Efficient total syntheses of phytoalexin and (±)-paniculidine B and C based on the novel methodology for the preparation of 1-methoxyindoles

Article abstract of DOI:10.1021/jo040134l

A general route to 2-unsubstituted-1-methoxyindoles, based on our methodology for the synthesis of 1-methoxyindoles, is reported. This synthesis renders accessibility to a variety of natural products possessing the said skeleton. A direct synthesis of phy

Full text of DOI:10.1021/jo040134l

Efficien t Tota l Syn th eses of P h ytoa lexin a n d (()-P a n icu lid in e B
a n d C Ba sed on th e Novel Meth od ology for th e P r ep a r a tion of
1-Meth oxyin d oles†
N. Selvakumar* and G. Govinda Rajulu‡
Department of Discovery Chemistry, Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur,
Hyderabad 500 049, India
selvakumarn@drreddys.com
Received February 10, 2004
A general route to 2-unsubstituted-1-methoxyindoles, based on our methodology for the synthesis
of 1-methoxyindoles, is reported. This synthesis renders accessibility to a variety of natural products
possessing the said skeleton. A direct synthesis of phytoalexin (1), (()-paniculidine B (2), and (()-
paniculidine C (3) is disclosed based on the methodology. The synthesis of paniculidine B (2) has
been achieved from aldehyde 10 in only two steps in 88% yield and in five steps from a methoxyindole
compound 8 obtained using our earlier methodology.
A number of alkaloids possessing a 2-unsubstituted-
1-methoxyindole structural framework have been isolated
and reported in the literature.1 These include phytoalexin
(1), an antifungal metabolite produced by wasabi (Wasa-
bia japonica. syn. Eutrema wasabi)2 and paniculidine B
(2) isolated from Murraya paniculata (Linn.) J ack. among
many others.3 Various parts of the latter plant are used
as a folk medicine for the treatment of stomachache and
toothache and also as a stimulant throughout the areas
ranging from India, southeast Asia, southern China,
Taiwan, etc. In our previous paper, we have disclosed a
new synthesis of substituted 1-methoxyindoles based on
a novel methodology.4 The methodology culminated in the
syntheses of a variety of 1-methoxyindoles such as the
structure 5 possessing different substituents (R) in the
second position starting from simple starting materials
such as 4 containing an activated methylene group that
in turn are available from aromatic nitrobenzenes.
However, the methodology was not amenable for the
syntheses of the large number of natural products pos-
sessing 2-unsubstituted-1-methoxyindole skeletons in-
cluding the title compounds.5 In an effort to substantiate
the usefulness of our earlier methodology for the syn-
theses of such compounds, we initiated a program to
convert the hitherto obtained 1-methoxyindole com-
pounds to the corresponding 2-unsubstituted compounds.
To that end, it was envisioned that the decarboxylation
of the methoxyindole compound analogous to structure
(5) Our efforts to generalize this methodology to the 2-unsubstituted-
1-methoxyindole skeleton resulted only in decarboxylated products as
shown below. The compound analogous to 4 (R ) H and E ) CO2Me)
under reaction conditions failed to yield the respective methoxyindole
compound analogous to structure 5. Similarly, the compound 4 (R )
n-propyl and E ) CO2Me) also resulted in the corresponding decar-
boxylated product. These results ascertained the requirement of an
activated methylene group for the key cyclization step.
† DRL Publication No. 359.
* Corresponding author. Phone: 91-40-23045439. Fax: 91-40-
23045438.
‡ On leave from Indian Institute of Technology, New Delhi for his
M.Tech thesis work.
(1) (a) Somei, M. Heterocycles 1999, 50, 1157. (b) Acheson, R. M. In
Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic
Press: San Diego, CA, 1990; Vol. 51, pp 105-175.
(2) Soledade, M.; Pedras, C.; Sorenson, J . L. Phytochemistry 1998,
49, 1959.
(3) Kinoshita, T.; Tatara, S.; Ho, F.-C.; Sankawa, U. Phytochemistry
1989, 28, 147 and references therein.
(4) (a) Selvakumar, N.; Reddy, B. Y.; Azhagan, A. M.; Khera, M.
K.; Babu, J . M.; Iqbal, J . Tetrahedron Lett. 2003, 44, 7065. (b)
Selvakumar, N.; Khera, M. K.; Reddy, B. Y.; Srinivas, D.; Azhagan,
A. M.; Iqbal, J . Tetrahedron Lett. 2003, 44, 7071.
10.1021/jo040134l CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/26/2004
J . Org. Chem. 2004, 69, 4429-4432
4429

Selvakumar and Rajulu
SCHEME 1 a
SCHEME 2 a
a
Reagents and conditions: (a) DIBAL-H, dry PhMe, -78 °C,
20 min, 98%; (b) methallyl chloride, Mg, THF, rt, 3 h, 99%; (c)
NaBH4, BF3‚OEt2, THF then NaOH, H2O2, 89%; (d) 10% Pd on
charcoal, H2, MeOH, 94%.
a
Reagents and conditions: (a) methyl cyanoacetate, NaH, THF,
0 f 60 °C, 79%; (b) K2CO3, THF, ethyl bromoacetate, 0 °C f rt,
79%; (c) NaCl, DMSO, 155 °C, 60%; (d) LiOH, 3:1 DMF-H2O, 0
°C f rt, 80% and then quinoline, Cu powder, 220 °C, 20 min, 88%;
(e) MeOH, cat. H2SO4, reflux, 72 h, 60%.
ing it to the corresponding ester, which is the naturally
occurring phytoalexin (1). Thus, the transformation of the
nitrile to the carbomethoxy group was smoothly effected
by a catalytic amount of sulfuric acid in refluxing meth-
anol.8 The spectral and analytical data of the synthetic
phytoalexin (1) were in accordance with literature values
in all aspects,2 confirming the structure of the cyano
indole compound 9.
5 (R ) CO2Et, E ) CN) would lead to the corresponding
2-unsubstituted methoxyindole, which in turn could be
elaborated to the natural products. Thus, we now report
a method for such conversion and the resultant 2-unsub-
stituted methoxyindole compound 9 was used as the
starting material for the highly efficient total syntheses
of phytoalexin (1) and (()-paniculidine B (2) and C (3).6
Having identified a method to obtain the cyano indole
compound 9 in gram quantities, we turned our attention
to complete the synthesis of the target compound 2. At
this stage, the synthesis warranted an introduction of a
four-carbon synthon such as methallyl bromide to achieve
the natural product 2. Thus, the nitrile functionality in
the indole compound 9 was converted to the correspond-
ing aldehyde 10 under standard conditions setting the
stage for introducing the four-carbon fragment (Scheme
2). While our efforts to introduce a four-carbon fragment
using the Grignard reagent derived from methallyl
bromide failed, the reaction was accomplished neatly
with the reagent obtained from methallyl chloride in
quantitative yield resulting in the advanced intermediate
11. Once the alcohol 11 was in hand, only deoxygenation
of the benzylic alcohol and a hydroboration of the
terminal double bond needed to be achieved to arrive at
the target compound. All our efforts to effect the deoxy-
genation of the alcohol 11, using reagents such as NaBH4
in TFA,9 Et3SiH in TFA,10 and TMSCI in acetonitrile,11
resulted in either demethoxylation of the N-methoxy
group or decomposition. At this juncture, we envisioned
that borane derived from the reagent combination of
NaBH4 and BF3‚OEt2 would effect not only the hydrobo-
ration of the olefinic functionality in alcohol 11 but also
the deoxygenation of the benzylic alcohol group in one
pot. Thus, the exposure of alcohol 11 to NaBH4 and BF3‚
OEt2 followed by treatment of the resultant reaction
Resu lts a n d Discu ssion
The cyano-ester 6, prepared along the lines of our
previous report,4 was alkylated with ethylbromoacetate
under basic conditions to afford the diester 7 (Scheme
1). The diester 7 underwent smooth rearrangement as
reported before leading to the indole 2-carboxylic acid
ester 8. Having the cyano-ester 8 in hand, we turned our
attention toward developing an effective method for the
decarboxylation of the carboethoxy group in the second
position. The hydrolysis of the carboethoxy group was
accomplished smoothly following the usual procedure to
afford the corresponding acid. At this juncture, literature
search for the decarboxylation of indole 2-carboxylic acids
revealed that Cu in quinoline at elevated temperature
leads to the corresponding indoles in good yields.7 Thus,
heating the acid, obtained from the ester 8, in doubly and
freshly distilled quinoline in the presence of Cu powder
neatly afforded the required decarboxylated indole com-
pound 9. Having succeeded in identifying a method to
effect the decarboxylation of the 1-methoxyindole com-
pound 8, we wished to confirm the structure of the
resultant 1-methoxyindole (9) unambiguously by convert-
(6) For a synthesis of this phytoalexin, see: Somei, M.; Tanimato,
A.; Orita, H,; Yamada, F.; Ohata, T. Heterocycles 2001, 54, 425. For a
synthesis of paniculidine B, see: Somei, M.; Ohnishi, H. Chem. Pharm.
Bull. 1985, 33, 5147.
(7) For decarboxylation of indole-2-carboxylic acids, see: J ones, G.
B.; Chapman. B. J . J . Org. Chem. 1993, 58, 5558 and references
therein.
(8) Pawlak, J . L.; Berchtold, G. A. J . Org. Chem. 1988, 53, 4063.
(9) Gribble, G. W.; Leese, R. M. Synthesis 1977, 172.
(10) Patiki, J .; Harvey, R. G. J . Org. Chem. 1987, 52, 2226.
(11) Sakai, T.; Miyata, K.; Utaka, M.; J akeda, A. Tetrahedron Lett.
1987, 28, 3817.
4430 J . Org. Chem., Vol. 69, No. 13, 2004

Syntheses of Phytoalexin and (()-Paniculidine B and C
4-Eth yl 1-Meth yl 2-Cya n o-2-(2-n itr op h en yl)su ccin a te
(7). Ethyl bromoacetate (0.9 mL, 8.2 mmol) was added to a
mixture of nitro-ester 6 (1.2 g, 5.46 mmol) and potassium
carbonate (2.26 g, 16.35 mmol) in dry THF (30 mL) at 0 °C
under argon. The reaction mixture was allowed to attain room
temperature over 3 h and was stirred for an additional 33 h.
The reaction mixture was diluted with ethyl acetate (200 mL)
and then washed with water and brine and dried. The residue
obtained upon concentration of the solvents was purified by
flash column chromatography with petroleum ether-dichlo-
romethane as an eluent to give the diester 7 (1.31 g, 79%) as
a colorless oil. 1H NMR (CDCl3): δ 1.18 (t, J ) 7.3 Hz, 3H),
3.51 and 3.68 (ABq, J ) 16.9 Hz, 2H), 3.84 (s, 3H), 4.02-4.15
(m, 2H), 7.62 (dt, J ) 1.5 and 7.6 Hz, 1H), 7.75 (dt, J ) 1.5
and 7.8 Hz, 1H), 8.06 (d, J ) 7.8 Hz, 1H), 8.14 (dd, J ) 1.5
and 7.8 Hz, 1H). 13C NMR (CDCl3): δ 167.8, 165.2, 147.2,
133.9, 131.8, 130.4, 128.0, 126.4, 116.5, 61.4, 54.3, 50.3, 40.5,
13.8. Mass (CI method): 307 (M+ + 1), 261. IR (neat): 1740,
mixture with basic H2O2 smoothly afforded paniculidine
B (2) in good yield. The spectral data of the synthetic
compound 2 were in agreement with the data reported
for the natural material.3 The synthesis of the target
product 2 has thus been achieved in eight steps in
22.8% overall yield from commercial materials and in
only two steps from the known methoxyindole carbalde-
hyde 106 in an impressive 88.1% yield. It is important to
note that the conversion of the carbaldehyde 10 to
paniculidine B (2) earlier in the literature consumed five
steps with a modest overall yield of 25%.6 In addition,
the earlier method needed an expensive reagent in one
of the steps and further involved a poor yielding step. In
the end, paniculidine B (2) was converted to paniculidine
C (3) under hydrogenolysis conditions in excellent yield.
The spectral data of the synthetic paniculidine C (3) were
in agreement with the data reported for the natural
product.3
In conclusion, we have reported a method to transform
the 2-substituted-1-methoxyindole compounds obtained
by using our reported methodology to the corresponding
2-unsubstituted-1-methoxyindole compounds. This opens
up a novel route to synthesize all natural products having
the 1-methoxyindole skeleton with no substituent in the
second position. The usefulness of the procedure was
further substantiated with the direct total syntheses of
phytoalexin (1), paniculidine B (2), and paniculidine C
(3) in good overall yields. Further work to complete the
syntheses of other natural products of this class such as
methoxybrassinin12 and lespedamine13 is underway in
our laboratory.
1534 cm-1
.
Eth yl 3-Cya n o-1-m eth oxy-1H-2-in d oleca r boxyla te (8).
A mixture of cyano-diester 7 (5.0 g, 16.34 mmol) and sodium
chloride (475 mg, 8.12 mmol) in dry DMSO (50 mL) was
immersed in a preheated oil bath at 150 °C and stirred over a
period of 20 min. The reaction mixture was allowed to cool to
room temperature and diluted with ethyl acetate (500 mL).
The resultant mixture was washed with water and brine and
dried. The residue obtained upon evaporation of the solvents
was purified by flash chromatography to give the cyano-ester
8 (2.4 g, 60%) as a colorless solid. Mp: 68 °C. 1H NMR
(CDCl3): δ 1.50 (t, J ) 7.3 Hz, 3H), 4.27 (s, 3H), 4.52 (q, J )
7.2 Hz, 2H), 7.36 (t, J ) 6.7 Hz, 1H), 7.50 (t, J ) 7.0 Hz, 1H),
7.58 (d, J ) 8.3 Hz, 1H), 7.82 (d, J ) 7.8 Hz, 1H). 13C NMR
(CDCl3): δ 157.5, 133.0, 128.8, 127.2, 123.8, 122.9, 120.8, 113.8,
109.8, 88.6, 66.9, 62.3, 14.0. Mass (CI method): 245 (M+ + 1),
215. IR (KBr): 2223, 1725, 1244 cm-1. Anal. Calcd for
C
13H12N2O3: C, 63.96; H, 4.95; N, 11.47. Found: C, 63.58; H,
4.93; N, 11.32.
Exp er im en ta l Section
1-Meth oxy-1H-3-in d oleca r bon itr ile (9). To a solution of
the cyano-ester 8 (1.865 g, 7.64 mmol) in DMF:H2O (3:1, 30
mL) was added powdered LiOH (549 mg, 22.88 mmol) por-
tionwise at 0 °C. After being stirred for 10 min at the same
temperature, the reaction mixture was allowed to warm to
room temperature and stirred for an additional 2 h. The
reaction mixture was neutralized with 2 N HCl and extracted
with ethyl acetate (3 × 100 mL). The combined organic layers
were washed with water and brine and dried. The residue
obtained upon evaporation of the solvents was suspended in
ether and filtered to obtain the corresponding cyano-acid (1.322
g, 80%) as a colorless solid. This compound was not stable for
analytical purposes and storage, and thus was taken to the
next step without further purification and characterization.
1H NMR (DMSO-d6): δ 4.25 (s, 3H), 7.41-7.78 (m, 4H). Mass
(electrospray method): 217 (M+ + 1). IR (KBr): 3300-2400
Gen er a l. Melting points are uncorrected. Unless otherwise
1
mentioned, all H NMR and 13C NMR spectra were recorded
at 200 and 50 MHz, respectively. Chemical shifts are reported
in δ units with respect to TMS as internal standard. Unless
otherwise mentioned all the solvents used were of LR grade.
Usually, the flash chromatography was done on silica gel
(100-200 mesh), using petroleum ether-ethyl acetate as
eluent unless otherwise reported. All the organic extracts were
dried over sodium sulfate after workup.
Meth yl 2-Cya n o-2-(2-n itr op h en yl)a ceta te (6). To a sus-
pension of NaH (60% in oil, 5.64 g, 141 mmol) in dry THF (200
mL) was successively added, at ice bath temperature under
argon, methyl cyanoacetate (7.5 mL, 85 mmol) over 5 min
followed by 2-fluoronitrobenzene (7.4 mL, 70 mmol). The
reaction mixture was refluxed overnight and then allowed to
cool to room temperature. The reaction mixture was carefully
quenched with saturated NH4Cl at ice bath temperature and
extracted with ethyl acetate (3 × 300 mL). The combined
organic layers were washed with water and brine and dried.
The residue obtained upon concentration of the solvents was
purified by flash column chromatography to give the cyano-
ester 6 (12.2 g, 79%) as a pale yellow oil, which solidified upon
storing in a refrigerator. Mp: 59 °C. 1H NMR (CDCl3): δ 3.87
(s, 3H), 5.69 (s, 1H), 7.61-7.79 (m, 3H), 8.25 (d, J ) 8.1 Hz,
1H). 13C NMR (CDCl3): δ 164.0, 147.0, 134.5, 131.6, 130.6,
(br), 2229, 1673 cm-1
.
A mixture of the above acid (1.0 g, 4.63 mmol) and copper
power (29 mg, 0.46 mmol) in doubly distilled quinoline (15 mL)
was immersed in a preheated oil bath at 220 °C. The reaction
mixture was stirred over a period of 20 min at the same
temperature and then allowed to attain ambient temperature.
The resultant mixture was neutralized with 2 N HCl and
extracted with ethyl acetate (3 × 75 mL). The combined
organic layers were washed with water and brine and dried.
The residue obtained upon evaporation of the solvents was
purified by flash chromatography to yield the nitrile 9 (700
mg, 88%) as a light yellow oil that solidified upon storing in a
refrigerator. Mp: 60 °C. 1H NMR (CDCl3): δ 4.17 (s, 3H),
7.31-7.43 (m, 2H), 7.52 (d, J ) 7.8 Hz, 1H), 7.76 (d, J ) 7.8
Hz, 1H), 7.78 (s, 1H). 13C NMR (CDCl3): δ 130.8, 129.2, 124.5,
124.0, 122.6, 119.9, 115.1, 109.1, 82.3, 67.0. Mass (CI
method): 173 (M++1), 143. IR (neat): 2222, 1238 cm-1. Anal.
Calcd for C10H8N2O: C, 69.74; H, 4.69; N, 16.28. Found: C,
69.27; H, 5.00; N, 16.26.
125.9, 125.0, 114.3, 54.1, 41.0. Mass (CI method): 221 (M+
1), 178. IR (neat): 2959, 2254, 1754 cm-1. Anal. Calcd for
10H8N2O4: C, 54.53; H, 3.66; N, 12.73. Found: C, 54.29; H,
+
C
3.59; N, 12.90.
(12) Takasugi, M.; Monde, K.; Katsui, N.; Shirata, A. Bull. Chem.
Soc. J pn. 1988, 61, 285.
(13) Morimoto, H.; Oshio, H. J ustus Liebigs Ann. Chem. 1965, 682,
212.
J . Org. Chem, Vol. 69, No. 13, 2004 4431

Selvakumar and Rajulu
1-(1-Meth oxy-1H-3-in d olyl)-3-m eth yl-3-bu ten -1-ol (11).
To a mixture of magnesium turnings (274 mg, 11.42 mmol)
and a crystal of iodine in dry THF (40 mL) was added
methallyl chloride (400 µL) under argon. When the reaction
mixture turned colorless, it was cooled in an ice bath and then
a solution of methallyl chloride (1.7 mL, 11.42 mmol) and
1-methoxyindole-3-carbaldehyde (10) (1.0 g, 5.71 mmol) in THF
(10 mL) was added over a period of 5 min. After being stirred
for 30 min at 0 °C, the reaction mixture was allowed to warm
to room temperature and stirred for an additional 3 h.
Saturated NH4Cl was added to the reaction mixture dropwise
at the same temperature and the mixture was extracted with
ether (3 × 75 mL). The combined organic layers were washed
with water (3 × 20 mL) and brine and dried. The residue
obtained upon evaporation of the solvents was purified by flash
chromatography to yield the alcohol 11 (1.31 g, 99%) as a light
yellow oil that is slightly unstable and should be consumed
within 2 days. 1H NMR (CDCl3): δ 1.84 (s, 3H), 2.10 (br s,
D2O exchangeable, 1H), 2.64 (d, J ) 6.8 Hz, 2H), 4.07 (s, 3H),
4.92 (d, J ) 6.8 Hz, 2H), 5.16 (t, J ) 6.3 Hz, 1H), 7.13 (t, J )
7.3 Hz, 1H), 7.23-7.30 (m, 2H), 7.43 (d, J ) 7.8, 1H), 7.73 (d,
J ) 7.8 Hz, 1H). 13C NMR (CDCl3): δ 132.7, 123.9, 122.2, 120.4,
119.3, 119.1, 112.9, 108.3, 68.1, 65.3, 35.4, 33.3, 22.4, 16.5.
Mass (CI method): 232 (M+ + 1), 214. IR (neat): 3393 (br),
1450 cm-1. HRMS: calcd for C14H17NO2 231.1259, found
231.1266.
Ack n ow led gm en t. We thank Dr. K. Anji Reddy for
his continued encouragement in this work. We would
like to record our special thanks to Dr. Sanjay Trehan
for some useful discussions. The help extended by Dr.
R. Rajagopalan is greatly acknowledged. Special thanks
are due to G. Sunil Kumar for having helped in pre-
paring one starting material. We appreciate the services
extended by the Analytical Research Department of
Discovery Research, Dr. Reddy’s Laboratories Ltd. for
having carried out all the analytical work.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure for compounds 1-3 and 10 and the 1H NMR and 13C
NMR spectra of compounds 1-3 and 6-11. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O040134L
4432 J . Org. Chem., Vol. 69, No. 13, 2004