First total synthesis of Louisianin A

Article abstract of DOI:10.1021/jo060935j

The first total synthesis of louisianin A, 4-allyl-6,7-dihydro-1- hydroxycyclopenta[c]pyridin-5-one, is achieved from 2-chloro-4-cyanopyridine 5 via seven steps in an overall 24% yield. The key step is a cyclization- decarboxylation sequence toward the formation of a cyclopentenone ring.

Full text of DOI:10.1021/jo060935j

11% overall yield (Kelly et al.),4 started from 3,5-dibromopy-
ridine. Syntheses of other members in the family have not
appeared in the literature. In this report we describe the first
total synthesis of louisianin A from a readily available starting
material 2-chloro-4-cyanopyridine (5).
First Total Synthesis of Louisianin A
Ching-Yao Chang,*,§ Hui-Ming Liu,† and Tahsin J. Chow‡
Department of Biotechnology and Bioinformatics, Asia
UniVersity, Wufeng, Taichung, 413, Taiwan, Republic of China,
Department of Industrial Safety and Health, Hung Kuang
UniVersity, Shalu, Taichung, 433, Taiwan, Republic of China,
and Institute of Chemistry, Academia Sinica, Taipei, 115,
Taiwan, Republic of China
The main structural feature of louisianins is a pyridine ring
fused with cyclopentenone. In the earlier synthetic design for
louisianin C (3), a symmetrical 3,5-diallyl-substituted pyridine
was used as a key intermediate.4 Ring closure at C(4) by either
of the two allyl groups resulted in an identical product. Such a
strategy, however, cannot be utilized successfully for the
synthesis of louisianins A (1) and B (2), in which the presence
of a hydroxyl group at C(2) breaks the symmetry of pyridine
ring. In the present design the two alkyl substituents at C(3)
and C(5) were introduced sequentially, so that the direction of
cyclopentenone ring closure could be effectively controlled.
The complete synthetic sequence is outlined in Scheme 1,
starting from the unsymmetrical 2-chloro-4-cyanopyridine (5).
Deprotonation of 5 at C(3) by lithium diisopropylamide (LDA)
at -78 °C,5 followed by iodination afforded 2-chloro-4-cyano-
3-iodopyridine (6) in 42% yield. The yield of 6 can be improved
to 68% by performing the reaction at -95 °C employing kinetic
control over site selectivity of deprotonation.6 A small coupling
constant (ca. 5 Hz) between the C(5) and C(6) of aromatic
protons verified their relative ortho-position, thus confirming
that iodination had occurred at C(3).
cychang@asia.edu.tw
ReceiVed May 5, 2006
The first total synthesis of louisianin A, 4-allyl-6,7-dihydro-
1-hydroxycyclopenta[c]pyridin-5-one, is achieved from 2-chlo-
ro-4-cyanopyridine 5 via seven steps in an overall 24% yield.
The key step is a cyclization-decarboxylation sequence
toward the formation of a cyclopentenone ring.
The chlorine atom at C(2) of 6 was transformed to a methoxy
group of 7 in 92% yield.7 The three-carbon side chain at C(3)
was added to yield 8 in good yield (95%) by coupling with
methyl acrylate under standard palladium(0)-catalyzed Heck
conditions.8 A large coupling constant (16 Hz) for the olefinic
protons, which appeared at δ 7.1 and 7.9, suggested a transoid
geometry of the double bond. Hydrogenation of 8 with 5% Pd/C
afforded 9 in 91% yield. The ester group was unaffected as
Louisianins A-D (1-4) were produced in the cultured broth
indicated by the persistence of a strong absorption at 1739 cm-1
.
The substituent at C(5) was introduced by bromination in
acetic acid to afford compound 10 regioselectively in 85%.9
The position of bromine was determined by the disappearance
of proton signal at δ 7.1 in 9, while maintaining the signal at δ
8.2 (H(6)) as a singlet. The bromine substituent was transformed
to an allyl group via Pd(0)-catalyzed Stille coupling to allyltri-
of Streptomyces sp. WK-4028, which has been isolated from a
soil sample collected in Louisiana (U.S.A.).1 Louisianin A
showed highly potent inhibition of the growth of testosterone-
responsive Shionogi carcinoma SC 115 cells with an IC50 value
of 0.6 µg/mL in the presence of 10-7 M testosterone.2 Louisianin
A has been converted to louisianin C, which was then isomerized
to louisianin D. Louisianins C and D exhibited potent suppres-
sion for the formation of cultured vascular endothelial cells in
vitro.3 To date, the only report concerning the synthesis of
louisianins, which detailed the preparation of louisianin C in
(4) Beierle, J. M.; Osimboni, E. B.; Metallinos, C.; Zhao, Y.; Kelly, T.
R. J. Org. Chem. 2003, 68, 4970-4972.
(5) (a) Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151-
169. (b) Cochennec, C.; Rocca, P.; Marsais, F.; Godard, A.; Que´guiner, G.
Synthesis 1995, 321-324 and references therein. (c) Cailly, T.; Fabis, F.;
Lemaˆıtre S.; Bouillon, A.; Rault, S. Tetrahedron Lett. 2005, 46, 135-137.
(6) (a) Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980, 21, 4137-
4140. (b) Karig, G.; Spencer, J. A.; Gallagher, T. Org. Lett. 2001, 3, 835-
838.
(7) (a) Tre´court, F.; Mallet, M.; Mongin, O.; Que´guiner, G. J. Org. Chem.
1994, 59, 6173-6178. (b) Ohtsu, H.; Itokawa, H.; Xiao, Z.; Su, C.-Y.;
Shih, C. C.-Y.; Chiang, T.; Chang, E.; Lee, Y.; Chiu, S.-Y.; Chang, C.;
Lee, K.-H. Bioorg. Med. Chem. 2003, 11, 5083-5090.
(8) (a) Plisson, C.; Chenault, J. Heterocycles 1999, 51, 2627-2638. (b)
Vallin, K. S. A.; Emilsson, P.; Larhed, M.; Hallberg, A. J. Org. Chem.
2002, 67, 6243-6246. (c) de Vries, A. H. M.; Mulders, J. M. C. A.;
Mommers, J. H. M.; Henderickx, H. J. W.; de Vries, J. G. Org. Lett. 2003,
5, 3285-3288. (d) Yasuda, N.; Hsiao, Y.; Jensen, M. S.; Rivera, N. R.;
Yang, C.; Wells, K. M.; Yau, J.; Palucki, M.; Tan, L.; Dormer, P. G.;
Volante, R. P.; Hughes, D. L.; Reider, P. J. J. Org. Chem. 2004, 69, 1959-
1966.
* Address correspondence to this author. Phone: +886-4-23323456. Fax:
+886-4-23316699.
§ Asia University.
† Hung Kuang University.
‡ Academia Sinica.
(1) Takamatsu, S.; Kim, Y.-P.; Hayashi, M.; Furuhata, K.; Takayanagi,
H.; Komiyama, K.; Woodruff, H. B.; Oˆ mura, S. J. Antibiot. 1995, 48, 1090-
1094.
(2) Komiyama, K.; Takamatsu, S.; Kim, Y.-P.; Matsumoto, A.; Taka-
hashi, Y.; Hayashi, M.; Woodruff, H. B.; Oˆ mura, S. J. Antibiot. 1995, 48,
1086-1089.
(3) Sunazuka, T.; Tian, Z.-M.; Harigaya, Y.; Takamatsu, S.; Hayashi,
M.; Komiyama, K.; Oˆ mura, S. J. Antibiot. 1997, 50, 274-275.
(9) Windscheif, P.-M.; Vo¨gtle, F. Synthesis 1994, 87-92.
10.1021/jo060935j CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/07/2006
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J. Org. Chem. 2006, 71, 6302-6304

SCHEME 1
magnesium sulfate, filtered, and concentrated in vacuo to afford a
brownish solid (2.82 g). The crude product was purified by flash
column chromatography eluting with hexane/EtOAc (10:1). Com-
pound 6 (1.80 g, 68%) was collected as a white solid. Mp 149-
150 °C; IR (KBr) 3071, 2233, 1582, 1557, 1429, 1339 1174 cm-1
;
1H NMR (400 MHz, CDCl3) δ 8.52 (d, J ) 4.8 Hz, 1H), 7.40 (d,
J ) 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 157.0, 149.1,
131.9, 125.3, 117.1, 99.3; MS (EI): m/z 264 (M+); HRMS (EI)
m/z calcd for C6H2N2ClI 263.8951, found 263.8954. Anal. Calcd
for C6H2N2ClI: C, 27.24; H, 0.76; N, 10.59. Found: C, 27.46; H,
0.67; N, 10.70.
4-Cyano-3-iodo-2-methoxypyridine (7). A solution of sodium
methoxide was freshly prepared by adding sodium (0.46 g, 20
mmol, 2 equiv) to methanol (30 mL) under nitrogen at 0 °C. To
this solution was added 2-chloro-4-cyano-3-iodopyridine (6) (2.645
g, 10 mmol), and the solution was stirred at room temperature for
16 h, while the reaction was monitored by thin-layer chromatog-
raphy (TLC). Upon completion the solvent was evaporated, and
distilled water (20 mL) was added. The resulting mixture was
extracted with ethyl acetate (3 × 30 mL). The combined extract
was dried over anhydrous magnesium sulfate, filtered, and con-
centrated in vacuo to yield a yellowish solid (2.84 g). The product
was purified by flash column chromatography eluting with hexane/
EtOAc (30:1) to afford 7 (2.39 g, 92%) as a white solid. Mp 163-
164 °C; IR (KBr) 2952, 2231, 1570, 1529, 1464, 1373, 1049 cm-1
;
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J ) 5.2 Hz, 1H), 7.05 (d,
J ) 5.2 Hz, 1H), 4.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
163.1, 147.3, 130.9, 119.8, 117.5, 85.0, 55.5; MS (EI): m/z 260
(M+); HRMS (EI) m/z calcd for C7H5N2OI 259.9447, found
259.9445. Anal. Calcd for C7H5N2OI: C, 32.32; H, 1.92; N, 10.77.
Found: C, 32.59; H, 1.95; N, 10.70.
n-butyltin.4,10 When compound 10 was treated with allyltri-n-
butyltin and Pd(PPh3)4 in DMF at 100 °C for 20 h, the products
were found to be a 8:1 mixture of 11 and a double bond migrated
isomer.10b The degree of isomerization can be depressed by
reducing the reacting time. An optimal yield of 87% without
double bond migration was achieved by completing the reaction
in 6.5 h.
The final step was a cyclization-decarboxylation sequence
for the generation of a fused cyclopenteone ring of louisianin
A. It was accomplished by deprotonation of 11 with LDA at 0
°C, followed by a nucleophilic attack on the cyano group to
close the ring. Hydrolysis under acidic conditions induced
decarboxylation to 1. In this process the methoxy group at C(2)
was also transformed to the desired hydroxy group. The yield
of this final step was remarkably good (61%). The spectral
features of louisianin A thus prepared were consistent with those
reported in the literature.1
(E)-Methyl 3-(4′-Cyano-2′-methoxypyridin-3′-yl)acrylate (8).
To a pressure-resistant glass tube containing 4-cyano-3-iodo-2-
methoxypyridine (7) (0.52 g, 2 mmol) in DMF (3 mL) were added
methyl acrylate (0.9 mL, 10 mmol, 5 equiv), triethylamine (0.34
mL, 2.4 mmol, 1.2 equiv), and tetrakis(triphenylphosphine)-
palladium (0.116 g, 5 mol %). The solution was frozen at 77 K,
and was degassed by pumping under vacuum. The tube was then
sealed and heated to 100 °C for 36 h. The reaction was cooled to
room temperature and was filtered through silica gel, which was
washed with ethyl acetate (3 × 30 mL). The combined solution
was concentrated in vacuo to obtain a yellowish solid (0.54 g).
The product was purified by flash column chromatography eluted
with hexane/EtOAc (10:1) to afford 8 (0.41 g, 95%) as a white
solid. Mp 113-114 °C; IR (KBr) 2958, 2235, 1724, 1574, 1553,
1394, 1313, 1051 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J
) 5.2 Hz, 1H), 7.89 (d, J ) 16 Hz, 1H), 7.18 (d, J ) 5.2 Hz, 1H),
7.07 (d, J ) 16 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 166.8,
162.2, 147.8, 134.6, 126.2, 122.0, 119.8, 119.3, 115.4, 54.5, 52.0;
MS (EI) m/z 218 (M+); HRMS (EI) m/z calcd for C11H10N2O3
218.0692, found 218.0699. Anal. Calcd for C11H10N2O3: C, 60.55;
H, 4.59; N, 12.84. Found: C, 60.77; H, 4.81; N, 12.82.
The total synthesis of louisianin A has been achieved starting
from 2-chloro-4-cyanopyridine 5 in seven steps with high yield.
The geometry of the final product was confirmed by spectral
comparison with authentic samples. We are actively pursuing
the synthesis of other members of the louisianin family, progress
toward which will be reported in due course.
Experimental Section
Methyl 3-(4′-Cyano-2′-methoxypyridin-3′-yl)propanoate (9).
A round-bottom flask containing 8 (0.79 g, 3.62 mmol) and Pd/C
(5%, 0.08 g) in methanol (20 mL) was flushed with hydrogen gas
three times. The mixture was stirred with a magnetic bar under
hydrogen at atmospheric pressure for 3 h. The solution was filtered
and concentrated in vacuo to obtain a viscous liquid (0.84 g). The
crude product was purified by flash column chromatography eluting
with hexane/EtOAc (5:1) to afford 9 (0.72 g, 91%) as a colorless
liquid. IR (neat, KBr) 2953, 2235, 1739, 1588, 1562, 1455, 1393,
2-Chloro-4-cyano-3-iodopyridine (6). To a solution of 2-chloro-
4-cyanopyridine (5) (1.39 g, 10 mmol) in dry THF (50 mL) was
added a LDA solution (12 mmol) at -95 °C under nitrogen over
a period of 2 min. A solution of iodine (3.8 g, 15 mmol, 1.5 equiv)
in THF (10 mL) was added at -95 °C over another 2 min. The
mixture was stirred overnight, then was quenched by the addition
of a saturated sodium sulfite solution (30 mL) at 0 °C. The resulting
mixture was extracted with ethyl acetate (3 × 50 mL). The extracts
were combined and washed with saturated sodium sulfite (15 mL)
and brine (15 mL). The organic phase was dried over anhydrous
1
1094 cm-1; H NMR (400 MHz, CDCl3) δ 8.15 (d, J ) 5.2 Hz,
1H), 7.05 (d, J ) 5.2 Hz, 1H), 3.99 (s, 3H), 3.70 (s, 3H), 3.14 (t,
J ) 7.8 Hz, 2H), 2.66 (t, J ) 7.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 172.2, 162.2, 145.6, 126.3, 122.0, 118.0, 115.6, 54.0,
51.6, 32.2, 24.3; MS (EI) m/z 220 (M+); HRMS (EI) m/z calcd
for C11H12N2O3 220.0848, found 220.0845. Anal. Calcd for
(10) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(b) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478-
5486.
J. Org. Chem, Vol. 71, No. 16, 2006 6303

C11H12N2O3: C, 60.00; H, 5.45; N, 12.72. Found: C, 60.15; H,
5.55; N, 12.67.
114.5, 53.9, 51.6, 35.1, 32.4, 24.6; MS (EI) m/z 260 (M+); HRMS
(EI) m/z calcd for C14H16N2O3 260.1161, found 260.1163. Anal.
Calcd for C14H16N2O3: C, 64.62; H, 6.15; N, 10.77. Found: C,
64.37; H, 6.14; N, 10.68.
Methyl 3-(5′-Bromo-4′-cyano-2′-methoxypyridin-3′-yl)pro-
panoate (10). To a solution of methyl 3-(4′-cyano-2′-methoxypy-
ridin-3′-yl)propanoate (9) (1.25 g, 5.68 mmol) and sodium acetate
(0.49 g, 5.98 mmol, 1.05 equiv) in glacial acetic acid (5 mL) was
added dropwise bromine (1.46 mL, 28.38 mmol, 5 equiv) at 10
°C. The solution was stirred at room temperature for 24 h. The
reaction was quenched by the addition of saturated sodium sulfite
solution (15 mL) at 0 °C. The resulting mixture was extracted with
ethyl acetate (3 × 30 mL). The combined extract was washed once
with saturated sodium sulfite solution (10 mL) and once with brine
(10 mL). The organic phase was dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to afford a white solid
(1.82 g). The product was purified by flash column chromatography
eluted with hexane/EtOAc (15:1) to give 10 (1.44 g, 85%) as a
white solid. Mp 99-100 °C; IR (KBr) 2952, 2240, 1739, 1560,
Louisianin A (1). To a solution of methyl 3-(5′-allyl-4′-cyano-
2′-methoxypyridin- 3′-yl)propanoate (11) (0.26 g, 1 mmol) in dry
THF (10 mL) was added a LDA solution (1.2 mmol) at 0 °C over
a period of 2 min. The reaction solution was stirred at 0 °C for
another 2 min, and then the reaction was quenched by the addition
of saturated ammonium chloride (5 mL). The resulting mixture was
extracted with ethyl acetate (3 × 20 mL). The combined organic
phase was dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to afford a yellow solid (0.28 g). The crude
product was dissolved in methanol (10 mL), and the solution was
treated with concentrated hydrochloric acid solution (5 mL) at 0
°C. The acidic solution was heated to reflux for 22 h. Methanol
was removed by evaporation, and the brownish residue was
extracted with ethyl acetate (5 × 20 mL). The combined extract
was washed once with saturated sodium bicarbonate solution (10
mL) and once with brine (10 mL), dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The yellowish crude
product (0.16 g) was purified by flash chromatography eluting with
hexane/EtOAc (1:3) to give 1 (0.116 g, 61%) as a white solid. Mp
187-188 °C; IR (KBr) 2929, 1716, 1665, 1614, 1448, 1427, 1199
cm-1; 1H NMR (400 MHz, CDCl3) δ 12.60 (br, 1H), 7.18 (s, 1H),
5.97-5.87 (m, 1H), 5.10-5.05 (m, 2H), 3.54 (d, J ) 6.8 Hz, 2H),
3.02-2.99 (m, 2H), 2.72-2.70 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 207.3, 164.2, 149.2, 144.6, 135.6, 132.3, 116.8, 116.2,
36.2, 31.3, 22.7; MS (EI) m/z 189 (M+); HRMS (EI) m/z calcd for
C11H11NO2 189.0790, found 189.0786.
1
1202, 1171, 1036 cm-1; H NMR (400 MHz, CDCl3) δ 8.27 (s,
1H), 3.97 (s, 3H), 3.70 (s, 3H), 3.15 (t, J ) 7.6 Hz, 2H), 2.66 (t,
J ) 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 172.0, 161.0,
146.9, 129.0, 124.8, 114.1, 112.0, 54.4, 51.8, 32.1, 25.0; MS (EI)
m/z 298 (M+); HRMS (EI) m/z calcd for C11H11N2O3Br 297.9953,
found 297.9955. Anal. Calcd for C11H11N2O3Br: C, 44.16; H, 3.68;
N, 9.37. Found: C, 44.17; H, 3.82; N, 9.30.
Methyl 3-(5′-Allyl-4′-cyano-2′-methoxypyridin-3′-yl)propanoate
(11). A solution of methyl 3-(5′-bromo-4′-cyano-2′-methoxypyridin-
3′-yl)propanoate (10) (0.897 g, 3 mmol) and allyltri-n-butyltin (1.12
mL, 3.6 mmol, 1.2 equiv) in DMF (5 mL) was degassed by bubbling
nitrogen through it for 30 min. Tetrakis(triphenylphosphine)-
palladium (0.35 g, 10 mol %) and the mixture was heated to 100
°C for 6.5 h. The reaction was allowed to cool to ambient
temperature and was then filtered through a silica gel pad to remove
palladium. The pad was washed with ethyl acetate (3 × 30 mL).
The combined solution was concentrated in vacuo to afford a
yellowish liquid (1.12 g), which was further purified by flash
column chromatography eluting with hexane/EtOAc (15:1) to afford
11 (0.678 g, 87%) as a colorless solid. Mp 51-52 °C; IR (KBr)
Acknowledgment. Support from the National Science
Council of the Republic of China (NSC 94-2113-M- 468-001)
is gratefully acknowledged. We thank the Department of
Chemistry, National Chung-Hsing University, Taichung, Tai-
wan, R.O.C. for analyzing NMR spectra.
Supporting Information Available: Experimental general
1
2953, 2230, 1740, 1587, 1561, 1472, 1393, 1079 cm-1; H NMR
1
information and H and 13C NMR spectra for compounds 6-11
(400 MHz, CDCl3) δ 8.01 (s, 1H), 5.98-5.88 (m, 1H), 5.17-5.08
(m, 2H), 3.97 (s, 3H), 3.69 (s, 3H), 3.49 (d, J ) 6.4 Hz, 2H), 3.13
(t, J ) 7.8 Hz, 2H), 2.65 (t, J ) 7.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 172.3, 160.7, 145.5, 134.6, 128.9, 126.1, 122.7, 117.4,
and louisianin A. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO060935J
6304 J. Org. Chem., Vol. 71, No. 16, 2006