Total synthesis of marine bisindole alkaloids, (+)-hamacanthins A, B and (-)-antipode of 0cis-dihydrohamacanthin B

Article abstract of DOI:10.1016/j.tet.2005.01.058

The total synthesis of the marine bisindole alkaloids, (+)-hamacanthins A (2a) and B (2b), and (-)-antipode of cis-dihydrohamacanthin B (2e) was achieved by transamidation-cyclization of N-(2-aminoethyl)-2-oxoethanamide 18 derived from (S)-indolylglycinol 10.

Full text of DOI:10.1016/j.tet.2005.01.058

Tetrahedron 61 (2005) 2309–2318
Total synthesis of marine bisindole alkaloids, (C)-hamacanthins
A, B and (K)-antipode of cis-dihydrohamacanthin B
*
Takashi Kouko, Ken Matsumura and Tomomi Kawasaki
Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose, Tokyo 204-8588, Japan
Received 29 November 2004; accepted 11 January 2005
Available online 2 February 2005
Abstract—The total synthesis of the marine bisindole alkaloids, (C)-hamacanthins A (2a) and B (2b), and (K)-antipode of cis-
dihydrohamacanthin B (2e) was achieved by transamidation–cyclization of N-(2-aminoethyl)-2-oxoethanamide 18 derived from (S)-
indolylglycinol 10.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
of (G)-dragmacidins A–C (1b–d), (G)-trans- and cis-
dihydrohamacanthin A (2c, 2d) and (G)-hamacanthins (2a,
2b).5 However, there are few examples of the total synthesis
of optical active alkaloids, namely (C)-dragmacidin F (1g)
derived from (K)-quinic acid,3e (C)-dragmacidin A (1b),
(C)-hamacanthin A (2a) and (K)-trans- and (K)-cis-
dihydrohamacanthin A (2c, 2d) as the antipode from (S)-
indolylglycinol,4c and (C)-hamacanthin B (2b) from (S)-
indolylethanediol.4b Herein, we describe the total synthesis
of (C)-hamacanthins A (2a), (C)-B (2b) and (K)-
antipode of cis-dihydrohamacanthin B (2e) via cyclization
and transamidation of N-(2-aminoethyl)-2-oxoethanamide
18 derived from (S)-indolylglycinol 10.
A growing number of bromoindole alkaloids are being
discovered from a variety of marine invertebrates, including
bryozoans, coelenterates, sponges and tunicates. Adding to
their interest is the fact that they display a wide range of
biological activity.1 The dragmacidins 1, 3,6-bisindole-
piperazine and -pirazinone alkaloids, have been isolated
from marine sponges Dragmacidon, Halicortex, Hexadella
and Spongosorites, and tunicate Didemmum candidum.1 A
number of these metabolites were shown to possess a wide
spectrum of pharmacological activities such as antifungal,
antiinflammatory, antitumor, antiviral and cytotoxic
activities, and inhibition of serine-threonine protain phos-
phatase and neural nitric synthetase.1 The piperazinone
alkaloid, hamacanthins 2, found in marine sponges
Hamacantha and Rhaphisia indicate significant anti-
microbial activities against C. albicans, C. neoformans
and Bacillus subtilis.2 Hamacanthin A (2a) is a 3,6-
bisindole derivative like dragmacidins 1, but hamacanthin
B (2b) is the 3,5-isomer, of which the substituent pattern is
fairly unusual in these alkaloids (Fig. 1).
2. Results and discussion
There are two synthetic methods of (S)-6-bromoindolyl-
glycinol 10, one using asymmetric aminohydroxylation
reported by Jiang’s group4c and the other lipase-mediated
resolution by us;6 however, the optical purity of (S)-10
obtained is insufficient for synthesis of optically pure natural
products. Initially, we attempted a preparative method for
optically pure (S)-10 as follows. Reaction of readily
available indolin-3-one 37 with the optically active ylide
48 in refluxing benzene smoothly proceeded with Wittig
olefination to give a mixture (1:3) of the (E)- and (Z)-
isomers of N-(3-indolylideneacety)oxazolidinone 5 in high
yield (Scheme 1).9 Since pure (Z)-olefin 5, of which the
configuration was confirmed by NOE experiment (Fig. 2),
was obtained from the mixture by recrystallization (32%),10
we attempted introduction of a nitrogen functional unit to
(Z)-5 through an indolenium intermediate 65a,6 (Scheme 1,
Table 1).
Since these alkaloids 1 and 2 are available from nature in
only minute amounts, efficient methods for the total
synthesis of 1 and 2 have been required to provide these
alkaloids and the related compounds for launching a
thorough biological investigation. Several groups have
accomplished the total synthesis of (G)-dragmacidins 13,4c
and (G)-hamacanthins 24 and we also reported the synthesis
Keywords: Bromoindole; Indolylglycinol; Oxazolidin-2-one; Absolute
configuration.
* Corresponding author. Tel./fax: C81 424 95 8763;
e-mail: kawasaki@my-pharm.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.058

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T. Kouko et al. / Tetrahedron 61 (2005) 2309–2318
Figure 1. Marine bisindole alkaroids.
When (Z)-5 was treated with benzamide or 1,1-dimethyl-
urea in the presence of methanesulfonic acid, the desired
indolylglycine 7 was not obtained at all but a diastereomeric
mixture (1:2) of N-(2-indolyl-2-methoxyacetyl)oxazolidi-
none 8, which was resulted from migration of the methoxy
group via 6 (Table 1, entries 1 and 2). Similar treatment of
(Z)-5 with urethane produced the desired product 7a (1:2.9)
in 23% yield, but 8 as a main product was still formed
(Table 1, entry 3). Reaction of (Z)-5 with tosylamide
proceeded stereoselectively to afford indolylglycine deriva-
tive 7b in 47% yield as a diastereoisomeric mixture (1:7), of
which separation was not easy (Table 1, entry 4). On
treatment with TMSN3, the desired reaction took place
smoothly to give azide derivative 7c in high yield, but with
lower diastereoselectivity (1:1.3). Fortunately, the mixture
could be easily separated on a normal column chromato-
graphy to obtain (2S)-2-azidoacetyloxazolidine 7c and (2R)-
epimer 7c in 38 and 52% yields, respectively (Table 1, entry
Scheme 1. Addition of nitrogen nucleophiles into indolinium intermediate 6.

T. Kouko et al. / Tetrahedron 61 (2005) 2309–2318
2311
N-acetylation of 10 followed by removal of the TBDMS
group from 11 with concd HCl (32%, 3 steps).
Next, we prepared (S)-N-(2-aminoethyl)-2-oxoethanamide
18 from (S)-glycinol 10 as a key synthetic intermediate for
optically active hamacanthins 2 according to our synthetic
method5c (Scheme 3). Tosylation of (S)-indolylglycinol 10
with p-toluenesulfonyl chloride at K20 8C provided N,O-
ditosylate 13 (82%), which was displaced with NaN3 at
80 8C leading to aminoazide 14 in 78% yield. Reduction of
azide 14 with triphenylphosphine-H2O followed by con-
densation with 6-bromoindol-3-yl-a-oxoacetyl chloride
(15) afforded amide 16 (79%, 2 steps). After detosylation
of 16 with 10% KOH in heating EtOH, a couple of indole
nitrogens in 17 were re-protected by acetylation to N-(2-
aminoethyl)-2-oxoethanamide 18 in 78% yield (2 steps).
Figure 2. NOE experimental of (Z)-isomer 5.
Table 1. Reaction of (Z)-5 with nitrogen nucleophiles
Entry
Nucleophile
Yield (%)
7
8
1
2
3
4
5
PhCONH2
Me2NCONH2
EtOCONH2
TsNH2
—
—
80 (1:2.0)a
86 (1:1.9)a
63 (1:2.0)a
—
7a:23 (1:2.9)b
7b:47 (1:7.0)b
7c:90 (1:1.3)a
We performed the total synthesis of optically active
hamacanthins A (2a) and B (2b) via biomimetic trans-
amidation–cyclization of 18 (Scheme 4). Removal of the
Boc group in 18 followed by heating an intermediate 19 in
dichloroethane provided 3,5-bisindolylpyrazinone 22 (65%)
and its regio-isomer 23 (33%). The formation of 23 is
explained in terms of intramolecular transamidation of 19 to
a five membered ring intermediate 20 followed by
cyclization of 21. Deacetylation of 22 and 23 with
ammonium hydroxide proceeded smoothly to afford
optically pure (C)-hamacanthins A (2a) and B (2b) in 87
and 82% yields, respectively. The spectra data of synthetic
products 2a and 2b are completely identical to those of
natural (C)-hamacanthins A and B, respectively.2a
TMSN3
—
a The ratio of diastereoisomers was calculated with isolated yields.
b The ratio of diastereoisomers was determined by HPLC.
5). Due to the lower stereoselectivity of 7c, we abandoned
attempts for an asymmetrical method and turned to another
measure to optically active 6-bromoindolylglycinol 10
using chemical resolution of 7c for total synthesis of
optically active hamacanthins 2.
When the mixture of (E)- and (Z)-isomers 5 was treated with
TMSN3 in the presence of methanesulfonic acid followed
by separation using column chromatography, (2S)- and
(2R)-7c were obtained in 41 and 56% yields (Scheme 2).
Azide (S)-7c was smoothly reduced with n-tributyl-
phosphine in the presence of 10% HCl at 0 8C to a resulting
amine, which was protected with Boc2O to give oxazo-
lidinylindolylglycine 9 (82% yield, 2 steps). The reductive
removal of the oxazolidinyl group from 9 with sodium
borohydride followed by hydrolysis with LiOH afforded
(C)-indolylglycinol 10 in 85% yield without epimeriza-
tion.11 The absolute configuration of (C)-glycinol 10 was
determined by transformation to known (C)-(S)-1-acetyl-
indolylglycinol 12,6 which was prepared by O-silylation and
Finally, we tried to synthesize cis-dihydrohamacanthin B
(2e), of which the absolute configuration was not yet
determined. Namely, reaction of 3,5-bisindolylpyrazinone
22 with sodium cyanoborohydride in methanol took place
with stereoselective reduction to give only (3R,5S)-isomer
of cis-dihydrohamacanthin B (2e) in 73% yield,12 whose
relative configuration was determined by its NOE experi-
1
ments (Fig. 3). The H and 13C NMR data of the resulting
compound are identical to those of natural cis-dihydro-
hamacanthin B (2e).2b However, the specific rotation
(K92.3) of the synthetic product was contrary to that
(C98.7) of the natural product.2b This demonstrates that the
Scheme 2. Reagents and conditions: (a) TMSN3, MeSO3H, MS 4A, CH2Cl2, 0 8C-rt, (S)-7c: 41%, (R)-7c: 56%; (b) n-Bu3P, 10% HCl, THF, 0 8C-rt; (c) Boc2O,
DMAP, CH2Cl2, 82% (2 steps); (d) NaBH4, THF–H2O, rt, then 10% LiOH, rt, 85%; (e) TBDMSCl, DMAP, Et3N, CH2Cl2, rt; (f) Ac2O, DMAP, CH2Cl2, rt,
51% (2 steps); (g) concd HCl, MeOH, rt, 62%.

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T. Kouko et al. / Tetrahedron 61 (2005) 2309–2318
Scheme 3. Reagents and conditions: (a) TsCl, DMAP, Et3N, CH2Cl2, K20 8C, 82%; (b) NaN3, DMF, 80 8C, 78%; (c) Ph3P, H2O, THF, reflux;
(d) 6-bromoindol-3-yl-a-oxoacetyl chloride 15, Et3N, THF, 0 8C-rt, 79% (2 steps); (e) 10% KOH, EtOH, reflux, 93%; (f) Ac2O, DMAP, THF, rt, 84%.
natural (C)-cis-dihydrohamacanthin B (2e) has (3S,5R)-
configuration.
(C)-hamacanthins A and B (2a, 2b) and (K)-antipode
of cis-dihydrohamacanthin B (2e) from the optically
pure (S)-indolylglycinol 10 through intermolecular
transamidation–cyclization. We also indicated that the
configuration of natural (C)-cis-dihydrohamacanthin B
(1e) is 3S,5R. Further work involving the synthesis of
dihydrohamacanthins 2c–e with natural configuration
3. Conclusion
In summary, we have demonstrated a synthetic method for
Scheme 4. Reagents and conditions: (a) HCO2H, CH2Cl2, rt; (b) pHZ4, 1,2-dichloroethane, reflux, 22: 65%, 23: 33% (2 steps); (c) NH4OH, THF–MeOH
(3:1), rt, 82%; (d) NH4OH, THF–MeOH (1:1), rt, 87%; (e) NaBH3CN, MeOH, rt, 73%.

T. Kouko et al. / Tetrahedron 61 (2005) 2309–2318
2313
4.31 (1H, dd, JZ8.8, 3.4 Hz, –CHH–), 4.75 (1H, dd, JZ8.8,
8.6 Hz, –CHH–), 5.56 (1H, dd, JZ8.6, 3.4 Hz, –CH–CH2–),
6.65 (1H, d, JZ2.0 Hz, –CH–OMe), 7.24–7.42 (6H, m,
Ar-H), 7.51 (1H, d, JZ8.3 Hz, Ar-H), 7.88 (1H, d, JZ
2.0 Hz, ]CH–), 8.52 (1H, br, Ar-H). 13C NMR (CDCl3,
100 MHz) d: 23.6, 50.4, 57.7, 70.3, 88.0, 111.6, 120.0,
122.3, 124.8, 125.4, 127.3, 127.8, 128.6, 129.1, 138.5,
146.0, 148.6, 153.5, 162.5, 169.5. MS (EI) m/z (%): 472
(MC2, 69), 470 (MC, 70), 430 (19), 428 (20), 399 (20), 397
(21), 309 (43), 307 (42), 267 (99), 265 (100), 252 (29), 250
(31), 240 (29), 238 (32). HRMS (EI) m/z calcd for
C22H19BrN2O5: 470.0477. Found: 470.0477. Anal. Calcd
for C22H19BrN2O5: C, 56.07; H, 4.06; N, 5.94. Found: C,
55.86; H, 4.09; N, 5.90.
Figure 3. NOE experimental of antipode of cis-2e.
from (2R)-2-azidoacetyloxazolidine 7c is now in
progress.
4. Experimental
4.1. General
4.2. General procedure for addition of nitrogen function
to olefin (Z)-5 and (E,Z)-5
All melting points are uncorrected, and were measured on a
Yanagimoto micromelting point apparatus. Optical
rotations were obtained on a JASCO DIP-140 digital
polarimeter. Optical purities were determined on a HPLC
(JASCO UV-975) instrument equipped with AD (Daicel
Chemical Ind., Ltd, Chiralpakw), OD (Daicel Chemical
Ind., Ltd, Chiralcelw) or Finepak SIL-5 column (JASCO
Corporation). IR spectra were recorded on a Shimadzu
FTIR-8100 or Shimadzu FTIR-8400s spectrophotometer.
1H and 13C NMR spectra were measured on a JEOL JNM-
AL 300 (300 MHz), JEOL JNM-GSX 400 (400 MHz) or
JEOL JNM-LA 500 (500 MHz) spectrometer with tetra-
methylsilane as an internal standard. J-Values are given in
Hertz. Mass spectra were recorded on a JEOL JMS-DX 302
or JEOL JMS 700 instrument with a direct inlet system
operating at 70 eV. Elemental analyses were obtained using
a Perkin–Elmer Model 240B elemental analyzer. Column
chromatography was carried out on silica gel (Kanto
Chemical Co. Inc, 230–400 mesh and Merck, 230–400
mesh).
Under nitrogen, methanesulfonic acid (139 mL, d 1.48,
2.1 mmol) was added to a mixture of (Z)-5 or (E,Z)-5
(100 mg, 0.21 mmol), nitrogen nucleophile (2.1 mmol) and
MS 4A (100 mg) in dry CH2Cl2 (3.0 mL) at 0 8C. After
stirring at room temperature for 1 h, the resulting mixture
was filtered on Celitew 545 to remove MS 4A. The filtrate
was washed with H2O (10 mL) and satd NaHCO3 (10 mL),
dried over MgSO4 and concentrated under reduced pressure
to give a residue. The residue was purified by silica gel
column chromatography with AcOEt–hexane (1:3) or
benzene–hexane (1:1) as eluent to afford indolylglycine 7
or/and N-(2-indolyl-2-methoxyacetyl)oxazolidinone 8 as
shown in Table 1.
4.2.1. (500R)-1-Acetyl-6-bromo-3-{10-methoxy-20-oxo-20-
(200-oxo-500-phenyl-300,100-oxazolidinyl)ethyl}indole (8).
Major diasteroisomer. Colorless crystals; Mp 160 8C
(AcOEt–hexane). IR (CHCl3) cmK1: 1778, 1715. 1H
NMR (CDCl3, 300 MHz) d: 2.63 (3H, s, CH3–CO), 3.29
(3H, s, CH3–O), 4.31 (1H, dd, JZ8.8, 3.3 Hz, –CHH–), 4.62
(1H, dd, JZ8.8, 8.6 Hz, –CHH–), 5.33 (1H, dd, JZ8.6,
3.3 Hz, –CH–CH2–), 6.19 (1H, s, –CH–OMe), 7.32–7.45
(6H, m, Ar-H), 7.63 (1H, s, Ar-H), 7.73 (1H, d, JZ8.5 Hz,
Ar-H), 8.65 (1H, d, JZ1.7 Hz, Ar-H). 13C NMR (CDCl3,
100 MHz) d: 24.0, 57.1, 58.0, 70.5, 74.9, 116.0, 119.4,
119.5, 122.1, 125.8, 126.5, 126.9, 127.2, 128.8, 129.1,
136.3, 138.4, 153.1, 168.2, 168.5. MS (EI) m/z (%): 472
(MC2, 13), 470 (MC, 13), 282 (98), 280 (100), 240 (95),
238 (98). HRMS (EI) m/z calcd for C22H19BrN2O5:
470.0477. Found: 470.0473.
4.1.1. (500R)-(Z)-1-Acetyl-6-bromo-2-methoxy-3-(20-oxo-
20-(200-oxo-500-phenyl-300,100-oxazolidinyl)ethylidene)indo-
line (5). A solution of indolin-3-one 3 (300 mg, 1.1 mmol)
and (4R-phenyl-1,3-oxazolidine-2-one-3-yl)carbomethyl-
enetriphenylphosphorane 4 (246 mg, 0.53 mmol) in
benzene (9 mL) was heated under reflux for 6 h. After
removal of the solvent, the residue was chromatographed on
a silica gel column with AcOEt–hexane (1:2) as eluent to
1
give indoline 5 (229 mg, 92%, E:ZZ1:3) as a solid. H
NMR (CDCl3, 300 MHz) d: 2.36 (3H!0.5, s, CH3–CO),
2.38 (3H!0.1, s, CH3–CO), 2.39 (3H!0.1, s, CH3–CO),
2.39 (3H!0.3, s, CH3–CO), 2.93 (3H!0.5, s, CH3–O–),
1.03 (3H!0.1, s, CH3–O–), 3.08 (3H!0.3, s, CH3–O–),
3.12 (3H!0.1, s, CH3–O–), 4.23–4.37 (1H, m, –CHH–),
4.71–4.80 (1H, m, –CHH–), 5.54–5.63 (1H, m, –CH–CH2–),
6.01 (1H!0.4, d, JZ1.3 Hz, –CH–OMe), 6.65 (1H!0.5, d,
JZ2.0 Hz, –CH–OMe), 6.78 (1H!0.1, d, JZ2.0 Hz, –CH–
OMe), 7.11–7.53 (6.2H, m, Ar-H and ]CH–), 7.87 (1H!
0.5, d, JZ2.0 Hz, ]CH–), 8.25 (1H!0.3, d, JZ8.6 Hz,
Ar-H), 8.53 (1H, br, Ar-H). The E,Z-mixture of 5 was
recrystalized with AcOEt–hexane to afford (Z)-5 (73 mg,
32%) as yellow crystals. Mp 219 8C (AcOEt–hexane). IR
(CHCl3) cmK1: 1778, 1682, 1628. 1H NMR (CDCl3,
300 MHz) d: 2.36 (3H, s, CH3–CO), 2.93 (3H, s, CH3–O–),
Minor diasteroisomer. Colorless crystals; Mp 75 8C
(AcOEt–hexane). IR (CHCl3) cmK1: 1778, 1715. 1H
NMR (CDCl3, 300 MHz) d: 2.53 (3H, s, CH3–CO), 3.41
(3H, s, CH3–O–), 4.20 (1H, dd, JZ9.3, 4.7 Hz, –CHH–),
4.73 (1H, dd, JZ9.3, 9.0 Hz, –CHH–), 5.50 (1H, dd, JZ9.0,
4.7 Hz, –CH–CH2–), 6.13 (1H, s, –CH–OMe), 6.84 (2H, dd,
JZ7.6, 1.5 Hz, Ar-H), 7.02 (2H, t, JZ7.6 Hz, Ar-H), 7.183
(1H, tt, JZ7.6, 1.5 Hz, Ar-H), 7.184 (1H, dd, JZ8.4,
1.5 Hz, Ar-H), 7.28 (1H, d, JZ8.4 Hz, Ar-H), 7.35 (1H, s,
Ar-H), 8.62 (1H, d, JZ1.5 Hz, Ar-H). 13C NMR (CDCl3,
100 MHz) d: 23.9, 57.4, 57.6, 70.3, 74.9, 116.0, 119.3,
119.3, 121.3, 125.7, 126.2, 126.8, 127.1, 128.61, 128.63,
136.1, 137.1, 152.9, 168.2, 168.9. MS (EI) m/z (%): 472
(MC2, 14), 470 (MC, 13), 282 (98), 280 (100), 240 (97),

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T. Kouko et al. / Tetrahedron 61 (2005) 2309–2318
1
238 (99). HRMS (EI) m/z calcd for C22H19BrN2O5:
470.0477. Found: 470.0476.
1717. H NMR (CDCl3, 270 MHz) d: 2.42 (3H, s, CH3–),
4.29 (1H, dd, JZ8.9, 4.0 Hz, –CHH–), 4.76 (1H, t, JZ
8.9 Hz, –CHH–), 5.52 (1H, dd, JZ8.9, 4.0 Hz, –CH–CH2–),
6.40 (1H, s, –CH–CO), 7.00 (1H, s, Ar-H), 7.09 (1H, d, JZ
7.3 Hz, Ar-H), 7.23 (1H, t, JZ7.3 Hz, Ar-H), 7.30–7.38
(5H, m, Ar-H), 8.65 (1H, d, JZ1.3 Hz, Ar-H). 13C NMR
(CDCl3, 68 MHz) d: 23.7, 56.5, 57.7, 70.3, 113.9, 119.7,
120.0, 120.6, 125.3, 126.3, 126.7, 127.6, 129.1, 129.2,
136.4, 137.5, 152.7, 168.2, 168.3. MS (EI) m/z (%): 483
(MC2, 15), 481 (MC, 17), 455 (28), 453 (28), 265 (34), 263
(35), 223 (99), 221 (100), 142 (34), 104 (57), 43 (37).
HRMS (EI) m/z calcd for C21H16BrN5O4: 481.0386. Found:
481.0391. Anal. Calcd for C21H16BrN5O4: C, 52.30; H,
3.34; N, 14.52. Found: C, 52.26; H, 3.39; N, 14.43.
4.2.2. (500R)-N-{1-(10-Acetyl-60-bromoindol-3-yl)-2-oxo-
2-(200-oxo-500-phenyl-300,100-oxazolidinyl)ethyl}ethoxy-
formamide (7a) (Table 1, entry 3). Yellow viscous oil. 1H
NMR (CDCl3, 300 MHz) d: 1.14–1.31 (3H, m, CH3–CH2–),
2.47 (3H!0.75, s, CH3–CO), 2.64 (3H!0.25, s, CH3–CO),
4.02–4.31 (3H, m, –CHH– and –CH2–CH3), 4.59 (1H!
0.25, dd, JZ8.8, 8.6 Hz, –CHH–), 4.74 (1H!0.75, dd, JZ
9.0, 8.8 Hz, –CHH–), 5.32 (1H!0.25, dd, JZ8.6, 3.5 Hz,
–CH–CH2–), 5.49 (1H!0.75, dd, JZ8.8, 4.5 Hz, –CH–
CH2–), 5.56 (1H!0.75, br, –NH–), 5.80 (1H!0.25, br,
–NH–), 6.83 (1H, d, JZ8.1 Hz, –CH–CO), 6.96–7.61 (8H,
m, Ar-H), 8.63 (1H!0.75, s, Ar-H), 8.68 (1H!0.25, d, JZ
1.5 Hz, Ar-H). HRMS (EI) m/z calcd for C24H22BrN3O6:
527.0692. Found: 527.0691. The ratio (1:2.9) of two
diastereoisomers was determined by HPLC.
4.3. Preparation of optical pure indolylglycinol 10
4.3.1. tert-Butyl (10S,500R)-N-{10-(1-Acetyl-6-bromoindol-
3-yl)-20-oxo-20-(200-oxo-500-phenyl-300,100-oxazolidinyl)-
ethylcarbamate (9). To a solution of azide (S)-7c (387 mg,
0.80 mmol) in THF (8 mL) and 10% HCl (0.3 mL),
n-tributylphosphine (0.40 mL, d 0.81, 1.6 mmol) was added
dropwise at 0 8C. The stirred reaction mixture was gradually
warmed to ambient temperature over 12 h. After removal of
the solvent, the residue was diluted with AcOEt (40 mL)
and washed with satd NaCl (5 mL). The organic layer was
dried over MgSO4 and concentrated under reduced pressure
to give a crude amine. A solution of the crude amine, DMAP
(9.8 mg, 0.08 mmol) and di-tert-butyl dicarbonate (0.9 mL,
d 0.95, 4.0 mmol) in CH2Cl2 (8 mL) was stirred at room
temperature for 3 days. After removal of the solvent, the
residue was purified by silica gel column chromatography
with AcOEt–hexane (1:1) as eluent to afford indolylglycine
9 (366 mg, 82%) as a colorless powder. Mp 110–115 8C
(AcOEt–hexane). [a]DZC121.0 (c 0.93, CHCl3). IR
(CHCl3) cmK1: 3495, 1786, 1713. 1H NMR (CDCl3,
300 MHz) d: 1.42 (9H, s, t-Bu), 2.45 (3H, s, CH3–CO),
4.22 (1H, dd, JZ9.0, 4.4 Hz, –CHH–), 4.73 (1H, t, JZ
9.0 Hz, –CHH–), 5.37 (1H, br d, JZ8.1 Hz, –NH–), 5.49
(1H, dd, JZ9.0, 4.4 Hz, –CH–CH2–), 6.79 (1H, d, JZ
8.1 Hz, –CH–NHBoc), 6.98 (2H, d, JZ7.4 Hz, Ar-H), 7.11
(1H, s, Ar-H), 7.13 (2H, t, JZ7.4 Hz, Ar-H), 7.22–7.28 (3H,
m, Ar-H), 8.63 (1H, s, Ar-H). 13C NMR (CDCl3, 100 MHz)
d: 23.8, 28.4, 49.9, 57.7, 70.1, 80.5, 116.3, 119.4, 119.5,
120.5, 125.3, 126.0, 126.6, 127.1, 128.8, 136.1, 137.6,
152.3, 154.7, 168.1, 169.7. MS (EI) m/z (%): 557 (MC2,
10), 555 (MC, 10), 501 (15), 499 (15), 367 (28), 365 (28),
311 (99), 309 (100), 269 (24), 267 (56), 265 (35), 225 (33),
223 (45), 164 (25), 57 (41). HRMS (EI) m/z calcd for
C26H26BrN3O6: 555.1005. Found: 555.1009. Anal. Calcd
for C26H26BrN3O6: C, 56.12; H, 4.71; N, 7.55. Found: C,
56.11; H, 4.74; N, 7.36.
4.2.3.
(5000R)-1-Acetyl-6-bromo-3-(10-[{(400-methyl-
phenyl)sulfonyl}amino]-20-oxo-20-{2000-oxo-5000-phenyl-
3000,1000-oxazolidinyl}ethyl)indole (7b) (Table 1, entry 4).
Colorless powder; Mp 232–235 8C (AcOEt–hexane). IR
(CHCl3) cmK1: 1784, 1718. 1H NMR (CDCl3, 300 MHz) d:
2.36 (3H, s, CH3–), 2.39 (3H, s, CH3–), 4.20 (1H, dd, JZ
9.2, 5.0 Hz, –CHH–), 4.67 (1H, dd, JZ9.2, 9.0 Hz, –CHH–),
5.35 (1H, dd, JZ9.0, 5.0 Hz, –CH–CH2–), 5.78 (1H, d, JZ
8.8 Hz, –NH–), 6.57 (1H, d, JZ8.8 Hz, –CH–NH–), 6.80
(1H, d, JZ8.4 Hz, Ar-H), 6.92 (1H, s, Ar-H), 6.93 (2H, dd,
JZ7.8, 1.6 Hz, Ar-H), 7.07–7.13 (5H, m, Ar-H), 7.24 (1H,
tt, JZ7.8, 1.6 Hz, Ar-H), 7.54 (2H, d, JZ8.5 Hz, Ar-H),
8.50 (1H, d, JZ1.7 Hz, Ar-H). 13C NMR (CDCl3,
100 MHz) d: 21.6, 23.7, 51.4, 57.7, 70.2, 114.9, 119.3,
119.4, 120.4, 125.7, 125.9, 126.2, 127.0, 127.1, 128.8,
128.9, 129.0, 136.0, 136.4, 137.1, 143.5, 152.2, 167.9,
168.7. MS (EI) m/z (%): 611 (MC2, 51), 609 (MC, 47), 456
(41), 454 (39), 421 (100), 419 (95), 382 (17), 380 (23), 379
(46), 377 (45), 251 (17), 249 (18), 224 (25), 222 (36), 155
(22), 132 (33), 91 (51). HRMS (EI) m/z calcd for C28H14-
BrN3O6S: 609.0569. Found: 609.0570. The ratio (1:7) of
two diastereoisomers was determined by HPLC.
4.2.4. (10R,500R)-1-Acetyl-3-{10-azido-20-oxo-20-(200-oxo-
500-phenyl-300,100-oxazolidinyl)ethyl}-6-bromoindole [(R)-
7c]. Yellow powder; Mp 148 8C (AcOEt–hexane). [a]DZ
K244.7 (c 0.37, CHCl3). IR (CHCl3) cmK1: 2110, 1782,
1
1717. H NMR (CDCl3, 270 MHz) d: 2.66 (3H, s, CH3–),
4.34 (1H, dd, JZ8.9, 3.6 Hz, –CHH–), 4.66 (1H, t, JZ
8.9 Hz, –CHH–), 5.40 (1H, dd, JZ8.9, 3.6 Hz, –CH–CH2–),
6.45 (1H, s, –CH–CO), 7.26–7.48 (6H, m, Ar-H), 7.58 (1H,
s, Ar-H), 7.64 (1H, d, JZ8.6 Hz, Ar-H), 8.68 (1H, d, JZ
1.7 Hz, Ar-H). 13C NMR (CDCl3, 68 MHz) d: 23.9, 56.6,
58.1, 70.4, 114.0, 119.8, 120.1, 121.0, 125.9, 126.0, 126.8,
127.6, 129.2, 129.5, 136.5, 137.9, 152.9, 167.7, 168.4. MS
(EI) m/z (%): 483 (MC2, 2), 481 (MC, 2), 455 (18), 453
(18), 223 (34), 221 (35), 163 (81), 133 (95), 104 (100), 91
(34), 77 (22), 43 (19). Anal. Calcd for C21H16BrN5O4: C,
52.30; H, 3.34; N, 14.52. Found: C, 52.32; H, 3.45; N, 14.13.
4.3.2. tert-Butyl (S)-N-[1-(6-bromoindol-3-yl)-2-hydroxy]-
ethylcarbamate (10). Sodium borohydride (75 mg,
1.99 mmol) in water (0.45 mL) was added to a solution of
indolylglycine 9 276 mg, 0.50 mmol) in THF (10 mL) at
room temperature. After stirring at the same temperature for
30 min, 10% LiOH (5 mL) was added. The reaction mixture
was stirred under the same conditions for 30 min. The
resulting mixture was concentrated under reduced pressure
to give a residue, which was extracted with AcOEt
(15 mL!2). The organic layer was washed with satd
4.2.5. (10S,500R)-1-Acetyl-3-{10-azido-20-oxo-20-(200-oxo-
500-phenyl-300,100-oxazolidinyl)ethyl}-6-bromoindole [(S)-
7c]. Yellow powder; Mp 148 8C (AcOEt–hexane). [a]DZ
C120.9 (c 0.28, CHCl3). IR (CHCl3) cmK1: 2110, 1784,

T. Kouko et al. / Tetrahedron 61 (2005) 2309–2318
2315
NaCl, dried over MgSO4 and evaporated to afford a residue.
The residue was chromatographed on a silica gel column
with AcOEt–hexane (2:1) as eluent to provide indolyl-
glycinol 10 (149 mg, 85%) as colorless crystals. Mp 161–
162 8C (acetone–hexane), O99%ee. [a]DZC19.1 (c 0.86,
CHCl3). IR (KBr) cmK1: 3399, 3273, 1671, 1617. 1H NMR
(acetone-d6, 300 Hz) d: 1.40 (9H, s, t-Bu), 2.82 (1H, br,
OH), 3.89 (2H, d, JZ4.2 Hz, –CH2–), 5.05 (1H, br, –CH–
CH2–), 6.05 (1H, br, –NH–Boc), 7.15 (1H, dd, JZ8.4,
1.8 Hz, Ar-H), 7.36 (1H, d, JZ1.8 Hz, Ar-H), 7.59 (1H, d,
JZ1.5 Hz, Ar-H), 7.65 (1H, d, JZ8.4 Hz, Ar-H), 10.24
(1H, br, indole-NH). 13C NMR (CDCl3, 100 MHz) d: 28.3,
50.1, 65.9, 79.9, 114.0, 114.4, 115.9, 120.0, 122.2, 123.0,
124.4, 136.8, 155.9. MS (EI) m/z (%): 356 (MC2, 13), 354
(MC, 13), 325 (26), 323 (26), 269 (97), 267 (100), 225 (27),
223 (31), 210 (22), 208 (22), 57 (38). HRMS (EI) m/z calcd
for C15H19BrN2O3: 354.0579. Found: 354.0584. Anal.
Calcd for C15H19BrN2O3: C, 50.72; H, 5.39; N, 7.89.
Found: C, 50.70; H, 5.37; N, 7.62.
extract was concentrated under reduced pressure to give a
residue, which was purified by silica gel chromatography
with AcOEt–hexane (1:1) as eluent to afford N-acetyl-
aminoalcohol 126 (28 mg, 62%) as colorless powder. Mp
143–145 8C (CH2Cl2–hexane); [lit.6 mp 142–143 8C].
[a]DZC38.3 (c 1.51, CHCl3); [lit.6 [a]DZC19.9 (c 1.18,
1
CHCl3), 88.1%ee]. H NMR (CDCl3, 300 MHz) d: 1.46
(9H, s, t-Bu), 2.61 (3H, s, CH3–CO), 4.01 (2H, br s, –CH2–),
5.06 (1H, br, –CH–CH2–), 5.14 (1H, br, –NH–), 7.407 (1H,
s, Ar-H), 7.412 (1H, dd, JZ8,4, 1.7 Hz, Ar-H), 7.47 (1H, d,
JZ8.4 Hz, Ar-H), 8.65 (1H, br, Ar-H).
4.4. Synthesis of hamacanthins A, B (2a,b) and cis-
dihydrohamacanthin B (2e)
4.4.1. tert-Butyl (S)-N-[1-{6-bromo-1-([4-methylphenyl]-
sulfonyl)indol-3-yl}-2-(4-methylphenyl)sulfonyloxy]-
ethylcarbamate (13). Under nitrogen atmosphere, a
solution of indolylglycinol 10 (701 mg, 1.98 mmol),
p-toluenesulfonyl chloride (3.76 g, 19.8 mmol), DMAP
(241 mg, 1.98 mmol) and triethylamine (2.8 mL, d 0.726,
19.8 mmol) in dry CH2Cl2 (20 mL) was kept at K208 for
20 h. The resulting mixture was washed with water (5 mL)
and satd NaCl (5 mL). The organic layer was dried over
MgSO4 and concentrated under reduced pressure to give a
residue. The residue was purified by silica gel column
chromatography with AcOEt–hexane (1:3) as eluent to
afford tosylate 13 as colorless powder. Mp 197 8C (AcOEt–
hexane); [lit.4c 190 8C dec]. IR (CHCl3) cmK1: 3441, 1713.
1H NMR (CDCl3, 300 MHz,) d: 1.42 (9H, s, t-Bu), 2.35 (3H,
s, CH3–), 2.40 (3H, s, CH3–), 4.24 (1H, dd, JZ10.0, 3.9 Hz,
–CHH–), 4.36 (1H, dd, JZ10.0, 4.5 Hz, –CHH–), 5.11 (2H,
br, –CHNH–), 7.14 (2H, d, JZ7.9 Hz, Ar-H), 7.18 (1H, d,
JZ8.7 Hz, Ar-H), 7.26 (1H, dd, JZ8.7, 1.5 Hz, Ar-H), 7.27
(2H, d, JZ7.9 Hz, Ar-H), 7.44 (1H, d, JZ0.9 Hz, Ar-H),
7.53 (2H, d, JZ8.3 Hz, Ar-H), 7.75 (2H, d, JZ8.3 Hz,
Ar-H), 8.09 (1H, d, JZ1.5 Hz, Ar-H).
4.3.3. tert-Butyl (S)-N-[1-(1-acetyl-6-bromoindol-3-yl)-2-
(tert-butyldimethylsilyloxy)]ethylcarbamate (11). Under
nitrogen, tert-butyldimethylsilyl chloride (739 mg,
4.91 mmol) was added in one portion to a solution of
indolylglycinol 10 (871 mg, 2.45 mmol), DMAP (30 mg,
0.25 mmol) and triethylamine (0.7 mL, d 0.73, 4.91 mmol)
in dry CH2Cl2 (25 mL) at room temperature. After stirring
under the same conditions for 12 h, the excess silyl chloride
was quenched with MeOH (12 mL). The solvent was
removed by evaporation to give a residue, which was
diluted with AcOEt (50 mL) followed by washing with
water (10 mL) and satd NaCl (10 mL). The organic layer
was dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by silica gel chromato-
graphy with AcOEt–hexane (1:3) as eluent to give a crude
product. A mixture of the crude, DMAP (299 mg,
2.45 mmol) and acetic anhydride (0.5 mL, d 1.08,
4.91 mmol) in dry CH2Cl2 (25 mL) was stirred at room
temperature under nitrogen for 36 h. After removal of the
solvent, the residue was chromatographed on a silica gel
column with AcOEt–hexane (1:3) as eluent to obtain
O-silyl-N-acetyl indolylglycinol 11 (632 mg, 51%) as
colorless crystals. Mp 102–103 8C (CH2Cl2–hexane).
[a]DZC19.7 (c 1.62, CHCl3). IR (KBr) cmK1: 3448,
1705. 1H NMR (CDCl3, 300 MHz) d: 0.01 (3H, s, CH3–Si–),
0.04 (3H, s, CH3–Si–), 0.89 (9H, s, t–Bu–Si–), 1.45 (9H, s,
t-Bu–O–), 2.59 (3H, s, CH3–CO), 3.93 (1H, dd, JZ10.2,
3.0 Hz, –CHH–), 4.01 (1H, dd, JZ10.2, 3.8 Hz, –CHH–),
5.00 (1H, br, –CH–CH2–), 5.08 (1H, d, JZ7.9 Hz, –NH–),
7.40 (1H, dd, JZ8.5, 1.7 Hz, Ar-H), 7.45 (1H, s, Ar-H),
7.49 (1H, d, JZ8.5 Hz, Ar-H), 8.65 (1H, s, Ar-H). 13C NMR
(CDCl3, 100 MHz) d: K5.3, K5.2, 18.4, 23.9, 25.9, 28.5,
48.5, 65.0, 79.9, 119.0, 119.7, 120.3, 121.7, 123.3, 126.7,
127.8, 136.2, 155.1, 168.0. HRMS (FAB) m/z calcd for
C23H36BrN2O4Si: 511.1628. Found: 511.1627.
4.4.2. tert-Butyl (S)-N-[2-Azido-1-{6-bromo-1-([4-
meethylphenyl]sulfonyl)indol-3-yl}]ethylcarbamate
(14). Under nitrogen atmosphere, a suspension of tosylate
13 (7.4 mg, 0.011 mmol) and sodium azide (7.3 mg,
0.11 mmol) in dry DMF (0.1 mL) was stirred at 80 8C for
1 h. After removal of the solvent, the residue was diluted
with AcOEt (10 mL). The mixture was washed with water
(5 mL) and satd NaCl (5 mL) and dried over MgSO4. The
organic layer was concentrated under reduced pressure to
give a residue, which was chromatographed on a silica gel
column with AcOEt–hexane (1:2) as eluent to afford N-Boc-
aminoazide 14 (4.7 mg, 78%) as colorless powder. Mp 161–
162 8C (AcOEt–hexane); [lit.4c 174–176 8C]. [a]DZC4.6
(c 0.95, CHCl3); [lit.4c [a]DZC4 (c 1.67, CHCl3)]. IR
(CHCl3) cmK1: 3445, 2109, 1709. 1H NMR (CDCl3,
300 MHz) d: 1.45 (9H, s, t-Bu), 2.32 (3H, s, CH3–), 3.72
(1H, d, JZ12.1, 4.2 Hz, –CHH–), 3.76 (1H, dd, JZ12.1,
5.0 Hz, –CHH–), 4.92 (1H, br, –CH–CH2–), 5.09 (1H, br,
–NH-Boc), 7.27 (2H, d, JZ8.4 Hz, Ar-H), 7.37 (1H, dd, JZ
8.4, 1.7 Hz, Ar-H), 7.41 (1H, d, JZ8.4 Hz, Ar-H), 7.53 (1H,
s, Ar-H), 7.77 (2H, d, JZ8.4 Hz, Ar-H), 8.16 (1H, d, JZ
1.7 Hz, Ar-H). 13C NMR (CDCl3, 100 MHz) d: 21.7, 28.4,
46.8, 54.1, 80.5, 116.7, 118.9, 120.4, 120.7, 123.9, 126.7,
126.7, 127.7, 130.0, 134.7, 135.6, 145.3, 154.7. MS (EI) m/z
(%): 535 (MC2, 1), 533 (MC, 1), 479 (23), 477 (22), 423
4.3.4. tert-Butyl (S)-N-[1-(1-acetyl-6-bromoindol-3-yl)-2-
hydroxy]ethylcarbamate (12). A solution of 11 (62 mg,
0.12 mmol) and concd HCl (12 mL) in MeOH (1.2 mL) was
stirred at room temperature for 30 min. After removal of the
solvent, the residue was diluted with water (5 mL) and
extracted with AcOEt (10 mL!2). The organic layer was
washed with satd NaCl (5 mL) and dried over MgSO4. The

2316
T. Kouko et al. / Tetrahedron 61 (2005) 2309–2318
(100), 421 (97), 379 (31), 377 (31), 155 (32), 92 (52), 57
(84). HRMS (EI) m/z calcd for C22H24BrN5O4S: 533.0732.
Found: 533.0724. Anal. Calcd for C22H24BrN5O4S: C,
49.44; H, 4.53; N, 13.10. Found: C, 49.25; H, 4.55; N, 12.82.
10.31 (1H, br, indole-NH), 11.38 (1H, br, indole-NH). 13C
NMR (acetone-d6, 100 MHz) dZ28.6, 44.4, 48.2, 78.9,
113.4, 114.9, 115.3, 115.8, 116.1, 117.1, 121.2, 122.6,
123.8, 123.9, 126.1, 126.2, 126.5, 137.9, 138.3, 139.9,
156.2, 163.4, 181.6. Anal. Calcd for C25H24Br2N4O4: C,
49.69; H, 4.00; N, 9.27. Found: C, 49.38; H, 4.09; N, 8.96.
4.4.3. (S)-N-[2-{6-bromo-1-([4-methylphenyl]sulfonyl)-
indol-3-yl}-2-{(tert-butoxy)carbonylamino}ethyl]2-(6-
bromoindol-3-yl)-2-oxoethanamide (16). A solution of
N-Boc-aminoazide 14 (605 mg, 1.1 mmol), triphenyl-
phosphine (594 mg, 2.3 mmol) and H2O (0.4 mL,
22.7 mmol) in THF (11 mL) was heated under reflux for
1 h. After removal of the solvent, a solution of 6-bromo-
indol-3-yl-a-oxoacetyl chloride (15) (487 mg, 1.70 mmol)
in dry THF (22 mL) was added to a solution of the residue
and triethylamine (237 mL, d 0.73, 1.7 mmol) in dry THF
(22 mL) under nitrogen at 0 8C. The reaction mixture was
stirred at room temperature for 1 h and concentrated under
reduced pressure to give a residue. AcOEt solution (50 mL)
of the residue was washed with water (20 mL) and satd
NaCl (20 mL). The organic layer was dried over MgSO4 and
evaporated to afford a crude product, which was chromato-
graphed on a silica gel column with AcOEt–hexane (1:2) as
eluent to provide amide 16 (677 mg, 79%) as a colorless
powder. Mp 241–243 8C (AcOEt–hexane). [a]DZK2.6 (c
0.77, acetone). IR (KBr) cmK1: 3378, 3247, 1688, 1624. 1H
NMR (acetone-d6, 300 MHz) d: 1.36 (9H, s, t-Bu), 2.20 (3H,
s, CH3–), 3.70 (1H, ddd, JZ13.4, 7.3, 6.0 Hz, –CHH–), 4.01
(1H, dt, JZ13.4, 6.8 Hz, –CHH–), 5.31 (1H, dd, JZ7.3,
6.8 Hz, –CH–CH2–), 6.57 (1H, br, –NH-Boc), 7.21 (2H, d,
JZ8.0 Hz, Ar-H), 7.421 (1H, dd, JZ8.4, 1.7 Hz, Ar-H),
7.424 (1H, dd, JZ8.4, 1.7 Hz, Ar-H), 7.74 (1H, d, JZ
8.4 Hz, Ar-H), 7.79 (1H, d, JZ1.7 Hz, Ar-H), 7.81 (2H, d,
JZ8.0 Hz, Ar-H), 7.85 (1H, s, Ar-H), 8.12 (1H, d, JZ
1.7 Hz, Ar-H), 8.25 (1H, d, JZ8.4 Hz, Ar-H), 8.40 (1H, br,
–NH–CH2–), 9.04 (1H, d, JZ3.1 Hz, Ar-H), 11.37 (1H, br,
indole-NH). 13C NMR (acetone-d6, 100 MHz) d: 21.3, 28.5,
43.2, 47.6, 79.3, 113.4, 115.9, 116.9, 117.2, 118.5, 122.4,
123.1, 123.9, 125.1, 126.3, 126.5, 127.1, 127.4, 129.6,
130.8, 135.4, 136.5, 137.9, 140.0, 146.2, 155.9, 163.4,
181.3. Anal. Calcd for C32H30Br2N4O6S: C, 50.67; H, 3.99;
N, 7.39. Found: C, 50.63; H, 4.08; N, 7.07.
4.4.5. (S)-N-[2-(1-Acetyl-6-bromoindol-3-yl)-2-{(tert-
butoxy)carbonylamino}ethyl]-2-(1-acetyl-6-bromoindol-
3-yl)-2-oxoethanamide (18). A solution of 17 (499 mg,
0.83 mmol), DMAP (101 mg, 0.83 mmol) and acetic
anhydride (0.4 mL, d 1.082, 4.13 mmol) in dry THF
(8.3 mL) was stirred at room temperature under nitrogen
for 12 h. The resulting mixture was evaporated to give a
residue, which was chromatographed on a silica gel column
with AcOEt–hexane (1:2) as eluent to afford acetate 18
(478 mg, 84%) as colorless powder. Mp 217–219 8C
(AcOEt–hexane). [a]DZK5.0 (c 0.12, DMSO). IR (KBr)
cmK1: 3345, 3310, 1732, 1700, 1676, 1647. 1H NMR
(DMSO-d6, 400 MHz) d: 1.33 (9H, s, t-Bu), 2.61 (3H, s,
CH3–), 2.75 (3H, s, CH3–), 3.50 (1H, dt, JZ13.3, 6.7 Hz,
–CHH–), 3.71 (1H, dt, JZ13.3, 6.2 Hz, –CHH–), 5.19 (1H,
dd, JZ6.7, 6.2 Hz, –CH–CH2–), 7.38 (1H, d, JZ9.0 Hz,
–NH-Boc), 7.44 (1H, d, JZ8.4 Hz, Ar-H), 7.60 (1H, d, JZ
8.6 Hz, Ar-H), 7.70 (1H, d, JZ8.4 Hz, Ar-H), 7.87 (1H, s,
Ar-H), 8.16 (1H, d, JZ8.6 Hz, Ar-H), 8.46 (1H, s, Ar-H),
8.51 (1H, s, Ar-H), 8.97 (1H, s, Ar-H), 9.09 (1H, br, –NH–
CH2–). 13C NMR (DMSO-d6, 100 MHz) d: 23.6, 23.7, 28.1,
43.1, 45.8, 78.1, 114.7, 117.3, 118.2, 118.4, 118.5, 120.8,
120.9, 122.8, 124.4, 125.9, 126.0, 127.8, 127.9, 135.2,
135.4, 138.4, 154.9, 162.1, 169.1, 169.9, 182.6. Anal. Calcd
for C29H28Br2N4O6: C, 50.60; H, 4.10; N, 8.14. Found: C,
50.65; H, 4.19; N, 8.14.
4.5. Preparation of pyrazinones 22 and 23 through
transamidation–cyclization
A solution of 18 (170 mg, 0.25 mmol) and HCO2H (14 mL)
in CH2Cl2 (14 mL) was stirred at room temperature for 16 h.
After removal of the solvent and excess HCO2H, the residue
was diluted with 1,2-dichroloethane (41 mL). The solution
was adjusted to pH 4 by adding dropwise HCO2H. The
solution was heated under reflux for 1 h and concentrated
under reduced pressure to give a residue. The residue was
chromatographed on a silica gel column with AcOEt–
hexane (2:1) as eluent to afford 3,5-pyrazinone 22 (92 mg,
65%) and 2,5-isomer 23 (47 mg, 33%), respectively.
4.4.4. (S)-N-[2-(6-Bromoindol-3-yl)-2-{(tert-butoxy)car-
bonylamino}ethyl]2-(6-bromoindol-3-yl)-2-oxoethana-
mide (17). A solution of amide 16 (677 mg, 0.89 mmol) and
10% KOH (60 mL) in EtOH (88 mL) was heated under
reflux for 1 h. The resulting mixture was concentrated under
reduced pressure to give a residue, which was extracted with
AcOEt (50 mL!2). The organic layer was washed with
satd NaCl, dried over MgSO4 and evaporated to afford a
crude product. The crude product was purified by silica gel
column chromatography with AcOEt–hexane (1:1) as eluent
to afford detosylated oxoethanamide 17 (499 mg, 93%) as
colorless powder. Mp 235–238 8C (AcOEt–hexane).
[a]DZC9.8 (c 0.53, acetone). IR (KBr) cmK1: 3378,
1674, 1634. 1H NMR (acetone-d6, 300 MHz) d: 1.35 (9H, s,
t-Bu), 3.71–3.81 (1H, m, –CHH–), 3.87–3.93 (1H, m,
–CHH–), 5.33 (1H, br, –CH–CH2–), 6.32 (1H, br, –NH-
Boc), 7.18 (1H, dd, JZ8.4, 1.8 Hz, Ar-H), 7.40 (1H, dd, JZ
8.4, 1.8 Hz, Ar-H), 7.44 (1H, d, JZ2.6 Hz, Ar-H), 7.60 (1H,
d, JZ1.8 Hz, Ar-H), 7.75 (1H, d, JZ8.4 Hz, Ar-H), 7.77
(1H, d, JZ1.8 Hz, Ar-H), 8.23 (1H, d, JZ8.4 Hz, Ar-H),
8.25 (1H, br, –NH–CO), 9.05 (1H, d, JZ2.0 Hz, Ar-H),
4.5.1. (S)-3,5-Bis(1-acetyl-6-bromoindol-3-yl)-1H,2H,
3H-diazin-6-one (22). Colorless powder; Mp O300 8C
(THF–hexane). [a]DZC177.6 (c 0.13, DMSO). IR (KBr)
cmK1: 3234, 1717, 1697. 1H NMR (DMSO-d6, 300 MHz) d:
2.65 (3H, s, CH3–), 2.71 (3H, s, CH3–), 3.57–3.66 (2H, m,
–CH2–), 5.35 (1H, dd, JZ10.5, 5.9 Hz, –CH–CH2–), 7.43
(1H, dd, JZ8.6, 1.8 Hz, Ar-H), 7.47 (1H, dd, JZ8.4,
1.8 Hz, Ar-H), 7.75 (1H, d, JZ8.4 Hz, Ar-H), 7.84 (1H, s,
Ar-H), 8.27 (1H, d, JZ8.6 Hz, Ar-H), 8.53 (1H, d, JZ
1.8 Hz, Ar-H), 8.54 (1H, d, JZ1.8 Hz, Ar-H), 8.78 (1H, s,
Ar-H), 8.84 (1H, br, –NH–). MS (EI) m/z: 572 (MC4, 29),
570 (MC2, 51), 568 (MC, 30), 291 (26), 289 (25), 223 (24),
221 (25), 197 (42), 195 (40), 43 (100). HRMS (EI) m/z calcd
for C24H18Br2N4O3: 567.9746. Found: 567.9746.

T. Kouko et al. / Tetrahedron 61 (2005) 2309–2318
2317
4.5.2. (S)-2,5-Bis(1-acetyl-6-bromoindol-3-yl)-1H,2H,
3H-diazin-6-one (23). Colorless powder; Mp 288–291 8C
(THF–hexane). [a]DZC76.2 (c 0.35, DMSO). IR (KBr)
cmK1: 3230, 1717, 1694. 1H NMR (acetone-d6, 300 MHz):
dZ2.66 (3H, s, CH3–), 2.75 (3H, s, CH3–), 4.25 (1H, dd,
JZ16.7, 9.9 Hz, –CHH–), 4.42 (1H, dd, JZ16.7, 4.4 Hz,
–CHH–), 5.24 (1H, dd, JZ9.9, 4.4 Hz, –CH–CH2–), 7.47
(1H, dd, JZ8.6, 2.0 Hz, Ar-H), 7.48 (1H, dd, JZ8.4,
1.8 Hz, Ar-H), 7.82 (1H, d, JZ8.4 Hz, Ar-H), 7.93 (1H, s,
Ar-H), 7.98 (1H, br, –NH–), 8.44 (1H, d, JZ8.6 Hz, Ar-H),
8.63 (1H, d, JZ1.8 Hz, Ar-H), 8.64 (1H, d, JZ2.0 Hz, Ar-
H), 8.85 (1H, s, Ar-H). MS (EI) m/z: 572 (MC4, 50), 570
(MC2, 99), 568 (MC, 51), 278 (89), 276 (86), 236 (89), 234
(86), 223 (44), 221 (40), 43 (100). HRMS (EI) m/z calcd for
C24H18Br2N4O3: 567.9746. Found: 567.9747. Anal. Calcd
for C24H18Br2N4O3: C, 50.55; H, 3.18; N, 9.83. Found: C,
50.36; H, 3.25; N, 9.44.
–CHH–), 4.13 (1H, dd, JZ16.2, 5.0 Hz, –CHH–), 4.98 (1H,
ddd, JZ16.2, 5.0 2.0 Hz, –CH–CH2–), 7.14 (1H, dd, JZ8.4,
1.8 Hz, Ar-H), 7.20 (1H, dd, JZ8.6, 1.8 Hz, Ar-H), 7.31
(1H, d, JZ2.4 Hz, Ar-H), 7.56 (1H, d, JZ1.8 Hz, Ar-H),
7.62 (1H, d, JZ1.8 Hz, Ar-H), 7.66 (1H, d, JZ8.4 Hz, Ar-
H), 8.29 (1H, d, JZ8.6 Hz, Ar-H), 8.41 (1H, d, JZ2.4 Hz,
Ar-H), 8.79 (1H, br, –NH–CO), 11.16 (1H, br, indole-NH),
11.59 (1H, br, indole-NH). 13C NMR (DMSO-d6, 100 MHz)
d: 46.1, 53.4, 110.8, 113.0, 113.8, 113.96, 114.00, 114.5,
120.5, 121.3, 123.0, 123.9, 124.3, 124.4, 124.8, 132.4,
136.8, 137.0, 157.1, 157.2. MS (EI) m/z: 488 (MC4, 40),
486 (MC2, 80), 484 (MC, 42), 236 (100), 234 (93), 225
(43), 223 (70), 221 (28), 197 (27), 195 (28). HRMS (EI) m/z
calcd for C20H14Br2N4O: 483.9535. Found: 483.9529.
4.5.5. (3S,5R)-3,5-Bis(6-bromoindol-3-yl)piperazinone-
2-one (2e): (K)-antiporde of cis-dihydrohamacanthin
B. A solution of 3,5-pyrazinone 22 (37.3 mg, 0.065 mmol)
and sodium cyanoborohydride (412 mg, 6.5 mmol) in
MeOH (4.3 mL) was stirred at room temperature for 2
days. The excess reductant in the resulting mixture was
quenched with water (1 mL). After removal of the solvent,
the residue was extracted with AcOEt (5 mL!3). The
combined organic layer was washed with satd NaCl (3 mL),
dried over MgSO4 and concentrated under reduced pressure
to give a crude product. The crude was purified by silica gel
column chromatography with MeOH–CH2Cl2 (1:5) as an
eluent to afford cis-dihydrohamacanthin B (2e) (23.4 mg,
73%) as a yellow powder. Mp 168–172 8C (AcOEt–
hexane). [a]DZK92.3 (c 0.66, acetone); [lit.2b [a]DZ
C98.7 (c 0.2, acetone)]. 1H NMR (acetone-d6, 300 MHz) d:
3.53 (1H, dt, JZ11.0, 3.7 Hz, –CHH–), 3.73 (1H, t, JZ
11.0 Hz, –CHH–), 4.67 (1H, dd, JZ11.0, 3.7 Hz, –CH–
CH2–), 5.03 (1H, s, –CH–CO), 7.14 (1H, dd, JZ8.4, 1.8 Hz,
Ar-H), 7.16 (1H, dd, JZ8.4, 1.8 Hz, Ar-H), 7.38 (1H, d, JZ
2.4 Hz, Ar-H), 7.41 (1H, d, JZ2.4 Hz, Ar-H), 7.53 (1H, d,
JZ1.8 Hz, Ar-H), 7.59 (1H, d, JZ1.8 Hz, Ar-H), 7.78 (1H,
d, JZ8.4 Hz, Ar-H), 7.83 (1H, d, JZ8.4 Hz, Ar-H), 10.23
(1H, br, indole-NH), 10.37 (1H, br, indole-NH). 13C NMR
(acetone-d6, 100 MHz) d: 49.8, 52.3, 58.9, 114.6, 114.9,
115.0, 115.2, 115.9, 116.1, 121.7, 122.1, 122.5, 122.7,
124.0, 125.7, 125.9, 126.8, 138.27, 138.32, 170.1. HRMS
(FAB) m/z calcd for C20H15Br2N4O: 484.9614. Found:
484.9609.
4.5.3. (S)-3,5-Bis(6-bromoindol-3-yl)-1H,2H,3H-diazin-
6-one (2b): hamacanthin B. A solution of 3,5-pyrazinone
22 (19 mg, 0.034 mmol) and NH4OH (0.7 mL) in THF–
MeOH (10 mL, 3:1) was stirred at room temperature for
10 h. After removal of the solvent, the residue was extracted
with AcOEt (5 mL!2). The organic layer was washed with
satd NaCl (5 mL) and dried over MgSO4. The extract was
concentrated under reduced pressure to give a crude
product, which was purified by silica gel column chroma-
tography with AcOEt–hexane (3:1) as eluent to afford
hamacanthin B (2b) (13 mg, 82%) as yellow powder. Mp
167–169 8C dec (Et2O–hexane). [a]DZC170.1 (cZ0.49,
MeOH); [lit.2a [a]DZC172 (c 0.1, MeOH)]. IR (KBr) cmK1
:
1
1672, 1580, 1447. H NMR (DMSO-d6, 300 MHz) d: 3.46
(1H, ddd, JZ12.4, 9.5, 1.9 Hz, –CHH–), 3.61 (1H, dt, JZ
12.4, 4.8 Hz, –CHH–), 5.24 (1H, dd, JZ9.5, 4.8 Hz, –CH–
CH2–), 7.12 (1H, dd, JZ8.4, 1.6 Hz, Ar-H), 7.17 (1H, dd,
JZ8.6, 1.6 Hz, Ar-H), 7.27 (1H, d, JZ2.4 Hz, Ar-H), 7.58
(1H, d, JZ1.6 Hz, Ar-H), 7.62 (1H, d, JZ1.6 Hz, Ar-H),
7.65 (1H, d, JZ8.6 Hz, Ar-H), 8.29 (1H, d, JZ8.4 Hz, Ar-
H), 8.41 (1H, d, JZ2.6 Hz, Ar-H), 8.51 (1H, br, –NH–CO),
11.14 (1H, br, indole-NH), 11.63 (1H, br, indole-NH). 13C
NMR (DMSO-d6, 100 MHz) d: 43.2, 53.6, 110.9, 113.7,
113.9, 114.1, 114.6, 114.7, 120.7, 121.1, 123.1, 123.6,
123.9, 124.79, 124.81, 132.6, 136.8, 137.1, 156.8, 156.9.
MS (EI) m/z: 488 (MC4, 5), 486 (MC2, 10), 484 (MC, 5),
291 (28), 289 (25), 223 (21), 221 (20), 197 (97), 195 (100),
116 (89), 89 (38). HRMS (EI) m/z calcd for C20H14Br2N4O:
483.9534. Found: 483.9540.
Acknowledgements
4.5.4. (S)-2,5-Bis(6-bromoindol-3-yl)-1H,2H,3H-diazin-
6-one (2a): hamacanthin A. A solution of 2,5-pyrazinone
23 (34 mg, 0.059 mmol) and NH4OH (0.5 mL) in THF–
MeOH (15 mL, 1:1) was stirred at room temperature for
10 h. After removal of the solvent, the residue was extracted
with AcOEt (5 mL!2). The organic layer was washed with
satd NaCl (5 mL) and dried over MgSO4. The extract was
concentrated under reduced pressure to give a crude
product, which was purified by silica gel column chroma-
tography with AcOEt–hexane (3:1) as eluent to afford
hamacanthin A (2a) (25 mg, 87%) as yellow powder. Mp
289 8C (acetone–hexane); [lit.4c mp 270–271 8C]. [a]DZ
C83.7 (c 0.47, MeOH); [lit.2a [a]DZC84 (c 0.1, MeOH)].
We thank N. Eguchi, T. Koseki and S. Kubota in the
Analytical Center of our University for microanalysis and
mass spectral measurements.
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2318
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