Enantioselective synthesis for the (-)-antipode of the pyrazinone marine alkaloid, hamacanthin A

Article abstract of DOI:10.1021/jo010265b

A short enantioselective total synthesis for the (-)-antipode of the antifungal marine alkaloid, hamacanthin A, (6R)-3,6-bis(6-bromoindol-3-yl)-5,6-dihydro-2(1H)-pyrazinone, is described. This synthesis proceeds through the coupling of 3-indolyl-αoxoacetyl chloride and 3-indolyl azidoethylamine, followed by intramolecular aza-Wittig type cyclization. A concise and useful approach for the synthesis of (1R)-1-(indol-3-yl)-2-azidoethylamine using the Sharpless asymmetric dihydroxylation reaction followed by stereospecific azidation is also presented.

Full text of DOI:10.1021/jo010265b

J . Org. Chem. 2001, 66, 4865-4869
4865
En a n tioselective Syn th esis for th e (-)-An tip od e of th e P yr a zin on e
Ma r in e Alk a loid , Ha m a ca n th in A
Biao J iang,* Cai-Guang Yang, and J un Wang
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, Peoples’ Republic of China
jiangb@pub.sioc.ac.cn
Received March 12, 2001
A short enantioselective total synthesis for the (-)-antipode of the antifungal marine alkaloid,
hamacanthin A, (6R)-3,6-bis(6-bromoindol-3-yl)-5,6-dihydro-2(1H)-pyrazinone, is described. This
synthesis proceeds through the coupling of 3-indolyl-R-oxoacetyl chloride and 3-indolyl azidoethy-
lamine, followed by intramolecular aza-Wittig type cyclization. A concise and useful approach for
the synthesis of (1R)-1-(indol-3-yl)-2-azidoethylamine using the Sharpless asymmetric dihydroxy-
lation reaction followed by stereospecific azidation is also presented.
In tr od u ction
lead compounds to new and more biologically active
agents, the formulation of a concise and general enanti-
oselective synthetic method for building the central chiral
heterocyclic moiety, and to determine the absolute con-
figurations of the optically active bis(indole) alkaloids,
is essential. In this report, we describe the first enanti-
oselective total synthesis of the (-)-antipode of hamacan-
thin A (1) as a typical example of a novel and general
method for the synthesis of optically active 3,6-bis(indol-
3-yl)-5,6-dihydro-2(1H)-pyrazinone derivatives.
Marine organisms are among the most promising
sources of a great variety of new biologically active
molecules. Over the past few years, a large number of
marine natural products containing the indole nucleus
have been isolated. Certain bis(indole) secondary me-
tabolites, containing either an imidazole- or piperazine-
derived spacer unit, exhibit a broad spectrum of powerful
biological activities.1 A new family of natural Hamacan-
thins isolated from a deep-water marine sponge has
become larger each year.2,3 Hamacanthin A, the first
member of this family isolated from Hamacantha sp, has
been reported to show significant antimicrobial activity
against Candida albicans and Cryptococcus neoformans.4
On the basis of NMR spectroscopy, its structure was
elucidated to be 3,6-bis(6-bromoindol-3-yl)-5,6-dihydro-
2(1H)-pyrazinone, but the absolute configuration has not
been assigned.2
Resu lts a n d Discu ssion
Retrosynthetically, a convergent route toward the (-)-
antipode of hamacanthin A (1) was simple disconnection
of the double bond, as illustrated in Figure 1. We found
that coupling of 3-indolyl-R-oxoacetyl chloride 3 and
3-indolyl-azidoethylamine 4, followed by intramolecular
aza-Wittig-type cyclization, could lead to the desired
product. Since the absolute configuration of hamacanthin
A has not been assigned, we chose to synthesize the (R)-
enantiomer. The required (R)-3-indolyl azidoethylamine
4 should be derived from (S)-indolyl ethanediol 5, which
was generated by asymmetric dihydroxylation of vinyl
indole 6.
Recently, several methods have been developed to
synthesize racemic, naturally occurring bis(indole) alka-
loids by constructing the central heterocyclic moiety
between the indole residues via the condensation of two
suitable indolyl precursors5 as a key step. For example,
synthesis of the racemic dragmacidin family, which has
a piperazine-derived spacer unit linking two indole rings
in a trans relationship,6 has been accomplished via the
successful construction of the piperazine ring system.7
However, to the best of our knowledge, there have been
few reports on the efficient synthesis of optically active
natural bis(indole) alkaloids.8 In view of our interest in
the synthesis of natural marine bis(indole) alkaloids as
The known 6-bromoindole 7 was prepared via Batcho-
Leimgruber indole synthesis from commercially available
4-bromo-2-nitrotoluene by reaction with dimethylforma-
mide dimethyl acetal followed by reduction of the inter-
(6) For other related bis(indole) natural alkaloids, see: (a) Tsujii,
S.; Rinehart, K. L.; Gunasekera, S. P.; Kashman, Y.; Cross, S. S.; Lui,
M. S.; Pomponi, S. A.; Diaz, M. C. J . Org. Chem. 1988, 53, 5446. (b)
Kohmoto, S.; Kashman, Y.; McConnell, O. J .; Rinehart, K. L.; Wright,
A.; Koehn, F. J . Org. Chem. 1988, 53, 3116. (c) Wright, A. E.; Pomponi,
S. A.; Cross, S. S.; McCarthy, P. J . Org. Chem. 1992, 57, 4772. (d)
Capon, R. J .; Rooney, F.; Murray, L. M.; Collins, E.; Sim, A. T. R.;
Rostas, J . A. P.; Butler, M. S.; Carrol, A. R. J . Nat. Prod. 1998, 61,
660. (e) Cutignano, A.; Bifulco, G.; Bruno, I.; Casapullo, A.; Gomez-
Paloma, L.; Riccio, R. Tetrahedron 2000, 56, 3743.
(1) For a review, see: Faulkner, D. J . Nat. Prod. Rep. 2001, 18, 1
and references therein.
(2) Gunasekera, S. P.; McCarthy, P. J .; Kelly-Borges, M. J . Nat.
Prod. 1994, 57, 1437.
(3) Casapullo, A.; Bifulco, G.; Bruno, I.; Riccio, R. J . Nat. Prod. 2000,
63, 447.
(4) For further interesting biological properties of hamacanthin A
described in the patent literature, see: Chem. Abstr. 1996, 124, 76517y;
Chem. Abstr. 1998, 129, 587d; Chem. Abstr. 2000, 133, 99589y.
(5) For the synthesis of indolylglycines, see: (a) Clark, B. P.; Harris,
J . R. Synth. Commun. 1997, 27, 4223. (b) J ohannsen, M. Chem.
Commun. 1999, 2233. (c) J iang, B.; Yang, C.-G.; Gu, X.-H. Tetrahedron
Lett. 2001, 42, 2545.
(7) (a) J iang, B.; Smallheer, J . M.; Amaral-Ly, C.; Wuonola, M. A.
J . Org. Chem. 1994, 59, 6823. (b) Kawasaki, T.; Enoki, H.; Matsumura,
K.; Ohyama, M.; Inagawa, M.; Sakamoto, M. Org. Lett. 2000, 2, 3027.
(c) Whitlock, C. R.; Cava, M. P. Tetrahedron Lett. 1994, 35, 371. (d)
Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett. 2000, 2, 3185.
(8) For a review, see: Gu, X.-H.; J iang, B. Chin. J . Org. Chem. 2000,
20, 168.
10.1021/jo010265b CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/12/2001

4866 J . Org. Chem., Vol. 66, No. 14, 2001
J iang et al.
Sch em e 1
SCl) and imidazole in CH2Cl2 in 94% yield. Several
methods have been reported for converting a secondary
alcohol to an azide group.14 Initially, we tried to convert
the secondary alcohol in 10 into the corresponding
mesylate or tosylate, followed by nucleophilic attack by
an azide ion to prepare azido compound 11. However,
when 10 was reacted with methanesulfonyl chloride or
tosyl chloride, only the starting material was recovered
due to steric hindrance of the secondary alcohol. Fortu-
nately, we found that the Mitsunobu procedure15 worked
well for our desired transformation. Thus, compound 10
was treated with diphenylphosphoryl azide (DPPA),
triphenylphosphine, and diethylazodicarboxylate (DEAD)
at -20 °C to lead to (R)-azidoindole 11 in 87% yield with
an inversion of configuration. Cleavage of the tert-
butyldimethyl silyl ether using tetrabutylammonium
fluoride (TBAF) in tetrahydrofuran gave indolyl azido
alcohol 12 in 98% yield. While the azido group in 12 was
reduced to an amino group using LiAlH4 at 0 °C followed
by protection of the resulting amino alcohol with (Boc)2O,
we found that LiAlH4 not only reduced the azido group,
but also induced partial debromination of the 6-bromo
substituent in the indole ring. After tosylation of the
alcohol, a mixture of 6-bromoindolyl aminoethanol 13a
and indolyl aminoethanol 13b in a ratio of 4:1 was
isolated in 70% yield in three steps. Displacement of the
tosylate group in 13a with sodium azide in DMF gave
the desired (R)-indolyl azidoethylamine 14 in 88% yield
(Scheme 2).
F igu r e 1.
mediate enamine with hydrazine hydrate in the presence
of Raney-Ni as a catalyst.9 3-Indolyl-R-oxoacetyl chloride
3 was prepared in 90% yield by heating 6-bromoindole 7
with oxalyl chloride in ether for 10 h.10a The requisite
vinyl indole 6 was prepared from 6-bromoindole 7 in high
yield by Vilsmeier-Haack reaction with phosphorus
oxychloride/dimethylformamide,7a,10 followed by Wittig
olefination of the N-tosyl-indole-3-carbaldehyde 911 with
methylenetriphenylphosphorane under typical Wittig
conditions.12 Osmium tetraoxide-catalyzed asymmetric
dihydroxylation (Sharpless AD reaction) has been well
studied for the construction of a chiral vicinal diol using
cinchona alkaloid as a chiral ligand and potassium
ferricyanide as a co-oxidant. The advantage of the Sharp-
less AD reaction is that the newly generated chiral carbon
center can be predicted based on the hydroquinidine and
hydroquinine chiral ligands in the AD-mixture re-
agents.13 Extension of this methodology to the asym-
metric oxidation of vinyl indole 6 was very successful.
Thus, compound 6 was subjected to AD-mix-R in tert-
butyl alcohol/water (1:1) for 10 h at 0 °C to give (S)-1-
(indol-3-yl)-1,2-ethanediol 5 in 92% yield with 99% ee.
The enantiomeric excess was determined by HPLC using
a chiral OD column with an eluent of 2-propanol/hexane
(2/8) (Scheme 1).
The primary hydroxyl group of 5 was selectively
protected with tert-butyldimethylsilyl chloride (TBDM-
With indolyl azidoethylamine 14 and 3-indolyl-R-
oxoacetyl chloride 3 in hand, we then turned to build the
central 5,6-dihydropyrazinone ring in hamacanthin A
(Scheme 3). Removal of the Boc group in 14 with CF3-
COOH in dichloromethane followed by coupling of the
resulting free azidoamine 4 with 3-indolyl-R-oxoacetyl
chloride 3 immediately gave bis(indolyl) azido-ketone 2
in 74% yield. Subsequent formation of the central chiral
pyrazinone ring was performed through a Staudinger-
aza Wittig sequence.16 Reaction of the azido group in 2
(9) (a) Maehr, H.; Smallheer, J . M. J . Org. Chem. 1981, 46, 1752.
(b) Dellar, G.; Djura, P.; Sargent, M. V. J . Chem. Soc., Perkin Trans.
1 1981, 1679. (c) Batcho, A. D.; Leimgruber, W. Org. Synth. 1984, 63,
214.
(10) (a) Da Settimo, A.; Saettone, M. F.; Nannipieri, E.; Barili, P.
Gazz. Chim. Ital. 1967, 97, 1304. (b) Schmidt, U.; Wild, J . Liebigs Ann.
Chem. 1985, 1882.
(11) Gulati, D.; Chauhan, P. M. S.; Pratap, R.; Bhakuni, D. S.
Indian. J . Chem. Sect. B 1994, 33, 10.
(12) (a) Bergamasco, R.; Porter, Q. N.; Yap, C. Aust. J . Chem. 1977,
30, 1531. (b) Pindur, U.; Pfeuffer, L. Monatsh. Chem. 1989, 120, 157.
(13) (a) J acobsen, E. N.; Marko´, I.; Mungall, W. S.; Schro¨der, G.;
Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 1968. (b) Sharpless, K.
B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J .; J eong,
K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L.
J . Org. Chem. 1992, 57, 2768. (c) Turpin, J . A.; Weigel, L. O.
Tetrahedron Lett. 1992, 33, 6563.
(14) (a) For a review, see: Lohray, B. B. Synthesis 1992, 1035. (b)
Chandrasekhar, S.; Reddy, M. V. Tetrahedron 2000, 56, 6339. (c)
Pearson, A. J .; Heo, J .-N. Tetrahedron Lett. 2000, 41, 5991. (d)
Hennings, D. D.; Williams, R. M. Synthesis 2000, 1310.
(15) Mitsunobu, O. Synthesis 1981, 1.

Synthesis for (-)-Antipode of Hamacanthin A
J . Org. Chem., Vol. 66, No. 14, 2001 4867
rotations were recorded on Perkin-Elmer 341MC instrument.
Infrared (IR) spectra were determined with a Shimadzu IR-
440 spectrometer. 1H NMR and 13C NMR spectra were
recorded on a Bruker AMX-300 or INOVA-600 instrument. The
chemical photoshifts are expressed in ppm and coupling
constants are given in Hz. Low-resolution mass spectra were
obtained on a VG-Quattro or HP-5969A spectrometer, and
high-resolution mass spectra were recorded on a Finnigan
MAT-95 spectrometer. Microanalyses were carried out at a
Heraeus Rapid-CHNO instrument. All moisture-sensitive
reactions were done under an argon atmosphere in oven dried
(150 °C) glassware. Flash chromatography was performed
using silica gel H (10-40 µm). Standard reagents and solvents
were purified according to known procedures.18
Sch em e 2
6-Br om o-3-in d olyl-r-oxoa cetyl Ch lor id e (3).10a 6-Bro-
moindole 7 (3.92 g, 20 mmol) in anhydrous ether (60 mL) was
refluxed with oxalyl chloride (3.81 g, 30 mmol) for 10 h. After
cooling to room temperature, hexane (50 mL) was added. The
solid was filtered off, washed with hexane several times, and
then dried under vacuum to give compound 3 (5.2 g, 90%) as
a yellow solid. mp 221 °C dec; IR (KBr) 3204, 1787, 1626 cm-1
;
1H NMR (DMSO-d6, 300 MHz) δ 12.63 (br s, 1H), 8.48 (s, 1H),
8.13 (d, J ) 8.5 Hz, 1H), 7.79 (s, 1H), 7.43 (d, J ) 8.5 Hz, 1H);
EIMS m/e (relative intensity) 287/285 (4/3).
Sch em e 3
N-Tosyl-6-br om oin d ole-3-ca r ba ld eh yd e (9). A mixture
of 6-bromoindole-3-carbaldehyde 87a,10 (3.05 g, 13.6 mmol),
tosyl chloride (4.75 g, 25 mmol), and anhydrous potassium
carbonate (5.52 g, 40 mmol) in anhydrous 2-butanone (100 mL)
was refluxed for 3 h. After filtration of the reaction mixture
without cooling, the filtrate was concentrated in vacuo. The
residue was purified by flash chromatography (silica, Hex/
AcOEt 6:1 and 2:1) to afford compound 9 (5.14 g, 100%) as a
white solid. mp 146-147 °C (lit.11 115 °C); IR (KBr) 1674 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 10.06 (s, 1H), 8.19 (s, 1H), 8.13
(s, 1H), 8.12 (d, J ) 10.7 Hz, 1H), 7.85 (d, J ) 8.6 Hz, 2H),
7.48 (dd, J ) 8.6 and 1.7 Hz, 1H), 7.33 (dd, J ) 8.6 and 0.6
Hz, 2H), 2.40 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 185.0, 146.5,
136.3, 135.8, 134.1, 130.5, 128.5, 127.2, 125.1, 123.7, 122.0,
120.1, 116.4, 21.7; EIMS m/e (relative intensity) 379/377 (63/
61), 155 (70). Anal. Calcd for C16H12BrNO3S+H2O: C, 48.48;
H, 3.54; N, 3.54. Found: C, 48.50; H, 3.30; N, 3.51.
N-Tosyl-6-br om o-3-vin ylin d ole (6). To a suspension of
methyltriphenylphosphonium bromide (4 g, 11.2 mmol) in
anhydrous THF (20 mL) was added dropwise n-butyllithium
(2.5 M in hexane, 4 mL) at -78 °C under vigorous stirring.
The mixture was then kept in an ice-water bath for 20 min,
and a solution of 9 (3.1 g, 8.20 mmol) in THF (40 mL) was
added to the clear solution. After further stirring for 20 min
at this temperature, the reaction mixture was allowed to reach
ambient temperature, and water (30 mL) was added to quench
the reaction. The water layer was extracted with ether, and
the organic phase was washed with brine and dried with
sodium sulfate. The solvent was removed, and the residue was
subjected to flash chromatography (silica, Hex/AcOEt 10:1) to
give 6 (2.8 g, 90%) as a white solid. mp 142-143 °C; IR (KBr)
with tributylphosphine in toluene at ambient tempera-
ture first gave the corresponding iminophosphorane 15,
which directly cyclized to afford the expected central 5,6-
dihydropyrazinone 16 in 97% yield. Upon treatment of
compound 16 with sodium hydroxide in refluxing metha-
nol to remove the tosyl group,17 the expected (-)-antipode
of hamacanthin A (1) was obtained in 88% yield with a
specific rotation of -79 (c 0.20, CH3OH). Comparison with
naturally isolated hamacanthin A, which has a positive
specific rotation of +84 (c 0.1, CH3OH), revealed that
natural hamacanthin A has an S-configuration.
1
3134, 1596, 1544 cm-1; H NMR (CDCl3, 300 MHz) δ 8.17 (d,
J ) 3.4 Hz, 1H), 7.77 (d, J ) 8.4 Hz, 2H), 7.58 (d, J ) 8.5 Hz,
1H), 7.56 (s, 1H), 7.38 (dd, J ) 8.5 and 1.7 Hz, 1H), 7.25 (d, J
) 8.4 Hz, 2H), 6.72 (dd, J ) 17.8 and 11.3 Hz, 1H), 5.75 (dd,
J ) 17.8 and 0.6 Hz, 1H), 5.35 (dd, J ) 11.3 and 1.0 Hz, 1H),
2.36 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 145.4, 136.1, 134.8,
130.0, 129.7, 127.8, 127.0, 126.8, 124.3, 121.5, 120.7, 118.6,
116.7, 115.8, 21.5; EIMS m/e (relative intensity) 377/375 (71/
68), 155 (19). Anal. Calcd for C17H14BrNO2S: C, 54.25; H, 3.72;
N, 3.72. Found: C, 54.47; H, 3.80; N, 3.48.
Exp er im en ta l Section
(S)-1-(N-Tosyl-6-br om oin d ol-3-yl)-1,2-eth a n ed iol (5). A
solution of AD-mix-R (12 g) in tert-butyl alcohol/water (100 mL,
1:1) was stirred vigorously at room temperature for 1 h. After
the reaction mixture was chilled with an ice-water bath,
compound 6 (3.0 g, 8.0 mmol) was added. Stirring was
continued over 10 h at 0 °C. The resulting mixture was allowed
Gen er a l. Melting points were measured on a WRS-1A
digital melting point apparatus and are uncorrected. Optical
(16) (a) For a review, see: Molina, P.; Vilaplana, M. J . Synthesis
1994, 1197. (b) Sugimori, T.; Okawa, T.; Eguchi, S.; Yashima, E.;
Okamoto, Y. Chem. Lett. 1997, 869. (c) Fresneda, P. M.; Molina, P.;
Sanz, M. A. Synlett 2000, 1190. (d) Kamal, A.; Laxman, E.; Reddy, P.
S. M. M. Tetrahedron Lett. 2000, 41, 8631.
(17) (a) Ponticello, G. S.; Baldwin, J . J . J . Org. Chem. 1979, 44, 4003.
(b) Muratake, H.; Natsume, M. Heterocycles 1989, 29, 783.
(18) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Oxford, 1988.

4868 J . Org. Chem., Vol. 66, No. 14, 2001
J iang et al.
to warm to room temperature for 3 h, quenched by the addition
of sodium sulfite (9 g), and stirred for an additional 2 h. The
aqueous layer was exacted with ethyl acetate (3 × 50 mL).
The combined organic layer was washed with water and brine
successively, dried over anhydrous sodium sulfate, filtered, and
concentrated to give a syrupy residue which was purified by
flash chromatography (silica, Hex/AcOEt 1:2) to give 5 (3.0 g,
13C NMR (CDCl3, 100 MHz) δ 145.6, 135.8, 134.5, 130.1, 127.5,
126.9, 126.8, 125.0, 121.0, 119.0, 117.5, 116.9, 65.0, 60.1, 21.6;
EIMS m/e (relative intensity) 436/434 (36/37), 155 (42); HRE-
IMS calcd for C17H15BrN4O3S: 434.0048; found: 434.0048.
Anal. Calcd for C17H15BrN4O3S: C, 46.90; H, 3.45; N, 12.87.
Found: C, 47.12; H, 3.80; N, 12.64.
(1R)-N-(ter t-Bu tyloxyca r bon yl)-1-(N-tosyl-6-br om oin -
dol-3-yl)-2-[(4-m eth ylph en -ylsu lfon yl)oxy]eth ylam in e (13).
To an ice-cooled suspension of LiAlH4 (172 mg, 4.5 mmol) in
freshly distilled THF (20 mL) under argon was injected a
solution of compound 12 (394 mg, 0.91 mmol) in THF (8 mL).
The reaction mixture was stirred for 1 h at this temperature,
diluted with dry THF (10 mL), and quenched with ethanol (1
mL). The resulting mixture was filtered through a short silica
column. The solvent was evaporated to furnish the crude
amine, which was used in the next step without purification.
To a mixture of the crude amine and Et3N (0.21 mL, 1.5
mmol) in dichloromethane (10 mL) was added di-tert-butyl
dicarbonate (327 mg, 1.5 mmol) in an ice-cooled bath. The
reaction was stirred at 0 °C for 4 h and diluted with dichlo-
romethane (10 mL), washed with water and brine, dried (Na2-
SO4), and concentrated in vacuo. The crude product (330 mg)
dissolved in CH2Cl2 (15 mL) was reacted with tosyl chloride
(127 mg, 0.67 mmol), Et3N (0.15 mL, 1 mmol), and DMAP (15
mg) for 5 h at room temperature. The mixture was washed
with water and brine and then dried (Na2SO4). After removal
of the solvent, the crude product was purified by flash
chromatography (silica, Hex/AcOEt 6:1) to afford compound
13a (335 mg, 56% yield in three steps) and compound 13b (74
mg, 14% yield).
92%) as a white solid in 99% ee. mp 65 °C; [R]20 ) +43.0 (c
D
1.47, CHCl3); IR (KBr) 3352 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 8.15 (d, J ) 1.6 Hz, 1H), 7.76 (d, J ) 8.4 Hz, 2H), 7.55 (s,
1H), 7.46 (d, J ) 8.4 Hz, 1H), 7.33 (dd, J ) 8.5 and 1.7 Hz,
1H), 7.25 (d, J ) 8.4 Hz, 2H), 5.02 (m, 1H), 3.84 (m, 2H), 2.72
(d, J ) 3.9 Hz, 1H), 2.36 (s, 3H), 2.18 (t, J ) 5.8 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 145.4, 135.8, 134.6, 130.0, 127.6,
127.8, 126.8, 126.6, 123.8, 121.8, 121.2, 118.6, 116.6, 68.3, 66.4,
21.5; EIMS m/e (relative intensity) 411/409 (8/8), 155 (62).
Anal. Calcd for C17H16BrNO4S: C, 49.76; H, 3.90; N, 3.41.
Found: C, 49.38; H, 4.20; N, 3.28.
(1S)-1-(N-Tosyl-6-br om oin d ol-3-yl)-2-[(ter t-bu tyld im e-
th ylsilyl)oxy]-1-eth a n ol (10). To a solution of 1,2-ethanediol
5 (2.68 g, 6.5 mmol) in 50 mL of dichloromethane at 0 °C was
added imidazole (1.33 g, 19.5 mmol), followed by tert-butyldim-
ethylsilyl chloride (1.18 g, 7.8 mmol). The mixture was stirred
at 0 °C for 30 min and then at room temperature for 12 h.
After removal of the solvent under reduced pressure, the
residue was purified by chromatography (silica, Hex/AcOEt
6:1). The desired compound 10 (3.2 g, 94%) was obtained as a
syrup. [R]20 ) +38.8 (c 1.10, CHCl3); IR (KBr) 3612 cm-1; 1H
D
NMR (CDCl3, 300 MHz) δ 8.16 (dd, J ) 2.0 and 0.6 Hz, 1H),
7.77 (d, J ) 8.4 Hz, 2H), 7.53 (d, J ) 0.9 Hz, 1H), 7.48 (dd, J
) 8.5 and 0.5 Hz, 1H), 7.34 (ddd, J ) 8.5, 1.7 and 0.6 Hz, 1H),
7.25 (d, J ) 8.4 Hz, 2H), 4.94 (m, 1H), 3.86 (dd, J ) 10.1 and
3.7 Hz, 1H), 3.73 (dd, J ) 10.1 and 7.9 Hz, 1H), 2.89 (d, J )
3.2 Hz, 1H), 2.36 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR
(CDCl3, 100 MHz) δ 145.4, 135.9, 135.1, 130.1, 128.1, 126.9,
126.6, 123.9, 121.7, 121.5, 118.5, 116.8, 68.3, 67.1, 25.9, 21.6,
18.3, -5.3; EIMS m/e (relative intensity) 524/522 (1/1), 155
(8). Anal. Calcd for C23H30BrNO4SSi: C, 52.67; H, 5.72; N, 2.67.
Found: C, 53.04; H, 5.77; N, 2.66.
Compound 13a : [R]20 ) -10.3 (c 0.78, CHCl3); IR (KBr)
D
1710 cm-1; H NMR (CDCl3, 300 MHz) δ 8.10 (d, J ) 1.6 Hz,
1
1H), 7.75 (d, J ) 8.4 Hz, 2H), 7.54 (d, J ) 8.3 Hz, 2H), 7.44 (d,
J ) 0.8 Hz, 1H), 7.26 (m, 2H), 7.17 (d, J ) 0.4 Hz, 1H), 7.15
(d, J ) 8.5 Hz, 2H), 5.12 (br, 1H), 5.04 (br, 1H), 4.36 (dd, J )
10.0 and 4.4 Hz, 1H), 4.24 (dd, J ) 10.0 and 3.8 Hz, 1H), 2.40
(s, 3H), 2.36 (s, 3H), 1.43 (s, 9H); ESIMS m/e 687.3 (M + Na).
Anal. Calcd for C29H31BrN2O7S2: C, 52.49; H, 4.68; N, 4.22.
Found: C, 52.70; H, 4.84; N, 4.35.
(1R)-1-(N-Tosyl-6-br om oin d ol-3-yl)-1-a zid o-2-[(ter t-bu -
tyld im eth ylsilyl)oxy]eth a n e (11). To a solution of compound
10 (2.4 g, 4.58 mmol) in anhydrous THF (40 mL) were added
triphenylphosphine (2.36 g, 9 mmol), diethyl azodicarboxylate
(40% in toluene, 4.2 mL, 9 mmol), and diphenylphosphoryl
azide (1.92 mL, 9 mmol) at -20 °C. The mixture was stirred
for 8 h and then allowed to warm to room temperature and
stirred overnight. The solvent was evaporated under reduced
pressure, and the residue was directly subjected to flash
chromatography (silica, Hex/AcOEt 20:1) to give intermediate
Compound 13b: IR (KBr) 1714 cm-1; 1H NMR (CDCl3, 300
MHz) δ 7.92 (d, J ) 8.3 Hz, 1H), 7.75 (d, J ) 8.4 Hz, 2H), 7.58
(d, J ) 8.3 Hz, 2H), 7.47 (s, 1H), 7.35-7.13 (m, 7H), 5.16 (br,
1H), 5.02 (br, 1H), 4.39 (dd, J ) 10.0 and 4.5 Hz, 1H), 4.27
(dd, J ) 10.0 and 4.1 Hz, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 1.43
(s, 9H); ESIMS m/e 607.4 (M + Na).
(1R)-N-(ter t-Bu tyloxyca r bon yl)-1-(N-tosyl-6-br om oin -
d ol-3-yl)-2-a zid oeth yla m in e (14). To a solution of compound
13a (210 mg, 0.32 mmol) in dry DMF (6 mL) was added sodium
azide (65 mg, 1 mmol) at room temperature. The mixture was
then stirred for 12 h at 80 °C. After being cooled to room
temperature, the mixture was diluted with water (30 mL) and
extracted with ethyl acetate (3 × 10 mL). The combined
organic layer was washed with water and brine and then dried
(Na2SO4). After removal of the solvent in vacuo, the crude
product was purified by flash chromatography (silica, Hex/
AcOEt 4:1) to afford compound 14 (150 mg, 88%) as a white
11 (2.19 g, 87%) as a syrup. [R]20 ) -84.6 (c 1.10, CHCl3); IR
D
(KBr) 2106 cm-1; H NMR (CDCl3, 300 MHz) δ 8.17 (d, J )
1
1.6 Hz, 1H), 7.76 (d, J ) 8.4 Hz, 2H), 7.62 (d, J ) 0.7 Hz, 1H),
7.44 (d, J ) 8.5 Hz, 1H), 7.37 (dd, J ) 8.5 and 1.7 Hz, 1H),
7.25 (d, J ) 8.4 Hz, 2H), 4.63 (m, 1H), 3.99 (dd, J ) 10.5 and
4.3 Hz, 1H), 3.93 (dd, J ) 10.5 and 6.4 Hz, 1H), 2.36 (s, 3H),
0.91 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 145.5, 135.7, 134.8, 130.1, 127.9, 126.84, 126.80, 125.0,
121.0, 118.8, 117.9, 116.8, 66.4, 59.3, 25.8, 21.6, 18.2, -5.5,
-5.6; EIMS m/e (relative intensity) 522/520 (6/5), 155 (23).
Anal. Calcd for C23H29BrN4O3SSi: C, 50.27; H, 5.28; N, 10.20.
Found: C, 50.47; H, 5.20; N, 10.14.
solid. mp 172-173 °C; [R]20 ) -2.4 (c 0.56, CHCl3); IR (KBr)
D
2103, 1691 cm-1; H NMR (CDCl3, 300 MHz) δ 8.16 (d, J )
1
1.4 Hz, 1H), 7.76 (d, J ) 8.4 Hz, 2H), 7.53 (d, J ) 0.8 Hz, 1H),
7.41 (d, J ) 8.5 Hz, 1H), 7.37 (dd, J ) 8.5 and 1.5 Hz, 1H),
7.27 (d, J ) 8.4 Hz, 2H), 5.09 (br, 1H), 4.91 (br d, J ) 7.5 Hz,
1H), 3.73 (m, 2H), 2.37 (s, 3H), 1.45 (s, 9H); 13C NMR (CDCl3,
150 MHz) δ 155.0, 145.6, 135.8, 134.9, 130.2, 127.8, 126.9,
124.1, 120.8, 120.6, 119.0, 116.9, 80.5, 54.1, 46.7, 29.7, 28.3,
21.6; EIMS m/e (relative intensity) 534 (0.6), 423/421 (100/
96),155 (24). Anal. Calcd for C22H24BrN5O4S: C, 49.44; H, 4.49;
N, 13.11. Found: C, 49.47; H, 4.56; N, 13.08.
(R)-2-Azido-2-(N-tosyl-6-br om oin dol-3-yl)-1-eth an ol (12).
To a solution of compound 11 (2.2 g, 4.01 mmol) in THF (30
mL) was added tetrabutylammonium fluoride (1 M in THF,
8.0 mL, 8.0 mmol). After stirring for 1 h at ambient temper-
ature, water (20 mL) was added to quench the reaction, and
the resulting mixture was extracted with ether. The organic
phase was dried over sodium sulfate, and concentrated in
vacuo. Purification by flash chromatography (silica, Hex/AcOEt
2:1) afforded ethanol 12 (1.7 g, 98%) as a syrup. [R]20D ) -125.4
(R)-6-Br om o-N-[(N-tosyl-6-br om oin dol-3-yl)azidoeth yl]-
r-oxoin d ole-3-a ceta m id e (2). To a stirred solution of com-
pound 14 (114 mg, 0.213 mmol) in CH2Cl2 (8 mL) was added
trifluoroacetic acid (0.8 mL, 10.3 mmol) in an ice-water bath
under argon. The reaction solution was stirred at room-
temperature overnight and quenched by the addition of water
(10 mL). The water phase was neutralized with aqueous 1 N
NaOH and extracted with CH2Cl2 (2 × 10 mL). The combined
1
(c 0.585, CHCl3); IR (KBr) 3340, 2105 cm-1; H NMR (CDCl3,
300 MHz) δ 8.18 (d, J ) 1.6 Hz, 1H), 7.77 (d, J ) 8.4 Hz, 2H),
7.63 (s, 1H), 7.46 (d, J ) 8.5 Hz, 1H), 7.38 (dd, J ) 8.5 and 1.6
Hz, 1H), 7.29 (d, J ) 8.4 Hz, 2H), 4.82 (t, J ) 6.1 Hz, 1H),
3.90 (t, J ) 6.1 Hz, 2H), 2.37 (s, 3H), 1.99 (t, J ) 6.3 Hz, 1H);

Synthesis for (-)-Antipode of Hamacanthin A
J . Org. Chem., Vol. 66, No. 14, 2001 4869
1
organic layer was washed with saturated NaHCO3 and brine
successively and then dried over Na2SO4. The result was
concentrated in vacuo to give a yellow oil, which was used in
the next step without purification.
5.05 (m, 1H), 4.14 (d, J ) 5.6 Hz, 2H), 2.19 (s, 3H); H NMR
(acetone-d6, 300 MHz) δ 8.58 (s, 1H), 8.35 (d, J ) 8.6 Hz, 1H),
8.13 (d, J ) 1.6 Hz, 1H), 7.80 (d, J ) 8.5 Hz, 1H), 7.75 (d, J )
1.7 Hz, 1H), 7.64 (d, J ) 0.9 Hz, 1H), 7.59 (d, J ) 8.4 Hz, 2H),
7.46 (dd, J ) 8.5 and 1.7 Hz, 1H), 7.34 (s, 1H), 7.25 (dd, J )
8.6 and 1.8 Hz, 1H), 5.20 (m, 1H), 4.33 (dd, J ) 16.5 and 5.9
Hz, 1H), 4.25 (dd, J ) 16.5 and 5.2 Hz, 1H), 2.21 (s, 3H); 13C
NMR (acetone-d6, 75 MHz) δ 158.96, 158.78, 146.9, 138.7,
137.3, 135.5, 134.0, 131.2, 129.2, 127.9, 127.8, 126.7, 126.4,
125.8, 124.9, 123.2, 123.1, 119.4, 117.6, 116.7, 115.6, 112.8,
To a solution of the crude product and triethylamine (42
µL, 0.3 mmol) in dry DMF (5 mL) cooled in an ice bath was
added a solution of 6-bromo-3-indolyl-R-oxoacetyl chloride 3
(63 mg, 0.22 mmol) in dry DMF (1 mL) dropwise. After 4 h,
water (20 mL) was added, and the resulting mixture was
extracted with ethyl acetate (3 × 10 mL). The combined
organic layer was washed with water and brine successively,
dried (Na2SO4), and concentrated in vacuo. Purification by
flash chromatography (silica, Hex/AcOEt 2:1) gave compound
53.4, 47.5, 21.7; EIMS m/e (relative intensity) 640 (18), 642/
79
638 (10/10), 641/637 (9/9), 155 (17); HREIMS calcd for C27H20
-
Br81BrN4O3S: 639.9602; found: 639.9606. Anal. Calcd for
C27H20Br2N4O3S: C, 50.63; H, 3.13; N, 8.75. Found: C, 50.89;
2 (107 mg, 74%) as a light yellow solid. mp 121 °C; [R]20
)
D
-28.8 (c 0.51, CHCl3); IR (KBr) 2106, 1637 cm-1
;
1H NMR
H, 3.31; N, 8.55.
(CDCl3, 300 MHz) δ 9.02 (d, J ) 3.0 Hz, 1H), 8.98 (br s, 1H),
8.22 (d, J ) 8.5 Hz, 1H), 8.16 (d, J ) 1.3 Hz, 1H), 7.86 (d, J )
8.8 Hz, 1H), 7.79 (d, J ) 8.4 Hz, 2H), 7.62 (d, J ) 0.7 Hz, 1H),
7.59 (d, J ) 1.4 Hz, 1H), 7.45-7.26 (m, 5H), 5.48 (m, 1H), 3.85
(m, 2H), 2.36 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 179.6,
161.5, 145.7, 138.5, 136.5, 135.8, 134.8, 130.3, 127.6, 127.1,
127.0, 126.9, 125.4, 124.4, 123.7, 120.6, 119.2, 119.1, 117.9,
116.9, 114.7, 113.3, 53.6, 45.1, 29.7, 21.6; ESIMS m/e 704.2
(M + Na). Anal. Calcd for C27H20Br2N6O4S: C, 47.37; H, 2.92;
N, 12.28. Found: C, 47.34; H, 3.20; N, 11.91.
(-)-An tip od e of Ha m a ca n th in A (1). A suspension of
compound 16 (28 mg, 0.044 mmol) and NaOH (18 mg, 0.45
mmol) in 6 mL of absolute methanol was refluxed for 1 h. After
the solvent was evaporated in vacuo, the residue was poured
into water (10 mL) and extracted with ethyl acetate (3 × 10
mL). The organic layer was washed with water and brine
successively, dried (Na2SO4), and concentrated in vacuo.
Purification by flash chromatography (silica, Hex/AcOEt 2:3)
gave compound 1 (18 mg, 88%) as a yellow solid. mp 275 °C;
1
[R]20 ) -79 (c 0.20, CH3OH); IR (KBr) 1670 cm-1; H NMR
D
(R)-3-(6-Br om oin d ol-3-yl)-6-(N-t osyl-6-b r om oin d ol-3-
yl)-5,6-d ih yd r o-2(1H)-p yr a zin on e (16). To a solution of
compound 2 (88 mg, 0.128 mmol) in dry toluene (4 mL) was
added tributylphosphine (50 µL, 0.197 mmol). The mixture was
stirred at room temperature for 2 h and then warmed to reflux
for 9 h under an argon atmosphere. After the removal of
toluene, the residue was subjected to flash chromatography
(silica, Hex/AcOEt 2:1 and 1:1) to give compound 16 (79 mg,
(DMSO-d6, 600 MHz) δ 11.61 (d, J ) 2.1 Hz, 1H), 11.17 (br,
1H), 8.80 (br, 1H), 8.42 (s, 1H), 8.30 (d, J ) 8.5 Hz, 1H), 7.68
(d, J ) 8.5 Hz, 1H), 7.64 (d, J ) 1.7 Hz, 1H), 7.57 (d, J ) 1.7
Hz, 1H), 7.32 (s, 1H), 7.23 (dd, J ) 8.5 and 1.8 Hz, 1H), 7.15
(dd, J ) 8.5 and 1.8 Hz, 1H), 4.99 (dd, J ) 8.4 and 5.1 Hz,
1H), 4.12 (dd, J ) 16.2 and 4.8 Hz, 1H), 4.07 (dd, J ) 16.2
and 9.0 Hz, 1H); EIMS m/e (relative intensity) 486 (100), 291/
289 (11/9); HREIMS calcd for C20H1479Br2N4O: 483.9560; found
483.9534.
97%) as a yellow solid. mp > 300 °C; [R]20 ) +22 (c 0.325,
D
1
acetone); IR (KBr) 1671 cm-1; H NMR (DMSO-d6, 300 MHz)
δ 11.69 (br d, J ) 2.6 Hz, 1H), 9.05 (br d, J ) 3.0 Hz, 1H),
8.44 (s, 1H), 8.25 (d, J ) 8.6 Hz, 1H), 8.01 (d, J ) 1.5 Hz, 1H),
7.80 (d, J ) 8.5 Hz, 1H), 7.69 (d, J ) 1.7 Hz, 1H), 7.60 (s, 1H),
7.59 (d, J ) 8.0 Hz, 2H), 7.48 (dd, J ) 8.5 and 1.7 Hz, 1H),
7.23 (dd, J ) 8.6 and 1.8 Hz, 1H), 6.94 (d, J ) 8.1 Hz, 2H),
Ack n ow led gm en t. We are grateful for financial
support from the Shanghai Municipal Committee of
Science and Technology.
J O010265B