S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1591–1593
1593
6. Michalets, E. L.; Williams, C. R. Clin. Pharmacokinet. 2000, 39, 49.
7. Gray, N. M.; Young, J. W. US Patent 5,629,328.
8. Sakaguchi, J.; Iwasaki, N.; Iwanage, Y.; Saito, T.; Takakhara, E.; Kato, H.;
Hanaoka, M. Chem. Pharm. Bull. 2001, 49, 424; McKinnell, R. M.; Armstrong, S.
R.; Beattie, D. T.; Choi, S.-K.; Fatheree, P. R.; Gendron, R. A. L. J. Med. Chem. 2009,
52, 5330.
NaH then MeI, which gave 10 in 77% isolated yield, with subse-
quent reduction of piperidin-2-one 10 with LiAlH4 in THF at reflux
giving piperidine 11 in 99% isolated yield. Hydrogenolytic N-deb-
enzylation of 11 gave primary amine 12. Subsequent N-acylation
of 12 with 2-methoxy-4-amino-5-chlorobenzoic acid 13 was
achieved via the mixed anhydride method,2 upon treatment of
13 with ethyl chloroformate and Et3N, and subsequent addition
of 12 to the reaction flask.17 Chromatographic purification gave
(+)-(3S,4R)-cisapride 14 in 64% isolated yield over the 2 steps
(Scheme 2).
9. For previous syntheses of ( )-(RS,SR)-cisapride, see ref 2 and Kim, B. J.; Pyun, D.
K.; Jung, H. J.; Kwak, H. J.; Kim, J. H.; Kim, E. J.; Jeong, W. J.; Lee, C. H. Synth.
Commun. 2001, 31, 1081; Cossy, J.; Molina, J. L.; Desmurs, J.-R. Tetrahedron Lett.
2001, 42, 5713. For a previous formal synthesis of (+)-(3S,4R)-cisapride, see:
Shirode, N. M.; Likhite, A. P.; Gumaste, V. K.; Rakeeb, A.; Deshmukh, A. S.
Tetrahedron 2008, 64, 7191.
10. N,N-Di-[3-(40-fluorophenoxy)propyl]-N-allylamine (the product of N-
dialkylation) was also isolated from this reaction in 10% yield.
11. Chesney, A.; Marko, I. E. Synth. Commun. 1990, 20, 3167.
3. Conclusion
12. Enantiopure (R)-
Reductive alkylation of (R)-
benzaldehyde and NaBH4 gave (R)-N-benzyl-N-(
subsequent deprotonation with BuLi in THF generated a pink solution of
lithium (R)-N-benzyl-N-( -methylbenzyl)amide 5.
a
-methylbenzylamine (99% ee) is commercially available.
-methylbenzylamine upon treatment with
-methylbenzyl)amine;
a
a
In conclusion, a concise asymmetric synthesis of the gastropr-
okinetic agent (+)-(3S,4R)-cisapride {(+)-(3S,4R)-N(1)-[30-(400-flu-
orophenoxy)propyl]-3-methoxy-4-(2000-methoxy-4000-amino-5000-
chlorobenzamido)piperidine} from commercially available starting
materials has been developed. The key step of this synthesis
employs the diastereoselective conjugate addition of lithium (R)-
N-benzyl-N-(-methylbenzyl)amide to tert-butyl 5-[N-30-(400-fluoro-
phenoxy)propyl-N-allylamino]pent-2-enoate and in situ enolate
oxidation with (ꢀ)-camphorsulfonyloxaziridine to set the
(3S,4R)-configuration found within the piperidine ring of the prod-
uct. This synthesis proceeds in 9 steps from commercially available
1-(40-fluorophenoxy)-3-bromopropane with an overall yield of
19%.
a
13. Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183; Davies, S. G.;
Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price
Mortimer, A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006, 17,
1793; Davies, S. G.; Mulvaney, A. W.; Russell, A. J.; Smith, A. D. Tetrahedron:
Asymmetry 2007, 18, 1554. For a review, see: Davies, S. G.; Smith, A. D.; Price, P.
D. Tetrahedron: Asymmetry 2005, 16, 2833.
14. Bunnage, M. E.; Chernega, A. N.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc., Perkin
Trans. 1 1994, 2373; Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc.,
Perkin Trans. 1 1994, 2385.
15. For applications of our aminohydroxylation procedure, see: Bunnage, M. E.;
Burke, A. J.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith,
A. D. Org. Biomol. Chem. 2003, 1, 3708; Abraham, E.; Candela-Lena, J. I.; Davies,
S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.; Sánchez-
Fernández, E. M.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2007, 18,
2510; Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.;
Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655; Abraham, E.; Brock, E. A.;
Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Perkins, J. H.;
Roberts, P. M.; Russell, A. J.; Sánchez-Fernández, E. M.; Scott, P. M.; Smith, A. D.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 1665; Davies, S. G.; Nicholson, R. L.;
Price, P. D.; Roberts, P. M.; Savory, E. D.; Smith, A. D. Tetrahedron: Asymmetry
2009, 20, 758; Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.
Org. Lett. 2011, 13, 1594; Csatayová, K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.;
Russell, A. J.; Thomson, J. E.; Wilson, D. L. Org. Lett. 2011, 13, 2606.
16. Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993, 58, 6109.
17. Also see: Janssen, C. G. M.; Lenoir, H. A. C.; Thijssen, J. B. A.; Knaeps, A. G.;
Heykants, J. J. P. J. Labelled Compd. Radiopharm. 1987, 24, 1493; Lee, J. S.; Oh, Y.
S.; Lim, J. K.; Yang, W. Y.; Kim, I. H.; Lee, C. W.; Chung, Y. H.; Yoon, S. J. Synth.
Commun. 1999, 29, 2547.
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