Stereodivergent synthesis of sulfoxide-containing oxazolidinone antibiotics

Author:

Gage James R,Perrault William R,Poel Toni-Jo,Thomas Richard C

Publisher

Elsevier BV

Subject

Organic Chemistry,Drug Discovery,Biochemistry

Reference11 articles.

1. Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.; Manninen, P. R.; Ulanowicz, D. A.; Garmon, S. A.; Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.; Zurenko, G. E. J. Med. Chem. 1996, 39, 673–679.

2. Gray, G. W.; Hird, M.; Toyne, K. J. Mol. Cryst. Liq. Cryst. 1991, 204, 43–64.

3. Beak, P.; Musick, T. J.; Chen, C. W. J. Am. Chem. Soc. 1988, 110, 3538–3542.

4. Sommer, L. H.; Kerr, G. T.; Whitmore, F. C. J. Am. Chem. Soc. 1948, 70, 434–435.

5. To EtMgBr (348.13 mmol, 1.18 equiv. in THF (530 ml) was added chlorotrimethylsilane (35.4 g, 325.85 mmol, 1.11 equiv.) with an exotherm from 22 to 43°C. The resultant MgBrCl solution was then cooled to give a slurry at −30°C. To a solution of 3 (85.00 g, 292.97 mmol) and 1,10-phenanthroline monohydrate (0.580 g, 2.93 mmol, 0.010 equiv.) in TMEDA (103.76 g, 892.9 mmol, 3.05 equiv.) and THF (1.15 l) was added EtMgBr in THF (243.2 g at 1.36 mol; 332 mmol; 1.13 equiv.) to the colorless to pink endpoint. The resultant solution was cooled to −26°C and butyllithium in hexane (163 g at 23.8 wt%, 590 mmol, 2.01 equiv.) was added over 1.5 h while maintaining −26 to −23°C. The MgBrCl slurry was added to the resultant dianion slurry while maintaining −25 to −19°C. A solution of tetrahydrothiopyran-4-one (44.39 g, 382 mmol, 1.30 equiv.) in THF (252 ml) was then added while maintaining −26 to −23°C. The reaction solution was then added to a solution of acetic acid (115 g, 1.92 mol, 6.54 equiv.) in water (570 ml) while maintaining 0 to 10°C. The phases were separated and the lower aqueous phase was back extracted with a mixture of MTBE (568 ml) and branched octanes (220 ml). The organics were then separately serial washed first with a mixture of ammonium chloride (43 g), aqueous ammonia (29.3 wt%, 43 g) and water (570 ml) followed by water (570 ml). The organics were combined and concentrated in vacuo to 1500 ml. A constant volume vacuum distillation was then performed while maintaining 1500 ml and adding branched octanes (3000 ml). Branched octanes (400 ml) were added and the slurry cooled to 3°C. The product was collected by vacuum filtration, washed with 3°C branched octanes (570 ml) and dried in a nitrogen stream to afford a white solid, 5 (86.20 g, 89.9%).

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