Design, development, and scale-up of a selective meso-epoxide desymmetrization process

Organic Process Research and Development

Volumn 11, Issue 3, 2007, Pages 546-559

  Varie, David L ^a   Beck, Christopher ^a   Borders, Sandra K ^a   Brady, Molly D ^a   Cronin, Jason S ^a   Ditsworth, Tracy K ^a   Hay, David A ^a   Hoard, David W ^a   Hoying, Richard C ^a   Linder, Ryan J ^a   Miller, Richard D ^a   Moher, Eric D ^a   Remacle, Jacob R ^a   Rieck III, John A ^a   Anderson, David D ^a   Dodson, Paul N ^a   Forst, Mindy B ^a   Pierson, Duane A ^a   Turpin, Joseph A ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 39049111612     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op060225f     Document Type: Article

References (60)

1. For reviews see: (a) O'Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439.
2. (b) Cox, P. J.; Simpkins, N. S. Tetrahedron: Asymmetry 1991, 2, 1.
3. (c) Eames, J. Eur. J. Org. Chem. 2002, 393.
4. (d) Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52, 14361.
5. (e) Magnus, A.; Bertilsson, S. K.; Andersson, P. G. Chem. Soc. Rev. 2002, 31, 223.
6. For general reviews see also: (f) Crandall, J. K.; Apparu, M. Org. React. 1983, 29, 245.
7. (g) Satoh, T. Chem Rev. 1996, 96, 3303.
8. (a) Moher, E. D.; Monn, J. A.; Pedregal-Tercero, C.; Collado, C. I.; Blanco-Urgoiti, J. G. PCT Int. Appl. WO 2003104217, 2003.
9. (b) Massey, S. M.; Monn, J. A.; Valli, M. J. Eur. Pat. Appl. 878463, 1998.
10. Hodgson, D. M.; Thompson, A. J.; Wadman, S.; Keats, C. J. Tetrahedron 1999, 55, 10815.
11. For example see: (a) Asami, M.; Ogawa, M.; Inoue, S. Tetrahedron Lett. 1999, 40, 1563.
12. (b) O'Brien, P.; Towers, T. T.; Voith, M. Tetrahedron Lett. 1998, 39, 8175.
13. (c) Hodgson, D. M.; Gibbs, A. R. Tetrahedron: Asymmetry 1996, 7, 407.
14. (d) Bhuniya, D.; DattaGupta, A.; Singh V. K. J. Org. Chem. 1996, 61, 6108.
15. (e) Hodgson, D. M.; Gibbs, A. R.; Drew, M. G. B. J. Chem. Soc., Perkin Trans. 1 1999, 3579.
16. (f) Milne, M.; Murphy, P. J. J. Chem. Soc., Chem. Commun. 1993, 884.
17. (g) Hodgson, D. M.; Witherington, J. Moloney, B. A. J. Chem. Soc., Perkin Trans. I 1994, 3373.
18. (h) Asami, M.; Takahashi, J.; Inoue, S. Tetrahedron: Asymmetry 1994, 5, 1649.
19. (i) Sodergen, M. K.; Bertilsson, S. K.; Andersson, P. G. J. Am. Chem. Soc. 2000, 122, 6610.
20. Commercially available from Sigma-Aldrich Chemical Company, Milwaukee, WI.
21. (a) Reference 4i.
22. (b) Modin, S. A.; Andersson, P. G. J. Org. Chem. 2000, 65, 6736.
23. (c) Andersson, P. G.; Sodergen, M. K.; Bertilsson, S. K.; Andersson, P. G. J. Org. Chem. 2002, 67, 1567.
24. Bambridge, K.; Begley, M. J.; Simpkins, N. S. Tetrahedron Lett. 1994, 35, 3391. For an example of asymmetric deprotonation of a sulfonium salt using the lithium amide of 13, see: McComas, C. C.; Van Vranken, D. L. Tetrahedron Lett. 2003, 44, 8203.
25. (a) Mimoun, H.; de saint Laumer, J. Y.; Giannini, L.; Scopelliti, R.; Floriani, C. J. Am. Chem. Soc. 1999, 121, 6158.
26. (b) Horner, L.; Dickerhof, K. Liebigs Ann. Chem. 1984, 1240.
27. The estimated cost to prepare diamine 13 on large scale was >$365/kg.
28. Several systems for the asymmetric rearrangement of meso-epoxides using a catalytic amount of a chiral lithium amide and an achiral stoichiometric base (e.g., LDA with DBU or lithiated imidazoles) have been reported. For leading references, see: (a) Reference 1c.
29. (b) Oxenford, S. J.; Wright, J. M.; O'Brien, P.; Panday, N.; Shipton, M. R. Tetrahedron Lett. 2005, 46, 8315 and references therein.
30. Prepared by reaction of 1,3-dimethoxybenzene with n-BuLi in diethyl ether.
31. Racemic and enantiomerically pure alcohol 3b have different crystal forms, based on X-ray powder diffraction patterns and melting points (122-124. °C and 112-112. °C, respectively). In addition, the racemate is significantly less soluble in the 65:35 heptane/MTBE crystallization solvent: 3 mg/mL vs 15 mg/mL for the single enantiomer (at 22 °C).
32. On laboratory scale, using a mechanical paddle stirrer, the maximum final concentration of 4b that enabled agitation of the lithium diamide was 0.25 M.
33. Aliquots of the reaction of 4b with 1.1 equiv dilthium-14 (entry 7) were quenched and assayed by NMR for conversion. After the 2 h, the ratio of starting material/product was 40:60 and remained constant thereafter. This suggests that the reaction may have occurred substantially during the addition of the epoxide solution, when the epoxide would be exposed to excess dilithium-14. After addition of one-half of the epoxide solution, only monolithium-14 would remain.
34. 2D gave 4b (89% recovery) with no measurable incorporation of deuterium, based on integration of the NH signal in the NMR spectrum.
35. Amino acid 16 has been prepared, as the trifluoroacetate salt, via reaction of 3b with neat trifluoroacetic acid. Further studies to confirm the presence of 16 in the aqueous layers of quenched reaction mixtures are in progress. No amide products, resulting from the reaction of chiral lithium amides with the ester of 4b, have been observed.
36. The reaction of epoxide diastereomer 4c with dilithium-13 provided alcohol 3c with only 61% ee. (Formula Presented) In this substrate simultaneous chelation with the epoxide and carbamate oxygens is not possible. A carbamate anion may be not be essential for bidentate coordination, however. Reaction of the N-Me epoxide i with dilithium-13 yielded alcohol ii with 85% ee (see Supporting Information). (Formula Presented)
37. Examples of epoxide rearrangements via removal of syn-β, α-, and anti-β hydrogen have been demonstrated via deuterium labeling and other studies. See for example (a) Thummel, R. P.; Rickborn, B. J. Am. Chem. Soc. 1970, 92, 2064 (syn-β elimination pathway).
38. (b) Morgan, K. M.; Gajewski, J. J. J. Org. Chem. 1996, 61, 820.
39. (c) Hodgson, D. M.; Gibbs, A. R. Tetrahedron Lett. 1997, 51, 8907.
40. (d) Hodgson, D. M.; Gibbs, A. R. J. Chem. Soc., Perkin Trans. 1 1999, 3679.
41. (e) Ramirez, A.; Collum, D. B. J. Am. Chem. Soc. 1999, 121, 11114.
42. (f) Morgan, K. M.; Gronert, S. J. Org. Chem. 2000, 65, 1461 (anti-β elimination pathway). Both solvent and conformational effects have been reported to impact the site of deprotonation. 3-Substituted cyclopentene oxides have been reported to show a preference for the syn-β-deprotonation pathway in the presence of chiral lithium amides. Based on the retention of deuterium labels in the α-positions of epoxide 4b (below), there is indication that the often observed syn-β elimination mechanism may be operating in this substrate. (Formula Presented)
43. For an asymmetric deprotonation of meso ketones with chiral magnesium amides, see for example: Anderson, J. D.; Garcia Garcia, P.; Hayes, D.; Henderson, K. W.; Kerr, W. J.; Moir, J. H.; Fondekar, K. P. Tetrahedron Lett. 2001, 42, 7111.
44. Diamine 17 was originally prepared from dibromopropane as described in reference 8b. For a recent use of catalytic dilithium-17 in the rearrangement of cyclcohexene oxide see: Equuey, O.; Alexakis, A. Tetrahedron Asymmetry 2004, 15, 1069.
45. Diamine 18: Kobayashi, Y.; Hayashi, N.; Kishi, Y. Org. Lett. 2002, 4, 411. The preparations of diamines 19-21 are described in the Supporting Information.
46. Crude reaction mixtures typically contained a 96:4 ratio of 17 and tertiary amine iii. The latter was removed by isolation of 17-dihydrochloride salt. (Formula Presented)
47. For a study of achiral rearrangements of epoxides with lithium tert-butoxide and lithium amide bases see: Saravanan, P.; DattaGupta, A.; Bhuniya, D.; Singh, V. K. Tetrahedron 1997, 53, 1855.
48. Park, K. H.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1998, 63, 113.
49. tert-Butyl methylmalonate was purchased in bulk quantities from Tateyama Kasei Co., Ltd, Toyama, Japan. A synthesis of 5b starting with tert-butyl acetoacetate has been reported: Larionov, O. L.; Kozhushkov, S. I.; de Meijere, A. Synthesis 2005, 158.
50. The cis-1,4-dichloro-2-butene used contained 3.9% trans-1,4-dichloro-2-butene and 1.0% 3,4-dicihloro-1-butene. In the preparation of 24, trans-1,4,dichloro-2-butene reacts with tert-butyl methylmalonate to give vinyl cyclopropane diastereomers iv and subsequently acids v, which are removed in the crystallization of 24. (Formula Presented)
51. (a) Depres, J. P.; Greene, A. E. Org. Synth. 1997, 75, 195.
52. (b) Depres, J. P.; Greene, A. E. J. Org. Chem. 1984, 49, 928.
53. Characterization data for major/minor epoxide diastereomers 4b and 4c were consistent with that reported for the analogous ethyl ester epoxides (ref 3). The observed epoxidation facial preference has been reported for several other 3-amide cyclopentene substrates. See, for example, refs 4a,b and O'Brien, P. O.; Childs, A. C.; Ensor, G. J.; Hill, C. L.; Kirby, J. P.; Dearden, M. J.; Oxenford, S. J.; Rosser, C. M. Org. Lett. 2003, 26, 4955.
54. The reaction was typically >80% complete 1 h after addition of the epoxide solution. For pilot-plant processing, end of reaction was defined as less than 2% epoxide 4b remaining. Levels of 4b greater than 2% were not substantially reduced in the crystallization of 3b or the subsequent intermediate 2b. As the reaction proceeds, it is possible that the effective concentration of epoxide is further reduced by nonproductive coordination with monolithium-17, which is present at substantially higher concentration than dilithium-17.
55. Sulfuric acid was used in preference to aqueous HCl, as the former salt does not precipitate from the reaction mixture, resulting in simpler layer separations.
56. Recovered 17-dihydrochloride used in a laboratory test provided alcohol 3b in 72% yield and 99.9% ee.
57. See data shown below. (Formula Presented)
58. Anneli, P. L.; Montanari, F.; Quici, S. Org. Synth. 1990, 69, 212 and references therein.
59. The extraction of the solution of 5b with dilute acid prevented the formation of small amounts of two, yet unidentified, non-polar impurities during the reaction.
60. The yield of the free basing was determined to be 93%, based on gravimetric assay of a sample of the free base 17 solution. This yield was consistent over multiple pilot-plant runs. The stoichiometry of the n-BuLi and epoxide 4b were calculated based on this yield.