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Supporting Information Supporting Information Mutasynthesis of Glycopeptide Antibiotics: Variations of Vancomycin’s AB-Ring Amino Acid 3,5-Dihydroxyphenylglycine Stefan Weist, Claudia Kittel, Daniel Bischoff, Bojan Bister, Volker Pfeifer, Graeme J. Nicholson, Wolfgang Wohlleben and Roderich D. Süssmuth* Department of Chemistry/Microbiology and Biotechnology, University of Tübingen, Auf der Morgenstelle,72076 Tübingen e-mail: [email protected] General. NMR measurements were obtained using a Bruker Avance 400 MHz NMR spectrometer. Chemical shifts are given in parts per million (ppm). Positions of hydrogen or carbon atoms at the aromatic ring systems are numbered clockwise starting with the aromatic carbon atom attached to the α-carbon. LC-ESI-MS experiments were recorded on an Agilent 1100 HPLC system coupled to a Bruker Esquire 3000plus ESI-MS-ion trap spectrometer with the individually described parameters. MS spectra were recorded using a Finnigan TSQ-70 triple- stage quadrupole mass spectrometer in EI mode (70 eV). Preparative HPLC was performed using a Waters system (Eschborn, Germany) equipped with a Waters 600 pump, a Waters 481 UV detector and a Waters 740 data module with a Nucleosil C-18 column (250 x 20 mm, 5µm; Grom, Herrenberg, Germany) by isocratic elution employing 5% acetonitrile (0.1% TFA) in water (0.1% TFA) at a flow of 10 mL/min at a run time of 10 min. ESI-FTICR-MS analyses were performed on a Bruker APEX II FTICR-MS spectrometer (Bruker-Franzen, Bremen, Germany). Flash column chromatography was carried out with Merck Kieselgel 60 (230-400 mesh) and TLC was performed using Merck silica gel F254 precoated aluminium sheets (Merck, Darmstadt, Germany). Unless otherwise noted, materials were obtained from commercial sources and used without further purification. Dry solvents were purchased from Fluka (Neu-Ulm, Germany). 3,5- dihydroxymandelic acid (DMA), 3,5-Dihydroxyphenylglycine (DPg) and 3,5- dihydroxyphenylacetic acid (DPA) were purchased from Sigma (Neu-Ulm). 3- hydroxyphenylacetic acid (3-HPA) and 3-methoxyphenylacetic acid (3-MeOPA) were purchased from ABCR (Karlsruhe, Germany). Mutants and bacterial strains. The mutant ∆dpgA was generated following a previously published procedure.[1] The mutant and the wild type strain of Amycolatopsis balhimycina (formerly A. mediterranei) were grown according to reported procedures.[1] Supplementation Experiments. Amino acids and other biosynthesis precursors (mandelic and phenylacetic acids) were supplemented as previously reported1 in 10 mL cultures with final concentrations of 1 mg/mL. Feeding experiments were repeated three times. All substances used for supplementation were tested for antimicrobial activity against Bacillus subtilis ATCC6633 before supplementation and did not show any antibiotic activity. For the inhibition assay, 20 µL of the culture filtrate were brought on a filter plate which was placed on a culture of B. subtilis and incubated for 24 h at 37°C. S1 Supporting Information JA0499389 Weist et al. LCMS Analyses. LC-ESI-MS for the characterization of glycopeptide antibiotics in supplemented culture filtrates was performed after pre-purification with solid phase extraction using Varian BondElut cartridges (Varian, Darmstadt, Germany; size: 100 mg) eluting with water and water/MeOH solutions (1 mL each of 0%, 50% and 100% MeOH), and the fraction containing 50% MeOH was used for the LC-MS-experiment with an injection volume of 20 µL. LC was performed using a 125x4 mm LiChroCart Purospher RP-C18 column (VWR, Darmstadt, Germany; particle size: 5µm) with a flow of 1.5 mL/min using a gradient from 10 to 70% MeCN (0.1% TFA) in water (0.1% TFA) in 5 min. Synthesis of Phenylglycines. General Procedure starting from aldehydes. A solution of the benzaldehyde derivative (10 mmol) in NH3/MeOH (7N, 50 mL) was cooled to 0°C. TMSCN (1.11 mL, 15 mmol, 1.5 eq) was added dropwise with stirring. After 10 min, the temperature was raised to 45°C and the mixture was stirred for 5 h. The solvent was removed in vacuo and the residue was purified by flash chromatography using chloroform/methanol (9/1) as the eluant to give the aminonitrile. Aminonitriles were hydrolyzed using 6N HCl (50 mL for a 10 mmol scale) by heating to reflux for 3-5 h until TLC (solvent: EtOAc/n-BuOH/H2O/HAc = 2/1/1/1) indicated completion of the reaction. Charcoal (100 mg) was added, the mixture refluxed for another 10 min and filtered. The solution was concentrated to 10 mL, and the amino acid started to precipitate. After Büchner funnel filtration, the amino acids were dried under vacuum. 3-Methoxyphenyl-α-aminoacetonitrile (1) yield: 82% 1HNMR (DMSO) δ = 7.30 (dd, J=7.8/8.1Hz, 1H, H-5), 7.08-7.04 (m, 2H, H-2, H-4), 6.91 (dd, J=8.3/2.3 Hz, 1H, H-6), 4.97 (s, 1H, H-α), 3.76 (s, 3H, OCH3). 13CNMR δ = 159.83, 140.34, 130.12, 122.55, 119.13, 114.04, 112.71, 55.54, 46.62. LRMS (rel. Intens.) m/z: 162 (M+, 100%), 146 (18), 136 (38), 131 (84), 119 (14), 109 (24), 94 (12), 77 (16), 65 (10), 39 (7). 3-Methoxyphenylglycine hydrochloride (3-MeOPg) (2) yield: 76% from (1) 1 + HNMR (DMSO) δ = 8.76 (br s, 3H, NH3 ), 7.37 (t, J=8.0Hz, 1H, H-5), 7.11 (s, 1H, H-2), 7.05 (d, J=8.1 Hz, 1H, H-6), 6.99 (dd, J=8.1/2.0Hz, 1H, H-4), 5.03 (d, J=4.6Hz, 1H, H-α), 3.77 (s, 3H, OCH3). 13CNMR δ = 169.51, 159.65, 137.13, 129.99, 120.47, 115.28, 113.87, 57.27, 55.59. HR-FTICR-MS: [M+H]+ m/z: calcd. 182.0811, found 182.0812. S2 Supporting Information JA0499389 Weist et al. 3,5-Dimethoxyphenyl-α-aminoacetonitrile (3) yield: 65% 1HNMR (DMSO) δ = 6.68 (d, J=2.2 Hz, 2H, H-2, H-6). 6.48 (t, J=2.0Hz, 1H, H-4), 4.94 (s, 1H, H-α), 3.76 (s, 6H, OCH3). 13CNMR δ = 160.97, 141.11, 122.42, 105.14, 100.13, 55.65, 46.70. 3,5-Dimethoxyphenylglycine hydrochloride (DMeOPg) (4) yield: 60% 1 H-NMR (D2O) δ = 6.67 (d, J=2.2Hz, 2H, H-2, H-6), 6.62 (t, J=2.2Hz, 1H, H-4), 5.09 (s, 1H, H-α), 3.79 (s, 6H, OCH3). 13CNMR δ = 168.72, 159.29, 131.99, 104.79, 100.17, 102.96, 54.69, 53.97. HR-FTICR-MS: [M+H]+ m/z: calcd. 212.0916, found 212.0904. (3-Hydroxy-5-methoxy)phenyl-α-aminoacetonitrile (5) yield: 60% 1HNMR (DMSO) δ = 9.61 (br s, 1H, OH), 6.54 (t, J=2.1Hz, 2H, H-2, H-6), 6.29 (dd, J=2.2/2.3Hz, 1H, H-4), 4.89 (s, 1H, H-α), 3.71 (s, 3H, OCH3), 2.73 (br s, 2H, NH2). 13CNMR δ = 160.91, 158.99, 140.85, 122.53, 106.56, 103.62, 101.08, 56.38, 55.39. LRMS (rel. Intens.) m/z: 178 (M+, 8), 152 ([M-CN]+, 7), 84 (92), 66 (100%), 45 (40). (3-Hydroxy-5-methoxyphenyl)glycine hydrochloride (HMeOPg) (6) yield: 65% 1 HNMR (D2O) δ =6.51 (s, 1H, H-6), 6.47 (s, 1H, H-4), 6.45 (s, 1H, H-2), 4.80 (s, 1H, H-α), 3.62 (s, 3H, OCH3). 13CNMR δ = 168.78, 158.80, 155.52, 132.15, 105.58, 103.65, 100.62, 54.45, 53.37. HR-FTICR-MS: [M+H]+ m/z: calcd. 198.0761, found 198.0759. S3 Supporting Information JA0499389 Weist et al. 3-Hydroxyphenylglycine hydrochloride (3-HPg) (7) This compound was obtained from 3-Methoxyphenylglycine via demethylation using 57% aqueous HI according to literature[2] and purified using HPLC. yield: 50% 1 HNMR (D2O) δ = 7.27 (t, J=8.1Hz, 1H, H-5), 6.87 (m, 3H, H-2, H-4, H-6), 4.87 (s, 1H, H-α). 13CNMR δ = 170.90, 155.59, 133.31, 130.36, 119.23, 116.30, 114.13, 56.32. HR-FTICR-MS: [M+H]+ (m/z): calcd. 168.0655, found 168.0653. Synthesis of phenylacetic acids, General procedure To a solution of the benzaldehyde or benzoic acid (10 mmol) in dry THF (20 mL) under argon was added BH3·THF (2 eq; 20 mL of a 1N solution in THF) at 0°C. The mixture was stirred for 12 h before it was quenched by portionwise addition of water (50 mL). The layers were separated and the water phase was extracted with ethyl ether (2 x 20 mL). The solvent was removed to give the crude benzyl alcohol which was used for the next step without further purification. To a solution of the benzyl alcohol (5 mmol) in dry THF (10 mL), phosphorus tribromide (1 eq) was added dropwise under argon. The mixture was stirred for 2 hours before being quenched with water (5 mL). After separation of both layers, the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined extracts were concentrated and purified by flash chromatography (hexanes:ethyl acetate 5:1) to yield the benzyl bromides. Benzyl bromides (5 mmol) were treated with dry sodium cyanide (1.5 eq) in dry N- methylpyrrolidone (5 mL). The mixture was stirred for 5 h before being diluted with brine. After extraction with ethyl ether and evaporation of the solvent, the crude nitriles (2 mmol) were hydrolyzed in conc. HCl (10 mL) at 70°C for 5 h. After dilution with water (20 mL) followed by extraction with ethyl ether (2 x 10 mL), the crude phenylacetic acids were purified by flash chromatography eluting with CHCl3:MeOH 90:5.
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