Concise, efficient and highly selective asymmetric synthesis of (+)-(3S,4R)-cisapride

Article abstract of DOI:10.1016/j.tetasy.2011.08.020

A concise asymmetric synthesis of the gastroprokinetic agent (+)-(3S,4R)-cisapride {(+)-(3S,4R)-N(1)-[3′-(4″-fluorophenoxy) propyl]-3-methoxy-4-(2″′-methoxy-4″′-amino- 5″′-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-(α- methylbenzyl)amide to tert-butyl 5-[N-3′-(4″-fluorophenoxy)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 product. This synthesis proceeds in 9 steps from commercially available 1-(4′-fluorophenoxy)-3-bromopropane with an overall yield of 19%.

Full text of DOI:10.1016/j.tetasy.2011.08.020

Tetrahedron: Asymmetry 22 (2011) 1591–1593
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Concise, efficient and highly selective asymmetric synthesis
of (+)-(3S,4R)-cisapride
⇑
Stephen G. Davies , Rosemary Huckvale, Thomas J. A. Lorkin, Paul M. Roberts, James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
A concise asymmetric synthesis of the gastroprokinetic agent (+)-(3S,4R)-cisapride {(+)-(3S,4R)-N(1)-[30-
(400-fluorophenoxy)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
Article history:
Received 18 August 2011
Accepted 25 August 2011
Available online 6 October 2011
employs the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(a-methylbenzyl)amide
to tert-butyl 5-[N-30-(400-fluorophenoxy)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 product. This synthesis proceeds in 9 steps from commercially available 1-(40-fluorophenoxy)-3-bro-
mopropane with an overall yield of 19%.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
allylamino]pent-2-enoate and in situ enolate oxidation with (ꢀ)-
camphorsulfonyloxaziridine [(ꢀ)-CSO] to set the (3S,4R)-configura-
( )-(RS,SR)-Cisapride {( )-(RS,SR)-N(1)-[30-(400-fluorophenoxy)
tion found within the piperidine ring of the final product.
propyl]-3-methoxy-4-(2000-methoxy-4000-amino-5000-chloro-
benzamido)piperidine} is
a
gastroprokinetic agent1 that was
developed by Janssen Pharmaceutica in the 1980s2 (Fig. 1). The
racemate was marketed (from 1993 onwards) under the trade
name PropulsidÒ as a treatment for gastroesophageal reflux dis-
ease,3 although it has also been used successfully in the treatment
of other gastrointestinal diseases such as chronic bowel constipa-
tion and irritable bowel syndrome.4 However, the adverse gastro-
intestinal (e.g., abdominal pain and diarrhoea) and cardiovascular
effects associated with the drug can be severe.5 Between 1993
and 1999 there were 341 cases of cardiac dysrhythmia attributed
to the use of PropulsidÒ, as well as 80 reported deaths, which ulti-
mately led to the voluntary withdrawal of the drug from market in
the USA in 2000, pending further research.6 It has been reported that
administration of the (+)-(3S,4R)-eutomer substantially reduces the
adverse effects associated with the racemate,7 and the biological
screening of compounds related to cisapride is still an active area
of research.8 As such, there is continued interest in the development
of methods to enable the efficient syntheses of analogues of cisa-
pride. Herein we report a concise and efficient asymmetric synthesis
of (+)-(3S,4R)-cisapride9 in 19% yield over 9 steps from commer-
cially available starting materials that should be readily amenable
to diversification. The key step of this synthesis employs the diaste-
N
O
OMe
O
N
H
OMe
NH
2
F
Cl
Figure 1. Structure of (+)-(3S,4R)-cisapride.
O
F
Br
O
F
NH
(i)
1
2, 87%
(ii)
CO2 tBu
(iii)
O
F
N
O
O
F
N
reoselective conjugate addition of lithium (R)-N-benzyl-N-(a-meth-
ylbenzyl)amide to tert-butyl 5-[N-30-(400-fluorophenoxy)propyl-N-
4, 70%, >99:1 dr
3
⇑
Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
Scheme 1. Reagents and conditions: (i) allylamine, K2CO3, NaI, THF, rt, 16 h; (ii)
acrolein, DBU, THF, ꢀ15 °C, 40 min; (iii) Ph3P@CHCO2tBu, THF, ꢀ15 °C to rt, 16 h.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.08.020

1592
S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1591–1593
4
13 was followed by in situ enolate oxidation upon treatment with
2. Results and discussion
(ꢀ)-CSO 614 to give
a-hydroxy-b-amino ester 7 as a single diaste-
Treatment of 1-(40-fluorophenoxy)-3-bromopropane
1 with
reoisomer which was isolated in 64% yield after chromatography.
The absolute (R,R,R)-configuration within 7 was assigned by anal-
ogy to the well established stereochemical outcome of our amin-
ohydroxylation process.14,15 The deallylation and cyclisation of 7
to give the corresponding piperidin-2-one 9 was achieved by
sequential treatment with Pd(PPh3)4 in the presence of N,N-dim-
ethylbarbituric acid as an allyl cation scavenger,16 followed by
heating a solution of the crude reaction mixture (containing 8) in
PhMe at reflux in the presence of PhCO2H. Chromatographic puri-
fication gave the desired piperidin-2-one 9 in 99% yield over 2
steps. O-Methylation of 9 was achieved upon treatment with
allylamine gave secondary amine 2 in 87% yield.10 Subsequent con-
version of 2 into a,b-unsaturated ester 4 was achieved by following
the procedure of Chesney and Marko,11 which involved conjugate
addition of 2 to acrolein at ꢀ15 °C to give b-amino aldehyde 3 that
was trapped by in situ Wittig reaction with tert-butyl (triphenyl-
phosphoranylidene)acetate to give a 77:23 mixture of (E):(Z) olefin
isomers. Purification gave the diastereoisomerically pure (E)-iso-
mer 4 (J2,3 = 16.2 Hz) in 70% yield (Scheme 1).
Diastereoselective conjugate addition of lithium (R)-N-benzyl-
N-(
a
-methylbenzyl)amide 5 (99% ee)12 to
a
,b-unsaturated ester
Ph
CO2tBu
Ph
N
O
F
N
CO2tBu
(i)
O
F
N
OH
4
7, 64%, >99:1 dr
(ii)
Ph
Ph
N
O
N
Ph
Ph
t
CO2 Bu
(iii)
O
F
N
H
O
N
OH
OH
8
9, 99%, >99:1 dr
F
(iv)
O
F
N
Ph
Ph
O
F
N
Ph
Ph
(v)
O
N
N
OMe
OMe
10, 77%, >99:1 dr
11, 99%, >99:1 dr
(vi)
O
F
N
O
OMe
Cl
O
N
(vii)
N
H
NH2
OMe
OMe
NH2
F
14, 64%, >99:1 dr
12
O
OMe
Ph
HO
N
Ph
N
Li
NH2
O
S
O2
Cl
(R)-5
6
13
Scheme 2. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(
dimethylbarbituric acid, CH2Cl2, 35 °C, 3 h; (iii) PhCO2H, PhMe, 80 °C, 16 h; (iv) NaH, THF, 0 °C, 1 h, then MeI, 0 °C to rt, 16 h; (v) LiAlH4, THF, 60 °C, 16 h; (vi) H2, Pd(OH)2/C,
MeOH, rt, 16 h; (vii) 13, ClCO2Et, Et3N, THF, rt, 16 h.
a-methylbenzyl)amide 5, THF, ꢀ78 °C, 2 h, then (ꢀ)-CSO 6, ꢀ78 °C to rt, 12 h; (ii) Pd(PPh3)4, N,N-

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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