Concise, protecting-group-free synthesis of (+)-nemonapride via Eu(OTf)3-catalyzed aminolysis of 3,4-epoxy alcohol

Article abstract of DOI:10.1248/cpb.c16-00568

A concise, protecting-group-free synthesis of the antipsychotic agent (+)-nemonapride has been achieved featuring a europium(III) trifluoromethanesulfonate (Eu(OTf)₃)-catalyzed C4 selective aminolysis of a 3,4-epoxy alcohol by benzylamine and a

Full text of DOI:10.1248/cpb.c16-00568

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Chem. Pharm. Bull. 65, 22–24 (2017)
Vol. 65, No. 1
Current Topics
Reversal or Control of the Innate Reactivity of Functional Groups
Communication to the Editor
following unprecedented results in terms of chemo- and regi-
oselectivity: (1) Eu(OTf)3 enabled the highly C3-selective ami-
nolysis of a 2,3-epoxy alcohol with aliphatic amines; (2) the
Eu(OTf)3/DTBMP system could be applicable to alcoholysis
of a 3,4-epoxy alcohol to give the corresponding C4-adduct
selectively. These serendipitous findings prompted us to exam-
ine a Eu(OTf)3-catalyzed aminolysis of a 3,4-epoxy alcohol27)
using an aliphatic 1° amine, the product of which we expected
would be promising feedstock for the expedient synthesis of
chiral β-hydroxy-pyrrolidines.33) Reported herein is a protect-
ing-group-free, enantioselective synthesis of the antipsychotic
agent (+)-nemonapride34–38) (1) featuring a Eu(OTf)3-catalyzed
C4-selective ring opening of a 3,4-epoxy alcohol by benzyl-
amine, and an expedient use of the resulting 4-benzylami-
no-1,3-diol product for constructing the β-hydroxy-pyrrolidine
skeleton.
On the condition that the Eu(OTf)3-catalyzed aminolysis
of a 3,4-epoxy alcohol proceeds via the inversion of the con-
figuration, (2R,3R)-(+)-nemonapride (1) was retrosynthetically
disconnected, as shown in Chart 1, in which several critical
issues are indicated. First, a Lewis acid-catalyzed C4-selective
ring opening of the 3,4-epoxy alcohol by an aliphatic 1° amine
has to be achieved as a practically acceptable level (4 to 3).
Concise, Protecting-Group-Free
Synthesis of (+)-Nemonapride via
Eu(OTf)3-Catalyzed Aminolysis of
3,4-Epoxy Alcohol
Shun-ichiro Uesugi, Yusuke Sasano, Shogo Matsui,
Naoki Kanoh, and Yoshiharu Iwabuchi*
Department of Organic Chemistry, Graduate School of
Pharmaceutical Sciences, Tohoku University; 6–3 Aoba,
Aramaki, Aoba-ku, Sendai 980–8578, Japan.
Received July 12, 2016; accepted October 20, 2016
A concise, protecting-group-free synthesis of the antipsy-
chotic agent (+)-nemonapride has been achieved featuring
a europium(III) trifluoromethanesulfonate (Eu(OTf)3)-cata-
lyzed C4 selective aminolysis of a 3,4-epoxy alcohol by ben-
zylamine and an expedient use of the resulting 4-benzylami-
no-1,3-diol product for constructing the pyrrolidine skeleton.
Key words chemoselectivity; aminolysis; 3,4-epoxy alcohol;
Lewis acid catalysis; protecting-group-free; nemonapride
A nucleophilic ring opening of a chiral epoxide substrate Second, highly chemoselective activation of the amino diol
in a regio- and stereocontrolled manner has enabled the must be realized in order to conduct the intended intramo-
construction of numerous molecules with contiguous stereo- lecular SN2 reaction, giving the β-hydroxy-pyrrolidine skeleton
genic centers.1,2) Along with expanding the scope of catalytic efficiently (3 to 2).
enantioselective epoxidation reactions, the structural diver-
The synthesis began with an enantioselective epoxidation
sity of chiral epoxides is increased,3–8) inspiring chemists to of an (E)-homoallyl alcohol by a Shi oxidation.6) Treatment
develop methods that conduct a selective nucleophilic ring of (E)-3-penten-1-ol 5 with Oxone® in the presence of Shi’s
opening of the epoxide.9–13) To date, a number of reagents and ketone6) (30mol%), n-Bu4NHSO4 (1.6mol%) and K2CO3
conditions that lead to the regio- and stereocontrolled instal- (5.8eq) in dimethoxymethane (DMM)/MeCN/aqueous buffer
lation of various nucleophiles have been developed employ- (pH 9.3) at −15°C gave 3,4-epoxy alcohol 4 in 76% yield and
ing Lewis acid catalysis.14) Among potential nucleophiles, 90% enantiomeric excess (ee) (Chart 2). The first key reaction,
N-nucleophiles,15) such as amines, azides, amides, carbamates, which represents an unprecedented Lewis acid-catalyzed ring
and so on, have received considerable attention because the opening of 3,4-epoxy alcohols using an aliphatic 1° amine as
reaction allows access to β-amino alcohols,16,17) which are the nucleophile, was found to proceed smoothly in the pres-
versatile intermediates for biologically active compounds, ence of 10mol% Eu(OTf)3 and 2.0eq of benzylamine in tolu-
chiral ligands, and catalysts. Due to the substantial issue of ene at 60°C to give a 2.9:1 regioisomeric mixture of amino
acid-base interaction, however, amines have rather limited use
in a Lewis acid-promoted or catalyzed nucleophilic ring open-
ing of epoxides: other than a few particular exceptions,18–22)
regio- and stereoselective aminolysis of epoxides could be
operative in the case when either aromatic amines23–28) or ac-
tivated substrates27,29) (benzylic or allylic epoxides) or a large
amount30,31) of Lewis acid are applied. Thus, state-of-the-art
aminolysis of epoxides with an aliphatic amine is still under
development in modern synthetic chemistry.
Previously, our group showed32) that europium(III) trifluo-
romethanesulfonate (Eu(OTf)3) catalyzes a highly C3-selective
alcoholysis of various 2,3-epoxy alcohols in the presence
of catalytic amounts of 2,6-di-tert-butyl-4-methylpyridine
(DTBMP) to give 3-substituted 1,2-diols, together with the
Chart 1. Retrosynthesis of (+)-Nemonapride (1)
*To whom correspondence should be addressed. e-mail: y-iwabuchi@m.tohoku.ac.jp
© 2017 The Pharmaceutical Society of Japan

Vol. 65, No. 1 (2017)
Chem. Pharm. Bull.
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Chart 2. Synthesis of (+)-Nemonapride (1)
diols in preference to 4-amino-1,3-diol 3 in 99% yield. After to Y. I.), and by the Platform Project for Supporting Drug
chromatographic purification, a 9:1 mixture of 3 and 3′ was Discovery and Life Science Research (Platform for Drug Dis-
eventually obtained. Note that the addition of DTBMP is not covery, Informatics, and Structural Life Science) from Japan’s
necessary, but heating was essential to promote the aminoly- Agency for Medical Research and Development (AMED).
sis reaction. It should be pointed out that other Lewis acids,
such as W(OEt)6,26) Ni(ClO4)2·6H2O,27) and LiOTf,31) which
Conflict of Interest The authors declare no conflict of
were reported to promote a highly regioselective nucleophilic interest.
ring opening of 2,3-epoxy alcohols and 3,4-epoxy alcohols
with various nucleophiles, resulted in unsatisfactory results
Supplementary Materials The online version of this ar-
in terms of efficiency and regioselectivity.39) The second key ticle contains supplementary materials.
reaction, that is, the alcohol-selective installation of sulfonyl
groups in the presence of 2° amine functionality, proceeded
smoothly on treatment of the mixture with 3.0eq of MsCl
in the presence of Et3N and N,N-dimethyl-4-aminopyridine
(DMAP) in CH2Cl2 at 0°C, with a concomitant 5-exo-tet-
type intramolecular SN2 reaction to construct the pyrrolidine
ring to give the known pyrrolidene 6 in 81% yield as a read-
ily separable product.40) Protecting-group-free synthesis of
nemonapride (1) was completed in 46% yield by following
Wei’s protocol37) involving azidation, Lindlar reduction of the
azide, and condensation with aromatic carboxylic acid 8.
In conclusion, we have demonstrated the synthetic use of
Eu(OTf)3-catalyzed C4-selective aminolysis with an aliphatic
amine by illustrating an enatioselective and protecting-group-
free synthesis of (+)-nemonapride. The synthetic sequence
developed in this study could be applicable to the rapid
construction of various chiral 2-substituted 3-hydroxypyrro-
lidines.
References and Notes
1) Carreira E. M., Kvaerno L., “Classics in Stereoselective Synthesis,”
Wiley-VCH, Weinheim, 2009.
2) Andrushko V., Andrushko N., “Stereoselective Synthesis of Drugs
and Natural Products,” Vols. 1 and 2, Wiley, Hoboken, 2013.
3) Gao Y., Klunder J. M., Hanson R. M., Masamune H., Ko S. Y.,
Sharpless K. B., J. Am. Chem. Soc., 109, 5765–5780 (1987).
4) Zhang W., Loebach J. L., Wilson S. R., Jacobsen E. N., J. Am.
Chem. Soc., 112, 2801–2803 (1990).
5) Irie R., Noda K., Ito Y., Katsuki T., Tetrahedron Lett., 32, 1055–
1058 (1991).
6) Tu Y., Wang Z.-X., Shi Y., J. Am. Chem. Soc., 118, 9806–9807
(1996).
7) Barlan A. U., Basak A., Yamamoto H., Angew. Chem. Int. Ed., 45,
5849–5852 (2006).
8) Olivares-Romero J. L., Li Z., Yamamoto H., J. Am. Chem. Soc.,
135, 3411–3413 (2013).
9) Hanson R. M., Chem. Rev., 91, 437–475 (1991).
10) Heravi M. M., Lashaki T. B., Poorahmad N., Tetrahedron Asymme-
try, 26, 405–495 (2015).
Acknowledgments This work was partly supported by
a Grant-in-Aid for Scientific Research on Innovative Areas
“Advanced Molecular Transformations by Organocatalysis”
11) Zhu Y., Wang Q., Cornwall R. G., Shi Y., Chem. Rev., 114, 8199–
8256 (2014).
12) Riera A., Moreno M., Molecules, 15, 1041–1073 (2010).
(No. 23105011 to Y. I.) from the Ministry of Education, Cul- 13) Sasaki M., Tanino K., Hirai A., Miyashita M., Org. Lett., 5, 1789–
1791 (2003).
ture, Sports, Science and Technology (MEXT) of Japan, by
14) Wang C., Luo L., Yamamoto H., Acc. Chem. Res., 49, 193–204
a Grant-in-Aid for Scientific Research (B) (No. 16H05072

24
Chem. Pharm. Bull.
39) The superiority of Eu(OTf)3
Vol. 65, No. 1 (2017)
(2016).
in the catalytic aminolysis of
15) Mailyan A. K., Eickhoff J. A., Minakova A. S., Gu Z., Lu P.,
Zakarian A., Chem. Rev., 116, 4441–4557 (2016).
16) Schneider C., Synthesis, 2006, 3919–3944 (2006).
17) Pineschi M., Eur. J. Org. Chem., 2006, 4979–4988 (2006).
18) Chini M., Crotti P., Favero L., Gardelli C., Macchia F., Pineschi M.,
Tetrahedron Lett., 35, 433–436 (1994).
3,4-epoxy-alcohol 4 was confirmed by comparison with other con-
ventional catalysts.
19) Sagawa S., Abe H., Hase Y., Inaba T., J. Org. Chem., 64, 4962–4965
(1999).
20) Bao H., Wu J., Li H., Wang Z., You T., Ding K., Eur. J. Org. Chem.,
2010, 6722–6726 (2010).
21) Procopio A., Gaspari M., Nardi M., Oliverio M., Rosati O., Tetrahe-
dron Lett., 49, 2289–2293 (2008).
22) Ollevier T., Nadeau E., Tetrahedron Lett., 49, 1546–1550 (2008).
23) Sekine A., Ohshima T., Shibasaki M., Tetrahedron, 58, 75–82
(2002).
24) Azoulay S., Manabe K., Kobayashi S., Org. Lett., 7, 4593–4595
(2005).
25) Wang C., Yamamoto H., Angew. Chem. Int. Ed., 53, 13920–13923
(2014).
26) Wang C., Yamamoto H., J. Am. Chem. Soc., 136, 6888–6891 (2014).
27) Wang C., Yamamoto H., J. Am. Chem. Soc., 137, 4308–4311 (2015).
28) Luo L., Yamamoto H., Org. Biomol. Chem., 13, 10466–10470
(2015).
29) Tang M., Pyne S. G., Tetrahedron, 60, 5759–5767 (2004).
30) Chini M., Crotti P., Flippin L. A., Gardelli C., Giovani E., Macchia
F., Pineschi M., J. Org. Chem., 58, 1221–1227 (1993).
31) Augé J., Leroy F., Tetrahedron Lett., 37, 7715–7716 (1996).
32) Uesugi S., Watanabe T., Imaizumi T., Shibuya M., Kanoh N., Iwa-
buchi Y., Org. Lett., 16, 4408–4411 (2014).
40) To gain insight into the origin of the chemoselectivity observed in
the mesylation of amonidiol 3, we conducted a set of competitive
experiments using simple substrates. N-Mesylation proceeded pref-
erentially in the case of primary amine and sterically less-hindered
secondary amine over the O-mesylation of primary alcohols (9 vs.
11; 13 vs. 15). The selectivity reversed in the case of sterically
congested secondary amines: O-mesylation of 13 proceeded pref-
erentially over the N-mesylation of secondary amine 17, indicating
that the innate N-selectivity would be overridden by steric factors.
33) Robertson J., Stevens K., Nat. Prod. Rep., 31, 1721–1788 (2014).
34) Iwanami S., Takashima M., Hirata Y., Hasegawa O., Usuda S., J.
Med. Chem., 24, 1224–1230 (1981).
35) Hoang C. T., Nguyen V. H., Alezra V., Kouklovsky C., J. Org.
Chem., 73, 1162–1164 (2008).
36) Handa S., Gnanadesikan V., Matsunaga S., Shibasaki M., J. Am.
Chem. Soc., 132, 4925–4934 (2010).
37) Huang W., Ma J.-Y., Yuan M., Xu L.-F., Wei B.-G., Tetrahedron, 67,
7829–7837 (2011).
38) Harada S., Sakai T., Takasu K., Yamada K., Yamamoto Y., Tomioka
K., J. Org. Chem., 77, 7212–7222 (2012).