Total syntheses of five indole alkaloids from the marine bryozoan Flustra foliacea

Article abstract of DOI:10.1021/jo0012647

A general, efficient, and conceptually new approach to the total syntheses of marine-derived indole alkaloids, including (±)-flustramines A (1) and B (2), (±)-flustramides A (3) and B (4), and (±)-debromoflustramine B (5), is outlined. The key step in the syntheses involves the conjugated addition of an organomagnesium species derived from prenyl bromide to 2-hydroxyindolenines. Compounds 1, 2, and 5 have been synthesized in five steps with 23%, 17%, and 16% overall yield, respectively, whereas flustramides 3 and 4 have been synthesized in only four steps with 24% and 18% overall yield, respectively, on the basis of 2-hydroxyindolenines.

Full text of DOI:10.1021/jo0012647

1186
J . Org. Chem. 2001, 66, 1186-1192
Tota l Syn th eses of F ive In d ole Alk a loid s fr om th e Ma r in e
Br yozoa n Flu str a folia cea
Martha S. Morales-R´ıos, Oscar R. Sua´rez-Castillo, J oel J . Trujillo-Serrato, and
Pedro J oseph-Nathan*
Departamento de Quı´mica del Centro de Investigacio´n y de Estudios Avanzados,
Instituto Polite´ctico Nacional, Apartado 14-740, Me´xico D. F., 07000 Mexico
pjoseph@nathan.chem.cinvestav.mx
Received August 21, 2000
A general, efficient, and conceptually new approach to the total syntheses of marine-derived indole
alkaloids, including (()-flustramines A (1) and B (2), (()-flustramides A (3) and B (4), and (()-
debromoflustramine B (5), is outlined. The key step in the syntheses involves the conjugated addition
of an organomagnesium species derived from prenyl bromide to 2-hydroxyindolenines. Compounds
1, 2, and 5 have been synthesized in five steps with 23%, 17%, and 16% overall yield, respectively,
whereas flustramides 3 and 4 have been synthesized in only four steps with 24% and 18% overall
yield, respectively, on the basis of 2-hydroxyindolenines.
Marine invertebrates of the phylum Bryozoa, order
in,10 pseudophrynamine A,11a pseudophrynaminol,11a,b
urochordamins,12 calycanthidine13 and chaetocin.13
Cheilostomata have been investigated heavily in recent
years as sources of interesting secondary metabolites.
Many of the novel compounds isolated from the cheilos-
tome bryozoan, namely Flustra foliacea, are bromoindole
alkaloids, most of which display interesting biological
activity.1 Antibacterial testing of the methylene chloride
extracts from F. foliacea shows strong activity against
Bacillus subtilis, while the crude petroleum ether ex-
tracts strongly inhibits plaque formation for influenza
virus.2 Flustramines A (1) and B (2) isolated from F.
foliacea3 were the first members of the family to be
identified. These molecules exhibit muscle relaxant activ-
ity affecting both skeletal and smooth muscle.1 A series
of novel marine-derived indole alkaloids, including the
flustramides A (3)4 and B (4)5 and the debromoflustra-
mine B (5),1b were reported between 1982-1994. These
alkaloids have in common the basic physostigmine
skeleton known from the minor group of terrestrial
alkaloids from Calabar bean (Physostigma venenosum
Balf), and some of them have two prenyl or inverted
prenyl units at the 8 and/or 3a positions as shown below.
Other closely related substances, from very diverse
biological origins, belonging to the pyrrolo[2,3-b]indole
class of alkaloids include mollenines A and B,6 fructi-
genines A and B,7 amauromines,8 aszonalenin,9 ardeem-
Because flustramines and related compounds are
available from Nature in only minute amounts and may
(8) (a) Takase, S.; Iwami, M.; Ando, T.; Okamoto, M.; Yoshida, K.;
Horiai, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J . Nat. Prod. 1984,
37, 1320-1323. (b) Takase, S.; Kawai, Y.; Uchida, I.; Tanaka, H.; Aoki,
H. Tetrahedron 1985, 41, 3037-3048. (c) Marsden, S. P.; Depew, K.
M.; Danishefsky, S. J . J . Am. Chem. Soc. 1994, 116, 11143-11144. (d)
Laws, I.; Mantle, P. G. Phytochemistry 1985, 24, 1395-1397. (e) de
Guzman, F. S.; Gloer, J . B.; Wicklow, D. T.; Dowd, P. F. J . Nat. Prod.
1992, 55, 931-939.
(9) Kimura, Y.; Hamasaki, T.; Nakajima, H.; Isogai, A. Tetrahedron
Lett. 1982, 23, 225-228.
(10) (a) Karwowski, J . P.; J ackson, M.; Rasmussen, R. R.; Humphrey,
P. E.; Poddig, J . B.; Kohl, W. L.; Scherr, M. H.; Kadam, S.; McAlpine,
J . B. J . Antibiot. 1993, 46, 374-379. (b) Hochlowski, J . P.; Mullally,
M. M.; Spanton, S. G.; Whittern, D. N.; Hill, P.; McAlpine. J . B. J .
Antibiot. 1993, 46, 380-386.
(11) (a) Spande, T. F.; Edwards, M. W.; Pannell, L. K.; Daly, J . W.;
Erspamer, V.; Melchiorri, P. J . Org. Chem. 1988, 53, 1222-1226. (b)
Crich, D.; Pavlovic, A. B.; Samy, R. Tetrahedron, 1995, 51, 6379-6384.
(12) Tsukamoto, S.; Hirota, H.; Kato, H.; Fusetani, N. Tetrahedron
Lett. 1993, 34, 4819-4822.
(13) (a) Kutney, J . P. In The Total Synthesis of Natural Products;
ApSimon, J ., Ed.; Wiley: New York, 1977; Vol. 3, 273-438. (b) Barrow,
C. J .; Cai, P.; Snyder, J . K.; Sedlock, D. M.; Sun, H. H. J . Org. Chem.
1993, 58, 6016-6021. (c) Weber, H. P. Acta Crystallogr. B, 1972, B28,
2945-2951.
* To whom correspondence should be addressed. Phone: (52) 5747-
7112. Fax: (52) 5747-7137.
(1) (a) Christophersen, C. Acta Chem. Scand. B 1985, 39, 517-529.
(b) Holst, P. B.; Anthoni, U.; Christophersen, C.; Nielsen, P. H. J . Nat.
Prod. 1994, 57, 997-1000.
(2) Laycock, M. V.; Wright, J . L. C.; Findlay, J . A.; Patil, A. D. Can.
J . Chem. 1986, 64, 1312-1316.
(3) (a) Carle´, J . S.; Christophersen, C. J . Am. Chem. Soc. 1979, 101,
4012-4013. (b) Carle´, J . S.; Christophersen, C. J . Org. Chem. 1980,
45, 1586-1589.
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Physiol. 1982, 71B, 523-524.
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Chem. Scand. B 1986, 40, 555-558.
(6) Wang, H.-j.; Gloer, J . B.; Wicklow, D. T.; Dowd, P. F. J . Nat.
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(7) Arai, K.; Kimura, K.; Mushiroda, T.; Yamamoto, Y. Chem.
Pharm. Bull. 1989, 37, 2937-2939.
10.1021/jo0012647 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/27/2001

Syntheses Indole Alkaloids from Flustra foliacea
J . Org. Chem., Vol. 66, No. 4, 2001 1187
Sch em e 1
be of significant interest for more detailed pharmacologi-
cal investigations, it was the goal of the current project
to develop efficient total syntheses for these indole
alkaloids. The first total synthesis of a member of this
family of natural products, debromoflustramine B (5), via
C3 alkylation of a tryptamine derivative was reported.14
This strategy was extended to the synthesis of flustra-
mine B (2),15 as well as to the diastereoselective synthesis
of 516 using, in this case, the cyclic tautomer of an
L-tryptophan derivative.17 Another approach to 5, via a
Claisen rearrangement as the key reaction, involves a
six-step sequence and 4.4% overall yield on the basis of
1-methoxyindole-3-carbaldehyde.18 To date, no published
syntheses for flustramine A (1) nor flustramides A (3)
and B (4) exist.
In our preliminary communication,19 we have demon-
strated the usefulness of the addition of an organomag-
nesium species to 2-hydroxyindolenines for introducing
an alkyl group at the C3 position of the indole nucleus
and, therefore, the preparation of suitable intermediates
for the synthesis of debromoflustramine B (5). To extend
the methodology developed for this compound, we now
describe a total synthesis of flustramine B (2) and the
first total syntheses of flustramine A (1) and flustramides
A (3) and B (4), demonstrating that this protocol is a
general and efficient approach for the total synthesis of
marine bryozoan Flustra foliacea alkaloids.
to increase the solubility of the starting materials.
Typically, when the 2-hydroxyindolenine 6a was stirred
with an excess (4 equiv) of prenylmagnesium bromide (3-
methyl-2-butenylmagnesium bromide) at -78 °C in an-
hydrous THF/ether, the products of the 1,4-addition, the
prenylated 2-oxofuro[2,3-b]indoline 8a (12:1 mixture of
endo/exo isomers as determined by 1H NMR) and the 1,1-
dimethylallyl isomer 7a (only endo isomer), were ob-
tained in a combined yield of 77% in a ratio of 61 (7a ):39
(8a ). The structures of both 7a and 8a were established
1
unequivocally by H and 13C NMR. On the basis of these
precedents, the reaction of the brominated 2-hydroxyin-
dolenine 6b with prenylmagnesium bromide was carried
out at -78 °C to afford the C3a-alkylated 2-oxofuroin-
dolines 7b (endo isomer) and 8b (as approximately 12:1
mixture of endo/exo isomers) in a combined yield of 76%
in a ratio of 53 (7b):47 (8b). The dependence of the C3/
C3a endo/exo ratios on the alkyl group at C3a is in line
with our previous observations.19
Taken together, our results seem to indicate in a first
glance that the nucleophilic addition involves the initial
complexation of the indolenine alkoxide of 6 and the
equilibrating mixture of prenylmagnesium bromide 9 and
its 1,1-dimethylallyl isomer 9′ leading to a secondary or
a quaternary carbon in adducts 10 or 10′ (Scheme 2).
Although it is known that the R vs γ equilibrium between
9 and 9′ lies heavily on the side of 9,23 our results show
that 7 is preferred over 8. By that account, it is possible
that simultaneous intramolecular electrophilic assistance
by the magnesium bond to the oxygen, and the prenyl
delivery at either the R or γ sites leads, via 10 (path A),
to the observed products 7 and 8. It is also conceivable
that an equilibrium between 10 and 10′ comes into play
leading analogously, via 10′ (path B), to R- and γ-adducts
7 and 8. Thus, formation of species 10 or 10′ is likely to
be the chemocontrolling step in the overall process.
Scheme 2 has to rely on a regiochemistry analysis rather
than on a quantitative prediction.
Resu lts a n d Discu ssion
Previously, we reported20 a flexible approach to 2-hy-
droxyindolenines 6 bearing different substitution pat-
terns on the benzene ring. These cyclic hemiaminals also
proved to be good substrates for further carbon-carbon
bond formation.21 The first step (Scheme 1) in the
synthesis of F. foliacea alkaloids involves the prenyl
reagent addition to 2-hydroxyindolenines 6 to provide a
ready access to a range of functionalized 2-oxofuro[2,3-
b]indolines 7 and 8. Prenyl ligand was found to add from
both the R and γ sites with high levels of chemoselectiv-
ity, as no competing 1,2-adducts were detected (Scheme
1).22
After exploring several reaction conditions, the best
yields for compounds 7 and 8 were obtained at -78 °C.
THF was used as a cosolvent in the Grignard reactions
(14) Muthusubramanian, P.; Carle´, J . S.; Christophersen, C. Acta
Chem. Scand. B 1983, 37, 803-807.
(15) Hino, T.; Tanaka, T.; Matsuki, K.; Nakagawa, M. Chem. Pharm.
Bull. 1983, 31, 1806-1808.
(16) Bruncko, M.; Crich, D.; Samy, R. J . Org. Chem. 1994, 59, 5543-
5549.
(17) Taniguchi, M.; Hino, T. Tetrahedron 1981, 37, 1487-1494.
(18) Somei, M.; Yamada, F.; Izumi, T.; Nakajou, M. Heterocycles
1997, 45, 2327-2330.
(19) Morales-R´ıos, M. S.; Sua´rez-Castillo, O. R.; J oseph-Nathan, P.
J . Org. Chem. 1999, 64, 1086-1087.
The one-pot hydrolytic decyanation of the R-cyano-γ-
lactones 7a , 7b, 8a , and 8b was conducted in refluxing
THF for 3-13 h, in the presence of wet alumina, to afford
the corresponding γ-lactones 11a , 11b, 12a , and 12b in
95%, 89%, 86%, and 64% yield, respectively. The yield of
12b was improved to 83% when the reaction was effected
at room temperature, although the reaction was mark-
(20) Compounds 6a and 6b were prepared in good overall yields by
treatment of the appropriately substituted 3-acetonitrilindole with an
alkyl carbonate in basic medium, followed by oxidation with either
HNO3/AcOH or CrO3/AcOH. See: Morales-R´ıos, M. S.; Bucio, M. A.;
J oseph-Nathan, P. J . Heterocycl. Chem. 1993, 30, 953-956.
(21) (a) Morales-R´ıos, M. S.; Bucio, M. A.; J oseph-Nathan, P.
Tetrahedron 1996, 52, 5339-5348. (b) Morales-R´ıos, M. S.; Garc´ıa-
Mart´ınez, C.; Bucio, M. A.; J oseph-Nathan, P. Monatsh. Chem. 1995,
126, 789-794. (c) Morales-R´ıos, M. S.; Bucio, M. A.; Garc´ıa-Mart´ınez,
C.; J oseph-Nathan, P. Tetrahedron Lett. 1994, 35, 6087-6088. (d)
Morales-R´ıos, M. S.; Bucio, M. A.; J oseph-Nathan, P. Tetrahedron Lett.
1994, 35, 881-882.
(23) (a) Whitesides, G. M.; Nordlander, J . E.; Roberts, J . D. Discus-
sions Faraday Soc., 1962, 34, 185-190. (b) Whitesides, G. M.; Nord-
lander, J . E.; Roberts, J . D. J . Am. Chem. Soc. 1962, 84, 2010-2011.
(c) Benkeser, R. A. Synthesis 1971, 347-358.
(22) For related 1,4-addition studies of prenyl Grignard reagent,
see: Lipshutz, B. H.; Hackmann, C. J . Org. Chem. 1994, 59, 7437-
7444.

1188 J . Org. Chem., Vol. 66, No. 4, 2001
Morales-R´ıos et al.
Sch em e 2
Sch em e 4
assumed that the electron-withdrawing N-CO2Me sub-
stituent deactivates the hydroxyl group at C2 toward
nucleophilic substitution to give the desired lactam. The
structure of 13 was established unequivocally by 1H and
13C NMR.
It was then of interest to investigate the possibility of
introducing the N8 prenyl group in the synthetic sequence
before effecting the lactamisation. Attempts to remove
the electron-withdrawing N-CO2Me substituent of com-
pound 11a with 10% KOH in EtOH or HCO2H26b resulted
solely in decomposition, while heating 11a (120-130 °C)
with KOH in aqueous EtOH in a sealed tube27 afforded
the desired deprotected product 14a , albeit in modest
yield. In view of these results, we tested MeONa/MeOH
at reflux as the cleavage method of the indoline ester
group and, to our pleasure, product 14a was obtained in
good yield. This compound proved to decompose slowly
on standing at room temperature and therefore it was
immediately N-alkylated by reaction with K2CO3 and
prenyl bromide in acetone at reflux to give 16a in a
combined yield of 60% for the two-step process (Scheme
5). Using this two-step sequence, compound 12a gave the
N-prenylated compound 17a , through 15a , in 70% overall
yield. Treatment of brominated lactone 11b or 12b with
MeONa/MeOH afforded 14b or 15b which was im-
mediately N-prenylated to produce the desired lactone
16b (68% overall yield) or 17b (60% overall yield). The
debrominated compounds 16a and 17a were then chosen
for study to further evaluate lactamisation and reduction
reactions. Stirring MeOH solutions of 16a or 17a with
methylamine at room temperature for few hours gave the
expected debromoflustramides A (18) or B (19) in high
yields (98% and 92%, respectively). The larger reaction
time required for the formation for 18 (5 h) as compared
to that of 19 (2 h) was not surprising taking into account
the greater steric hindrance of the bulky 1,1-dimethyl-
allyl group in 16a , which could retard formation of the
open ring 2-hydroxyindoline intermediary. Further re-
duction of 18 or 19 with LiAlH4 in refluxing THF gave
debromoflustramines A (20) or B (5) in near-quantitative
yields (Scheme 5). The spectral properties of 5 are
Sch em e 3
edly sluggish and required 5 days for complete decyana-
tion. No intermediates were detected during the reactions
(Scheme 3) and a mechanism involving two successive
pseudopericyclic [4 + 2] hydration processes has been
proposed for the decyanation.24,25
1
identical (IR, H and 13C NMR, EIMS) to those reported
When γ-lactone 11a was treated with methylamine at
room temperature, a single product, γ-hydroxyamide 13,
was obtained which by heating in methanol and aqueous
HCl to reflux gave back γ-lactone 11a (Scheme 4).26 We
for the marine natural product debromoflustramine B,
except for the optical activity.1b,16
On the basis of these precedents, we next examined
the lactamization of 16b or 17b required for the synthesis
of the brominated natural products 3 or 4. As shown in
Scheme 6, treatment of lactones 16b or 17b with me-
thylamine in MeOH at room temperature provided flus-
tramides A (3) or B (4) in 98% isolated yields. The final
reduction of 3 or 4 turned out to be somewhat delicate
due to the inherent lability of the aromatic bromides
(24) Morales-R´ıos, M. S.; Sua´rez-Castillo, O. R.; Garc´ıa-Mart´ınez,
C.; J oseph-Nathan, P. Synthesis 1998, 1755-1759.
(25) For earlier examples of pseudopericyclic reactions, see: (a) Ross,
J . A., Seiders, R. P.; Lemal, D. M. J . Am. Chem. Soc. 1976, 98, 4325-
4327. (b) Wagenseller, P. E.; Birney, D. M.; Roy, D. J . Org. Chem. 1995,
60, 2853-2859. (c) Ham, S.; Birney, D. M. J . Org. Chem. 1996, 61,
3962-3968. (d) Birney, D. M. J . Org. Chem. 1996, 61, 243-251.
(26) Similar observations have been reported before: (a) Wijnberg,
J . B. P. A.; Speckamp, W. N. Tetrahedron 1978, 34, 2399-2404. (b)
Marino, J . P.; Bogdan, S.; Kimura, K. J . Am. Chem. Soc. 1992, 114,
5566-5572.
(27) Ikeda, M.; Matsugashita, S.; Tamura, Y. J . Chem. Soc., Perkin
Trans. 1 1977, 1770-1772.

Syntheses Indole Alkaloids from Flustra foliacea
J . Org. Chem., Vol. 66, No. 4, 2001 1189
Sch em e 5
Sch em e 6
containing the 3a-alkylhexahydropyrrolo[2,3-b]indole ring
system are currently in progress in our laboratory.
Exp er im en ta l Section
Gen er a l Meth od s. Dry THF and ether were obtained by
distillation over sodium. All the commercial grade reagents
were used without further purification. Melting points are
uncorrected. Analytical thin-layer chromatography (TLC) was
performed on silica gel 60 F254 coated aluminum sheets (0.25
mm thickness) with a fluorescent indicator. Visualization was
accomplished with UV light (254 nm). Flash chromatography
was performed using silica gel 60 (230-400 mesh) from
Aldrich. IR spectra were obtained using a Perkin-Elmer 16F
PC FT spectrophotometer. NMR spectra were recorded on
Varian XL-300GS and Mercury 300 spectrometers working at
1
300 and 75.4 MHz for H and 13C, respectively. Chemical shifts
are reported in ppm downfield from tetramethylsilane. Elec-
tron impact mass spectra (EIMS) were recorded on a Hewlett-
Packard 5989A spectrometer at an ionizing voltage of 70 eV.
High-resolution (HR) mass spectra were measured on a J EOL
J MS-SX 102A spectrometer. Microanalytical determinations
were performed by the Microanalytical Laboratory, Elbach,
Germany.
Gen er a l P r oced u r e for Gr ign a r d Ad d ition . To a pre-
cooled (-78 °C) stirred suspension of the Grignard reagent,
prepared from prenyl bromide (30.0 mmol) and Mg turnings
(3.5 g, 0.14 mol) in dry ether (50 mL) under argon at 25 °C,
was added dropwise a solution of 6 (3.5 mmol) in THF/ether
(25/25 mL) over a 0.5 h period. The reaction was completed in
2 h at -78 °C, quenched with saturated NH4Cl solution (10
mL), and diluted with EtOAc (150 mL). The organic layer was
separated, washed with saturated NH4Cl solution (2 × 15 mL),
and dried over Na2SO4. The reaction products 7 and 8 were
then purified by silica gel column chromatography.
toward the nonselective nature of LiAlH4.28 Convertion
of brominated lactams 3 or 4 into the corresponding
tetrahydropyrroles 1 or 2 was then accomplished by
treatment with alane-N,N-dimethylethylamine complex
at room temperature for 45 min in excellent yields (96%
and 97%, respectively) (Scheme 6). This completes the
total synthesis of flustramines A (1) and B (2). The
1
spectral properties of 1-4 are identical (IR, H and 13C
NMR) to those reported for the marine natural products
flustramines A4 and B4 and flustramides A5 and B,6
respectively, except for the optical activity.
In summary, we have described a practical, efficient,
and general approach to the total syntheses of five
marine indole alkaloids including flustramines A (1) and
B (2), flustramides A (3) and B (4), and debromoflustra-
mine B (5) via the conjugated addition of an organomag-
nesium species derived from prenyl bromide to 2-hydroxy-
indolenines. This approach provides a widely potential
route to a variety of marine F. foliacea alkaloids carrying
the basic physostigmine skeleton. Further applications
of this methodology toward the construction of alkaloids
Meth yl 3-Cya n o-3a -(2-m eth yl-3-bu ten -1-yl)-2-oxo-2,3,-
3a ,8a -tetr a h yd r o-8H-fu r o[2,3-b]in d ole-8-ca r boxyla te 7a .
Prepared from methyl Z-1-carbomethoxy-2-hydroxy-3-indoli-
nylidencyanoacetate 6a as colorless crystals (537 mg, 47%):
mp 168-169 °C (CH2Cl2-hexane); Rf 0.19 (3:2 ether/hexane);
1
IR (CHCl3) νmax 2934, 2254, 1789, 1732, 1604, 1480 cm-1; H
NMR (DMSO-d6) δ 7.78 (1H, br s), 7.69, (1H, br d, J ) 7.8
Hz), 7.50 (1H, td, J ) 7.8, 1.2 Hz), 7.26 (1H, td, J ) 7.7, 1.1
Hz), 6.48 (1H, s), 5.93, (1H, dd, J ) 17.3, 10.8 Hz), 5.40 (1H,
s, ex. D2O), 5.20 (1H, d, J ) 17.3), 5.12 (1H, d, J ) 10.8), 3.89
(3H, s), 1.07 (3H, s), 1.06 (3H, s); 13C NMR (DMSO-d6) δ 166.6,
151.6, 141.3, 140.3, 130.7, 127.1, 126.6, 123.7, 116.2, 115.0,
114.9, 93.3, 59.6, 53.7, 41.1, 39.2, 22.3, 21.9; EIMS m/z (relative
(28) Brown, H. C.; Krishamurthy, S. J . Org. Chem. 1969, 34, 3918-
3922.

1190 J . Org. Chem., Vol. 66, No. 4, 2001
Morales-R´ıos et al.
intensity) 326 (M+, 68); HRMS (FAB) m/e 326.1267 (M+,
(DMSO-d6) δ 7.67 (1H, br s), 7.41 (1H, br d, J ) 7.6 Hz), 7.35
(1H, td, J ) 7.6, 1.2 Hz), 7.13 (1H, td, J ) 7.5, 1.1 Hz), 6.29
(1H, s), 5.90, (1H, dd, J ) 17.3, 10.8 Hz), 5.10 (1H, dd, J )
10.8, 1.1 Hz), 5.04 (1H, dd, J ) 17.3, 1.1), 3.84 (3H, s), 3.27
(1H, d J ) 18.2 Hz), 2.89 (1H, d, J ) 18.2 Hz), 1.01 (3H, s),
0.89 (3H, s); 13C NMR (DMSO-d6) δ 173.7, 152.0, 142.8, 140.1,
132.1, 129.5, 126.2, 123.8, 114.9, 114.6, 93.4, 57.9, 53.5, 40.2,
36.2, 22.4, 22.0; EIMS m/z (relative intensity) 301 (M+, 39),
C
18H18N2O4 requires 326.1267). Anal. Calcd for C18H18N2O4:
C, 66.25; H, 5.56; N, 8.58; O, 19.61. Found: C, 66.19; H, 5.62;
N, 8.46; O; 19.73.
Meth yl 6-Br om o-3-cya n o-3a -(2-m eth yl-3-bu ten -2-yl)-2-
oxo-2,3,3a ,8a -tetr a h yd r o-8H-fu r o[2,3-b]in d ole-8-ca r boxy-
la te 7b. Prepared from methyl Z-6-bromo-1-carbomethoxy-2-
hydroxy-3-indolinylidencyanoacetate 6b as colorless crystals
(570 mg, 40%): mp 218-220 °C (EtOAc/hexane); Rf 0.43 (2:3
EtOAc/hexane); IR (KBr) νmax 2966, 2258, 1788, 1722, 1604,
233 (33), 188 (100); HRMS (FAB) m/e 301.1329 (M+, C17H19
-
NO4 requires 301.1314).
1
1442 cm-1; H NMR (DMSO-d6) δ 7.90 (1H, br s), 7.60, (1H,
Meth yl 6-Br om o-3a -(2-m eth yl-3-bu ten -2-yl)-2-oxo-2,3,-
3a ,8a -tetr a h yd r o-8H-fu r o[2,3-b]in d ole-8-ca r boxyla te 11b.
Prepared from 7b as colorless crystals, the reaction reached
completion at reflux in 9 h (245 mg, 89%): mp 138-140 °C
(ether/hexane); Rf 0.52 (2:3 EtOAc/hexane); IR (CHCl3) νmax
3020, 1779, 1722, 1596 cm-1; 1H NMR (DMSO-d6) δ 7.86 (1H,
br s), 7.44 (1H, d, J ) 8.1 Hz), 7.39 (1H, dd, J ) 8.2, 1.8 Hz),
6.36 (1H, s), 5.95, (1H, dd, J ) 17.3, 10.8 Hz), 5.17 (1H, dd, J
) 10.8, 1.1 Hz), 5.10 (1H, dd, J ) 17.3, 1.1), 3.93 (3H, s), 3.33
(1H, d J ) 18.3 Hz), 2.97 (1H, d, J ) 18.3 Hz), 1.07 (3H, s),
1.00 (3H, s); 13C NMR (DMSO-d6) δ 173.3, 151.8, 142.4, 141.5,
131.6, 128.0, 126.4, 122.0, 117.1, 115.0, 93.4, 57.7, 53.6, 40.1,
35.8, 22.3, 21.7; EIMS m/z (relative intensity) 379/381 (M+,
22/22), 282/284 (25/25), 266/268 (92/100).
d), 7.47 (1H, dd, J ) 8.3, 1.9 Hz), 6.48 (1H,s), 5.90 (1H, dd, J
) 17.3, 10.7 Hz), 5.40 (1H, s, ex. D2O), 5.20 (1H, d, J ) 17.3
Hz), 5.12 (1H, d, J ) 10.9), 3.90 (3H, s), 1.08 (3H, s), 1.05 (3H,
s); 13C NMR (DMSO-d6) δ 166.3, 151.4, 141.8, 141.0, 128.8,
126.5, 126.2, 123.6, 117.7, 116.4, 114.8, 93.3, 59.4, 54.0, 41.1,
39.9, 22.3, 21.8; EIMS m/z (relative intensity) 404/406 (M+,
18/17), 292/294 (61/65); HRMS (FAB) m/e 404.0366 (M+,
C18H17BrN2O4 requires 404.0372). Anal. Calcd for C18H17
-
BrN2O4: C, 53.35; H, 4.23; Br, 19.72; N, 6.91. Found: C, 53.18;
H, 4.35; Br, 19.65; N, 6.73.
Meth yl 3-Cya n o-3a -(3-m eth yl-2-bu ten -1-yl)-2-oxo-2,3,-
3a ,8a -tetr a h yd r o-8H-fu r o[2,3-b]in d ole-8-ca r boxyla te 8a .
Prepared from 6a as colorless crystals (335 mg, 30%): mp
108-110 °C (ether/hexane); Rf 0.23 (3:2 ether/hexane); IR
(CHCl3) νmax 3018, 2258, 1800, 1732, 1600, 1484 cm-1; 1H NMR
(DMSO-d6), diastereomeric ca. 12:1 endo/exo ratio δ (endo
isomer) 7.73 (1H, br s), 7.58, (1H, br d, J ) 7.7 Hz), 7.45 (1H,
td, J ) 7.6, 1.3 Hz), 7.22 (1H, td, J ) 7.6, 1.1 Hz), 6.42 (1H, s),
5.18 (1H, s, ex. D2O), 4.97 (1H, br t, J ) 7.5 Hz), 3.87 (3H, s),
2.68 (1H, 2d, J ) 14.3, 7.1 Hz), 2.61 (1H, dd, J ) 14.3, 8.4
Hz), 1.63 (3H, s), 1.47 (3H, s); 13C NMR (DMSO-d6) δ 165.4,
151.8, 140.0, 137.0, 130.2, 128.5, 125.7, 123.9, 116.4, 115.0,
114.2, 95.1, 53.9, 53.6, 41.6, 34.6, 25.5, 17.7; 1H NMR (DMSO-
d6) δ (exo isomer) 7.73 (1H, br s), 7.50, (1H, br d, J ) 7.7 Hz),
7.38 (1H, td, J ) 7.7, 1.3 Hz), 7.16 (1H, td, J ) 7.5, 1.1 Hz),
6.58 (1H, s), 5.12 (1H, s), 4.81 (1H, br t, J ) 7.6 Hz), 3.87 (3H,
s), 2.84 and 2.61 (2H, 2dd, J ) 14.2, 8.4 and 14.2, 7.1 Hz),
1.55 (3H, s), 1.42 (3H, s); EIMS m/z (relative intensity) 326
(M+, 72), 214 (53), 69 (100); HRMS (FAB) m/e 326.1269 (M+,
Meth yl 3a -(3-Meth yl-2-bu ten -1-yl)-2-oxo-2,3,3a ,8a -tet-
r a h yd r o-8H-fu r o[2,3-b]in d ole-8-ca r boxyla te 12a . Prepared
from 8a as a colorless oil, the reaction reached completion at
reflux in 3.5 h (186 mg, 86%): Rf 0.55 (2:3 EtOAc/hexane); IR
(CHCl3) νmax 2936, 1780, 1719, 1604, 1483 cm-1 1H NMR
;
(DMSO-d6) δ 7.67 (1H, br s), 7.40 (1H, dd, J ) 7.5, 0.6 Hz),
7.33 (1H, td, J ) 7.5, 1.3 Hz), 7.13 (1H, td, J ) 7.5, 1.1 Hz),
6.24 (1H, s), 4.95, (1H, br t, J ) 7.5 Hz), 3.85 (3H, s), 3.06
(1H, d J ) 17.8 Hz), 2.93 (1H, d, J ) 17.8 Hz), 2.51 (2H, s),
1.60 (3H, s), 1.45 (3H, s); 13C NMR (DMSO-d6) δ 173.9, 152.3,
139.6, 135.4, 134.0, 128.9, 124.6, 123.9, 117.6, 114.5, 114.4,
95.1, 53.2, 51.8, 38.7, 34.8, 25.5, 17.7; EIMS m/z (relative
intensity) 301 (M+, 85), 233 (62), 204 (42), 188 (100).
Meth yl 6-Br om o-3a -(3-m eth yl-2-bu ten -1-yl)-2-oxo-2,3,-
3a ,8a -tetr a h yd r o-8H-fu r o[2,3-b]in d ole-8-ca r boxyla te 12b.
Prepared from 8b as a colorless oil, the reaction reached
completion at reflux in 3 h (175 mg, 64%) or at rt in 5 days
(228 mg, 83%): Rf 0.53 (2:3 EtOAc/hexane); IR (CHCl3) νmax
3032, 1783, 1727, 1600, 1480, 1442 cm-1; 1H NMR (DMSO-d6)
δ 7.80 (1H, br s), 7.38 (1H, d, J ) 8.2 Hz), 7.32 (1H, dd, J )
8.1, 1.7 Hz), 6.25 (1H, s), 4.95, (1H, br t, J ) 7.5 Hz), 3.87
(3H, s), 3.05 (1H, d J ) 18.0 Hz), 2.95 (1H, d, J ) 18 Hz), 2.52
(2H, d, J ) 5.6 Hz), 1.61 (3H, s), 1.46 (3H, s); 13C NMR (DMSO-
d6) δ 173.8, 152.2, 141.2, 135.8, 133.7, 126.7, 126.6, 121.5,
117.5, 117.3, 95.3, 53.6, 51.8, 38.5, 34.7, 25.6, 17.8; EIMS m/z
(relative intensity) 379/381 (M+, 40/40), 311/313 (35/34), 266/
268 (94/100).
C
18H18N2O4 requires 326.1267).
Meth yl 6-Br om o-3-cya n o-3a -(3-m eth yl-2-bu ten -1-yl)-2-
oxo-2,3,3a ,8a -tetr a h yd r o-8H-fu r o[2,3-b]in d ole-8-ca r boxy-
la te 8b. Prepared from 6b as colorless crystals (510 mg,
36%): mp 123-125 °C (ether/hexane); Rf 0.56 (2:3 EtOAc/
hexane); IR (CHCl3) νmax 2960 2258, 1802, 1736, 1598, 1444
1
cm-1; H NMR (DMSO-d6), diastereomeric ca. 12:1 endo/exo
ratio δ (endo isomer) 7.86 (1H, br s), 7.49, (1H, d, J ) 8.3 Hz),
7.44 (1H, dd, J ) 8.3, 1.8 Hz), 6.41 (1H, s), 5.18 (1H, s, ex.
D2O), 4.99 (1H, br t, J ) 7.6 Hz), 3.89 (3H, s), 2.69 (1H, 2d, J
) 14.3, 7.4 Hz), 2.61 (1H, dd, J ) 14.3, 8.4 Hz), 1.64 (3H, s),
1.46 (3H, s); 13C NMR (DMSO-d6) δ 166.5, 151.7, 141.4, 137.3,
128.0, 127.5, 126.8, 123.0, 117.7, 116.1, 114.1, 95.1, 53.8, 53.7,
41.4, 34.4, 25.5, 17.4; 1H NMR (DMSO-d6) δ (exo isomer) 7.86
(1H, br s), 7.49, (1H, d, J ) 8.3 Hz), 7.36 (1H, dd, J ) 8.3, 1.8
Hz), 6.54 (1H, s), 5.12 (1H, s), 4.82 (1H, br t, J ) 7.6 Hz), 3.89
(3H, s), 2.85 and 2.72 (2H, 2dd, J ) 14.2, 8.4 and 14.2, 7.4
Hz), 1.57 (3H, s), 1.44 (3H, s); EIMS m/z (relative intensity)
404/406 (M+, 31/31), 292/294 (49/46), 69 (100); HRMS (FAB)
m/e 404.0377 (M+, C18H17BrN2O4 requires 404.0372).
Meth yl 2-Hyd r oxy-3-(2-m eth yl-3-bu ten -2-yl)-3-[2-oxo-
2-(m eth yla m in o)eth yl]-2,3-d ih yd r o-1H-in d ole-1-ca r boxy-
la te 13. Excess methylamine (10 mL) was condensed at -78
°C in a flask containing 11a (0.150 g, 0.50 mmol). The cooling
bath was removed, and the reaction mixture was stirred until
the excess methylamine evaporated. The residue was purified
by crystallization from ether to afford 13 (162 mg, 98%) as
colorless crystals: mp 137-139 °C; Rf 0.13 (1:1 EtOAc/hexane);
1
IR (CHCl3) νmax 2958, 1706, 1648, 1602, 1486, cm-1; H NMR
Gen er a l P r oced u r e for Hyd r olytic Decya n a tion . A
mixture of the appropriate R-cyano-γ-lactone 7 or 8 (0.72
mmol) and alumina (650 mg) in 3.0% aqueous THF (6 mL)
was stirred at reflux or at rt, as described below for each case,
until TLC analysis showed complete loss of starting material.
After the mixture was cooled to rt, the alumina was filtered
off and washed with EtOAc (5 × 20 mL). The filtrate and the
eluates were combined and evaporated to afford the corre-
sponding crude γ-lactone 11 or 12 which was purified by flash
chromatography on silica gel (2:3 EtOAc/hexane).
(DMSO-d6) δ 8.64 (1H, q, J ) 4.5 Hz), 8.48 (1H, br d, J ) 11.0
Hz), 7.61 (1H, br s), 7.18 (1H, td, J ) 7.6, 1.3 Hz), 7.06 (1H,
dd, J ) 7.5, 1.0 Hz), 6.92 (1H, td, J ) 7.5, 1.1 Hz), 5.56 (1H,
dd, J ) 16.5, 11.5 Hz), 5.41, (1H, d, J ) 11.0 Hz), 4.97 (1H, d,
J ) 17.3 Hz), 4.96 (1H, d, J ) 8.8 Hz), 3.74 (3H, s), 2.36 (3H,
d, J ) 4.5 Hz), 2.91 (1H, d J ) 14.8 Hz), 2.79 (1H, d, J ) 14.8
Hz), 0.93 (3H, s), 0.84 (3H, s); 13C NMR (DMSO-d6) δ 173.3,
152.8, 143.1 141.5, 130.9, 128.0, 125.5, 121.4, 113.8, 113.6,
87.3, 55.8, 52.5, 42.4, 35.4, 25.7, 22.0, 21.3; EIMS m/z (relative
intensity) 332 (M+, 9), 263 (70), 231 (100), 204 (44).
Meth yl 3a -(2-Meth yl-3-bu ten -2-yl)-2-oxo-2,3,3a ,8a -tet-
r a h yd r o-8H-fu r o[2,3-b]in d ole-8-ca r boxyla te 11a . Prepared
from 7a as a colorless oil, the reaction reached completion at
reflux in 16 h (206 mg, 95%): Rf 0.53 (2:3 EtOAc/hexane); IR
Gen er a l P r oced u r e for N8-P r en yla tion . To a solution of
11 or 12 (0.125 g, 0.41 mmol) in MeOH (15 mL) at 0 °C was
added NaH (0.83 mmol). The mixture was heated at reflux
for 2 h, and the volatiles were evaporated. The residue was
dissolved in EtOAc (100 mL) and saturated aqueous NH4Cl
(CHCl3) νmax 2938, 1779, 1718, 1604, 1483 cm-1 1H NMR
;

Syntheses Indole Alkaloids from Flustra foliacea
J . Org. Chem., Vol. 66, No. 4, 2001 1191
(5 mL). The organic phase was washed with brine (3 × 20 mL),
and the combined aqueous phases were extracted with EtOAc
(3 × 20 mL). The combined organic phases were dried over
Na2SO4 and evaporated to give the crude product 14 or 15
which was used in the next step without purification.
The crude compound 14 or 15 was heated to reflux with
added acetone (15 mL), K2CO3 (0.167 g, 1.2 mmol) and prenyl
bromide (1.2 mmol). The insoluble part was removed by
filtration and washed with acetone (2 × 25 mL). The combined
organic phases were dried over Na2SO4 and evaporated to
afford the corresponding crude N-prenylated compund 16 or
17, which was purified by flash chromatography on silica gel
(1:3 EtOAc/hexane).
3a -(2-Meth yl-3-bu ten -2-yl)-8-(3-m eth yl-2-bu ten -1-yl)-2-
oxo-2,3,3a ,8a -tetr a h yd r o-8H-fu r o[2,3-b]in d ole 16a . Pre-
pared from 11a as a colorless oil, the reaction reached
completion in 36 h (77 mg, 60%): Rf 0.47 (1:3 EtOAc/hexane);
IR (CHCl3) νmax 2920, 1760, 1606, 1488 cm-1; 1H NMR (DMSO-
d6) δ 7.20 (1H, br d, J ) 7.9 Hz), 7.15 (1H, td, J ) 7.7, 1.2 Hz),
6.76 (1H, td, J ) 7.7, 0.9 Hz), 6.56 (1H, br d, J ) 7.8 Hz), 6.00
(1H, dd, J ) 17.3, 10.8 Hz), 5.90 (1H, s), 5.28 (1H, br t, J )
6.7 Hz), 5.12 (1H, dd, J ) 10.8, 1.2 Hz), 5.05 (1H, dd, J ) 17.3,
1.2 Hz), 4.00 (1H, dd, J ) 15.1, 6.2 Hz), 3.87 (1H, dd, J ) 14.4,
7.3 Hz), 3.15 (1H, d, J ) 17.9 Hz), 2.75 (1H, d, J ) 17.9 Hz),
1.74 (6H, s), 1.02 (3H, s), 0.91 (3H, s); 13C NMR (DMSO-d6) δ
174.6, 148.2, 143.6, 135.3, 130.8, 129.0, 125.3, 119.8, 118.4,
114.2, 107.0, 100.2, 58.0, 42.2, 40.0, 37.4, 25.5, 22.3, 22.0, 17.7;
EIMS m/z (relative intensity) 311 (M+, 85); HRMS (FAB) m/e
311.1896 (M+, C20H25NO2 requires 311.1885).
6-Br om o-3a-(2-m eth yl-3-bu ten -2-yl)-8-(3-m eth yl-2-bu ten -
1-yl)-2-oxo-2,3,3a ,8a -tetr a h yd r o-8H-fu r o[2,3-b]in d ole 16b.
Prepared from 11b as a colorless oil, the reaction reached
completion in 80 h (109 mg, 68%): Rf 0.51 (1:3 EtOAc/hexane);
IR (CHCl3) νmax 3018, 1766, 1598, 912 cm-1; 1H NMR (DMSO-
d6) δ 7.14 (1H, d, J ) 7.9 Hz), 6.90 (1H, dd, J ) 7.9, 1.7 Hz),
6.73 (1H, d, J ) 1.7 Hz), 5.97 (1H, dd, J ) 17.4, 10.8 Hz), 5.90
(1H, s), 5.25 (1H, br t, J ) 6.2 Hz), 5.11 (1H, dd, J ) 10.8, 1.3
Hz), 5.04 (1H, dd, J ) 17.4, 1.3 Hz), 4.01 (1H, dd, J ) 15.2,
6.2 Hz), 3.86 (1H, dd, J ) 15.1, 7.4 Hz), 3.14 (1H, d, J ) 18.1
Hz), 2.77 (1H, d, J ) 18.1 Hz), 1.74 (6H, s), 1.00 (3H, s), 0.92
(3H, s); 13C NMR (DMSO-d6) δ 174.2, 149.7, 143.1, 135.7, 130.3,
126.8, 121.9, 120.6, 119.0, 114.3, 109.6, 99.5, 57.6, 41.9, 39.8,
36.8, 25.3, 22.2, 21.8, 17.6; EIMS m/z (relative intensity) 389/
391 (M+, 25/25), 320/322 (19/19), 252/254 (28/30), 224/226 (52/
49), 69 (100).
278 (179/181); HRMS (FAB) m/e 390.1069 (M+ + H, C20H24
-
BrNO2 requires 390.1069).
Gen er a l P r oced u r e for La cta m iza tion . To a solution of
the appropriate lactone 16a (0.32 mmol), 17a (0.32 mmol), 16b
(0.23 mmol), or 17b (0.23 mmol) in MeOH (10 mL) was added
NH2Me (2 mL of a 2.0 M solution in MeOH, 4 mmol). The
reaction mixture was stirred for 5, 2, 24, or 15 h, respectively,
at rt. The mixture was evaporated, and the resultant crude
lactam 18, 3, 19, or 4 was purified by silica gel flash column
chromatography (1:1 EtOAc/hexane).
1-Meth yl-3a-(2-m eth yl-3-bu ten -2-yl)-8-(3-m eth yl-2-bu ten -
1-yl)-2-oxo-2,3,3a ,8a -t e t r a h yd r o-8H -p yr r olo[2,3-b]in -
d ole, Debr om oflu str a m id e A (18). Prepared from 16a as a
colorless oil (102 mg, 98% yield): Rf 0.45 (1:1 EtOAc/hexane);
IR (CHCl3) νmax 2934, 1678, 1602, 1492 cm-1; 1H NMR (DMSO-
d6) δ 7.13 (1H, br d, J ) 7.4 Hz), 7.12 (1H, br t, J ) 7.6 Hz),
6.93 (1H, br t, J ) 7.4 Hz), 6.51 (1H, br d, J ) 7.8 Hz), 5.92
(1H, dd, J ) 17.3, 10.9 Hz), 5.33 (1H, br t, J ) 6.6 Hz), 5.13
(1H, dd, J ) 10.9, 1.2 Hz), 5.08 (1H, dd, J ) 17.3, 1.5 Hz),
5.05 (1H, s), 4.09 (1H, dd, J ) 15.9, 6.7 Hz), 3.97 (1H, dd, J )
15.9, 6.7 Hz), 2.82 (1H, d, J ) 17.1 Hz), 2.79 (3H, s), 2.44 (1H,
d, J ) 17.1 Hz), 1.78 (3H, s), 1.76 (3H, s), 1.02 (3H, s), 0.92
(3H, s); 13C NMR (DMSO-d6) δ 171.5, 149.5, 143.9, 134.0, 132.4,
128.6, 124.9, 121.5, 117.5, 114.0, 107.6, 84.7, 55.2, 45.7, 40.9,
39.1, 27.2, 25.4, 22.5, 21.5, 17.9; EIMS m/z (relative intensity)
324 (M+, 22); HRMS (FAB) m/e 324.2199 (M+, C21H28N2O
requires 324.2202).
1-Meth yl-3a ,8-bis(3-m eth yl-2-bu ten -1-yl)-2-oxo-2,3,3a ,-
8a -tetr a h yd r o-8H-p yr r olo[2,3-b]in d ole, Debr om oflu str a -
m id e B (19). Prepared from 17a as a colorless oil (96 mg, 92%
yield): Rf 0.43 (1:1 EtOAc/hexane); IR (CHCl3) νmax 2930, 1678,
1
1604, 1488 cm-1; H NMR (DMSO-d6) δ 7.08 (1H, br d, J )
8.0 Hz), 7.06 (1H, td, J ) 7.9, 1.3 Hz), 6.68 (1H, td, J ) 7.8,
0.8 Hz), 6.53 (1H, br d, J ) 7.8 Hz), 5.20 (1H, br t, J ) 6.8
Hz), 4.98 (1H, br t, J ) 7.4 Hz), 4.80 (1H, s), 4.07 (1H, dd, J
) 15.7, 6.7 Hz), 3.91 (1H, dd, J ) 16.1, 7.1 Hz), 2.75 (3H, s),
2.68 (1H, d, J ) 17.1 Hz), 2.47 (1H, d, J ) 17.1 Hz), 2.38 (1H,
dd, J ) 14.6, 7.8 Hz), 2.30 (1H, dd, J ) 14.8, 6.8 Hz), 1.72
(3H, s), 1.70 (3H, s), 1.65 (3H, s), 1.51 (3H, s); 13C NMR
(DMSO-d6) δ 171.5, 149.0, 135.2, 134.4, 134.3, 128.3, 123.2,
121.0, 119.1, 118.3, 108.5, 86.2, 49.4, 45.9, 41.4, 36.9, 27.2, 25.7,
25.4, 17.8 (2C); EIMS m/z (relative intensity) 324 (M+, 38),
187 (100); HRMS (FAB) m/e 324.2201 (M+, C21H28N2O requires
324.2202).
6-Br om o-3a-(2-m eth yl-3-bu ten -2-yl)-8-(3-m eth yl-2-bu ten -
1-yl)-2-oxo-2,3,3a ,8a -t e t r a h yd r o-8H -p yr r olo[2,3-b]in -
d ole, F lu str a m id e A (3). Prepared from 16b as a colorless
oil (91 mg, 98% yield): Rf 0.35 (1:1 EtOAc/hexane); IR (CHCl3)
3a ,8-Bis(3-m eth yl-2-bu ten -1-yl)-2-oxo-2,3,3a ,8a -tetr a h y-
d r o-8H-fu r o[2,3-b]in d ole 17a . Prepared from 12a as a
colorless oil, the reaction reached completion in 36 h (90 mg,
70%): Rf 0.46 (1:3 EtOAc/hexane); IR (CHCl3) νmax 2916, 1762,
1608, 1488 cm-1; 1H NMR (DMSO-d6) δ 7.18 (1H, dd, J ) 7.3,
1.1 Hz), 7.13 (1H, td, J ) 7.7, 1.3 Hz), 6.74 (1H, td, J ) 7.5,
0.9 Hz), 6.58 (1H, br d, J ) 7.7 Hz), 5.69 (1H, s), 5.25 (1H,
ddq, J ) 9.0, 6.2, 1.4 Hz), 5.07 (1H, ddq, J ) 8.4, 7.1, 1.3 Hz),
3.98 (1H, dd, J ) 15.0, 6.1 Hz), 3.84 (1H, dd, J ) 14.9, 7.6
Hz), 2.97 (1H, d, J ) 17.5 Hz), 2.80 (1H, d, J ) 17.5 Hz), 2.37
ν
max 3006, 1680, 1594, 1492 cm-1; 1H NMR (CDCl3) δ 6.92 (1H,
d, J ) 8.0 Hz), 6.81 (1H, dd, J ) 8.0, 1.8 Hz), 6.57 (1H, d, J )
1.8 Hz), 5.78 (1H, dd, J ) 17.3, 10.9 Hz), 5.26 (1H, br t, J )
6.7 Hz), 5.12 (1H, dd, J ) 10.9, 1.1 Hz), 5.05 (1H, dd, J ) 17.3,
1.1 Hz), 4.83 (1H, s), 3.93 (2H, d, J ) 6.7 Hz), 2.85 (3H, s),
2.84 (1H, d, J ) 17.6 Hz), 2.55 (1H, d, J ) 17.6 Hz), 1.77 (3H,
s), 1.75 (3H, s), 1.03 (3H, s), 0.93 (3H, s); 13C NMR (CDCl3) δ
172.6, 151.1, 143.3, 135.7, 131.7, 126.2, 122.5, 120.7, 120.3,
114.6, 110.9, 85.9, 55.4, 46.3, 41.2, 39.4, 27.9, 25.6, 22.6, 21.8,
18.1; EIMS m/z (relative intensity) 402/404 (M+, 6/6), 333/335
(20/20), 265/267 (63/61), 208/210 (16/16), 69 (100).
(2H, d, J ) 7.3 Hz), 1.73 (6H, s), 1.64 (3H, s), 1.47 (3H, s); 13
C
NMR (DMSO-d6) δ 174.7, 147.4, 135.5, 134.5, 132.8, 128.6,
123.7, 119.6, 118.7, 118.5, 107.1, 101.5, 52.1, 41.9, 39.3, 34.1,
25.5, 25.4, 17.7, 17.6; EIMS m/z (relative intensity) 311 (M+,
50); HRMS (FAB) m/e 311.1895 (M+, C20H25NO2 requires
311.1885).
6-Br om o-3a ,8-bis(3-m eth yl-2-bu ten -1-yl)-2-oxo-2,3,3a ,-
8a -tetr a h yd r o-8H-p yr r olo[2,3-b]in d ole, F lu str a m id e B
(4). Prepared from 17b as a colorless oil (91 mg, 98% yield):
Rf 0.32 (1:1 EtOAc/hexane); IR (CHCl3) νmax 3026, 1682, 1596,
6-Br om o-3a ,8-bis(3-m eth yl-2-bu ten -1-yl)-2-oxo-2,3,3a ,-
8a -tetr a h yd r o-8H-fu r o[2,3-b]in d ole 17b. Prepared from
12b as a colorless oil, the reaction reached completion in 80 h
(96 mg, 60%): Rf 0.41 (1:3 EtOAc/hexane); IR (CHCl3) νmax
3012, 1770, 1600, 1484 cm-1; 1H NMR (DMSO-d6) δ 7.13 (1H,
d, J ) 7.8 Hz), 6.89 (1H, dd, J ) 7.9, 1.7 Hz), 6.77 (1H, d, J )
1.7 Hz), 5.69 (1H, s), 5.23 (1H, br t, J ) 7.0 Hz), 5.03 (1H, br
t, J ) 7.5 Hz), 4.01 (1H, dd, J ) 14.9, 6.2 Hz), 3.83 (1H, dd, J
) 14.9, 7.8 Hz), 2.97 (1H, d, J ) 17.7 Hz), 2.82 (1H, d, J )
17.7 Hz), 2.39 (2H, d, J ) 7.3 Hz), 1.74 (3H, s), 1.73 (3H, s),
1.64 (3H, s), 1.47 (3H, s); 13C NMR (DMSO-d6) δ 174.4, 149.2,
136.1, 134.8, 132.3, 125.5, 121.7, 121.0, 119.0, 118.2, 109.9,
101.0, 51.8, 41.8, 39.1, 34.0, 25.5, 25.4, 17.7 (2C); EIMS m/z
(relative intensity) 389/391 (M+, 14/15), 321/323 (85/85), 276/
1
1488 cm-1; H NMR (CDCl3) δ 6.87 (1H, d, J ) 7.2 Hz), 6.83
(1H, dd, J ) 7.2, 1.4 Hz), 6.60 (1H, d, J ) 1.5 Hz), 5.18 (1H,
br t, J ) 6.7 Hz), 4.95 (1H, br t, J ) 7.4 Hz), 4.73 (1H, s), 3.96
(1H, dd, J ) 16.4, 6.6 Hz), 3.88 (1H, dd, J ) 16.3, 7.4 Hz),
2.87 (3H, s), 2.64 (2H, s), 2.38 (1H, dd, J ) 14.4, 7.7 Hz), 2.30
(1H, dd, J ) 14.4, 6.8 Hz), 1.75 (3H, s), 1.74 (3H, s), 1.70 (3H,
s), 1.56 (3H, s); 13C NMR (CDCl3) δ 172.8, 150.6, 136.0 (2C),
134.3, 124.4, 122.2, 121.5, 120.1, 118.2, 111.7, 87.4, 49.5, 46.6,
41.7, 37.4, 28.0, 26.0, 25.7, 18.1 (2C); EIMS m/z (relative
intensity) 402/404 (M+, 36/35), 333/335 (24/22), 265/267 (100/
97); HRMS (FAB) m/e 403.1398 (M+ + H, C21H27BrN2O
requires 403.1385).

1192 J . Org. Chem., Vol. 66, No. 4, 2001
Morales-R´ıos et al.
Gen er a l P r oced u r e for La cta m Red u ction . To a stirred
solution of LAH (2.50 mmol in 10 mL of dry THF) was added
the appropriate lactam 18 or 19 (0.100 g, 0.31 mmol) in THF
(5 mL), and the mixture was heated at reflux for 3 h. After
the mixture was cooled to 0 °C, the reaction was quenched by
adding dropwise EtOAc (120 mL), washed with brine, dried
over Na2SO4, and evaporated. The resultant crude tetrahydro-
pyrrole 20 or 5 was purified by silica gel flash column
chromatography (EtOAc).
removed by filtration and washed with EtOAc (3 × 10 mL).
The combined organic phases were washed with brine, dried
over Na2SO4 and evaporated to afford the crude flustramine
A (1) or B(2), which was purified by flash chromatography on
silica gel (EtOAc).
6-Br om o-1-m eth yl-3a-(2-m eth yl-3-bu ten -2-yl)-8-(3-m eth -
yl-2-bu ten -1-yl)-1,2,3,3a ,8,8a -h exa h yd r op yr r olo[2,3-b]in -
d ole, F lu str a m in e A (1). Prepared from 3 as a colorless oil
(71 mg, 96%): Rf 0.40 (5:95 MeOH/CHCl3); IR (CHCl3) νmax
1
1-Meth yl-3a-(2-m eth yl-3-bu ten -2-yl)-8-(3-m eth yl-2-bu ten -
1-yl)-1,2,3,3a ,8,8a -h exa h yd r op yr r olo[2,3-b]in d ole, Debr o-
m oflu str a m in e A (20). Prepared from 18 as a colorless oil
(94 mg, 98%): Rf 0.48 (EtOAc); IR (CHCl3) νmax 2934, 1600,
2970, 1592, 1488, 1372 cm-1; H NMR (CDCl3) δ 6.90 (1H, d,
J ) 7.9 Hz), 6.69 (1H, dd, J ) 7.9, 1.8 Hz), 6.48 (1H, d, J )
1.8 Hz), 5.95 (1H, dd, J ) 17.4, 10.9 Hz), 5.22 (1H, br t, J )
6.6 Hz), 5.06 (1H, dd, J ) 10.9, 1.5 Hz), 4.99 (1H, dd, J ) 17.4,
1.1 Hz), 4.34 (1H, s), 3.84 (2H, br d, J ) 7.00 Hz), 2.65 (1H,
m), 2.43 (1H, m), 2.42 (3H, s), 2.23 (1H, m), 1.73 (1H, m), 1.73
(6H, s), 1.00 (3H, s), 0.95 (3H, s); 13C NMR (CDCl3) δ 153.5,
144.9, 134.5, 132.5, 125.7, 121.7, 120.9, 119.0, 113.0, 109.2,
89.4, 63.4, 53.2, 45.8, 41.3, 37.8, 34.5, 25.6, 23.5, 22.5, 18.0;
EIMS m/z (relative intensity) 388/390 (M+, 22/23), 319/321 (96/
100); HRMS (FAB) m/e 389.1607 (M+ + H, C21H29BrN2
requires 389.1592).
1
1490 cm-1; H NMR (CDCl3) δ 7.08 (1H, dd, J ) 7.4, 1.3 Hz),
7.05 (1H, td, J ) 7.5, 1.3 Hz), 6.60 (1H, td, J ) 7.4, 1.0 Hz),
6.39 (1H, d, J ) 7.8 Hz), 5.98 (1H, dd, J ) 17.3, 10.9 Hz), 5.27
(1H, br t, J ) 6.6 Hz), 5.06 (1H, dd, J ) 10.9, 1.2 Hz), 4.99
(1H, dd, J ) 17.3, 1.2 Hz), 4.33 (1H, s), 3.90 (1H, dd, J ) 15.9,
6.5 Hz), 3.82 (1H, dd, J ) 15.9, 7.4 Hz), 2.65 (1H, m), 2.43
(1H, m), 2.43 (3H, s), 2.25 (1H, m), 1.79 (1H, m), 1.73 (3H, s),
1.71 (3H, s), 1.03 (3H, s), 0.95 (3H, s); 13C NMR (CDCl3) δ
152.5, 145.4, 133.8, 133.3, 127.7, 124.7, 121.8, 116.5, 112.6,
106.5, 89.1, 63.6, 53.2, 46.4, 41.5, 37.6, 34.7, 25.6, 23.6, 22.7,
18.0; EIMS m/z (relative intensity) 310 (M+, 45), 241 (100);
HRMS (FAB) m/e 310.2401 (M+, C21H30N2 requires 310.2409).
1-Meth yl-3a ,8-bis(3-m eth yl-2-bu ten -1-yl)-1,2,3,3a ,8,8a -
h exa h yd r op yr r olo[2,3-b]in d ole, Debr om oflu str a m in e B
(5). Prepared from 19 as a colorless oil (94 mg, 98%): Rf 0.12
(EtOAc); IR (CHCl3) νmax 2930, 1678, 1602, 1488 cm-1; 1H NMR
(CDCl3) δ 7.04 (1H, td, J ) 7.5, 1.4 Hz), 6.97 (1H, dd, J ) 6.9,
1.3 Hz), 6.65 (1H, td, J ) 7.7, 1.3 Hz), 6.41 (1H, br d, J ) 7.8
Hz), 5.17 (1H, br t, J ) 7.2 Hz), 4.97 (1H, br t, J ) 7.9 Hz),
4.26 (1H, s), 3.93 (1H, dd, J ) 15.9, 5.8 Hz), 3.80 (1H, dd, J )
16.1, 7.2 Hz), 2.67 (1H, m), 2.56 (1H, m), 2.48 (3H, s), 2.42
(2H, d, J ) 7.5 Hz), 2.05 (1H, m), 1.91 (1H, m), 1.71 (3H, s),
1.70 (3H, s), 1.65 (3H, s), 1.59 (3H, s); 13C NMR (CDCl3) δ
151.8, 135.7, 134.0, 133.3, 127.5, 122.8, 121.4, 120.8, 117.4,
107.2, 91.4, 57.0, 52.8, 46.8, 39.0, 38.4, 38.0, 25.9, 25.7, 18.1
18.0; EIMS m/z (relative intensity): 310 (M+, 45), 241 (100);
HRMS (FAB) m/e 311.2477 (M+ + H, C21H30N2 requires
311.2487).
6-Br om o-1-m eth yl-3a,8-bis(3-m eth yl-2-bu ten -1-yl)-1,2,3,-
3a ,8,8a -h exa yd r op yr r olo[2,3-b]in d ole, F lu str a m in e B (2).
Prepared from 4 as a colorless oil (72 mg, 97%): Rf 0.38 (5:95
MeOH/CHCl3); IR (CHCl3) νmax 2966, 2934, 1598, 1486, 1448
1
cm-1; H NMR (CDCl3) δ 6.80 (1H, d, J ) 7.8 Hz), 6.74 (1H,
dd, J ) 7.8, 1.7 Hz), 6.50 (1H, d, J ) 1.6 Hz), 5.13 (1H, br t,
J ) 6.5 Hz), 4.93 (1H, br t, J ) 7.2 Hz), 4.29 (1H, s), 3.88 (1H,
dd, J ) 16.4, 5.5 Hz), 3.79 (1H, dd, J ) 16.2, 7.2 Hz), 2.67
(1H, m), 2.55 (1H, m), 2.47 (3H, s), 2.39 (2H, d, J ) 7.1 Hz),
2.04 (1H, m), 1.86 (1H, m), 1.72 (3H, s), 1.71 (3H, s), 1.65 (3H,
s), 1.57 (3H, s); 13C NMR (CDCl3) δ 153.0, 134.8, 134.7, 133.8,
123.9, 121.3, 120.6, 120.3, 119.9, 110.0, 91.6, 56.8, 52.7, 46.2,
38.9, 38.2, 38.0, 25.9, 25.7, 18.1 (2C); EIMS m/z (relative
intensity) 388/390 (M+, 38/39), 319/321 (96/100); HRMS (FAB)
m/e 389.1577 (M+ + H, C21H29BrN2 requires 389.1592).
Ack n ow led gm en t. This research was partially sup-
ported by CONACYT (Mexico). O.R.S.-C. gratefully
acknowledges CONACYT for a doctoral fellowship. The
authors thank I. Q. Luis Velasco Ibarra (Instituto de
Qu´ımica, UNAM) for recording the HRMS.
Gen er a l P r oced u r e for Selective La cta m Red u ction .
To a stirred solution of 3 or 4 (77 mg, 0.19 mmol in 10 mL of
dry THF) was added alane-N,N-dimethylethylamine complex
(0.6 mL of a 0.5 M solution in toluene, 0.3 mmol) and the
reaction mixture was stirred for 45 min at rt. The reaction
was quenched by adding slowly a mixture of THF-H2O (1:1,
10 mL) followed by EtOAc (70 mL). The insoluble part was
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of the natural products 1-5. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0012647