Synthesis of the heterocyclic core of the D-series GE2270

A straightforward enantiomerically pure synthesis of the heterocyclic core of the D-series GE2270 is reported. The synthetic strategy combines the Hantzsch thiazole’s building condensation with a cross-coupling reaction including direct C–H hetarylation to build and connect step-by-step thiazolyl moieties to the 5-bromopicolinate as readily available starting material.

Reactions were performed using oven dried glassware under inert atmosphere of dry argon or nitrogen and monitored by thin-layer chromatography with silica gel 60 F254 pre-coated aluminium plates (0.25 mm). Visualization was performed under UV light and phosphomolybdic acid or KMnO 4 oxidation. Chromatographic purification of compounds was achieved with 60 silica gel (40-63 m).

Solvents and reagents:
Toluene and CH 2 Cl 2 were dried by refluxing over CaH 2 and then distilled.
Unless otherwise noted, all reagent-grade chemicals and solvents were used as supplied (analytical or HPLC grade) without prior purification.
Melting points were measured on a WME Kofler hot-stage with a precision of +/− 2 °C and are uncorrected.
Infrared spectra (IR) were recorded on a PerkinElmer Spectrum 100 Series FT-IR spectrometer.
Liquids and solids were applied on the Single Reflection Attenuated Total Reflectance (ATR) Accessories. Data are reported in cm −1 .
Optical rotations were determined with a Perkin-Elmer 341 polarimeter with a water-jacketed 10 cm cell. Specific rotations are reported in 10 −1 deg cm 2 g −1 and concentrations in g per 100 mL. were charged in a Schlenk flask. It was then evacuated and backfilled three times with N 2 and then anhydrous degassed dioxane (2.0 mL) was added and the reaction mixture was stirred at 110 °C in a preheated oil bath for 1 hour. Then the mixture was cooled to room temperature and chloropyridine (5) (170 mg, 0.50 mmol), freshly dried K 3 PO 4 (531 mg, 2.50 mmol), degassed dioxane (0.5 mL) and degassed water (0.5 mL) were added and the mixture was stirred at 110 °C for further 14 hours. Then the mixture was filtered through a Celite® pad and washed with EtOAc. Water was added and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: petroleum ether/EtOAc, 1:1 to 3:7) affording 10 (213 mg, 0.49 mmol, 99%) as a colorless solid.  Schlenk flask. It was then evacuated and backfilled three times with N 2 and then anhydrous degassed dioxane (0.45 mL) was added and the reaction mixture was stirred at 110 °C in a preheated oil bath for 1 hour. Then the mixture was cooled to room temperature and chloropyridine (7)   To a stirred solution of azide 12 (2.4 g, 10.2 mmol) in a mixture of dioxane/H 2 O (1:3, 80 mL) at 0 °C was slowly added tin(II) chloride dihydrate (11.5 g, 50.1 mmol). Then the mixture was allowed to warm to room temperature and stirred for 5 hours. The mixture was then carefully treated at 0 °C with a saturated aqueous NaHCO 3 solution to reach pH 8-9 after which benzyl chloroformate (2.2 mL, 15.0 mmol) was added. The mixture was stirred at room temperature for further 18 hours.
Then the mixture was carefully hydrolyzed with HCl (3N), filtered through a Celite® pad. The filtrate was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: petroleum ether/EtOAc, 9:1 to 7:3) affording 13 (3.9 g, 11.6 mmol, 96%) as a white solid.
To a stirred solution of amino alcohol 13 (1.90 g, 5.53 mmol) in anhydrous DMF (11 mL) were added imidazole (4.13 g, 16.59 mmol) and TBDMSCl (1.67 g, 11.08 mmol) and the mixture was stirred for 16 hours. Then the mixture was concentrated in vacuo. Water was added and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water, twice with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: petroleum ether/EtOAc, 95:5 to 85:15) affording 14 (2.50 g, 5.46 mmol, 99%) as a colorless oil.
[α] D 20 54.1 (c 1.05, CHCl 3 ). To a stirred solution of ester 14 (2.50 g, 5.46 mmol) in a mixture of DME/H 2 O (1:1, 30 mL) at 0 °C was added lithium hydroxide monohydrate (0.32 g, 7.64 mmol). Then the mixture was allowed to warm to room temperature and stirred for 72 hours. The mixture was then carefully treated at 0 °C with HCl (3 N). The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude product was crushed with pentane and filtered to afford 15 (2.22 g, 5.17 mmol, 96%) as a white solid.

IR
To a stirred solution of acid 15 (2.15 g, 5.00 mmol) in anhydrous THF (25 mL) at 0 °C were added DCC (1.28 g, 6.21 mmol) and N-hydroxysuccinimide (0.71 g, 6.21 mmol). The mixture was allowed to warm to room temperature and stirred for 16 hours. Then the mixture was filtered through a Celite® pad and concentrated in vacuo. The resulting residue was dissolved in AcOEt (25 mL) and cooled to 0 °C. An ammonium hydroxide solution (30% in H 2 O, 7 mL) was slowly added then the mixture was allowed to warm to room temperature and stirred for 3 hours. Then the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. To a stirred solution of crude amide in anhydrous DME (13 mL) was added the Lawesson's reagent (1.3 g, 3.26 mmol) and the mixture was stirred at room temperature for 36 hours before it was filtered through a Celite® pad and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: petroleum ether/Et 2 O, 9:1 to 1:1) affording 16 (1.60 g, 3.60 mmol, 72% over three steps) as a white solid.
To a stirred solution of ketone 9 (40 mg, 0.074 mmol) in anhydrous CH 2 Cl 2 (0.4 mL) at 0 C were  To a stirred solution of thioamide 16 (22 mg, 49 mol) in anhydrous DMF (2 mL) at 20 °C were added MS 4° (40 mg) and bromoketone 17 (25 mg, 40 mol). The mixture was allowed to warm to 0 °C and was stirred at this temperature for 14 hours. Then the mixture was filtered through a Celite® pad and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: petroleum ether/EtOAc, 9:1 to 1:1) affording the title compound (31 mg, 31 mol, 78%) which was dissolved in anhydrous DME (1 mL) and cooled at 40 °C before 2,6-lutidine (50 L, 0.40 mmol) and trifluoroacetic anhydride (20 L, 0.15 mmol) were added. The mixture was allowed to warm to 20 °C and stirred at this temperature for 12 hours. Then NEt 3 was added until pH 8-9, water was added and the aqueous layer was extracted three times with CH 2 Cl 2 . The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: petroleum ether/EtOAc, 95:5 to 8:2) affording 18 (26 mg, 27 mol, 85% over two steps) as a yellow solid.