Synthesis of Marine Natural Product (2S,5S)-Pyrrolidine-2,5-dicarboxylic Acid

Article abstract of DOI:10.1055/s-2003-41075

A five-step synthesis of marine natural product (2S,5S)-pyrrolidine-2,5- dicarboxylic acid (1) has been described starting from methyl ester of BOC-protected (S)-proline via stereoselective electrochemical oxidation with introduction of the methoxy group at C₅-position by S _N2-substitution of the cyano group followed by hydrolysis in 13% overall yield.

Full text of DOI:10.1055/s-2003-41075

2
304
SHORT PAPER
Synthesis of Marine Natural Product (2S,5S)-Pyrrolidine-2,5-dicarboxylic
1
Acid
S
G
ynthesis of Marin
a
e
N
atura
l
P
n
roduct (2
S
,5
d
S
)-Pyrrolidin
a
e-2,5-dicar
v
boxylic
A
ci da di Sunilkumar, Dendukuri Nagamani, Narshinha P. Argade,* Krishna N. Ganesh*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Fax +91(20)5893153; E-mail: argade@dalton.ncl.res.in; E-mail: kng@ems.ncl.res.in
Received 25 June 2003; revised 7 July 2003
The methyl ester of BOC-protected (S)-proline 2 on
stereoselective electrochemical oxidation at 230 mA cur-
rent in methanol using tetrabutylammonium tetra-
Abstract: A five-step synthesis of marine natural product (2S,5S)-
pyrrolidine-2,5-dicarboxylic acid (1) has been described starting
from methyl ester of BOC-protected (S)-proline via stereoselective
electrochemical oxidation with introduction of the methoxy group fluoroborate (TBATFB) as an electrolyte furnished a
at C -position by S 2-substitution of the cyano group followed by mixture of 5-methoxylated proline derivatives 3 and 4 in
5
N
1
hydrolysis in 13% overall yield.
a 7:3 ratio (by H NMR) in 95% yield. The mixture of di-
Keywords: (S)-proline, stereoselective oxidation, (2S,5S)-pyrroli- astereomers 3 and 4 was not separable using column chro-
dine-2,5-dicarboxylic acid, natural product synthesis
matography. The mixture of compounds 3 plus 4 on
treatment with trimethylsilyl cyanide (1.1 equiv) in
dichloromethane at –30 ºC gave the mixture of cyano
compounds 5 and 6, with complete inversion of configu-
The (2S,5S)-pyrrolidine-2,5-dicarboxylic acid (1) has
been isolated as a marine natural product from the red
2
1
ration at C , in a 7:3 ratio (by H NMR) in 70% yield. The
5
mixture of cyano compounds 5 and 6 were easily separat-
ed by column chromatography on neutral alumina. The
major cis-isomer 5 in the mixture of 5 plus 6 or pure 5 on
alga Schizmenia dubyi and it has been used as a potential
3
chiral building block in -lactam synthesis, as an elegant
4
chiral auxiliary in asymmetric synthesis and in the syn-
thesis of peptides and proteins with unusual conforma- treatment with potassium tert-butoxide (1 equiv) in THF
5
tional properties of therapeutic utility. To date eight at room temperature underwent very smooth isomeriza-
synthesis of 1, starting from enantiomerically pure (S)- tion to furnish the thermodynamically more stable trans-
5
–8
(S)-O-benzyl-glycidol,9 isomer 6 in 80% yield, but with complete racemization.
pyroglutamate derivatives,
1
0,11
pyrrolidine derivatives,
and meso-dimethyl 2,5-dibro- We searched for conditions to obtain the desired trans-
1
2
moadipate, using a variety of elegant synthetic strategies isomer 6, without loss of optical purity. The trans-cya-
noester 6 in refluxing 6 N hydrochloric acid yielded the
hydrochloride salt of the natural product 1 in 92% yield
and the conversion of hydrochloride salt to 1 using propy-
are known in the literature. The provision of new synthetic
routes to this useful natural product and chiral building
block 1 is a challenging task of current interest and herein
5
6
lene oxide treatment in 87% yield is known. The hydro-
we report a stereoselective synthesis of 1 starting from
readily available (S)-proline derivative 2 via an electro-
chloride salt of 1 on reaction with methanol–thionyl
chloride followed by base induced neutralization of the
hydrochloride formed yielded the trans dimethyl ester 8 in
1
3
chemical oxidation (Scheme 1).
2
Scheme 1 (i) Electrochemical oxidation (Carbon electrode, 230 mA/28 cm ), MeOH, TBATFB (0.5 M solution), 0–15 ºC, 10 h (95%,
3
:4 = 7:3); (ii) TMSOTf (0.1 equiv), TMSCN (1.1 equiv), CH Cl , – 35 ºC, 30 min (70%, 5:6 = 7:3); (iii) t-BuOK (1 equiv), THF, r.t., 6 h (80%,
2 2
racemic mixture); (iv) 6 N HCl, reflux, 24 h (92%); (v) SOCl , MeOH, r.t., 12 h (75%); (vi) H O, reflux, 24 h (92%).
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SYNTHESIS 2003, No. 15, pp 2304–2306
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Advanced online publication: 23.09.2003
DOI: 10.1055/s-2003-41075; Art ID: Z09003SS.pdf
Georg Thieme Verlag Stuttgart · New York
©

SHORT PAPER
Synthesis of Marine Natural Product (2S,5S)-Pyrrolidine-2,5-dicarboxylic Acid
2305
2
5
7
5% yield, which on refluxing in water for 24 hours fur- Yield: 1.4 g (70%); more polar, thick oil; [ ]
D
+41.8 (c 0.665,
CHCl3).
nished the natural product (2S,5S)-pyrrolidine-2,5-dicar-
–
1
boxylic acid (1) in 92% yield. The analytical and spectral IR (Neat): 2246, 1745, 1713 cm .
data obtained for 1 and 8 were in complete agreement with
1
H NMR (CDCl , 200 MHz): = 1.35–1.55 (m, 9 H), 2.10–2.45 (m,
The enantiomerically pure cis-iso- 4 H), 3.75 (s, 3 H), 4.20–4.45 (m, 1 H), 4.50–4.70 (m, 1 H).
3
5
–12,14
the reported data.
mer 5 on repetition of a similar reaction sequence gave the
meso-diester 7 and diacid 9.
13
C NMR (CDCl , 50 MHz): = 27.8 (28.3), 29.2 (29.5), 30.0, 47.3,
3
5
1.9, 58.5 (59.1), 81.4 (81.8), 117.9 (118.1), 152.1, 171.5 (171.7).
In summary, starting from readily available (S)-proline MS: m/z (%) = 254 (4), 195 (100), 181 (35), 153 (38), 95 (100).
derivative 2, we have demonstrated a synthesis of a chiral
Anal. Calcd for C H O N (254.26): C, 56.69; H, 7.13; N, 10.99.
1
2
18
4
2
building block and a marine natural product (2S,5S)-pyr-
rolidine-2,5-dicarboxylic acid (1) in five-steps in 13%
overall yield. Similarly, our work on the total synthesis of
bioactive natural products bulgecinine and bulgecins1
via electrochemical oxidation of 3-hydroxyproline is in
progress in our laboratory.
Found: C, 56.83; H, 6.97; N, 10.76.
Minor isomer 6
Yield: 0.69 g (30%); (less polar), thick oil; [ ]D25 – 93.7 (c 0.365,
CHCl3).
3b
–
1
IR (CHCl ): 2241, 1746, 1711 cm .
3
1
H NMR(CDCl , 200 MHz): = 1.30–1.60 (m, 9 H), 2.00–2.60 (m,
3
4
H), 3.70 (s, 3 H), 4.25–4.50 (m, 1 H), 4.55–4.80 (m, 1 H).
1
Melting points are uncorrected. H NMR spectra were recorded on
1
3
C NMR (CDCl , 50 MHz): = 27.4 (27.7), 28.1 (28.5), 29.1
3
Bruker NMR spectrometer with TMS as an internal standard. Opti-
cal rotations were recorded on Bellingham Stanley Ltd Polarimeter.
Column chromatographic separations were done on 230–400 silica
gel and neutral alumina. Petroleum ether with a bp range of 60–
(29.4), 47.2 (47.4), 51.9, 58.2 (58.6), 81.3 (81.7), 118.4, 152.3,
1
71.7 (171.9).
MS: m/z = 254 (4), 195 (25), 95 (100).
8
0 °C was used. Proline was obtained from the SRL Chemical Co.
Anal. Calcd for C H O N (254.26): C, 56.69; H, 7.13; N, 10.99.
Found: C, 56.56; H, 7.06; N, 11.03.
1
2
18
4
2
All other reagents used were obtained from Lancaster Chemical
Company.
(
2S,5S)-Pyrrolidine-2,5-dimethyldicarboxylate (8)
Methyl (2S)-N-(tert-Butoxycarbonyl)-5(R/S)-methoxyproline-
carboxylate (3 + 4)
Solution of isomer 6 (0.4 g, 1.57 mmol) in 6 N HCl (10 mL) was
refluxed for 24 h, the reaction mixture was concentrated under vac-
uo to obtain the hydrochloride salt of dicarboxylic acid; yield: 0.28
g (92%). The resultant salt was dissolved in MeOH (20 mL) and
cooled to 0 °C and SOCl (0.25 mL) was added dropwise. The reac-
tion mixture was further stirred at r.t. for 12 h and concentrated un-
der vacuo. The residue was treated with sat. aq. NaHCO solution
and the aqueous layer was extracted with EtOAc (3 × 10 mL), dried
over Na SO , and concentrated in vacuo to obtain 8; yield: 0.2 g
Methyl ester of N-(tert-butoxycarbonyl)-L-proline (2, 8.0 g, 34.9
mmol) was dissolved in a 0.5 M solution of tetrabutylammonium
tetrafluroborate in MeOH (100 mL). The reaction mixture was
cooled to 5 °C in an ice bath and the stirred solution was oxidized at
a carbon anode and cathode using a constant current (230 mA/28
2
2
3
cm ) for 10 h. The reaction mixture was concentrated under vacuo
and the residue was washed with Et O (3 × 75 mL) leaving the sup-
2
2
4
porting electrolyte as a crystalline solid. The combined ether layers
were concentrated in vacuo to get the crude product as an oil, which
was purified by chromatography on silica gel by isocratic elution
using EtOAc–petroleum ether (1:9) as eluant to obtain the mixture
of diastereomers 3 and 4; yield: 8.32 g (95%); thick oil.
25
(
75%); thick oil; [ ]D – 38.0 (c 0.001, CHCl3).
–
1
IR (CHCl ): 3005, 1741 cm .
3
1
H NMR (CDCl , 300 MHz): = 1.80–2.05 (m, 2 H), 2.05–2.25 (m,
3
2
13
H), 2.90 (br s, 1 H), 3.70 (s, 6 H), 3.90–4.05 (m, 2 H).
–
1
IR (CHCl ): 1747, 1712 cm .
3
C NMR (CDCl , 125 MHz): = 28.8, 51.8, 59.2, 174.7.
3
1
H NMR (CDCl , 200 MHz): = 1.35–1.55 (m, 9 H), 1.65–2.50 (m,
3
MS: m/z (%) = 187 (21), 128 (69).
4
5
H), 3.40–3.45 (m, 3 H), 3.70–3.80 (m, 3 H), 4.15–4.45 (m, 1 H),
.10–5.35 (m, 1 H).
(
2S,5R)-Pyrrolidine-2,5-dimethyldicarboxylate (9)
1
3
Repitition of the above procedure with 5 furnished 7; yield: 75%;
thick oil.
C NMR (CDCl , 50 MHz): = 26.9, 28.0, 30.0, 30.9, 32.3, 51.6
3
(
(
54.9), 55.6 (55.9), 58.7 (59.1), 80.3, 88.4 (89.7), 153.9, 172.8
173.0).
–1
IR (CHCl ): 3000, 1740 cm .
3
Anal. Calcd for C H O N (259.28): C, 55.59; H, 8.16; N, 5.40.
Found: C, 55.37; H, 8.27; N, 5.63.
1
1
2
21
5
H NMR (CDCl , 300 MHz): = 1.85–2.00 (m, 2 H), 2.05–2.20 (m,
H), 2.77 (br s, 1H), 3.73 (s, 6 H), 3.75–3.85 (m, 2 H).
3
2
1
3
C NMR (CDCl , 125 MHz): = 29.4, 51.8, 59.8, 174.2.
3
Methyl (2S)-N-(tert-Butoxycarbonyl)-5(R/S)-cyanoprolinecar-
boxylate (5 + 6)
MS: m/z (%) = 187 (25), 128 (60).
The mixture of 3 and 4 (2.46 g, 9.5 mmol) was dissolved in anhyd
CH Cl (25 mL) and cooled to –35 °C by a cryostat. To this was
(2S,5S)-Pyrrolidine-2,5-dicarboxylic Acid (1)
2
2
added 1% of TMSOTf (0.25 mL) and TMSCN (1.46 mL, 10.9
mmol) in a drop wise fashion at –35 °C with stirring. The reaction
mixture was further stirred for 30 min and diluted with MeOH (1
mL). The reaction mixture was concentrated under vacuo and the
residue was purified by column chromatography on neutral alumina
using EtOAc–petroleum ether, (3:22) to obtain the diastereomeric
nitriles.
The solution of diester 8 (200 mg, 1.08 mmol) in water (10 mL) was
refluxed for 24 h, concentrated in vacuo and dried to obtain 1; yield:
1
2
0.16 g (92%); free flowing solid; mp 278 °C (lit. 272–277 °C);
2
5
12
25
[ ]D –105 (c 0.001, H O), (lit. [ ]
–108).
2
D
IR (Nujol): 3170, 1710 cm–1.
1
H NMR (D O, 500 MHz): = 2.05–2.15 (m, 2 H), 2.30–2.40 (m, 2
2
H), 4.28– 4.35 (m, 2 H).
Major isomer 5
1
3
C NMR (D O, 125 MHz): = 28.2, 60.9, 172.6.
2
Synthesis 2003, No. 15, 2304–2306 © Thieme Stuttgart · New York

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306
G. Sunilkumar et al.
SHORT PAPER
MS: m/z (%) = 159 (6).
(3) (a) Lowe, G.; Ridley, D. D. J. Chem. Soc., Perkin Trans. 1
1973, 2024. (b) Kurihara, M.; Kamiyama, K.; Kobayashi,
(
2S,5R)-Pyrrolidine-2,5-dicarboxylic Acid (1)
The repitition of the above procedure with 7 furnished 9; yield:
2%; mp 268 °C.
S.; Ohno, M. Tetrahedron Lett. 1985, 26, 5831; and
references cited therein 2a,b.
9
(4) (a) Whitesell, J. Chem. Rev. 1989, 89, 1581. (b)Kawanami,
Y.; Ito, Y.; Kitagawa, T.; Taniguchi, Y.; Katsuki, T.;
Yamaguchi, M. Tetrahedron Lett. 1984, 25, 857.
(c) Uchikawa, M.; Hanamoto, T.; Katsuki, T.; Yamaguchi,
M. Tetrahedron Lett. 1986, 27, 4577. (d) Katsuki, T.;
Yamaguchi, M. Tetrahedron Lett. 1987, 28, 651.
–
1
IR (Nujol): 3170, 1709 cm .
1
H NMR (D O, 500 MHz): = 1.95–2.15 (m, 2 H), 2.20–2.40 (m, 2
2
H), 4.15–4.30 (m, 2 H).
1
3
C NMR (D O, 125 MHz): = 28.4, 61.0, 172.5.
2
(e) Kawanami, Y.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
MS: m/z = 159 (5).
Soc. Jpn. 1987, 60, 4190. (f) Takano, S.; Moriya, M.;
Iwabuchi, Y.; Ogasawara, K. Tetrahedron Lett. 1989, 30,
Methyl N-(tert-Butoxycarbonyl)-5-cyanoprolinecarboxylate
(
3805. (g) Ghosez, L.; Chen, L. Y. Tetrahedron Lett. 1990,
31, 4467. (h) Yamamoto, Y.; Ohmori, H.; Sawada, S. Synlett
1991, 319. (i) Katsuki, T.; Yamaguchi, M. J. Synth. Org.
)-6
To the solution of t-BuOK (48 mg) in THF (5 mL) was added the
solution of the major cyano isomer 5 (0.1 g, 0.39 mmol) in THF (3
mL) at 0 °C and the reaction mixture was stirred at r.t. for 6 h. The
reaction mixture was diluted with brine (3 mL) and extracted with
EtOAc (3 × 10 mL), dried over Na SO and concentrated in vacuo
to obtain ( )-6, yield 80 mg (80%).
1H NMR and IR spectral data were identical with (–)-6.
Chem. 1986, 44, 532.
(
(
5) Xia, Q.; Ganem, B. Tetrahedron Lett. 2002, 43, 1597.
6) Ohta, T.; Hosoi, A.; Kimura, T.; Nozoe, S. Chem. Lett. 1987,
2
4
2091.
(
7) Langlois, N.; Rojas, A. Tetrahedron 1993, 49, 77.
(8) Ezquerra, J.; Rubio, A.; Pedregal, C.; Sanz, G.; Rodriguez, J.
H.; García Ruano, J. L. Tetrahedron Lett. 1993, 34, 4989.
(
9) Takano, S.; Moriya, M.; Iwabuchi, Y.; Ogasawara, K.
Acknowledgment
Tetrahedron Lett. 1989, 30, 3805.
(
(
(
(
10) Thaning, M.; Wistrand, L. G. Acta Chem. Scand. 1992, 46,
94.
11) Baldwin, J. E.; Hulme, C.; Schofield, C. J. J. Chem. Res.,
Synop. 1992, 6, 173.
12) Yamamoto, Y.; Hoshino, J.; Fujimoto, Y.; Ohmoto, J.;
Sawada, S. Synthesis 1993, 298.
13) (a) Shono, T.; Matsumura, Y.; Tsubata, K. Org. Synth. 1984,
NPA thanks Department of Science and Technology, New Delhi,
for financial support.
1
References
(
(
1) NCL Communication No. 6648.
2) (a) Impellizzeri, G.; Mangiafico, S.; Oriente, G.; Piattelli,
M.; Sciuto, S.; Fattorusso, E.; Magno, S.; Santacroce, C.;
Sica, D. Phytochemistry 1975, 14, 1549. (b) Sato, M.; Sato,
Y.; Tsuchiya, Y. Nippon Suisan Gakkaishi 1981, 47, 1605;
Chem. Abstr. 1982, 97: 3787.
63, 206. (b) Barrett, A. G. M.; Pilipauskas, D. J. Org. Chem.
1991, 56, 2787.
(14) The stereochemical assignments are based on the optical
rotation of the known compounds.
Synthesis 2003, No. 15, 2304–2306 © Thieme Stuttgart · New York