Practical synthesis of a renin inhibitor via a diastereoselective dieckmann cyclization

Organic Letters

Volumn 12, Issue 22, 2010, Pages 5146-5149

  Gauvreau, Danny ^a   Hughes, Greg J ^a   Lau, Stephen Y W ^a   McKay, Daniel J ^a   O'Shea, Paul D ^a   Sidler, Rick R ^a   Yu, Bing ^a   Davies, Ian W ^a  

^a MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

AZO COMPOUND; DRUG DERIVATIVE; FUSED HETEROCYCLIC RINGS; MK 8141; MK-8141; PROTEINASE INHIBITOR; RENIN; TOLUENE;

ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; CYCLIZATION; DRUG ANTAGONISM; STEREOISOMERISM; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

AZO COMPOUNDS; BICYCLO COMPOUNDS, HETEROCYCLIC; CRYSTALLOGRAPHY, X-RAY; CYCLIZATION; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; PROTEASE INHIBITORS; RENIN; STEREOISOMERISM; TOLUENE;

EID: 78449307484     PISSN: 15237060     EISSN: 15237052     Source Type: Journal    
DOI: 10.1021/ol102131e     Document Type: Article

References (26)

1. Skeggs, L. T., Dovens, F. E., Levins, M., Lentz, K., and Kahn, J. R. The Renin-Angiotensin System; Jonhson, J. A. and Anderson, R. R., Eds.; Plenum Press: New York, 1980; p 1.
2. MacGregor, G. A.; Markandu, N. D.; Roulston, J. E.; Jones, J. C.; Morton, J. J. Nature 1981, 291, 329-331
3. For recent reviews, see: Carey, R. M.; Stragy, H. M. Endocr. Rev. 2003, 24, 261-271
4. Persson, P. B. J. Physiol. 2003, 552, 667-671
5. Re, R. N. Med. Clin. North Am. 2004, 88, 19-38
6. Brewster, U. C.; Perazella, M. A. Am. J. Med. 2004, 116, 263-272
7. Aneja, A.; El-Atat, F.; McFarlane, S. I.; Sowers, J. R. Recent Prog. Horm. Res. 2004, 59, 169-205
8. Maibaum, J.; Stutz, S.; Goschke, R.; Rigollier, P.; Yamagushi, Y.; Cumin, F.; Rahuel, J.; Baum, H. P.; Cohen, N. C.; Schnell, C. R.; Fuhrer, W.; Gruetter, M. G.; Schilling, W.; Wood, J. M. J. Med. Chem. 2007, 50, 4832-4844
9. Bezençon, O.; Bur, D.; Weller, T.; Richard-Bildstein, S.; Remen, L.; Sifferlen, T.; Corminboeuf, O.; Grisostomi, C.; Boss, C.; Prade, L.; Delahaye, S.; Treiber, A.; Strickner, P.; Binker, C.; Hess, P.; Steiner, B.; Fischli, W. J. Med. Chem. 2009, 52, 3689-3702
10. To the best of our knowledge, this type of desymmetrizing diastereoselective Dieckmann approach has not been previously disclosed in the literature. For a conceptually distinct diastereoselective Dieckmann approach, see
11. Boger, D. L.; McKie, J. A.; Nishi, T.; Ogiku, T. J. Am. Chem. Soc. 1997, 119, 311
12. Groth, U.; Kesenheimer, C.; Kreye, P. Synlett 2006, 14, 2223
13. Kawabata, T.; Watanabe, T. Heterocycles 2008, 76, 1593
14. It is believed that the acidity of the 1,1,1-trifluoroethanol allows for an easier proton exchange during the Michael addition.
15. The 1-naphthyl susbtrate could not be evaluated in the Dieckmann cyclization since the double-Michael addition failed using (1-naphthyl) ethylamine.
16. Johnson, F. Chem. Rev. 1968, 68, 375
17. Quick, J.; Mondello, C.; Humora, M.; Brennan, T. J. Org. Chem. 1978, 43, 2705
18. Neipp, C.; Martin, S. F. J. Org. Chem. 2003, 68, 8867
19. See Supporting Information for X-ray and computational calculation data.
20. Ho, T.-L.; Lin, Y.-J. J. Chin. Chem. Soc. 1997, 44, 261 Ho and Line have found Dieckmann cyclizations of analogous N- benzyl thiomorpholine substrates to be similarly challenging
21. Two plausible pathways allow to access the major diastereomer: (a) selective deprotonation of the less hindered methylene, followed by ketene formation, then deprotonation of the more hindered methylene and cyclization on the ketene; or (b) selective deprotonation of the less hindered methylene, followed by proton-transfer and cyclization.
22. Gauvreau, D.; Huffman, M. A.; Hughes, G.; Itoh, T.; Yin, J.; Lau, S.; O'Shea, P. WO 2008088690 A2. July 24, 2008.
23. Lau, S. Y. W.; Hughes, G.; O'Shea, P. D.; Davies, I. W. Org. Lett. 2007, 9, 2239
24. (aq) in THF at 67 °C.
25. Wu, G.; Huang, M.; Richards, M.; Poirier, M.; Wen, X.; Draper, R. W. Synthesis 2003, 11, 1657
26. The use of (S)-α-methylbenzylamine lead to the preparation of the opposite enantiomer of MK-8141.