A short, simple and general approach for the synthesis of (3S,4S)-3-methoxy-4-methylamino pyrrolidine and (3S,4R)-3-methoxy-4-methylamino pyrrolidine

Article abstract of DOI:10.1016/S0040-4039(03)01362-5

A general and efficient stereoselective approach for the synthesis of (3S,4S) and (3S,4R)-3-methoxy-4-methylamino pyrrolidines, a part of the structure of AG-7352, a naphthyridine antitumor agent and quinoline antibacterial compounds has been described.

Full text of DOI:10.1016/S0040-4039(03)01362-5

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Tetrahedron Letters 44 (2003) 5687–5689
A short, simple and general approach for the synthesis of
(3S,4S)-3-methoxy-4-methylamino pyrrolidine and
(3S,4R)-3-methoxy-4-methylamino pyrrolidineꢀ
A. Ravi Kumar, J. Santhosh Reddy and B. Venkateswara Rao*
Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500 007 India
Received 14 March 2003; revised 21 May 2003; accepted 30 May 2003
Abstract—A general and efficient stereoselective approach for the synthesis of (3S,4S) and (3S,4R)-3-methoxy-4-methylamino
pyrrolidines, a part of the structure of AG-7352, a naphthyridine antitumor agent and quinoline antibacterial compounds has been
described.
© 2003 Elsevier Ltd. All rights reserved.
Biologically active chiral and non-racemic pyrrolidines
are commonly found in subunits of natural and unnatu-
ral products.1 Okada et al.2,3 showed that a new series
of quinoline compounds, e.g. 1a, bearing a 3-methoxy-
4-amino chiral pyrrolidine derivative at C-7 showed
higher in vivo and in vitro antibacterial activity against
gram +ve and gram −ve bacteria. The pyrrolidine skele-
ton possesses 3-methoxy-4-amino or 3-methoxy-4-
methylamino groups both in syn and anti
configurations. Tsuzuki et al.4,5 also showed that
(3S,4S)-3-methoxy-4-methylaminopyrrolidines attached
to the naphthyridine ring at C-7 in AG-7352 1, a new
type of antitumor agent, showed potent activity equal
or superior to those of cisplatin and etopside.6 The
amino and hydroxy moieties in the erythro form are
also present in a pyrrolidine containing balanol ana-
logue,7 which is a very effective inhibitor of Protein
Kinase C (PKC). Hence these novel pyrrolidine moi-
eties must contribute to the activity of the above com-
pounds. Therefore, we undertook the synthesis of these
3,4-disubstituted pyrrolidines and developed a new gen-
eral strategy for the preparation of both syn and anti
compounds 3a and 2a. Although an approach3 towards
the synthesis of 3a is known, it is racemic and the chiral
pyrrolidine 3a was obtained only after resolution. Also
two approaches4 are known for 2a based on an SN2
displacement reaction and chiral resolution from tar-
taric acid. Herein we present a short, stereoselective and
general approach for both 2a and 3a starting from
isoascorbic acid and ascorbic acid, respectively (Fig. 1).
Our approach to the synthesis of (S,S)-pyrrolidine 2b is
outlined in Scheme 1. D-Isoascorbic acid was converted
into the diol 4 by the sequence of reactions reported
earlier.8 The primary alcohol was converted into its
azide 6 via the tosylate using TsCl–Py and NaN3 in
Figure 1.
2
Keywords: regioselective cyclization; amino ditosylated compounds; SN displacement; chiral pyrrolidines.
ꢀ IICT Communication Number: 030307.
* Corresponding author. Tel.: +91-40-27160512; fax: +91-40-27160512; e-mail: venky@iict.ap.nic.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01362-5

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A. R. Kumar et al. / Tetrahedron Letters 44 (2003) 5687–5689
Scheme 1. Reagents and conditions: (a) p-TsCl, Py, 0°C, 12 h,
93%; (b) NaN3, DMF, 80°C, 8 h, 96%; (c) NaH, MeI, DMF,
0°C–rt, 6 h, 91%; (d) PTSA (cat.), MeOH, rt, 10 h, 83%; (e)
p-TsCl, Et3N, DCM, rt, 24 h, 83%; (f) TPP, MeOH, reflux, 12
h then (Boc)2O, Et3N, THF, 14 h, 48%; (g) NaN3, DMF,
80°C, 8 h, 84%; (h) Pd/C, H2, EtOH, rt, 2 h, then Et3N,
(Boc)2O, DCM, 96%.
Scheme 2. Reagents and conditions: (a) p-TsCl, Py, 0°C, 12 h,
89%; (b) NaN3, DMF, 80°C, 8 h, 92%; (c) NaH, MeI, DMF,
0°C–rt, 6 h, 94%; (d) PTSA (cat.), MeOH, rt, 10 h, 83%; (e)
p-TsCl, Et3N, DCM, rt, 24 h, 87%; (f) TPP, MeOH, reflux, 12
h then (Boc)2O, Et3N, THF, 14 h, 52%; (g) NaN3, DMF,
80°C, 3 days, 75%; (h) Pd/C, H2, EtOH, rt, 2 h, then Et3N,
(Boc)2O, DCM, 95%; (i) MeI, NaH, DMF, 0°C to rt, 2 h,
94%.
DMF. The azidoalcohol thus obtained was protected as
the methylether using MeI/NaH to give compound 7.
Under acidic conditions (cat. amount of PTsA in
MeOH) compound 7 underwent isopropylidine cleav-
age to furnish the diol 8,9 which was converted into
ditosyl derivative 9 using TsCl/Et3N. Reaction of com-
pound 9 in TPP/MeOH at reflux resulted in azide
reduction and regioselective cyclization to give the
pyrrolidine derivative, which was subsequently Boc
protected to give 10.
Spectral data for some selected compounds:
Compound 2b: [h]D25=−18.6 (c 0.6, MeOH) [(lit.4 [h]2D5=
−18.1 (c 1.08, MeOH)]; IR (neat, cm−1): 3318, 2924,
1
1688, 1414, 1168; H NMR (200 MHz, CDCl3): l 1.46
(s, 18H), 3.21–3.44 (m, 3H), 3.41 (s, 3H), 3.61 (dd, 1H,
J=5.5 Hz, 12 Hz), 3.62–3.8 (m, 1H), 3.98–4.12 (m, 1H),
4.6 (bs, 1H); FABMS m/z 317 (M++1).
Compound 3b: [h]2D5=+ 51.7 (c 0.65, MeOH) [(lit.3
[h]2D5=+53.7 (c 1.00, MeOH)]; IR (neat, cm−1): 2931,
Next, the tosyl group in compound 10 underwent SN2
displacement with NaN3 in DMF to furnish azide 11
which on further reduction with Pd/C, H2 and protec-
tion with (Boc)2O afforded compound 2b whose spec-
tral and analytical data were in agreement with the
reported values.4 Compound 2b, after N-methylation
and Boc deprotection was coupled with the naph-
thyridine moiety to give AG-7352 1, which has been
reported in the literature.5
1
2358, 1695, 1404, 1366, 1156, 879, 757; H NMR (300
MHz, CDCl3): 1.48 (s, 9H), 1.49 (s, 9H), 2.89 (s, 3H),
3.32 (s, 3H), 3.36–3.61 (m, 4H), 3.9 (m, 1H), 4.6 (m,
1H). FABMS m/z 331 (M++1).
Acknowledgements
A.R.K. and J.S.R. thank CSIR and U.G.C. New Delhi,
for research fellowships. We also thank Dr. J. S. Yadav
and Dr. G. V. M. Sharma for their support and encour-
agement and Dr. A. C. Kunwar (NMR Group) for
fruitful discussions.
Pyrrolidine 3b was synthesized from
L-ascorbic acid
using the same strategy following the sequence of reac-
tions described in Scheme 2. In this case conversion of
compound 18 to its azide 19 required heating the
reaction mixture for 3 days at 80°C. This may be due to
steric hindrance resulting from the ‘trans’ configuration
in compound 18. On treatment with Pd/C, H2 the azide
group in 19 was reduced to the amine which was
protected as its Boc derivative and N-methylated to
give 3b whose spectral and analytical data were in
agreement with the assigned structure. Compound 3b,
after Boc deprotection, was coupled with the quinoline
moiety reported in the literature.3
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