Enantioselective synthesis of a highly potent selective serotonin reuptake inhibitor. An application of imidazolidinone catalysis to the alkylation of indoles with an αβ-disubstituted αβ-unsaturated aldehyde

Organic Letters

Volumn 7, Issue 16, 2005, Pages 3437-3440

  King, H Dalton ^a   Meng, Zhaoxing ^a   Denhart, Derek ^a   Mattson, Ronald ^a   Kimura, Roy ^a   Wu, Dedong ^a   Gao, Qi ^a   Macor, John E ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALDEHYDE; BMS 594726; BMS-594726; CYCLOPENTANE DERIVATIVE; IMIDAZOLE DERIVATIVE; INDOLE DERIVATIVE; SEROTONIN UPTAKE INHIBITOR;

ARTICLE; CATALYSIS; CHEMISTRY; STEREOISOMERISM; SYNTHESIS;

ALDEHYDES; CATALYSIS; CYCLOPENTANES; IMIDAZOLES; INDOLES; SEROTONIN UPTAKE INHIBITORS; STEREOISOMERISM;

EID: 23944499068     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol051000c     Document Type: Article

References (19)

1. (a) Baldwin, D. S. Hum. Psychopharmacol. 2001, 16, S93-S99.
2. (b) Spinks, D.; Spinks, G. Curr. Med. Chem. 2002, 9, 799-810.
3. (a) Rosen, R. C.; Lane, R. M.; Menza, M. J. Clin. Psychopharmacol. 1999, 19, 67-85.
4. (b) Waldingeri, M. D.; Berendsen, H. H. G.; Blok, B. F. M.; Olivier, B.; Holstege, G. Behav. Brain Res. 1998, 92, 111-118.
5. Taber, M. T.; Wright, R. N.; Molski, T. F.; Clarke, W. J.; Brassil, P. J.; Denhart, D. J.; Mattson, R. J.; Lodge, N. J. Pharmacol. Biochem. Behav. 2005, 80, 521-528.
6. Schmitz, W. D.; Denhart, D. J.; Brenner, A. B.; Ditta, J. L.; Mattson, R. J.; Mattson, G. K.; Molski, T. F.; Macor, J. E. Bioorg. Med. Chem. Lett. 2005, 15, 1619-1621.
7. Boy, K. M.; Dee, M.; Yevich, J.; Torrente, J.; Gao, Q.; Iben, L.; Stark, A.; Mattson, R. J. Bioorg. Med. Chem. Lett. 2004, 14, 4467-4470.
8. Toda, N.; Tago, K.; Marumoto, S.; Takami, K.; Ori, M.; Yamada, N.; Koyama, K.; Naruto, S.; Abe, K.; Yamazaki, R.; Hara, T.; Aoyagi, A.; Abe, Y.; Kaneko, T.; Kogen, H. Bioorg. Med. Chem. 2003, 11, 4389-4415.
9. Denhart, D.; Ditta, J.; King, D.; Macor, J.; Marcin, L.; Mattson, R.; Meng, Z. WO 026237, 2004; Chem. Abstr. 2004, 140, 303528.
10. Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172-1173.
11. Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458-2460.
12. Denhart, D. J.; Mattson, R. J.; Ditta, J. L.; Macor, J. E. Tetrahedron Lett. 2004, 45, 3803-3805.
13. Catalyst 3a gives no detectable 10a in the analogous reaction. However, it is reported in ref 10 that 5-cyanoindole reacts with acrolein at -25°C in the presence of 3a to give the corresponding 3-substituted propionaldehyde product in modest yield.
14. Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987, 87, 779-794.
15. Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 2890-2891.
16. 4 reduction, the cis alcohol was isolated and characterized. Details are supplied in Supporting Information.
17. 3 solvent.
18. Taggi, A. E.; Hafez, A. M.; Dudding, T.; Lectka, T. Tetrahedron 2002, 58, 8351-8356.
19. Preliminary experiments with other simple α-branched enals show that this reaction is very sensitive to steric effects. In the reaction of an acyclic substrate, trans-2-methyl-2-butenal, and indole under identical conditions with catalyst 3b, product 3-(3-indoyl)-2-methylbutanal was obtained in only 33% yield, 10-19% ee after 4 days. In this case we reason that there is a greater degree of rotational freedom in the iminium intermediate leading to a lack of facial discrimination in the attack of indole. Expanding the cyclic enal system to 1-cyclohexene-1-carboxaldehyde, reaction with indole under identical conditions requires 7 days to obtain only a 13% yield of trans-5-2-(3-indoyl)- cyclohexanecarboxaldehyde. Enantioselectivity, though, was equivalent to that of 8 (80% ee), indicating similar facial discrimination. The combination of variable stereoselectivity and low reactivity in these model systems suggests that the general utility of catalysis with 3b in other branched systems may be limited.