Total synthesis of marine bisindole alkaloid (+)-cis-dihydrohamacanthin B

Article abstract of DOI:10.1055/s-2007-965907

The total synthesis of the marine bisindole alkaloid (+)-cis- dihydrohamacanthin B was achieved from optically pure (R)-indolylglycinol. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965907

PAPER
669
Total Synthesis of Marine Bisindole Alkaloid (+)-cis-Dihydrohamacanthin B
Total
S
ynthesis of
a
(+)-cis-Dih
z
ydrohamac
u
a
nthin B hiro Higuchi, Ryousuke Takei, Takashi Kouko, Tomomi Kawasaki*
Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose, Tokyo 204-8588, Japan
Fax +81(042)4958764; E-mail: kawasaki@my-pharm.ac.jp
Received 20 October 2006; revised 1 December 2006
H
N
Abstract: The total synthesis of the marine bisindole alkaloid
(+)-cis-dihydrohamacanthin B was achieved from optically pure
(R)-indolylglycinol.
H
N
O
Br
Key words: bromoindole, indolylglycinol, oxazolidin-2-one, pyr-
azine, Staudinger reduction
Br
N
H
N
N
H
O
hamacanthin A (1a)
Br
Br
A growing number of bromoindole alkaloids are being
discovered from a variety of marine invertebrates, includ-
ing bryozoans, coelenterates, sponges and tunicates. Add-
ing to their interest is the fact that they display a wide
range of biological activity.1 The bisindole dihydropyrazi-
none alkaloids, hamacanthin A (1a) and B (1b), found in
the marine sponges, Hamacantha, Rhaphisia and Spon-
gosorites, indicate significant antimicrobial activity
against Candida albicans, Cryptococcus neoformans and
Bacillus subtilis.2a Also, 1a and 1b show potent antibacte-
rial activity against methicillin-resistant strains via inhibi-
tion of sortase A (Srt A) activity.2b,c Recently,
dihydrohamacanthin A (2a,b) and B (2c) (Figure 1) have
been isolated from the marine sponges, Rhaphisia lacazei
and Spongosorites sp.3 These compounds show moderate
to significant cytotoxicity to several cancer cell lines.3b
N
N
N
H
H
hamacanthin B (1b)
H
N
H
O
N
Br
Br
N
H
N
H
cis-dihydrohamacanthin A (2a)
trans-dihydrohamacanthin A (2b)
H
N
O
Br
Br
N
H
N
H
N
H
cis-dihydrohamacanthin B (2c)
Figure 1 Bisindole dihydropyrazinone alkaloids 1a,b and 2a–c
Since only small quantities of dihydrohamacanthins 2
were available from nature, efficient methods for the total
synthesis of these compounds have been required to pro-
vide these alkaloids and the related compounds for
launching a thorough biological investigation.
O
O
N3
OH
N3
R
N
O
S
Ph
S
Br
The total synthesis of racemic hamacanthins 1, cis- and
trans-dihydrohamacanthins A (2a,b) have been accom-
plished by several groups and us.4 However, there are few
example of the total synthesis of optical active alkaloids,
namely, (+)-hamacanthin A (1a), (–)-antipodes of cis- and
trans-dihydrohamacanthins A (2a,b), from indolylglyci-
nol,5a and (–)-antipode of 1a and (+)-hamacanthin B (1b)
from (S)-indolylethanediol.5b,c Recently, we have synthe-
sized (+)-hamacanthin A (1a) and B (1b), and (–)-anti-
pode of cis-dihydrohamacanthin B (2c) from azide (S,R)-
3 via (S)-4, and revealed that the natural 2c has (+)-
(3S,5R)-configuration (Scheme 1).6 Herein we describe
the first asymmetric total synthesis of natural cis-(+)-di-
hydrohamacanthin B (2c) via (R)-indolylglycinol 4.
Br
N
N
Ac
Ac
(S,R)-3
(S)-4
H
N
O
3
5
Br
Br
N
H
N
H
N
H
(–)-antipode of 2c
Scheme 1 Total synthesis of antipode of cis-dihydrohamacanthin B
(2c)
For the synthesis of natural cis-(+)-dihydrohamacanthin B
(2c), we attempted two routes to (R)-indolylglycinol 4
from azides (R,R)-5 or (R,S)-3, as the diastereomer and
enantiomer of (S,R)-3, respectively (Scheme 2).7
SYNTHESIS 2007, No. 5, pp 0669–0674
Advanced online publication: 25.01.2007
x
x
.
x
x
.2
0
0
7
DOI: 10.1055/s-2007-965907; Art ID: F17206SS
© Georg Thieme Verlag Stuttgart · New York

670
K. Higuchi et al.
PAPER
Reaction of readily available indolin-3-one 710 with the
optically active ylide 811 in refluxing benzene smoothly
proceeded with Wittig olefination to give a diastereomeric
mixture of N-(3-indolylideneacetyl)oxazolidinone 9 in
high yield. When the mixture of 9 was treated with
TMSN3 in the presence of methanesulfonic acid, (S,S)-5
and (R,S)-3 were obtained in 52% and 43% yields, respec-
tively.12 Azide (R,S)-3 was smoothly reduced with n-Bu3P
in the presence of 10% HCl at 0 °C to the resulting amine,
which was treated with Boc2O to give oxazolidinylind-
lylglycine 10 in 58% yield. The reductive removal of the
oxazolidinone moiety from 10 with sodium borohydride13
followed by hydrolysis with LiOH afforded (R)-(–)-in-
dolylglycinol 4 in 83% yield without epimerization.14
H
O
N
3
5
Br
Br
N
H
N
N
H
H
N3
OH
(+)-2c
(natural)
R
Br
N
Ac
O
O
(R)-4
N3
S
N
Ph
R
O
O
Br
O
R
N
N3
R
O
N
O
(R,S)-3
Ac
O
Ph
O
a
N
+
Br
Ph3P
Br
S
OMe
N
O
Ph
N
Ac
Ac (R,R)-5
(S)-8
7
Scheme 2 Synthetic plan for natural cis-dihydrohamacanthin B (2c)
O
O
O
O
S
According to the previously reported Staudinger reduc-
tion of (S,R)-3 with n-Bu3P/HCl–H2O,6 (R,R)-5 was simi-
larly treated resulting in a complex mixture. Further
attempts of this reaction using Ph3P, n-Bu3P and t-Bu3P
under several conditions other than tricyclohexyl phos-
phine (Cy3P) were failed.8,9 Thus, the reduction of (R,R)-
5 with Cy3P/H2O followed by treatment with (Boc)2O
produced (R,R)-6 in 45% yield (Scheme 3). But several
attempts to effect reductive elimination of the oxazolidi-
none moiety of (R,R)-6 to (R)-4 were unsuccessful. Since
compared with the ready conversion of (S,R)-3 to (S)-4
(Scheme 1),6 this conversion of diastereomeric (R,R)-5 to
(R)-4 was troublesome, we decided to investigate another
access to (R)-4 from enantiomeric (R,S)-3 (Scheme 2).
N3
S
N
O
N
O
b
Ph
Ph
Br
Br
OMe
N
N
Ac
(S,S)-5 52%
Ac
9
+
O
O
O
O
N3
S
BocHN
N
O
N
O
c
Ph
Ph
R
Br
Br
N
N
10
Ac
Ac
(R,S)-3 43%
Preparation of the azide (R,S)-3 was performed by our re-
d
ported method6 as shown in Scheme 4.
BocHN
OH
O
O
Br
N
H
R
BocHN
N
O
Ph
Cy3P, THF–H2O, 0 °C,
then Boc2O, DMAP, CH2Cl2
45%
(R)-4
R
(R,R)-5
Br
Scheme 4 Reagents and conditions: (a) benzene, reflux, 8 h, 96%;
(b) TMSN3, MeSO3H, 4 Å MS, CH2Cl2, 0 °C to r.t., 1 h; (c) n-Bu3P,
10% HCl, THF, 0 °C to r.t., 12 h, then Boc2O, DMAP, CH2Cl2, r.t., 3
d, 58%; (d) NaBH4, THF–H2O, r.t., 30 min, then aq 10% LiOH, r.t.,
30 min, 83%.
N
Ac
(R,R)-6
BocHN
OH
Treatment of (R)-(–)-4 with tosyl chloride at –20 °C pro-
vided N,O-ditosylate, which was displaced with NaN3 at
80 °C leading to aminoazide 11 in 73% yield in two steps
(Scheme 5). Reduction of azide 11 with Ph3P/H2O fol-
lowed by condensation with 6-bromoindole-3-yl-a-
oxoacetyl chloride (12) afforded amide 13 in 72% yield.
After detosylation of 13 with 10% KOH in refluxing
R
Br
N
Ac
(R)-4
Scheme 3 Attempted preparation of indolylglycinol (R)-4 from
azide (R,R)-5
Synthesis 2007, No. 5, 669–674 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (+)-cis-Dihydrohamacanthin B
671
BocHN
N3
O
BocHN
OH
Cl
a, b
c
O
Br
Br
Br
N
N
H
N
H
Ts
12
(R)-4
11
H
N
H
N
O
O
d, e
Br
Br
Br
Br
O
O
BocHN
BocHN
N
N
N
N
H
Ac
Ts
Ac
13
14
H
N
H
N
O
O
g
f
Br
Br
Br
Br
N
N
H
N
Ac
N
N
N
H
H
Ac
15
cis-(+)-dihydrohamacanthin B (2c)
Scheme 5 Reagents and conditions: (a) TsCl, DMAP, Et3N, CH2Cl2, –20 °C, 20 h, 92%; (b) NaN3, DMF, 80 °C, 1 h, 79%; (c) Ph3P, H2O,
THF, reflux, 1 h, then 12, Et3N, THF, 0 °C to r.t., 1 h, 72%, (d) 10% KOH, EtOH, reflux, 1 h, 76%; (e) Ac2O, DMAP, THF, r.t., 12 h, 80%; (f)
HCO2H, CH2Cl2, r.t., 16 h, then EtOH, reflux, 1 h, 71%; (g) NaBH3CN, MeOH, r.t., 1 d, 67%.
Hertz. Mass spectra were recorded on a JEOL JMS-DX 302 or
JEOL JMS 700 instrument with a direct inlet system. Elemental
analyses were obtained using a PerkinElmer Model 240B elemental
analyzer. Column chromatography was carried out on a silica gel
(Kanto Chemical Co. Inc., 230–400 mesh and Merck, 230–400
mesh).
EtOH, the indole nitrogens were protected by acetylation
to give N-(2-aminoethyl)-2-oxoethanamide 14 in 60%
yield (2 steps). Removal of the Boc group in 14 followed
by refluxing in ethanol provided 3,5-bisindolylpyrazinone
15 in 71% yield. Finally, stereoselective reduction of 15
with sodium cyanoborohydride gave only (3S,5R)-cis-di-
hydrohamacanthin B (2c) in 67% yield, whose relative
configuration was determined by its NOE experiment
(Figure 2). The spectral data and specific rotation of syn-
thetic 2c were completely identical to those of the natural
product.
(5¢¢S)-(Z)-1-Acetyl-6-bromo-2-methoxy-3-{2¢-oxo-2¢-(2¢¢-oxo-5¢¢-
phenyl-3¢¢,1¢¢-oxazolidinyl)ethylidene}indoline (9)
A solution of indolin-3-one 7 (7.0 g, 25 mmol) and (S)-8 (17 g, 37
mmol) in benzene (200 mL) was refluxed for 8 h. After removal of
the solvent, the residue was chromatographed on a column of silica
gel with EtOAc–hexane (1:2) as eluent to give indoline 9 (11 g,
96%) as a yellowish solid; mp 215–217 °C. Major Z-isomer was as-
signed and minor E-isomer was inseparable.
H
O
N
IR (CHCl3): 1778, 1681, 1628 cm–1.
Br
Br
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 3 H, CH3CO), 2.92 (s, 3
H, CH3O), 4.30 (dd, J = 8.7, 3.3 Hz, 1 H, CHH), 4.75 (t, J = 8.7 Hz,
1 H, CHH), 5.55 (dd, J = 8.7, 3.3 Hz, 1 H, CHCH2), 6.65 (d, J = 1.8
Hz, 1 H, CHOMe), 7.25–7.43 (m, 6 H, ArH), 7.48 (d, J = 6.6 Hz, 1
H, ArH), 7.86 (d, J = 1.8 Hz, 1 H, CH), 8.52 (br, 1 H, ArH).
N
H
H
H
N
H
N
H
Figure 2 NOE experiment of (+)-dihydrohamacanthin B (2c)
13C NMR (100 MHz, CDCl3): d = 23.5, 50.2, 57.6, 70.2, 87.9,
111.6, 119.9, 122.2, 124.8, 125.4, 127.2, 127.7, 128.5, 129.0, 138.4,
145.9, 148.4, 153.5, 162.4, 169.6.
MS (EI, 70 eV): m/z (%) = 472 (M + 2, 58), 470 (M+, 56), 430 (20),
428 (20), 309 (33), 307 (33), 267 (99), 265 (100), 252 (30), 250
(31), 240 (46), 238 (49).
In summary, we have achieved a total synthesis of natural
cis-dihydrohamacanthin B (2c) from indoline-3-one 7 in
2.6% overall yield for 11 steps via optically pure (R)-in-
dolylglycinol 4.
HRMS (EI): m/z calcd for C22H19BrN2O5: 470.0477; found:
470.0472.
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 (Daisel Chemical Ind., Ltd., Chiralpak), OD
(Daisel Chemical Ind., Ltd., Chiralcel) or Finepak SIL-5 column
(JASCO Corporation). IR spectra were recorded on a Shimadzu
FTIR-8400s spectrophotometer. 1H and 13C NMR spectra were
measured on a JEOL JNM-AL300 (300 MHz), JEOL JMN-GSX
400 (400 MHz) or JEOL JNM-LA 500 (500 MHz) spectrometer
with tetramethylsilane as an internal standard. J values are given in
1-Acetyl-6-bromo-3-{1¢-azido-2¢-oxo-2¢-(2¢¢-oxo-5¢¢-phenyl-
3¢¢,1¢¢-oxazolidinyl)ethyl}indoles [(1¢R,5¢¢S)-3 and (1¢S,5¢¢S)-5]
Under N2, MeSO3H (1.4 mL, 11 mmol) was added to a mixture of
indoline 9 (0.5 g, 1.1 mmol), TMSN3 (1.4 mL, 11 mmol) and 4 Å
MS (0.5 g) in anhyd CH2Cl2 (50 mL) at 0 °C. After stirring at r.t. for
1 h, the resulting mixture was filtered on Celite to remove 4 Å MS.
The filtrate was washed with H2O (900 mL) and aq sat. NaHCO3
(900 mL), dried (MgSO4), and concentrated under reduced pres-
sure. The residue was purified by column chromatography on silica
Synthesis 2007, No. 5, 669–674 © Thieme Stuttgart · New York

672
K. Higuchi et al.
PAPER
gel with EtOAc–hexane (1:3) as eluent to afford azide (S,S)-5 (0.27
g, 52%) and (R,S)-3 (0.22 g, 43%) as white solids.
MS (EI, 70 eV): m/z (%) = 557 (M + 2, 3), 555 (M+, 3), 457 (15),
455 (15), 311 (36), 309 (35), 267 (100), 265 (93), 225 (77), 223
(88), 117 (36).
(1¢R,5¢¢S)-3
Mp 145–148 °C; [a]D20 –120.9 (c 0.28, CHCl3).
IR (CHCl3): 2108, 1782, 1717 cm–1.
HRMS (EI): m/z calcd for C26H26BrN3O6: 555.1005; found:
555.1003.
tert-Butyl (R)-N-{1-(6¢-Bromoindol-3¢-yl)-2-hydroxy}ethyl-
carbamate [(R)-4]
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H, CH3), 4.28 (dd,
J = 8.9, 4.0 Hz, 1 H, CHH), 4.76 (t, J = 8.9 Hz, 1 H, CHH), 5.52 (dd,
J = 8.9, 4.0 Hz, 1 H, CHCH2), 6.40 (s, 1 H, CHCO), 6.99 (s, 1 H,
ArH), 7.09 (d, J = 7.3 Hz, 2 H, ArH), 7.21–7.38 (m, 5 H, ArH), 8.65
(d, J = 1.5 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 23.6, 56.4, 57.5, 70.1, 113.7,
119.4, 119.7, 120.2, 125.0, 126.0, 126.4, 127.2, 128.78, 128.84,
136.0, 137.2, 152.3, 167.7, 167.8.
MS (EI, 70 eV): m/z (%) = 483 (M + 2, 4), 481 (M+, 4), 455 (49),
453 (46), 425 (42), 423 (39), 382 (36), 380 (39), 265 (32), 264 (32),
263 (29), 262 (27), 223 (96), 222 (67), 221 (100), 220 (54), 142
(39), 132 (76), 104 (53).
NaBH4 (0.35 g, 9.2 mmol) in H2O (2.0 mL) was added to a solution
of indolylglycine 10 (1.4 g, 2.3 mmol) in THF (40 mL) at r.t. After
stirring at the same temperature for 30 min, aq 10% LiOH (25 mL)
was added. The mixture was stirred under the same conditions for
30 min. The resulting mixture was concentrated to give a residue,
which was extracted with EtOAc (3 × 20 mL). The combined organ-
ic layers were washed with brine (15 mL), dried (MgSO4) and evap-
orated. The residue was chromatographed on a column of silica gel
with EtOAc–hexane (2:1) as eluent to provide indolylglycinol (R)-
4 (0.68 g, 83%) as colorless crystals; mp 161–162 °C; [a]D20 –21.7
(c 0.86, CHCl3).
IR (CHCl3): 3472, 3441, 3331, 3019, 1703 cm–1.
HRMS (EI): m/z calcd for C21H16BrN5O4: 481.0385; found:
1H NMR (300 MHz, CDCl3): d = 1.45 (s, 9 H, t-C4H9), 2.57 (br, 1
H, OH), 3.98 (br s, 2 H, CH2), 5.09 (br s, 2 H, CHCH2, NHBoc),
7.12 (d, J = 2.7 Hz, 1 H, ArH), 7.23 (dd, J = 8.7, 1.8 Hz, 1 H, ArH),
7.49 (d, J = 1.5 Hz, 1 H, ArH), 7.50 (d, J = 8.7 Hz, 1 H, ArH), 8.30
(br, 1 H, indol-NH).
13C NMR (100 MHz, CDCl3): d = 28.3, 50.1, 65.8, 79.9, 114.0,
114.2, 115.8, 120.0, 122.3, 122.9, 124.4, 136.9, 155.9.
MS (EI, 70e V): m/z (%) = 356 (M + 2, 6), 354 (M+, 7), 325 (23),
323 (24), 269 (98), 267 (100), 239 (16), 237(15), 225 (32), 223 (41),
210 (49), 208 (48), 130 (14), 129 (28), 117 (20).
481.0381.
(1¢S,5¢¢S)-5
Mp 145–147 °C.
IR (CHCl3): 2110, 1782, 1716 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.65 (s, 3 H, CH3), 4.33 (dd,
J = 9.0, 3.9 Hz, 1 H, CHH), 4.66 (t, J = 8.7 Hz, 1 H, CHH), 5.40 (dd,
J = 8.4, 3.6 Hz, 1 H, CHCH2), 6.45 (s, 1 H, CHCO), 7.33–7.48 (m,
6 H, ArH), 7.58 (s, 1 H, ArH), 7.64 (d, J = 8.4 Hz, 1 H, ArH), 8.68
(d, J = 1.5 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 24.0, 56.6, 58.1, 70.4, 113.9,
119.6, 119.9, 120.8, 125.76, 125.80, 126.7, 127.4, 129.0, 129.3,
136.3, 137.7, 152.7, 167.5, 168.1.
HRMS (EI): m/z calcd for C15H19BrN2O3: 354.0579; found:
354.0578.
MS (EI, 70 eV): m/z (%) = 483 (M + 2, 4), 481 (M+, 4), 455 (41),
453 (40), 265 (30), 264 (24), 263 (30), 262 (20), 223 (95), 222 (51),
221 (100), 220 (39), 142 (32), 132 (33), 104 (40).
tert-Butyl (R)-N-2-Azido-1-(6¢-bromo-1¢-tosylindol-3¢-yl)ethyl-
carbamate (11)
Under N2, a solution of indolylglycinol (R)-4 (94 mg, 0.27 mmol),
p-toluenesulfonyl chloride (0.51 g, 2.7 mmol), DMAP (32 mg, 0.27
mmol) and Et3N (0.37 mL, 2.7 mmol) in anhyd CH2Cl2 (4.0 mL)
was stirred at –20 °C for 20 h. The resulting mixture was washed
with H2O and brine. The organic layer was dried (MgSO4) and con-
centrated. The residue was purified by column chromatography on
silica gel with EtOAc–hexane (1:3) as eluent to afford the interme-
diate N,O-ditosylate (0.16 g, 92%) as a colorless powder.
HRMS (EI): m/z calcd for C21H16BrN5O4: 481.0385; found:
481.0388.
tert-Butyl (1R¢,5S¢¢)-N-{1-(1¢-Acetyl-6¢-bromoindol-3¢-yl)-2-oxo-
2-(2¢¢-oxo-5¢¢-phenyl-3¢¢,1¢¢-oxazolidinyl)}ethylcarbamate (10)
To a solution of azide (R,S)-3 (2.0 g, 4.0 mmol) in THF (40 mL) and
aq 10% HCl (1.5 mL), was added Bu3P (2.0 mL, 8.1 mmol) was
added dropwise at 0 °C. The stirred mixture was gradually warmed
to r.t. over 12 h. After removal of the solvent, the residue was dilut-
ed with EtOAc (200 mL) and the EtOAc layer was washed with
brine (30 mL). The organic layer was dried (MgSO4) and concen-
trated under reduced pressure to give the crude amine. A solution of
the crude amine, DMAP (50 mg, 0.404 mmol) and di-tert-butyl di-
carbonate (4.6 mL, 20 mmol) in CH2Cl2 (40 mL) was stirred at r.t.
for 3 d. After removal of the solvent, the residue was purified by
column chromatography on silica gel with EtOAc–hexane (1:1) as
eluent to afford indolylglycine 10 (1.3 g, 58%) as a colorless pow-
der; mp 111–114 °C.
N,O-Ditosylate
Mp 190 °C; [a]D20 +10.6 (c 0.94, CHCl3).
IR (CHCl3): 1360, 1240 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (s, 9 H, t-C4H9), 2.36 (s, 3 H,
CH3), 2.40 (s, 3 H, CH3), 4.24 (dd, J = 9.9, 3.6 Hz, 1 H, CHH), 4.36
(dd, J = 9.9, 4.2 Hz, 1 H, CHH), 5.03 (br s, 1 H, CHNH), 5.12 (br,
1 H, CHNH), 7.13–7.29 (m, 6 H, ArH), 7.43 (d, J = 0.9 Hz, 1 H,
ArH), 7.54 (d, J = 6.6 Hz, 2 H, ArH), 7.75 (d, J = 6.6 Hz, 2 H, ArH),
8.10 (d, J = 1.5 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 21.5, 21.6, 28.5, 47.1, 71.0, 79.6,
116.9, 118.5, 120.8, 122.0, 125.8, 127.1, 127.6, 128.2, 128.7, 130.3,
130.6, 130.9, 133.2, 135.4, 136.2, 145.6, 146.6.
IR (CHCl3): 3445, 3020, 1784, 1709 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42 (s, 9 H, t-C4H9), 2.46 (s, 3 H,
CH3CO), 4.22 (dd, J = 9.0, 4.2 Hz, 1 H, CHH), 4.73 (t, J = 9.0 Hz,
1 H, CHH), 5.37 (br d, J = 8.4 Hz, 1 H, NH), 5.49 (dd, J = 9.0, 4.5
Hz, 1 H, CHCH2), 6.79 (d, J = 8.1 Hz, 1 H, CHNHBoc), 6.98 (d,
J = 7.5 Hz, 2 H, ArH), 7.10–7.29 (m, 6 H, ArH), 8.63 (s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 23.6, 28.2, 49.7, 57.5, 69.9, 80.3,
116.1, 119.2, 119.3, 120.3, 125.1, 125.8, 126.5, 126.9, 128.6, 135.9,
137.4, 152.1, 154.5, 168.0, 169.5.
HRMS (FAB): m/z calcd for C29H31BrN2O7S2: 662.0756; found:
662.0755.
Under N2, a suspension of the above N,O-ditosylate (0.16 g, 0.25
mmol) and NaN3 (0.16 g, 2.5 mmol) in anhyd DMF (2.0 mL) was
stirred at 80 °C for 1 h. After removal of the solvent, the residue was
diluted with EtOAc (20 mL). The mixture was washed with H2O (10
mL) and brine (5 mL), and then dried (MgSO4). The organic layer
Synthesis 2007, No. 5, 669–674 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (+)-cis-Dihydrohamacanthin B
673
was concentrated and the residue was purified by column chroma-
tography on silica gel with EtOAc–hexane (1:2) as eluent to afford
N-Boc-aminoazide 11 (0.10 g, 79%) as a colorless powder.
Detosylated Oxoethanamide
Mp 234–236 °C; [a]D20 –10.1 (c 0.63, acetone).
IR (KBr): 3375, 1674, 1632 cm–1.
1H NMR (400 MHz, acetone-d6): d = 1.37 (s, 9 H, t-C4H9), 3.71–
3.80 (m, 1 H, CHH), 3.87–3.95 (m, 1 H, CHH), 5.33 (br, 1 H,
CHCH2), 6.32 (br, 1 H, NHBoc), 7.18 (dd, J = 8.7, 2.4 Hz, 1 H,
ArH), 7.40 (dd, J = 8.7, 1.8 Hz, 1 H, ArH), 7.44 (d, J = 1.5 Hz, 1 H,
ArH), 7.61 (d, J = 1.5 Hz, 1 H, ArH), 7.72 (d, J = 8.7 Hz, 1 H, ArH),
7.77 (d, J = 1.5 Hz, 1 H, ArH), 8.24 (d, J = 8.4 Hz, 1 H, ArH), 9.05
(d, J = 3.0 Hz, 1 H, ArH), 10.3 (br, 1 H, indole-NH), 11.32 (br, 1 H,
indole-NH).
11
Mp 167–170 °C; [a]D20 –5.4 (c 0.92, CHCl3).
IR (CHCl3): 3439, 2108, 1709 cm–1.
1H NMR (400 MHz, acetone-d6): d = 1.40 (s, 9 H, t-C4H9), 2.35 (s,
3 H, CH3), 3.76–3.86 (m, 2 H, CH2), 5.16 (dd, J = 13.6, 7.2 Hz, 1 H,
CHCH2), 6.63 (br, 1 H, NHBoc), 7.39 (d, J = 8.0 Hz, 2 H, ArH),
7.44 (dd, J = 8.4, 2.0 Hz, 1 H, ArH), 7.68 (d, J = 8.0 Hz, 1 H, ArH),
7.80 (d, J = 1.2 Hz, 1 H, ArH), 7.87 (d, J = 8.0 Hz, 2 H, ArH), 8.14
(d, J = 1.6 Hz, 1 H, ArH).
13C NMR (100 MHz, acetone-d6): d = 21.5, 28.5, 47.7, 54.4, 79.5,
116.9, 118.7, 122.3, 122.5, 125.4, 127.2, 127.5, 129.1, 130.9, 135.4,
136.3, 146.5, 155.5.
MS (EI, 70 eV): m/z (%) = 535 (M + 2, 1), 533 (M+, 1), 479 (19),
477 (18), 451 (23), 449 (23), 423 (100), 421 (96), 379 (35), 378
(19), 377 (36), 376 (12), 296 (35), 294 (35), 155 (33), 91 (45), 57
(40).
13C NMR (100 MHz, acetone-d6): d = 28.6, 44.4, 48.2, 78.8, 113.4,
114.9, 115.3, 115.8, 116.2, 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.
HRMS (FAB): m/z calcd for C25H25Br2N4O4: 603.0243; found:
603.0236.
A solution of the above detosylated oxoethanamide (0.30 g, 0.50
mmol), Ac2O (0.23 mL, 2.5 mmol), and DMAP (61 mg, 0.50 mmol)
in anhyd THF (5 mL) was stirred at r.t. under N2 for 12 h. The re-
sulting mixture was evaporated and the residue was chromato-
graphed on a column of silica gel with EtOAc–hexane (1:2) as
eluent to afford acetate 14 (0.27 g, 80%) as a colorless powder.
HRMS (EI): m/z calcd for C22H24BrN5O4S: 533.0732; found:
533.0725.
(R)-2-(6¢¢-Bromoindol-3¢¢-yl)-{N-2¢-(6¢¢¢-bromo-1¢¢¢-tosylindol-
3¢¢¢-yl)-2¢-(tert-butoxycarbonylamino)ethyl}-2-oxoethanamide
(13)
14
Mp 224–227 °C; [a]D20 +4.17 (c 0.12, DMSO).
IR (KBr): 3348, 3304, 1730, 1701, 1676, 1647 cm–1.
A solution of N-Boc-aminoazide 11 (0.54 g, 1.0 mmol), Ph3P (0.56
g, 2.1 mmol) and H2O (0.37 mL) in THF (10 mL) was heated under
reflux for 1 h. After removal of the solvent, a solution of 12 (0.45 g,
1.6 mmol) in anhyd THF (20 mL) was added to a solution of the res-
idue in Et3N (0.22 mL, 1.6 mmol) in anhyd THF (20 mL) under N2
at 0 °C. The mixture was stirred at r.t. for 1 h and concentrated un-
der reduced pressure. The residue was diluted with EtOAc (30 mL)
and the EtOAc layer was washed with H2O (5 mL) and brine (5
mL). The organic layer was dried (MgSO4) and evaporated. The
crude product was chromatographed on a column of silica gel with
EtOAc–hexane (1:2) as eluent to provide amide 13 (0.55 g, 72%) as
a colorless powder; mp 240–243 °C; [a]D20 +2.53 (c 0.66, acetone).
1H NMR (300 MHz, DMSO-d6): d = 1.40 (s, 9 H, t-C4H9), 2.68 (s,
3 H, CH3), 2.83 (s, 3 H, CH3), 3.57 (dt, J = 13.6, 6.6 Hz, 1 H, CHH),
3.78 (dt, J = 12.5, 6.6 Hz, 1 H, CHH), 5.26 (d, J = 6.6 Hz, 1 H,
CHCH2), 7.46 (d, J = 8.8 Hz, 1 H, NHBoc), 7.52 (d, J = 8.6 Hz, 1
H, ArH), 7.68 (dd, J = 8.6, 1.8 Hz, 1 H, ArH), 7.77 (d, J = 8.2 Hz, 1
H, ArH), 7.94 (s, 1 H, ArH), 8.24 (d, J = 8.6 Hz, 1 H, ArH), 8.54 (d,
J = 1.6 Hz, 1 H, ArH), 8.59 (d, J = 1.6 Hz, 1 H, ArH), 9.05 (s, 1 H,
ArH), 9.17 (br s, 1 H, NHCH2).
13C NMR (100 MHz, DMSO-d6): d = 23.6, 23.7, 28.1, 43.1, 45.8,
78.1, 114.7, 117.3, 118.2, 118.40, 118.45, 120.8, 120.9, 122.8,
124.4, 125.9, 126.0, 127.8, 127.9, 135.3, 135.4, 138.5, 154.9, 162.1,
169.1, 169.9, 182.6.
IR (KBr): 3458, 3343, 1674, 1633 cm–1.
1H NMR (400 MHz, acetone-d6): d = 1.36 (s, 9 H, t-C4H9), 2.20 (s,
3 H, CH3), 3.71 (ddd, J = 19.6, 7.2, 6.0 Hz, 1 H, CHH), 4.03 (dt,
J = 19.6, 7.2 Hz, 1 H, CHH), 5.31 (d, J = 7.6 Hz, 1 H, CHCH2), 6.57
(br, 1 H, NHBoc), 7.21 (d, J = 7.6 Hz, 2 H, ArH), 7.42 (dt, J = 8.4,
1.6 Hz, 2 H, ArH), 7.72–7.86 (m, 5 H, ArH), 8.1 (s, 1 H, ArH), 8.25
(d, J = 8.4 Hz, 1 H, NHCH2), 8.41 (br, 1 H, ArH), 9.05 (d, J = 1.2
Hz, 1 H, ArH), 11.37 (br, 1 H, indole-NH).
13C NMR (100 MHz, acetone-d6): 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, 138.0, 140.0, 146.2,
155.9, 163.4, 181.3.
HRMS (FAB): m/z calcd for C29H29Br2N4O6: 687.0454; found:
687.0455.
(R)-3,5-Bis(1¢-acetyl-6¢-bromoindol-3¢-yl)-5,6-dihydropyrazin-
2(1H)-one (15)
A solution of 14 (0.18 g, 0.25 mmol) and HCO2H (15 mL) in
CH2Cl2 (15 mL) was stirred at r.t. for 16 h. After removal of the sol-
vent and excess HCO2H, the residue was diluted with EtOH (41
mL). The solution was refluxed for 1 h and concentrated under re-
duced pressure. The residue was chromatographed on a column of
silica gel with EtOAc–hexane (2:1) as eluent to afford 3,5-pyr-
azinone 15 (85 mg, 71%) as a colorless powder; mp >300 °C;
[a]D20 –176.5 (c 0.15, DMSO).
HRMS (FAB): m/z calcd for: C32H31Br2N4O6S: 757.0331; found:
757.0321.
IR (KBr): 3445, 1707, 1695, 1585 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.65 (s, 3 H, CH3), 2.71 (s, 3
H, CH3), 3.57–3.66 (m, 2 H, CH2), 5.34 (dd, J = 10.1, 5.5 Hz, 1 H,
CHCH2), 7.42 (d, J = 8.4 Hz, 1 H, ArH), 7.47 (d, J = 8.4 Hz, 1 H,
ArH), 7.75 (d, J = 8.4 Hz, 1 H, ArH), 7.83 (s, 1 H, ArH), 8.27 (d,
J = 8.4 Hz, 1 H, ArH), 8.52 (s, 1 H, ArH), 8.54 (s, 1 H, ArH), 8.78
(s, 1 H, ArH), 8.85 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 23.7, 23.8, 42.2, 53.8, 114.9,
117.4, 117.8, 118.0, 118.4, 120.3, 121.6, 124.1, 124.7, 125.9, 126.8,
126.9, 127.8, 132.6, 135.4, 135.8, 156.0, 156.3, 169.2, 169.5.
(R)-2-(1¢¢-Acetyl-6¢¢-bromoindol-3¢¢-yl)-{N-2¢-(1¢¢¢-acetyl-6¢¢¢-
bromoindol-3¢¢¢-yl)-2¢-(tert-butoxycarbonylamino)ethyl}-2-oxo-
ethanamide (14)
A solution of amide (0.55 g, 0.72 mmol) and 10% KOH (48 mL) in
EtOH (65 mL) was refluxed for 1 h. The resulting mixture was con-
centrated under reduced and the residue was extracted with EtOAc
(3 × 30 mL). The organic layer was washed with brine (15 mL),
dried (MgSO4), and evaporated. The crude product obtained was
purified by column chromatography on silica gel with EtOAc–hex-
ane (1:1) as eluent to afford the intermediate detosylated oxoetha-
namide (0.36 g, 76%) as a colorless powder.
Synthesis 2007, No. 5, 669–674 © Thieme Stuttgart · New York

674
K. Higuchi et al.
PAPER
HRMS (FAB): m/z calcd for C24H19Br2N4O3: 568.9824; found:
568.9824.
Rostas, J. A. P.; Butler, M. S.; Carroll, A. R. J. Nat. Prod.
1998, 61, 660. (g) Cutignano, A.; Bifulco, G.; Bruno, I.;
Casapullo, A.; Gomez-Paloma, L.; Riccio, R. Tetrahedron
2000, 56, 3743.
(3R,5S)-3,5-Bis(6¢-bromoindol-3¢-yl)piperazin-2-one [cis-Dihy-
drohamacanthin B, (2c)]
(2) (a) Gunasekera, S. P.; McCarthy, P. J.; Kelly-Borges, M. J.
Nat. Prod. 1994, 57, 1437. (b) Oh, K. B.; Mar, W.; Kim, S.;
Kim, J. Y.; Oh, M. N.; Kim, J. G.; Shin, D.; Sim, C. J.; Shin,
J. Bioorg. Med. Chem. Lett. 2005, 15, 4927. (c) Oh, K. B.;
Mar, W.; Kim, S.; Kim, J. Y.; Lee, T. H.; Kim, J. G.; Shin,
D.; Sim, C. J.; Shin, J. Biol. Pharm. Bull. 2006, 29, 570.
(3) (a) Casapullo, A.; Bifulco, G.; Bruno, I.; Riccio, R. J. Nat.
Prod. 2000, 63, 447. (b) Bao, B.; Sun, Q.; Yao, X.; Hong, J.;
Lee, C. O.; Sim, C. J.; Im, K. S.; Jung, J. H. J. Nat. Prod.
2005, 68, 711.
(4) (a) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett.
2002, 4, 941. (b) Kawasaki, T.; Ohno, K.; Enoki, H.;
Umemoto, Y.; Sakamoto, M. Tetrahedron Lett. 2002, 43,
4245. (c) Kawasaki, T.; Kouko, T.; Totsuka, H.; Hiramatsu,
K. Tetrahedron Lett. 2003, 44, 8849. (d) Garg, N. K.;
Stoltz, B. M. Tetrahedron Lett. 2005, 46, 2423.
(5) (a) Yang, C. G.; Wang, J.; Tang, X. X.; Jiang, B.
Tetrahedron: Asymmetry 2002, 13, 383. (b) Jiang, B.;
Yang, C. G.; Wang, J. J. Org. Chem. 2001, 66, 4865.
(c) Jiang, B.; Yang, C. G.; Wang, J. J. Org. Chem. 2002, 67,
1396.
A solution of 3,5-pyrazinone 15 (56 mg, 0.098 mmol) and
NaCNBH3 (62 mg, 0.98 mmol) in MeOH (6 mL) was stirred at r.t.
for 1 d. The excess of reducing agent in the resulting mixture was
quenched with H2O (2 mL). After removal of the solvent, the resi-
due was extracted with EtOAc (5 × 8 mL). The combined organic
layers were washed with brine (5 mL), dried (MgSO4) and concen-
trated. The crude product obtained was purified by column chroma-
tography on silica gel with MeOH–CH2Cl2 (1:10) as eluent to afford
cis-dihydrohamacanthin B (2c; 32 mg, 67%) as a yellow powder;
mp 171–174 °C; [a]D20 +89.7 (c 0.2, acetone).
IR (CHCl3): 3281, 3265, 1645 cm–1.
1H NMR (400 MHz, acetone-d6): d = 3.50 (dt, J = 10.8, 3.6 Hz, 1 H,
CHH), 3.70 (t, J = 10.8 Hz, 1 H, CHH), 4.63 (dd, J = 11.2, 3.6 Hz,
1 H, CHCH2), 4.99 (s, 1 H, CHCO), 7.04 (d, J = 3.6 Hz, 1 H, NH-
CO), 7.09 (dd, J = 8.4, 1.6 Hz, 1 H, ArH), 7.12 (dd, J = 8.4, 1.6 Hz,
1 H, ArH), 7.32 (d, J = 2.0 Hz, 1 H, ArH), 7.35 (d, J = 2.4 Hz, 1 H,
ArH), 7.47 (d, J = 1.6 Hz, 1 H, ArH), 7.54 (d, J = 1.6 Hz, 1 H, ArH),
7.76 (d, J = 8.0 Hz, 1 H, ArH), 7.79 (d, J = 8.4 Hz, 1 H, ArH), 10.2
(br, 1 H, indole-NH), 10.3 (br, 1 H, indole-NH).
13C NMR (100 MHz, acetone-d6): d = 49.9, 52.3, 58.9, 114.6, 114.8,
115.0, 115.2, 115.9, 116.2, 121.7, 122.1, 122.5, 122.7, 124.0, 125.6,
125.9, 126.8, 138.26, 138.34, 170.1.
(6) Kouko, T.; Matsumura, K.; Kawasaki, T. Tetrahedron 2005,
61, 2309.
(7) In the former synthesis of unnatural 2c from (S,R)-3, its
diastereomer (R,R)-5 was also obtained.6 So, we initially
used (R,R)-5 for the approach to natural 2c.
HRMS (FAB): m/z calcd for C20H15Br2N4O: 484.9613; found:
484.9627.
(8) The catalytic hydrogenation (H2, Pd/BaSO4) of (R,R)-4 was
also not successful.
(9) (a) Review: Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron
1992, 48, 1353. (b) For more recent review for oraganic
azides, see; Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V.
Angew. Chem. Int. Ed. 2005, 44, 5188. (c) There are some
difficulties for reducing this type azide, see; Bänteli, R.;
Brun, I.; Hall, P.; Metternich, R. Tetrahedron Lett. 1999, 40,
2109. (d) See also: Ami, E.; Rajesh, S.; Wang, J.; Kimura,
T.; Hayashi, Y.; Kiso, Y.; Ishida, T. Tetrahedron Lett. 2002,
43, 2931.
(10) Kawasaki, T.; Nonaka, Y.; Matsumura, K.; Monai, M.;
Sakamoto, M. Synth. Commun. 1999, 29, 3251.
(11) Lee, K.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 5590.
(12) As described in the previous report,6 there was no facial
selectivity between E- and Z-isomers of 8 at the azidation
step.
Acknowledgment
We thank N. Eguchi, T. Koseki and S. Kubota in the Analytical
Center of our University for microanalysis and mass spectral mea-
surements.
References
(1) (a) Kohmoto, S.; Kashman, Y.; McConnell, O. J.; Rinehart,
K. L. Jr.; Wright, A.; Koehn, F. J. Org. Chem. 1988, 53,
3116. (b) Morris, S. A.; Andersen, R. J. Tetrahedron 1990,
46, 715. (c) Fahy, E.; Potts, B. C. M.; Faulkner, D. J.; Smith,
K. J. Nat. Prod. 1991, 54, 564. (d) Wright, A. E.; Pomponi,
S. A.; Cross, S. S.; McCarthy, P. J. Org. Chem. 1992, 57,
4772. (e) Murray, L. M.; Lim, T. K.; Hooper, J. N. A.;
Capon, R. J. Aust. J. Chem. 1995, 48, 2053. (f) Capon, R.
J.; Rooney, F.; Murray, L. M.; Collins, E.; Sim, A. T. R.;
(13) Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron
Lett. 1998, 39, 7067.
(14) The enantiomeric excess of 10 was determined by its HPLC
compared with that of racemic sample.
Synthesis 2007, No. 5, 669–674 © Thieme Stuttgart · New York