptomyces argillaceus. It consists of a tricyclic aglycone and five deoxyhexoses that form a disaccharide and a trisaccharide chain, which are important for target interaction and therefore for the antitumor activity. Using a combinatorial biosynthesis approach, we have generated nine mithramycin derivatives, seven of which are new compounds, with alterations in the glycosylation pattern. The wild-type S. argillaceus strain and the mutant S. argillaceus M7U1, which has altered D-oliose biosynthesis, were used as hosts to express various "sugar plasmids", each one directing the biosynthesis of a different deoxyhexose. The newly formed compounds were purified and characterized by MS and NMR. Compared to mithramycin, they contained different sugar substitutions in the second (D-olivose, D-mycarose, or D-boivinose instead of D-oliose) and third (D-digitoxose instead of D-mycarose) sugar units of the trisaccharide as well as in the first (D-amicetose instead of D-olivose) sugar unit of the disaccharide. All compounds showed antitumor activity against different tumor cell lines. Structure-activity relationships are discussed on the basis of the number and type of deoxyhexoses present in these mithramycin derivatives.
An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors
European Journal of Medicinal Chemistry
ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesised an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Grampositive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Grampositive strains in the 1-50 µM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 µM, 1.56 µM, 0.78 µM and 0.72 µM, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 µM on both strains, 2 and MIC value of 32 µM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action. IV subunit A; ParE, topoisomerase IV subunit B; PC, principal component; RA, residual activity; TBTU, N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uroniumtetrafluoroborate; THF, tetrahydrofuran; topo IV, topoisomerase IV; VISA, vancomycin-intermediate Staphylococcus aureus. chlorine atoms are slightly smaller than the bromine atoms and thus fit better into the adenine binding pocket not only of E. coli DNA gyrase, but also into the slightly smaller binding pockets of S. aureus DNA gyrase and topoisomerase IV [17].