A scalable synthesis of 2S-hydroxymutilin via a modified rubottom oxidation

Journal of Organic Chemistry

Volumn 74, Issue 1, 2009, Pages 478-481

  Wang, Huan ^a   Andemichael, Yemane W ^a   Vogt, Frederick G ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMICAL EQUATIONS; PLEUROMUTILIN; SCALABLE SYNTHESES; SELECTIVE OXIDATIONS; SILYL ENOL ETHERS;

CHEMICAL REACTIONS; ETHERS; OXIDATION; SILANES;

SYNTHESIS (CHEMICAL);

DITERPENES; KETONES; MOLECULAR CONFORMATION; OXIDATION-REDUCTION; POLYCYCLIC COMPOUNDS; STEREOISOMERISM;

EID: 58149289850     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo801969e     Document Type: Article

References (27)

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4. Brooks, G.; Hunt, E. PCT Int. Appl. WO 2001074788 Al, 2001.
5. (a) 2S-Hydroxymutilin has been prepared via O-H insertion of 2-diazomutilin: see ref 3. However, large-scale application of this method is limited by the high cost of the diazotization reagent and the stability of the intermediates.
6. (b) 2S-Hydroxymutilin has been obtained in the microbial hydroxylation of mutilin, see: Hanson, R. L.; Matson, J. A.; Brzozowski, D. B.; LaPorte, T. L.; Springer, D. M.; Patel, R. N. Org. Process Res. Dev. 2002, 6, 482.
7. Direct oxidation of the enolate was also investigated. The oxidation with molecular oxygen often suffered from overoxidation to the diketone. Oxidation of the enolate with Davis oxaziridine was successful on a small scale, but was not deemed as a long-term option due to availability and safety concerns of the reagent.
8. For the X-ray structure of mutilin see: (a) Dobler, M.; Dürr, B. G. Cryst. Struct. Commun. 1975, 4, 259.
9. (b) Pilati, T. Acta Crystallogr. 1995, C51, 2676.
10. For a brief discussion of its conformation, see: (c) Boeckman, R. K.; Springer, D. M.; Alessi, T. R. J. Am. Chem. Soc. 1989, 111, 8284.
11. Emde, H.; Domsch, D.; Feger, H.; Frick, U.; Götz, A.; Hergott, H. H.; Hofmann, K.; Kober, W.; Krägeloh, K.; Oesterle, T.; Steppan, W.; West, W.; Simchen, G. Synthesis 1982, 1.
12. For a general review on the Rubottom oxidation, see: Wolfe, J. P. Rubottom oxidation In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; Wiley: New York, 2007, pp 282-290.
13. The Rubottom oxidation was also attempted with in situ generated peroxyimidic acid and dioxirane. Unfortunately, hydrolysis of the silyl enol ether became a serious side reaction in both cases. A significant amount of olefin epoxidation was also observed when methyl(trifluoromethyl)dioxirane was used as the oxidant.
14. For an example of double oxidation under Rubottom conditions, see: Horiguchi, Y.; Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1989, 30, 3323.
15. The acid-catalyzed rearrangement from mutilin to the 4-epimutilin skeleton is well known: Berner, H.; Schulz, G.; Schneider, H. Tetrahedron 1980, 36, 1807.
16. 3-buffered mCPBA in THF.
17. Bretherick's Handbook of Reactive Chemical Hazards; Urben, P. G., Ed.; Butterworth-Heinemann: Burlington, MA, 1999.
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20. (c) Gleiter, R.; Staib, M.; Ackermann, U. Liebigs Ann. 1995, 1655.
21. (a) The trapping of silyloxy carbocation with MCBA has been reported: Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org. Chem. 1975, 40, 3427.
22. (b) For a related example see: Rubottom, G. M.; Gruber, J. M.; Boeckman, R. K.; Ramaiah, M.; Medwid, J. B. Tetrahedron Lett. 1978, 19, 4603.
23. For evidence in the intermediacy of the siloxycarbocation, see ref 14b.
24. An intramolecular pathway is also possible: as the bulky silyl group presumably resides on the less crowded α face, the acetate could attack the oxonium ion 10 from the β-face and the resultant stereoisomer would undergo a 1,4-silicon shift to generate the α-hydroxyketone moiety. However, the corresponding 2-silyloxy product was never isolated.
25. Pleuromutilin 1 was obtained from fermentation.
26. The process could be further streamlined by using propyl acetate as a single solvent through oxidation, desilylation, and isolation, allowing the entire sequence to be conducted in one reaction vessel without formal isolation of the intermediates, while providing 2S-hydroxymutilin in 58% overall yield.
27. For a detailed spectroscopic and computational study of 2S-hydroxymutilin, see: Vogt, F. G.; Spoors, G. P.; Su, Q.; Andemichael, Y. W.; Wang, H.; Potter, T. C.; Minick, D. J. J. Mol. Struct. 2006, 797, 5.