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

Article abstract of DOI:10.1016/j.tetlet.2004.08.167

Facile chemoenzymatic enantioselective synthesis of (3S,4S)-3-methoxy-4- methylaminopyrrolidine, a key intermediate for a new quinolone antitumor compound AG-7352 has been described. This methodology illustrates the preparation of 3-azido-1-benzyloxycarbo

Full text of DOI:10.1016/j.tetlet.2004.08.167

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8057–8059
Chemoenzymatic synthesis of (3S,4S)- and
(3R,4R)-3-methoxy-4-methylaminopyrrolidine
Ahmed Kamal,a,* Ahmad Ali Shaik,a Mahendra Sandbhor,a
M. Shaheer Malika and Harumi Kagab
aBiotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bNational Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Japan
Received 6 August 2004;revised 20 August 2004;accepted 27 August 2004
Available online 17 September 2004
Abstract—Facile chemoenzymatic enantioselective synthesis of (3S,4S)-3-methoxy-4-methylaminopyrrolidine, a key intermediate
for a new quinolone antitumor compound AG-7352 has been described. This methodology illustrates the preparation of 3-azido-
1-benzyloxycarbonyl-4-hydroxypyrrolidine starting from diallylamine via 1-benzyloxycarbonyl-3-pyrroline obtained by ring-closing
metathesis (RCM) employing GrubbsÕ catalyst. Enzymatic transesterification employing PS-C lipase gave (3S,4S)-3-azido-1-benzyl-
oxycarbonyl-4-hydroxypyrrolidine in >99% ee, which upon methylation of the hydroxyl group followed by sequential reactions gave
the desired intermediates, (3S,4S)-1-tert-butoxycarbonyl-3-tert-butoxycarbonylamino-4-methoxypyrrolidine.
Ó 2004 Published by Elsevier Ltd.
A large number of synthetic and naturally occurring
biologically important compounds contain chiral pyrro-
lidines as subunits in their structures.1 Tsuzuki and
co-workers2,3 have recently developed a novel antitumor
agent quinolone framework that has a 3-methoxy-4-
methylaminopyrrolidine group 2a at the C-7 position
(AG-7352, 1). This compound has been claimed to
possess equal or superior antitumor activity to those
of cisplatin and etoposide against human breast, ovar-
ian, and colon cancers implanted in nude mice.4 Some
quinolone related compounds show antitumor activity
with inhibition of eukaryotic topoisomerase II.5 3-Meth-
oxy-4-methylaminopyrrolidine 2a is a key intermediate
for the synthesis of 1 and it is also an intermediate
for related biologically important heterocyclic com-
pounds.6,7 Recently, a structure activity relationship
study carried out for 7-substituted 1,4-dihydro-4-oxo-
1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids has
shown that the stereochemistry of the 7-substituted
pyrrolidine group effects the in vitro and in vivo cytotoxi-
city of these compounds,8 thus illustrating the
importance of the preparation of this pyrrolidine inter-
mediate in optically pure form. There are very few
methods that have been reported for the stereospecific
synthesis of this biologically active pyrrolidine interme-
diate. These methods involve either a chiron approach2,9
or an optical resolution of a racemate.3 In view of
our interest for the development of chemoenzymatic
methodologies, it was considered of interest to develop
a chemoenzymatic route for the preparation of the
optically active precursor 2b. Herein, we wish to report
an efficient chemoenzymatic synthesis of 2b starting
from diallylamine involving ring-closing metathesis
and lipase mediated resolution.
O
CO2H
MeO
NHR
N
N
N
MeHN
MeO
N
R1
N
S
(S,S)
2a R=Me, R1=H
2b R= R1=Boc
AG-7352 (1)
In the present synthetic strategy, commercially available
diallylamine 3 was employed as the starting material for
the construction of the pyrrolidine ring. The amine func-
tionality of compound 3 was protected with CbzCl
before ring-closing metathesis employing GrubbsÕ cata-
lyst to give N-Cbz-3-pyrroline 5. The epoxide 6 was
*
Corresponding author. Tel.: +91 40 27193157;fax: +91 40
27193189;e-mail: ahmedkamal@iict.res.in
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.08.167

8058
A. Kamal et al. / Tetrahedron Letters 45 (2004) 8057–8059
i
ii
HO
N3
N3
HO
N3
AcO
N
N
H
N
i
Cbz
Cbz
+
N
N
N
3
4
5
Cbz
Cbz
(3R,4R)-8
Cbz
(3S,4S)-7
(3R,4R)-7
iii, iv
( )-7
ii
O
HO
N3
v
Scheme 2. Reagents and conditions: (i) lipase PS-C, vinyl acetate,
diisopropylether, 10h;(ii) K 2CO3, methanol, 2h.
N
Cbz
N
Cbz
7
6
ether (3S,4S)-9 using MeI/NaH. The pyrrolidine azide
(3S,4S)-9 was reduced to its amine under mild condi-
tions employing PPh3 in THF–H2O followed by protec-
tion with (Boc)2O to give (3S,4S)-10. Compound
(3S,4S)-10 upon Cbz deprotection under extremely mild
Scheme 1. Reagents and conditions: (i) CbzCl, Et3N, CH2Cl2, rt, 10h,
98%;(ii) (Pcy 2)2Cl2Ru@CHph, CH2Cl2, rt, 6h, 96%;(iii) NBS,
DMSO–H2O, rt, 2h, 89%;(iv) 1N NaOH, rt, 1h, 76%;(v) NaN
1,4-dioxane–H2O, reflux, 12h, 85%.
,
3
conditions
employing
poly(methylhydrosiloxane)
obtained from 5 via its bromohydrin and epoxide 6
upon treatment with NaN3 yielded the required interme-
(PMHS) over 10% Pd/C in ethanol followed by treat-
ment with (Boc)2O gave the required product (3S,4S)-
2b with >99% ee. The other enantiomer (3R,4R)-7
obtained by employing the same reaction sequence
was converted to (3R,4R)-2b with 81% ee (Scheme 3).
The absolute configurations of the compounds have
been confirmed by comparison of their rotation values
with those previously reported.17
diate ( )-trans-3-azido-1-Cbz-4-hydroxypyrrolidine
7
(Scheme 1). In view of our interest in enzyme mediated
kinetic resolutions of chiral building blocks,10 we carried
out the lipase mediated resolution of compound ( )-7. A
number of lipases from different sources11 were exam-
ined for this process and it was observed that lipases
from Pseudomonas cepacia particularly in their immobi-
lized forms, that is, PS-C (lipase immobilized on ceramic
particles) and PS-D (lipase immobilized on diatom-
aceous earth) gave interesting results with respect to
conversion and enantioselectivity. Moreover, the effect
of various solvents was also investigated for this transe-
sterification process employing PS-C lipase.12 Diisoprop-
yl ether provided suitable conversion with high enantio-
selectivity employing vinyl acetate as an acylating
agent (Scheme 2). The lipase catalyzed transesterifica-
tion13 of ( )-trans-3-azido-1-Cbz-4-hydroxypyrrolidine
7 using PS-C lipase and vinyl acetate in diisopropyl
ether afforded (3S,4S)-7 (46% yield, >99% ee)14
and (3R,4R)-8 (52% yield, 81% ee).15 The deacetylation
of (3R,4R)-8 using anhydrous K2CO3 in methanol gave
(3R,4R)-7 with 81% ee.16
In summary, an efficient chemoenzymatic methodology
has been developed for the preparation of (3S,4S)-2b a
key intermediate required for the synthesis of the novel
quinolone antitumor agent AG-7352 1. This protocol
provides excellent enantiomeric excess through lipase
PS-C mediated kinetic resolution. Moreover this meth-
od utilizes a simple and inexpensive starting material,
diallylamine for building the pyrrolidine ring. Addition-
ally this method describes the synthesis of both the
enantiomers of this key intermediate 2b in high degree
of enantiopurity.
Acknowledgements
The enantiomerically enriched (3S,4S)-3-azido-1-Cbz-4-
hydroxypyrrolidine 7 obtained by the lipase mediated
kinetic resolution of ( )-7 was converted to its methyl
One of the authors (A.K.) is thankful to the Department
of Science and Technology, New Delhi and the Japan
Society for the Promotion of Science for the award of
MeO
NHBoc
MeO
N3
MeO
NHBoc
iv, v
HO
N3
ii, iii
i
N
N
N
N
Boc
Cbz
Cbz
Cbz
(3S,4S)-2b
(3S,4S)- 9
(3S,4S)-10
(3S,4S)-7
MeO
NHBoc
HO
N3
i
ii, iii
iv, v
(3R,4R)- 9
(3R,4R)- 10
N
N
Boc
Cbz
(3R,4R)-2b
(3R,4R)-7
Scheme 3. Reagents and conditions: (i) MeI, NaH, DMF, rt, 6h, 72%;(ii) PPh 3, THF–H2O, rt, 2h;(iii) (Boc) 2O, Et3N, rt, 6h, 93%;(iv) PHMS, 10%
Pd/C, EtOH;(v) (Boc) 2O, Et3N, rt, 8h, 95%.

A. Kamal et al. / Tetrahedron Letters 45 (2004) 8057–8059
8059
A.;Sandbhor, M. Biorg. Med. Chem. Lett. 2002, 12, 1735;
(c) Kamal, A.;Khanna, G. B. R.;Ramu, R.;Krishnaji, T.
Tetrahedron Lett. 2003, 44, 4783;(d) Kamal, A.;Ramana,
K. V.;Rao, M. V. J. Org. Chem. 2001, 66, 997.
JSPS Invitation fellowship to work in Japan. Three
other authors (A.A.S., M.S., and M.S.M.) are also
thankful to CSIR, New Delhi for the award of research
fellowship.
11. Different lipases were screened, among them Pseudomonas
cepacia (PS-C) gives good enantioselectivity within 10h
compared to PS-D. Pseudomonas cepacia lipase (PS),
Pseudomonas fluorescens (AK-20), Lipozyme immobilized
from Mucor miehei, Candida rugosa lipase gave lower
enantioselectivities. There were no significant conversions
by employing lipases from Candida antartica, Porcine
pancreas, and Candida cylindracea.
References and notes
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The
12. A number of solvents such as diisopropyl ether, toluene,
THF, tert-butyl methyl ether, and hexane were examined
for this protocol. It was observed that diisopropyl ether
was efficient for this lipase mediated resolution, whereas
toluene takes longer (2days) reaction times and gave
comparatively low enantioselectivity. The results employ-
ing THF, tert-butyl methyl ether, and hexane were not
satisfactory.
2. Tsuzuki, Y.;Chiba, K.;Hino, K. Tetrahedron: Asymmetry
2001, 12, 1739.
3. Tsuzuki, Y.;Chiba, K.;Hino, K. Tetrahedron: Asymmetry
2001, 12, 2989.
13. General procedure for lipase mediated transesterification:
To a solution of ( )-trans-3-azido-1-Cbz-4-hydroxypyrro-
lidine 7 (1mmol) in diisopropyl ether (10mL) was added
lipase PS-C (1equiv w/w), vinyl acetate (6mmol). The
suspension was shaken at 150rpm at 40°C. The reaction
mixture was monitored by chiral HPLC analysis until it
reached about 50% conversion (10h). The reaction was
filtered and the filtrate was washed with water followed by
brine. The organic layer was dried over anhydrous sodium
sulfate, concentrated under reduced pressure, and purified
by silica gel column chromatography. The enantiopurity
of the products (3S,4S)-7 and (3R,4R)-8 were determined
by a chiral HPLC using Chiralcel OD column (hexane–
isopropanol, 80:20) with 0.5mL/min flow rate and com-
pared with the corresponding racemic products.
4. (a) Tomita, K.;Tsuzuki, Y.;Shibamori, K.;Kashimoto,
S.;Chiba, K. 217th ACS National Meeting, 1999;Abstract
249;(b) Chiba, K.;Tsuzuki, Y.;Tomita, K.;Mizuno, K.;
Sato, Y. 218th ACS National Meeting, 1999;Abstract 127.
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132.
25
14. Compound (3S,4S)-7: tR = 15.49min; ½aꢀD +14.3 (c 1.06,
CHCl3).
15. Compound (3R,4R)-8: tmajor = 18.97, tminor = 17.61min;
25
½aꢀD ꢁ17.7 (c 1.02, CHCl3).
25
16. Compound (3R,4R)-7: tmajor = 19.19, tminor = 15.49min;
½aꢀD ꢁ10.6 (c 1.02, CHCl3).
17. Spectral data for compounds (3S,4S)-2b and (3R,4R)-2b:
25
Compound (3S,4S)-2b: ½aꢀD ꢁ18.7 (c 1.01, MeOH) {lit.2
25
25
½aꢀD ꢁ18.1 (c 1.08, MeOH)}. Compound (3R,4R)-2b: ½aꢀD
8. Tsuzuki, Y.;Tomita, K.;Shibamori, K.;Sato, Y.;
Kashimoto, S.;Chiba, K. J. Med. Chem. 2004, 47, 2097.
9. Kumar, A. R.;Reddy, J. S.;Rao, B. V. Tetrahedron Lett.
2003, 44, 5687.
10. (a) Kamal, A.;Shaik, A. A.;Sandbhor, M.;Malik, M. S.
Tetrahedron: Asymmetry 2004, 15, 935–938;(b) Kamal,
+14.7 (c 1.1, MeOH);IR (neat): 3318, 2924, 1685, 1410,
1163cmꢁ1; H NMR (200MHz, CDCl3): d 1.46 (18H, s),
1
3.2–3.46 (3H, m), 3.42 (3H, s), 3.64 (1H, dd, J = 5.5,
12Hz), 3.75–3.84 (1H, m), 3.96–4.09 (1H, m), 4.69 (1H, br
s);FABMS ( m/z): 317 (M++1).