Stereoselective synthesis of (3R,4S)-3-methoxy-4-methylaminopyrrolidine

Article abstract of DOI:10.1016/j.tetlet.2004.11.033

An efficient stereoselective approach for the synthesis of (3R,4S)-3-methoxy-4-methylaminopyrrolidine, a part of the structure of quinoline antibacterial compound (1a) and the naphthyridine antitumour agent (1b) has been described.

Full text of DOI:10.1016/j.tetlet.2004.11.033

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 323–324
Stereoselective synthesis of
(3R,4S)-3-methoxy-4-methylaminopyrrolidineq
A. Madhan and B. Venkateswara Rao*
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 17 September 2004; revised 28 October 2004; accepted 5 November 2004
Available online 25 November 2004
Abstract—An efficient stereoselective approach for the synthesis of (3R,4S)-3-methoxy-4-methylaminopyrrolidine, a part of the
structure of quinoline antibacterial compound (1a) and the naphthyridine antitumour agent (1b) has been described.
Ó 2004 Elsevier Ltd. All rights reserved.
Chiral and nonracemic pyrrolidines are found as sub-
units in many biologically active natural and unnatural
products.1 Okada et al.2,3 showed that a new series of
quinoline compounds, for example, (1a), bearing a
(3R,4S)-3-methoxy-4-methylaminopyrrolidine, had the
highest in vivo and excellent in vitro antibacterial activ-
ity against pathogens such as Gram+ve and Gramꢀve
bacteria and were chosen for further evaluation of
their biological activities. Tsuzki et al.4 also
reported that (3R,4S)-3-methoxy-4-methylaminopyrrol-
idine attached to the naphthyridine ring at C-7 of (1b)
led to potent cytotoxic activity against murine P388 leu-
kemia cells.
droxyl units,5 we developed recently an approach for
the synthesis of chiral pyrrolidines5g (S,S)-3 and (S,R)-
4 in optically pure form. Prior to our work there was
only one reported approach for the synthesis of 2,
whereby the chiral compound was obtained after resolu-
tion.3 Herein we present a short stereoselective approach
for the synthesis of 2 starting from commercially avail-
able (R)-2,3-O-isopropylidene glyceraldehyde.5e
Our approach to the synthesis of pyrrolidine 2 is out-
lined in Scheme 1. (R)-2,3-O-Isopropylidene glyceralde-
hyde 5 was converted into 6 by the imine addition
reaction reported by Cativiela and co-workers6 This ap-
proach was utilised by us earlier for the synthesis of (ꢀ)-
In continuation of our interest in the synthesis of biolog-
ically active compounds having vicinal amino and hy-
cytoxazone and azasugars.5a,e Compound 6 on treat-
25
ment with 60% AcOH at rt gave diol 7, ½aꢁ ꢀ25.2 (c
D
NH2
O
O
COOH
COOH
F
NHMe
MeO
N
N
N
N
N
MeHN
MeHN
.HCl
F
N
H
.2 HCl
N
S
MeO
MeO
(1a)
(1b)
(R,S) - 2
BocNH
OMe
BocMeN
OMe
N
N
Boc
Boc
(S,R) - 4
(S,S) - 3
q IICT Communication No.: 040927.
*
Corresponding author. Tel.: +91 040 27160123x2614; fax: +91 040 27160512; e-mail: venky@iict.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.033

324
A. Madhan, B. V. Rao / Tetrahedron Letters 46 (2005) 323–324
O
O
OH
OH
O
O
HO
HO
TBSO
ref.5e, 6
H
a
b
O
NBnBoc
6
NBnBoc
7
NBnBoc
8
5
OMe
OMe
OMe
HO
TBSO
c
d
e
OH
NBnBoc
NBnBoc
NBnBoc
9
11
10
MeO
NBnMe
MeO
NHMe
OMe
HO
f
g
h
OH
N
N
NBnMe
12
Bn
13
H. 2 HCl
2
Scheme 1. Reagents and conditions: (a) 60% AcOH, rt, 12h, 84%; (b) TBS-Cl, imidazole, DCM, 0°C to rt, 8h, 75%; (c) MeI, AG2O, DMF, 0°C to
rt, 12h, 82%, (d) TBAF, THF, 0°C to rt, 8h, 84%; (e) O3, DCM, NABH4, MeOH; ꢀ78°C to rt, 12h, 75%; (f) LiAlH4, THF, reflux, 6h, 75%; (g)
Tf2O, 2,6-lutidine, DCM, ꢀ78°C, 30min, BnNH2, DCM, ꢀ78°C to rt, 24h, 77%; (h) H2, Pd/C, MeOH, HCl, rt, 12h, 85%.
Asymmetry 1996, 7, 927–964; (c) OÕHagan, D. Nat. Prod.
Rep. 1997, 14, 637–651.
2. Okada, T.; Ezumi, K.; Yamakawa, M.; Sato, H.; Tsuji, T.;
Tsushima, T.; Motokawa, K.; Komatsu, Y. Chem. Pharm.
Bull. 1993, 41, 126–131.
3. Okada, T.; Sato, H.; Tsuzi, T.; Tsushima, T.; Nakai, H.;
Yoshida, T.; Matsuura, S. Chem. Pharm. Bull. 1993, 41,
132–138.
4. Tsuzuki, Y.; Tomita, K.; Shibamori, K.; Sato, Y.; Kashi-
moto, S.; Chiba, K. J. Med. Chem. 2004, 47, 2097–
2109.
5. (a) Madhan, A.; Kumar, A. R.; Rao, B. V. Tetrahedron:
Asymmetry 2001, 12, 2009–2011; (b) Bhaskar, G.; Rao, B.
V. Tetrahedron Lett. 2003, 44, 915–917; (c) Kumar, A. R.;
Bhaskar, G.; Madhan, A.; Rao, B. V. Synth. Commun.
2003, 33, 2907–2916; (d) Kumar, A. S.; Haritha, B.; Rao, B.
V. Tetrahedron Lett. 2003, 44, 4261–4263; (e) Madhan, A.;
Rao, B. V. Tetrahedron Lett. 2003, 44, 5641–5643; (f) Ravi
Kumar, A.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5645–
5647; (g) Ravi Kumar, A.; Santosh Reddy, J.; Rao, B. V.
Tetrahedron Lett. 2003, 44, 5687–5689; (h) Bhaskar, G.;
Kumar, V. S.; Rao, B. V. Tetrahedron: Asymmetry 2004,
15, 1279–1283.
1.0, CHCl3), which on further reaction with TBDMS-Cl/
25
D
imidazole afforded 8, ½aꢁ ꢀ27.7 (c 1.0, CHCl3). Methyl-
25
D
CHCl3). Desilylation of 9 with TBAF (0.1M soln in
ation of 8 using MeI/Ag2O gave 9, ½aꢁ ꢀ15.7 (c 1.0,
25
THF) resulted in 10, ½aꢁ ꢀ16.9 (c 1.0, CHCl3), which
25
D
was subjected to ozonolysis followed by NaBH4 reduc-
tion to give 11, ½aꢁ ꢀ1.59 (c 1.0, CHCl3). Treatment
25
D
of 11 with LiAlH4 gave the N-methylated compound
12, ½aꢁ ꢀ11.9 (c 1.0, CHCl3). Compound 12 on cyclisa-
D
tion with Tf2O/BnNH2 afforded 137 in 77% yield. Pyr-
rolidine 13, underwent debenzylation with H2/Pd,C
finally to afford the target molecule 2, as its HCl salt8
with 1H NMR spectral and physical data in good agree-
ment with the literature.3
In conclusion, a general and highly efficient stereoselec-
tive synthesis of (3R,4S)-3-methoxy-4-methylamino-
pyrrolidine 2 has been achieved (10% overall yield),
which is a useful procedure for making this compound
on large scale. This approach is likely to be of value in
making other analogues.
6. Badorrey, R.; Cativiela, C.; Diaz-de-villegas, M. D.; Gal-
vez, J. A. Synthesis 1997, 747–749.
25
7. Spectral data for compound 13: ½aꢁD ꢀ44.5 (c 0.6, CHCl3),
Acknowledgements
IR (neat, cmꢀ1): 2922, 2788, 1744, 1435, 1211, 755; 1H
NMR (300MHz, CDCl3): d 2.19 (s, 3H), 2.60 (dd, 1H,
J = 3.0, 10.5Hz), 2.65–2.75 (m, 1H), 2.89–2.99 (m, 2H),
3.11 (dd, 1H, J = 4.5, 10.5Hz), 3.36 (s, 3H), 3.46 (d, 1H,
J = 12.8Hz), 3.62–3.76 (m, 3H), 3.81–3.87 (m, 1H), 7.17–
7.31 (m, 10H). FABMS m/z 311 (M++1).
One of the authors (A.M.) thanks the CSIR, New Delhi
for a research fellowship. We also thank Dr. J. S. Yadav
and Dr. A. C. Kunwar for their support and
encouragement.
8. Spectral data for compound 2: mp 179–181°C [(lit.3 181–
25
25
182°C)]; ½aꢁD ꢀ52.0 (c 0.75, MeOH) [lit.3 ½aꢁD ꢀ53.1 (c 1.03,
MeOH)]; IR (neat, cmꢀ1): 3272, 2931, 2363, 1644, 1444, 1022;
1H NMR (400MHz, CD3OD): d 2.81 (s, 3H), 3.37–3.58 (m,
2H), 3.55 (s, 3H), 3.77–3.95 (m, 2H), 4.15 (1H, m), 4.40 (1H,
m); 13C NMR (CD3OD, 75MHz): d 77.3, 59.9, 57.7, 45.2, 33.2.
References and notes
1. (a) Attygalle, A. B.; Morgan, D. E. Chem. Soc. Rev. 1984,
13, 245–278; (b) Pichon, M.; Figadere, B. Tetrahedron: