A modular and enantioselective synthesis of the pleuromutilin antibiotics

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Science  02 Jun 2017:
Vol. 356, Issue 6341, pp. 956-959
DOI: 10.1126/science.aan0003
  • Fig. 1 Pleuromutilins and 12-epi-pleuromutilins are promising classes of antibiotics.

    (A) Structures of selected pleuromutilins and 12-epi-pleuromutilins. Pleuromutilins are active against predominantly Gram-positive pathogens, whereas 12-epi-pleuromutilins display extended spectrum activity, including activity against Gram-negative pathogens. (B) Retrosynthetic analysis of the mutilin scaffold. The synthetic fragments 7 and 8 were used in the synthesis of pleuromutilins.

  • Fig. 2 Stereoselective syntheses of the coupling fragments.

    (A) Synthesis of the enimide 7. Reagents and conditions: (1) Zn(CH3)2, copper(II) triflate [Cu(OTf)2] (0.5 mol %), L* (1.0 mol %), toluene, 0°C, then CH3Li, –78°C, then methylcyanoformate, –78°C; (2) iodomethane, sodium tert-butoxide (t-BuONa), CH3OH, 0°C, 71%; (3) potassium bis(trimethylsilyl)amide (KHMDS), N-phenyl triflimide, tetrahydrofuran (THF), –78°C; (4) CO (1 atm), tetravinyltin, LiCl, tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] (5 mol %), dimethylformamide (DMF), 40°C; (5) Cu(OTf)2 (5 mol %), (CH2Cl)2, 70°C; (6) diethylaluminum cyanide (Et2AlCN), THF, 0°C, then di-iso-butylaluminum hydride (DIBALH), –78°C, then 0.01 M NaOH, CH3OH–H2O (5:1), 0°C; (7) trimethylsilyl trifluoromethanesulfonate (TMSOTf), bis(trimethylsilyl)ethylene glycol, CH2Cl2, 30°C; and (8) CH3Li, toluene, 0°C, then di-tert-butyl dicarbonate, 0°C. (B) Synthesis of the bifunctional iodoether 8. Reagents and conditions: (1) sodium bis(trimethylsilyl)amide (NaHMDS), para-methoxybenzyl chloromethyl ether (PMBOCH2Cl), THF, –78°C to 20°C; (2) LiAlH4, Et2O, 0°C; and (3) PPh3, I2, imidazole, THF, 70°C.

  • Fig. 3 Synthesis of (+)-12-epi-mutilin (4) and (+)-11,12-di-epi-mutilin (26) from 7 and 8.

    Reagents and conditions: (1) t-BuLi, 8, Et2O, –45°C, then 7, –45°C, then HCl, THF, 0°C; (2) KHMDS, N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (Comins’ reagent), THF, –78°C; (3) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), CH2Cl2, pH 7 buffer, 20°C; (4) Dess-Martin periodinane (DMP), CH2Cl2, 20°C; (5) bis(cyclooctadiene)nickel(0) [Ni(cod)2] (30 mol %), 1,3-bis-(2,6-di-iso-propylphenyl)imidazol-2-ylidene (IPr, 30 mol %), triethylsilane, THF, 20°C, then tetra-n-butylammonium fluoride (TBAF), 20°C; (6) DMP, CH2Cl2, 20°C; (7) SmI2, THF, CH3OH, 20°C; (8) Na, EtOH, 20°C; (9) HCl, H2O, CH3OH, THF, 20°C; (10) (i) SmI2, THF, H2O, 20°C; (ii) lithium triethylborohydride (LiEt3BH), THF, 20°C; (11) Na, EtOH, 20°C, then HCl, H2O, CH3OH, THF, 20°C.

  • Fig. 4 Synthesis of (+)-12-epi-pleuromutiln (29), (+)-pleuromutilin (1), and (+)-11,12-di-epi-pleuromutilin (32).

    Reagents and conditions: (1) 1-(trifluoroacetyl)imidazole, ethyl acetate (EtOAc), –78°C; (2) O-trifluoroacetylglycolic acid, 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC), 4-dimethylaminopyridine (DMAP), 20°C, then CH3OH, NaHCO3, 20°C; (3) 1-(trifluoroacetyl)imidazole, EtOAc, –78°C; (4) O-tritylglycolic acid, EDC, DMAP, 20°C, then CH3OH, NaHCO3, 20°C; (5) Et2Zn, DMF, 100°C, then HCl, 20°C; (6) O-tritylglycolic acid, EDC, DMAP, 20°C; (7) HCl, 20°C.

Supplementary Materials

  • A modular and enantioselective synthesis of the pleuromutilin antibiotics

    Stephen K.Murphy,Mingshuo Zeng, Seth B. Herzon

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