A facile synthesis of CD45 protein tyrosine phosphatase inhibitor marine natural product pulchellalactam

Article abstract of DOI:10.1055/s-2004-822407

A facile five-step route to the naturally occurring CD45 protein tyrosine phosphatase inhibitor, (Z)-pulchellalactam, with 64% overall yield has been demonstrated starting from citraconimide (5) via regioselective NaBH₄ reduction, catalytic hydrogenation, resin-catalyzed dehydration, W-BOC protection, and stereoselective condensation pathway.

Full text of DOI:10.1055/s-2004-822407

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SHORT PAPER
A Facile Synthesis of CD45 Protein Tyrosine Phosphatase Inhibitor Marine
Natural Product Pulchellalactam1
F
acile Synthe
s
i
is of
P
v
am
prakasam Mangaleswaran, Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Fax +91(20)25893153; E-mail: argade@dalton.ncl.res.in
Received 17 February 2004; revised 29 March 2004
take the advantage of such type of regioselective reduc-
Abstract: A facile five-step route to the naturally occurring CD45
protein tyrosine phosphatase inhibitor, (Z)-pulchellalactam, with
64% overall yield has been demonstrated starting from citraconim-
ide (5) via regioselective NaBH4 reduction, catalytic hydrogenation,
tion of maleimides for an efficient synthesis of 10
(Scheme 2). Citraconimide (5) underwent a highly regio-
selective NaBH4-reduction to exclusively give the corre-
resin-catalyzed dehydration, N-BOC protection, and stereoselective sponding hydroxylactam 6 in ca 100% yield. The
condensation pathway.
palladium on charcoal-catalyzed hydrogenation of 6 fur-
nished a mixture of the two stereoisomers of 7 in ca 100%
yield, in a 1:2 ratio (by 1H NMR spectrum). Such type of
hydroxylactams on treatment with p-toluenesulfonic acid
(p-TSA) are known to undergo polymerization reac-
tions.12 We systematically studied the dehydration of 7
under acidic conditions. p-TSA in refluxing benzene gave
the desired product 10 only in 25–30% yields. The lactam
7 on heating in glacial HOAc at 80 ºC for one hour fur-
nished 10 with 50–55% yield. Finally, we could effect an
efficient conversion of 7 to 10 using the strong acidic resin
Amberlyst. The resin-catalyzed dehydration of 7 in re-
fluxing CH3CN gave the desired 4-methyl-3-pyrrolin-2-
one (10)13 in 92% yield. We surmise that the above dehy-
dration process of 7 to 10 takes place via intermediate 9
and a very facile in situ prototopic shift.14 The conversion
of 9 to 10 could be because of conjugation of the carbon-
carbon double bond with the carbonyl group. The lactam
10 on reaction with BOC-anhydride in CH3CN at room
temperature gave the BOC-protected lactam 11 in 85%
yield. The lactam 11 under Li et al. conditions6 exclusive-
ly furnished the bioactive natural product (Z)-pulchella-
lactam (1) in 82% yield. The analytical and spectral data
obtained for 1 were in complete agreement with the re-
ported data.5–7 Starting from citraconimide (5), pulchella-
lactam (1) was obtained in five-steps with 64% overall
yield.
Key words: CD45 PTP inhibitor, pulchellalactam, citraconimide,
two reductions, resin-catalyzed dehydration, synthesis
Recently, a receptor-like transmembrane protein tyrosine
phosphatase, CD45,2 has been shown to play a crucial role
in activation of both B and T cells.3 CD45 therefore rep-
resents a therapeutic target for various autoimmune and
chronic anti-inflammatory diseases.4 As a part of efforts
to find enzyme inhibitors from microbiological sources,
Alvi et al.5 identified the marine fungus Corollospora pul-
chella extract with very potent CD45 activity and a novel
pulchellalactam (1) was isolated from the crude extract as
an active component. Recently, Li et al.6 reported the first
total synthesis of 1 in six steps and 32% overall yield from
BOC-glycine. Very recently, Parsons et al.7 reported a
second four-step synthesis of 1 with 10% overall yield
starting from 2-methylhexan-3-one via a metal catalyzed
radical cyclization pathway. Development of new effi-
cient synthetic routes to 1 for the realistic supply of the
natural product is a challenging task of current interest.6,7
In our continuing interest8 to provide new synthetic routes
to bioactive natural products using cyclic anhydrides as
potential precursors, we herein report a facile five-step
synthesis of 1 starting from citraconimide (5) via a double
reductive dehydration pathway.
Alkyl and dialkyl substituted maleic anhydrides are
known9 to undergo highly regioselective NaBH4-reduc-
tions at the hindered/relatively more hindered carbonyl
group to directly form the corresponding g-butyrolactones
3. Similar regioselectivity has been also observed10 during
the NaBH4-reductions of alkyl and dialkyl substituted ma-
leimides, but these reactions stop with the formation of
corresponding 5-hydroxy-g-lactams 4 (Scheme 1). Such
type of tight regiocontrol during the NaBH4 reductions
has not been observed11 with the corresponding alkyl and
vicinal dialkyl substituted succinimides. We planned to
Scheme 1
In summary, we have demonstrated an efficient approach
to 4-methyl-3-pyrrolin-2-one and completed a facile syn-
thesis of the bioactive natural product pulchellalactam us-
SYNTHESIS 2004, No. 10, pp 1560–1562
Advanced online publication: 16.06.2004
DOI: 10.1055/s-2004-822407; Art ID: Z03304SS
© Georg Thieme Verlag Stuttgart · New York
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SHORT PAPER
Facile Synthesis of Pulchellalactam
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Scheme 2 Reagents, conditions and yields: (i) NaBH4 (1 equiv), EtOH, –40 ºC, 1 h (ca 100%); (ii) Pd/C, H2, MeOH, r.t., 2 h (ca 100%); (iii)
(a) p-TSA (cat.), benzene, reflux, 3 h (25–30%), (b) HOAc, 80 ºC, 1 h (50–55%), (c) Amberlyst resin, CH3CN, reflux, 2 h (92%); (iv) (BOC)2O
(1.5 equiv), DMAP, CH3CN, r.t., 3 h (85%); (v) NaH, THF, isobutyraldehyde, r.t., 5 min. (82%).
give saturated hydroxylactam 7; yield:1.15 g (ca 100%); thick col-
orless oil.
IR (CHCl3): 3261, 1672, 1460 cm–1.
ing a new synthetic approach. We feel that the present
approach is general and can be used to design a synthetic
library of pulchellalactam analogues.
1H NMR (200 MHz, CD3OD): d = 1.05 (d, J = 6 Hz, 2 H), 1.07 (d,
J = 8 Hz, 1 H), 1.57–2.75 (complex m, 3 H), 4.77 (d, J = 2 Hz, 0.33
H), 5.01 (d, J = 6 Hz, 0.67 H).
Melting points are uncorrected. 1H NMR spectra were recorded on
a Bruker AC 200 NMR spectrometer (200 MHz), Bruker MSL 300
NMR spectrometer, and Bruker DRX 500 NMR spectrometer with
TMS as an internal standard. The 13C NMR spectra were recorded
on a Bruker AC 200 NMR spectrometer (50 MHz), Bruker MSL
300 NMR spectrometer (75 MHz), and Bruker DRX 500 NMR
spectrometer (125 MHz). Mass spectra were recorded on a Finnigan
Mat 1020 mass spectrometer at 70 eV. Column chromatographic
separations were carried out on ACME silica gel (60–120 mesh).
Petroleum ether with a bp range of 60–80 ºC was used. NaBH4, pal-
ladium on carbon (10 wt%), p-toluenesulfonic acid, Amberlyst res-
in, di-t-butyl carbonate, NaH, dimethylaminopyridine, and
isobutyraldehyde were obtained from Aldrich Chemical Co. Citra-
conimide (5) was prepared from citraconic anhydride by using the
known procedure.15
MS: m/z = 115, 98, 70, 57, 46.
Anal. Calcd for C5H9NO2: C, 52.16; H, 7.88; N, 12.17. Found: C,
51.97; H, 7.96; N, 12.28.
4-Methyl-3-pyrrolin-2-one (10)
To a solution of sat. hydroxylactam 7 (575 mg, 5 mmol) in anhyd
CH3CN was added Amberlyst resin (100 mg) and the reaction mix-
ture was refluxed under Ar atmosphere for 2 h. The reaction mixture
was allowed to reach r.t. and then it was filtered and concentrated
under reduced pressure to give a residue. Silica gel column chro-
matographic purification of the residue using EtOAc and MeOH
mixture (98:2) gave pure lactam 10; yield: 446 mg (92%); colorless
crystalline solid; mp 110–111 °C.
IR (CHCl3): 3460, 1717, 1688, 1261, 1215 cm–1.
5-Hydroxy-4-methyl-3-pyrrolin-2-one (6)
1H NMR (500 MHz, CDCl3): d = 2.06 (s, 3 H), 3.90 (s, 2 H), 5.83
NaBH4 (1.60 g, 40 mmol) was added at –30 ºC to a solution of cit-
raconimide (5; 4.44 g, 40 mmol) in absolute EtOH (60 mL). After
the reaction mixture was stirred at –30 °C to –40 ºC for 50 min, the
excess NaBH4 was quenched at –40 ºC by adding drop-wise 10%
aqueous HOAc to pH 7. The solvent was evaporated under reduced
pressure at r.t. and the residue was extracted with acetone (50 mL).
Filtration and evaporation of the extract in vacuo afforded 6; yield:
4.52 g (ca 100%); colorless crystalline solid; mp 163–164 °C
(EtOAc).
IR (Nujol): 3202, 1711, 1665, 1645, 1460 cm–1.
1H NMR (500 MHz, CD3OD): d = 2.05 (s, 3 H), 5.36 (s, 1 H), 5.74
(s, 1 H).
(s, 1 H), 6.35–6.50 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 15.3, 51.7, 122.3, 158.5, 176.0.
Anal. Calcd for C5H7NO: C, 61.83; H, 7.27; N, 14.42. Found: C,
62.01; H, 7.13; N, 14.37.
N-tert-Butoxycarbonyl-4-methyl-3-pyrrolin-2-one (11)
A solution of DMAP (31 mg, 0.25 mmol) in anhyd CH3CN (3 mL)
was added drop-wise to a mixed solution of lactam 10 (243 mg, 2.5
mmol) and di-t-butyl carbonate (818 mg, 3.75 mmol) in CH3CN (12
mL) at r.t. under N2 atmosphere and the mixture was stirred for 3 h.
The reaction mixture was concentrated under vacuum at r.t. to give
a residue. Silica gel column chromatographic purification of the res-
idue using a petroleum ether and EtOAc mixture (7:3) gave thick
colorless oil 11; yield: 420 mg (85%).
13C NMR (125 MHz, CD3OD): d = 13.5, 83.5, 122.4, 163.5, 175.5.
MS: m/z = 113, 98, 85, 69, 39.
Anal. Calcd for C5H7NO2: C, 53.09; H, 6.24; N, 12.38. Found: C,
53.26; H, 6.33; N, 12.41.
IR (CHCl3): 1774, 1724, 1643, 1445 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.51 (s, 9 H), 2.06 (d, J = 2 Hz, 3
H), 4.18 (s, 2 H), 5.82 (br s, 1 H).
5-Hydroxy-4-methyl-2-pyrrolidinone (7)
13C NMR (50 MHz, CDCl3): d = 15.5, 28.0, 54.3, 82.6, 122.8, 149.4,
A mixture of hydroxylactam 6 (1.13 g, 10 mmol) and Pd/C catalyst
(30 mg) in MeOH (15 mL) was subjected to hydrogenation at hy-
drogen balloon pressure for 2 h at r.t. The reaction mixture was fil-
tered through celite and the filtrate was concentrated in vacuo to
158.1, 169.7.
Anal. Calcd for C10H15NO3: C, 60.89; H, 7.67; N, 7.10. Found: C,
61.02; H, 7.77; N, 7.23.
Synthesis 2004, No. 10, 1560–1562 © Thieme Stuttgart · New York

1562
S. Mangaleswaran, N. P. Argade
SHORT PAPER
(4) (a) Hooft van Huijsduijnen, R. Gene 1998, 225, 1.
(b) Trowbridge, J. S. J. Biol. Chem. 1991, 266, 23571.
(c) Janeway, C. A. Annu. Rev. Immunol. 1992, 10, 645.
(d) Trowbridge, I. S. Annu. Rev. Immunol. 1994, 12, 85.
(e) Neel, B. G. Curr. Opin. Immunol. 1997, 9, 405.
(5) Alvi, K. A.; Casey, A.; Nair, B. G. J. Antibiot. 1997, 51, 515.
(6) Li, W.-R.; Lin, S. T.; Hsu, N.-M.; Chern, M.-S. J. Org.
Chem. 2002, 67, 4702.
5-(Z)-Isobutylidene-4-methyl-1,5-dihydropyrrol-2-one (Pulch-
ellalactam, 1)
A solution of N-BOC lactam 11 (197 mg, 1 mmol) in anhyd THF (5
mL) was treated with 60% NaH (62 mg, 1.52 mmol) at r.t. and
stirred for 5 min. Isobutyraldehyde (0.28 mL, 3 mmol) was added
to the mixture and stirred for 5 more min. The reaction mixture was
concentrated in vacuo at r.t. to give a residue. The residue was dis-
solved in CH2Cl2 (30 mL), which was then washed with 5% HCl (10
mL), aq NaHCO3 (10 mL), and brine (10 mL). The organic layer
was dried over Na2SO4, filtered, and concentrated in vacuo. Silica
gel column chromatographic purification of the residue using a pe-
troleum ether and EtOAc mixture (7:3) afforded (Z)-pulchellalac-
tam (1) as thick colorless oil; yield: 124 mg (82%).
(7) Bryans, J. S.; Chessum, N. E. A.; Huther, N.; Parsons, A. F.;
Ghelfi, F. Tetrahedron 2003, 59, 6221.
(8) (a) Kar, A.; Argade, N. P. Tetrahedron 2003, 59, 2991.
(b) Kar, A.; Argade, N. P. Tetrahedron Lett. 2002, 43, 6563.
(c) Kar, A.; Argade, N. P. J. Org. Chem. 2002, 67, 7131.
(d) Mhaske, S. B.; Argade, N. P. Synthesis 2002, 323.
(e) Mhaske, S. B.; Argade, N. P. J. Org. Chem. 2001, 66,
9038. (f) Mangaleswaran, S.; Argade, N. P. J. Chem. Soc.,
Perkin Trans. 1 2001, 1764. (g) Mangaleswaran, S.;
Argade, N. P. J. Org. Chem. 2001, 66, 5259.
IR (CHCl3): 3209, 1682, 1464, 1215 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.11 (d, J = 6 Hz, 6 H), 2.08 (s, 3
H), 2.55–2.90 (m, 1 H), 5.12 (d, J = 8 Hz, 1 H), 5.86 (s, 1 H), 8.81
(br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 11.8, 22.9, 27.6, 120.0, 121.1,
137.5, 148.8, 171.5.
(h) Deshpande, A. M.; Natu, A. A.; Argade, N. P. Synthesis
2001, 702.
(9) (a) Assante, G.; Camarda, L.; Merlini, L.; Nasini, G. Gazz.
Chim. Ital. 1979, 109, 151. (b) Kayser, M. M.; Breau, L.;
Eliev, S.; Morand, P.; Ip, H. S. Can. J. Chem. 1986, 64, 104.
(10) (a) Mase, N.; Nishi, T.; Hiyoshi, M.; Ichihara, K.; Bessho, J.;
Yodo, H.; Takabe, K. J. Chem. Soc., Perkin Trans. 1 2002,
707. (b) Nagasaka, T.; Esumi, S.; Ozawa, N.; Kosugi, Y.;
Hamaguchi, F. Heterocycles 1981, 16, 1987.
Anal. Calcd for C9H13NO: C, 71.49; H, 8.66; N, 9.27. Found: C,
71.55; H, 8.81; N, 9.15.
Acknowledgments
S. M. thanks CSIR, New Delhi, for the award of a research fel-
lowship. N. P. A. thanks the Department of Science and Technolo-
gy, New Delhi, for financial support.
(c) Deshpande, A. M. Ph.D. Dissertation; University of
Kolhapur: India, 2002.
(11) (a) Wijnberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W.
N. Tetrahedron 1978, 34, 179. (b) Wijnberg, J. B. P. A.;
Speckamp, W. N.; Schoemaker, H. E. Tetrahedron Lett.
1974, 46, 4073.
(12) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N.
Tetrahedron 1975, 31, 1437.
(13) Ojima, I.; Korda, A.; Shay, W. R. J. Org. Chem. 1991, 56,
4024.
(14) Baker, J. T.; Sifniades, S. J. Org. Chem. 1979, 44, 2798.
(15) Kuehne, P.; Hesse, M. Tetrahedron 1993, 49, 4575.
References
(1) NCL Communication No. 6660.
(2) Bolen, J. B.; Thompson, P. A.; Eiseman, E.; Horak, I. D.
Adv. Cancer Res. 1991, 57, 103.
(3) (a) Gould, K. L.; Moreno, S.; Tonks, N. K.; Nurse, P.
Science 1990, 250, 1573. (b) Koretzky, G. A.; Picus, J.;
Schultz, T.; Weiss, A. Proc. Natl. Acad. Sci. U.S.A. 1991, 88,
2037. (c) Weaver, C. T.; Pingel, J. T.; Nelson, J. O.; Thomas,
M. L. Mol. Cell. Biol. 1991, 11, 4415. (d) Donovan, J. A.;
Koretzky, G. A. J. Am. Soc. Nephrol. 1993, 4, 976.
Synthesis 2004, No. 10, 1560–1562 © Thieme Stuttgart · New York