Enantioselective total synthesis of eudistomidins G, H, and I

Article abstract of DOI:10.1016/j.tet.2012.05.071

Asymmetric first total synthesis of eudistomidins G, H, and I, tetrahydro-β-carboline alkaloids from the Okinawan marine tunicate Eudistoma glaucus, has been accomplished with the Bischler-Napieralski reaction and the Noyori catalytic asymmetric hydrogen-transfer reaction. The absolute configurations of eudistomidins G, H, and I were confirmed from comparison of the ¹H and ¹³C NMR, and CD spectral data of synthetic and natural eudistomidins G, H, and I, respectively.

Full text of DOI:10.1016/j.tet.2012.05.071

Tetrahedron 68 (2012) 6186e6192
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective total synthesis of eudistomidins G, H, and I
*
Haruaki Ishiyama, Kazuaki Yoshizawa, Jun’ichi Kobayashi
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 April 2012
Received in revised form 18 May 2012
Accepted 19 May 2012
Available online 26 May 2012
Asymmetric first total synthesis of eudistomidins G, H, and I, tetrahydro-b-carboline alkaloids from the
Okinawan marine tunicate Eudistoma glaucus, has been accomplished with the BischlereNapieralski
reaction and the Noyori catalytic asymmetric hydrogen-transfer reaction. The absolute configurations of
eudistomidins G, H, and I were confirmed from comparison of the 1H and 13C NMR, and CD spectral data
of synthetic and natural eudistomidins G, H, and I, respectively.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Eudistomidins G, H, and I
Eudistoma glaucus
Absolute configuration
1. Introduction
unique structure and bioactivity of eudistomidins1e3 possessing
a tetrahydro-b-carboline moiety have prompted studies of its total
Eudistomidins G (1), H (2), and I (3) were new tetrahydro-
b
-
syntheses. First Takayama4 group accomplished total synthesis of
the proposed structure for eudistomidin B,3 and indicated that the
proposed structure was incorrect from comparison of the NMR data
of their synthetic compounds with those reported for eudistomidin
B. Recently, we have revised the structure of eudisotomidin B as 4,
which is an analog of eudistomidin G (1), from comparison of the
carboline alkaloids, in which 2 and 3 possessed a unique fused-
tetracyclic ring, isolated from the Okinawan marine tunicate
Eudistoma glaucus1,2 (Fig. 1). The structures including the relative
stereochemistry of the two stereogenic centers in 1e3 were eluci-
dated mainly on the basis of extensive NMR experiments. The ab-
solute configurations at C-1 in 1e3 were deduced to be R from the
CD spectra. Eudistomidin G (1) showed cytotoxicity against murine
NMR data, [a]D values, and CD data of natural product with those of
synthetic compound.1 In this paper, we describe the first total
syntheses of 1e3 and establish the absolute stereochemistry of
1e3.
leukemia cells L1210 (IC50, 4.8
mg/mL) in vitro, while eudistomidins
H (2) and I (3) did not show such activity (IC50, >10.0
mg/mL). The
Br
Br
Br
Br
1
NMe
1
NMe
1
NMe
1
NMe
N
H
HN
N
H
HN
Me
N
N
R
R
R
R
10H
10H
10H
10H
N
S
S
N
S
S
Me
Me
Me
eudistomidin G (1)
eudistomidin H (2)
eudistomidin I (3)
eudistomidin B (4)
Fig. 1. Structures of eudistomidins G (1), H (2), I (3), and B (4).
* Corresponding author. Tel.: þ81 11 706 3239; fax: þ81 11 706 4989; e-mail address: jkobay@pharm.hokudai.ac.jp (J. Kobayashi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.071

H. Ishiyama et al. / Tetrahedron 68 (2012) 6186e6192
6187
2. Results and discussion
6-Bromotryptamine (7) was prepared as shown in Scheme 2
by using known method. Nitroaldol condensation reaction of
6-bromoindole-3-carboxaldehyde (9) and nitromethane with
AcONH4 afforded 10.8 Reduction of 10 with LiAlH4 in THF provided
6-bromotryptamine (7).9
According to known strategy, N-Fmoc-N-Me-Phe (8) was yiel-
ded as shown in Scheme 3. Protection of the amino group in 11 with
FmoceCl and Na2CO3 afforded 12. Acid-catalyzed condensation of
the Fmoc-protected amino acid (12) with paraformaldehyde
As outlined retrosynthetically in Scheme 1, eudistomidin H (2)
could be obtained by cyclocondensation5 of eudistomidin G (1)
with paraformaldehyde, which could be provided by the Noyori
catalytic asymmetric hydrogen-transfer reaction6a of 5. Dihydro-
b
-
carboline 5 could be derived from amide 6 via BischlereNapieralski
reaction,7 which is conceived to be obtained through condensation
of tryptamine 7 and carboxylic acid 8.
Br
Br
Br
Noyori asymmetric
hydrogen-transfer
1
1
NMe
N
1
NMe
Cyclocondensation
N
H
N
H
N
10 H
10H
10
N
Me
Fmoc
N
Me
HN
Me
eudistomidin G (1)
eudistomidin H (2)
5
Br
CO2H
Bischler-Napieralski
reaction
Fmoc
N
H
NH2
O
NH
N
Me
S
Br
+
1
10
Fmoc
N
Me
N
H
7
8
6
Scheme 1. Retrosynthetic analysis of eudistomidins G (1) and H (2).
O
NO2
a
H
Br
Br
N
H
N
H
9
10
NH2
Br
b
N
H
7
Scheme 2. Synthesis of 6-bromotryptamine (7). Reagents and conditions: (a) MeNO2, AcONH4, reflux, 1.5 h (79%); (b) LiAlH4, THF, reflux, 2 h (73%).
CO2H
CO2H
b
Fmoc
a
N
H
H2N
S
S
(S)-Phe (11)
12
O
O
CO2H
Fmoc
N
S
c
N
S
Me
Fmoc
8
13
Scheme 3. Synthesis of N-Fmoc-N-Me-Phe (8). Reagents and conditions: (a) FmoceCl, Na2CO3, dioxane, 0 ꢀCwrt, 22 h (82%); (b) paraformaldehyde, TsOH$H2O, reflux, 30 min; (c)
TFA, Et3SiH, CHCl3, 0 ꢀCwrt, 2 h (85% for 2 steps).

6188
H. Ishiyama et al. / Tetrahedron 68 (2012) 6186e6192
formed an oxazolidinone 13. Treatment of oxazolidinone 13 with
excess Et3SiH in 1:1 TFAeCHCl3, resulted in ring opening with re-
duction to provide N-Fmoc-N-Me-Phe (8).10
reaction of 17 and nitromethane with AcONH4 afforded 18.11
Treatment of 18 with NaBH4 and BF3$OEt2 in THF yielded 5-
bromotryptamine (19).4,11e13
With both 6-bromotryptamine (7) and N-Fmoc-N-Me-Phe (8) in
hand, the stage was set to the amidation (Scheme 4). Treatment of
Treatment of 5-bromotryptamine (19) with carboxylic acid
(8) in the presence of EDC and HOBt provided amide 20. The
Br
CO2H
N
O
NH
NH2
H
b
Fmoc
a
1
N
S
Br
10
+
Me
Fmoc
N
S
N
H
Me
6
7
8
Br
Br
1
NH
1
N
H
Fmoc
N
d
c
N
H
R
10H
10
S
N
Fmoc
N
Me
S
Me
5
14
Br
Br
Br
1
NMe
1
NMe
N
N
R
Fmoc
1
NMe
f
e
R
R
H
10H
N
10H
R
10 H
S
HN
Me
S
N
Me
N
S
Me
15: R = H
15a: R = CH2OH
eudistomidin G (1)
eudistomidin H (2)
Scheme 4. Synthesis of eudistomidins G (1) and H (2). Reagents and conditions: (a) HOBt, EDC, CH2Cl2, 0 ꢀCwrt, 2 h (82%); (b) POCl3, benzene, reflux, 1.5 h (78%); (c) (S,S)-TsDPEN-
Ru(II), HCO2H/Et3N (5:2), DMF, rt, 13 h (96%); (d) HCHO aq, NaBH3CN, MeCN, ꢁ40 ꢀC, 1 h, 15 (95%); (e) DBU, CH2Cl2, rt, 30 min (68%); (f) paraformaldehyde, benzene, reflux, 1 h (65%).
Br
6-bromotryptamine 7 with carboxylic acid 8 in the presence of EDC
and HOBt provided amide (6). The BischlereNapieralski reaction7 of
6 with POCl3 in benzene yielded dihydro-b-carboline (5). To in-
Br
O
a
b
H
troduce the required stereochemistry at C-1 in 5, Noyori asym-
N
H
N
H
metric hydrogen-transfer reaction6a was applied. The asymmetric
reduction of dihydro-b-carboline (5) was accomplished with
16
17
(S,S)-TsDPEN-Ru(II) complex in DMF and a HCO2H-Et3N mixture to
afford 14 (dr>10:1 from 1H NMR analysis).6b Treatment of 14 with
HCHO (2 equiv) and NaBH3CN in acetonitrile at room temperature
gave 15 (36%) and 15a (36%). Optimization of the reaction condition
led us to find the conditions employing HCHO (7 equiv) and
NaBH3CN in acetonitrile at ꢁ40ꢀ to provide 15 in 95% yield. Removal
of Fmoc group in 15 with DBU furnished eudistomidin G (1), having
(1R,10S)-configuration. Cyclocondensation5 of eudistomidin G (1)
with paraformaldehyde yielded eudistomidin H (2), successively.
1H and 13C NMR of the synthetic 1 and 2 were coincident with
those of natural eudistomidins G and H, respectively. CD spectral
data of the synthetic 1 and 2 showed same Cotton curve pattern of
natural eudisomidins G and H, respectively. Thus, the absolute
configurations at C-1 and C-10 of eudistomidins G and H were
confirmed to be 1R, 10S, respectively.
Br
Br
NH2
NO2
c
N
H
N
H
19
18
Scheme 5. Synthesis of 5-bromotryptamine (19). Reagents and conditions: (a) POCl3,
DMF, 0 ꢀCwrt, 30 min (98%); (b) MeNO2, AcONH4, reflux, 1.5 h (76%); (c) (1) NaBH4,
BF3$OEt2, THF, reflux, 2 h; (2) 1 N HCl, 85 ꢀC, 2 h (82%).
BischlereNapieralski cyclization7 of 20 in benzene afforded dihy-
dro-b
-carboline (21). Noyori asymmetric hydrogen-transfer reac-
-carboline (22), which
tion6a of 21 in DMF afforded tetrahydro-
b
was methylated with HCHO and NaBH3CN to yield 23 in 87%. Re-
moval of Fmoc group in 23 with DBU furnished eudistomidin B (4),
having (1R,10S)-configuration. Treatment of eudistomidin B (4)
with paraformaldehyde in benzene yielded eudistomidin I (3).
5-Bromotryptamine (19) was prepared as shown in Scheme 5
by using known method. Vilsmeier reaction of 5-bromoindole
(16) with POCl3 in DMF provided 17.11 Nitroaldol condensation

H. Ishiyama et al. / Tetrahedron 68 (2012) 6186e6192
6189
1H and 13C NMR of the synthetic 3 were identical with those of
natural eudistomidin I. CD spectral data of the synthetic 3 showed
same Cotton curve pattern of natural eudisomidin I. Thus, the ab-
solute configurations at C-1 and C-10 of eudistomidin I were con-
firmed to be 1R, 10S.
acetone-d6 were used as internal references for 1H and 13C NMR
spectra, respectively. ESI mass spectra were recorded on a Thermo
Fisher Scientific Exactive or JEOL JMS-T100LP spectrometer. Silica
gel column chromatography was carried out on Wakogel C-200
(75e150 mm) or C-300 (45e75 mm). Analytical thin layer chro-
matography (TLC) was carried out on Merck Kieselgel 60 F254 plates
with visualization by ultraviolet, anisaldehyde stain solution,
phosphomolybdic acid stain solution, and/or Dragendorff’s reagent.
Reagents and solvents were purified by standard means. All re-
actions sensitive to oxygen or moisture were conducted under an
argon atmosphere.
3. Conclusion
In conclusion, the first total synthesis of eudistomidin G, H, and I
has been accomplished with the BischlereNapieralski reaction and
the Noyori catalytic asymmetric hydrogen-transfer reaction. The
absolute configurations at C-1 and C-10 of eudistomidins G, H, and I
were confirmed to be 1R, 10S, from comparison of the 1H and 13C
NMR and CD spectral data of synthetic and natural eudistomidins G,
H, and I, respectively (Scheme 6).
4.2. Experimental details
4.2.1. 6-Bromo-3-(2-nitroethyl)indole (10). To
a solution of 6-
bromoindole-3-carboxaldehyde (550 mg, 2.46 mmol) and
9
4. Experimental
AcONH4 (193 mg, 2.46 mmol) in nitromethane (7.5 ml) was
refluxed for 1.5 h. After cooling to room temperature, this solution
was concentrated and purified by a silica gel column chroma-
tography (n-hexane/AcOEt 6:1/4:1/2:1/1:1/1:2) to yield
nitroolefin 10 (519 mg, 1.94 mmol, 79%) as a red solid; Mp
203e205 ꢀC; 1H NMR (400 MHz, DMSO-d6) dH 12.27 (1H, s), 8.36
(1H, d, J¼13.7 Hz), 8.23 (1H, d, J¼8.7 Hz), 8.00 (1H, d, J¼13.7 Hz),
7.93 (1H, d, J¼8.7 Hz), 7.69 (1H, d, J¼1.8 Hz), 7.31(1H, dd, J¼8.7,
1.8 Hz).
4.1. General experimental
Optical rotations were recorded on a JASCO P-1030 polarimeter
at the sodium D line (589 nm). The UV and CD spectra were mea-
sured with a Shimadzu UV-1600PC and JASCO J-720 spectrometers,
respectively. The IR spectrum was taken on a JASCO FT/IR-5300
spectrometer and absorbance bands are reported in wavenumber
(cmꢁ1). 1H and 13C NMR spectra were recorded on a Bruker AMX-
600 (600 MHz), JEOL ECA500 (500 MHz), and/or ECX400P
(400 MHz) spectrometer. The 7.26 and 77.0 ppm resonances of
residual CDCl3 and the 2.05 and 29.8 ppm resonances of residual
4.2.2. 6-Bromotryptamine (7). To
a solution of nitroolefin 10
(153 mg, 0.57 mmol) in THF (5.3 ml) at 0 ꢀC was added LiAlH4
(135 mg, 3.56 mmol) and refluxed for 2 h. After cooling at 0 ꢀC, the
Br
Br
N
CO2H
O
NH
H
NH2
10
Fmoc
a
1
b
N
S
10
+
Fmoc
N
Me
S
Me
N
H
19
8
20
Br
Br
1
1
NH
N
c
N
N
d
R
H
H
10H
10
Fmoc
N
S
Fmoc
N
Me
S
Me
22
21
Br
Br
Br
1
NMe
1
NMe
N
H
HN
1
NMe
e
R
N
f
N
R
10H
10H
R
H
10H
S
S
N
S
Fmoc
N
Me
Me
Me
eudistomidin B (4)
eudistomidin I (3)
23
Scheme 6. Synthesis of eudistomidin I (3). Reagents and conditions: (a) HOBt, EDC, CH2Cl2, 0 ꢀCwrt, 2 h (74%); (b) POCl3, benzene, reflux, 2 h (76%); (c) (S,S)-TsDPEN-Ru(II), HCO2H/
Et3N (5:2), DMF, rt, 18 h (82%); (d) HCHO aq, NaBH3CN, MeCN, ꢁ40 ꢀC, 2 h (87%); (e) DBU, CH2Cl2, rt, 30 min (87%); (f) paraformaldehyde, benzene, reflux, 1 h (71%).

6190
H. Ishiyama et al. / Tetrahedron 68 (2012) 6186e6192
reaction mixture was slowly quenched with satd Rochelle aq
(15 ml), stirred at room temperature for 30 min and extracted with
Et2O (10 ml). The combined organic layers were washed with sat
Rochelle aq (15 ml), water (15 ml) and brine (15 ml), dried over
Na2SO4, filtered, and concentrated in vacuo to yield amine 7
(100 mg, 0.42 mmol, 73%) as an amber oil; 1H NMR (400 MHz,
CDCl3) dH 8.12 (1H, s), 7.51 (1H, d, J¼1.8 Hz), 7.47 (1H, d, J¼8.7 Hz),
7.21 (1H, dd, J¼8.7, 1.8 Hz), 7.02 (1H, d, J¼1.8 Hz), 3.02 (2H,
t, J¼6.9 Hz), 2.88 (2H, t, J¼6.6 Hz).
39.69, 34.29, 34.05, 30.45, 29.70, 25.13, 24.89; ESIMS m/z 644 and
646 ([MþNa]þ, 1:1); HRMS (ESIþ) C35H32O3N379BrNaþ ([MþNa]þ)
requires 644.1593; found 644.1592.
4.2.6. Cyclization of amide (6). To a solution of amide 6 (556 mg,
0.89 mmol) in benzene (22 ml) was added POCl3 (0.58 ml,
6.24 mmol) and refluxed for 1.5 h. The reaction mixture was di-
luted with AcOEt (30 ml), washed with 5% NaHCO3 (30 ml), water
(30 ml), and brine (30 ml), dried over Na2SO4, filtered, and con-
centrated in vacuo. The mixture was purified by a silica gel column
chromatography (CHCl3/AcOEt 50:1/40:1/30:1) to yield dihy-
4.2.3. 9-Fluorenylmethoxycarbonyl-
L
-phenylalanine (12). To a solu-
tion of -phenylalanine 11 (0.96 g, 5.81 mmol) in dioxane (7.5 ml)
and 10% Na2CO3 aq (15 ml) was added FmoceCl (1.50 g,
L
dro-b-carboline 5 (421 mg, 0.70 mmol, 78%) as a yellow amor-
phous solid; Mp 47e49 ꢀC; ½a D24
ꢃ
ꢁ16.6 (c 0.5, acetone), IR (KBr)
5.79 mmol) in dioxane (15 ml). The reaction mixture was stirred at
nmax 3276, 3026, 2945, 2838, and 1669 cmꢁ1 1H NMR (400 MHz,
;
0
ꢀC for 4 h and room temperature for 18 h, added water (400 ml)
CDCl3) dH 9.93 (1H, s), 7.74e7.12 (16H, m), 5.70 (1H, br t, J¼7.8 Hz),
4.57 (1H, m), 4.11 (3H, overlapping), 3.90 (1H, m), 3.29 (2H, m),
2.88 (2H, m), 2.78 (3H, s); 13C NMR (100 MHz, CDCl3) dC 158.59,
157.94, 144.36, 143.66, 141.76, 141.63, 138.06, 137.61, 129.34, 129.03,
128.61, 128.22, 127.51, 127.17, 125.53, 127.27, 124.74, 123.96, 121.36,
120.46, 120.41, 118.28, 116.98, 115.90, 115.85, 68.69, 57.23, 49.13,
47.52, 33.85, 28.69, 19.46; ESIMS m/z 604 and 606 ([MþH]þ, 1:1);
HRMS (ESIþ) C35H31O2N379Brþ ([MþH]þ) requires 604.1600; found
604.1581.
and washed with Et2O (2ꢂ200 ml). The aqueous layer was acidified
with cHCl, filtered and dried to yield Fmoc- -Phe 12 (1.91 g,
L
4.93 mmol, 82%) as a white powder; Mp 182e183 ꢀC; 1H NMR
(400 MHz, CDCl3) dH 7.78e7.14 (13H, m), 5.18 (1H, d, J¼8.2 Hz), 4.70
(1H, m), 4.45 (1H, m), 4.37 (1H, m), 4.21 (1H, m), 3.20 (1H, m), 3.14
(1H, m).
4.2.4. N-Fluorenylmethoxycarbonyl-N-methyl-
L-phenylalanine
(8). To a solution of Fmoc- -Phe 12 (740 mg, 1.91 mmol) in toluene
L
(40 ml) was added 75% paraformaldehyde (395 mg) and p-tolue-
nesulfonic acid monohydrate (44 mg, 0.23 mmol) and refluxed for
30 min with azeotropic water removal. After cooling to room
temperature, the organic layer was washed with 1 N NaHCO3 aq
(2ꢂ20 ml), dried over Na2SO4, filtered, and concentrated in vacuo to
yield oxazolidine 13 as an oil. To a solution of the oxazolidine 13
(970 mg, 2.43 mmol) in CHCl3 (10 ml) was added TFA (10 ml) and
Et3SiH (0.55 ml, 3.44 mmol). The reaction mixture was stirred for
16 h at room temperature and concentrated in vacuo. The oil
was dissolved in CHCl3 and reconcentrated three times and
purified by a silica gel column chromatography (n-hexane/acetone
4.2.7. Reduction of 3,4-dihydro-
b-carboline (5). To a solution of
dihydro- -carboline 5 (224 mg, 0.37 mmol) in DMF (3.8 ml) was
b
added HCO2HeEt3N (0.19 ml, 5:2 v/v), degassed with Ar gas,
added (S,S)-TsDPEN-Ru(II) (8.9 mg, 0.015 mmol, 4.1 mol %)
and stirred for 13 h. The reaction mixture was added 5% NaHCO3
aq (80 ml), extracted with AcOEt (80 ml) and washed H2O
(2ꢂ80 ml) and brine (80 ml). The organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. The mixture was
purified by a silica gel column chromatography (CHCl3/AcOEt
40:1/30:1/20:1/10:1/ 5:1) to yield (1R)-tetrahydro-b-car-
boline 14 (215 mg, 0.35 mmol, 96%) as a red amorphous solid; Mp
7:1/4:1/2:1/1:1/1:2) to yield N-Fmoc-N-methyl-Phe
8
79e81 ꢀC; ½a 2D4
ꢃ þ25.6 (c 0.5, acetone), IR (film) nmax 3321, 3023,
(826 mg, 2.06 mmol, 85%, 2 steps) as a white powder; Mp
137e138 ꢀC; 1H NMR (400 MHz, CDCl3) (isomer I) dH 7.76e6.95
(13H, m), 4.88 (1H, br q) 4.36 (2H, br m) 4.21 (1H, br s), 3.39 (1H, br
d), 3.14 (1H, br t), 2.80 (3H, d, J¼3.2 Hz); (isomer II) dH 7.76e6.95
(13H, m), 4.56 (2H, m), 4.36 (2H, br m), 4.16 (1H, br s), 3.14 (1H, br t),
2.78 (3H, s).
2925, and 1678 cmꢁ1; 1H NMR (400 MHz, CDCl3) dH 9.02 (1H, br s),
7.73e7.18 (16H, m), 4.95 (1H, br s), 4.33 (2H, m), 4.08 (2H, m), 3.41
(1H, br d), 3.21(1H, m) 3.01 (2H, m) 2.85 (3H, s), 2.79 (1H, over-
lapping), 2.72 (1H, m); 13C NMR(100 MHz, CDCl3) dC 157.81, 143.92,
143.71, 141.30, 137.81, 136.97, 128.85, 128.78, 128.68, 127.69, 127.18,
126.92, 126.46, 125.10, 124.98, 122.43, 121.14, 119.98, 119.87, 119.17,
114.97, 114.21, 110.27, 67.81, 57.33, 47.06, 43.59, 35.04, 22.22; ESIMS
m/z 606 and 608 ([MþH]þ, 1:1); HRMS (ESIþ) C35H33O2N3Brþ
([MþH]þ) requires 606.1751; found 606.1747.
4.2.5. Amidation of 6-bromotryptamine (7) and N-Fmoc-N-methyl-
Phe (8). To a solution of amine 7 (100 mg, 0.42 mmol) and N-Fmoc-
N-methyl-Phe 8 (173 mg, 0.43 mmol) in CH2Cl2 (4.5 ml) at 0 ꢀC was
added HOBt$H2O (66 mg, 0.43 mmol) and EDC$HCl (82 mg,
0.43 mmol). The reaction mixture was stirred at room temperature
for 2 h. The mixture was concentrated in vacuo, diluted with CHCl3
(5 ml), and washed with 5% HCl aq (3ꢂ5 ml), 5% NaHCO3 aq (5 ml),
water (5 ml), and brine (5 ml). The organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. The mixture was puri-
4.2.8. N-Methylation of (1R)-tetrahydro-
tion of (1R)-tetrahydro- -carboline 14 (49 mg, 0.081 mmol) in
MeCN (1.7 ml) at -40 ꢀC was slowly added 37% HCHO (44
l,
b-carboline (14). To a solu-
b
m
0.59 mmol) and NaBH3CN (42 mg, 0.67 mmol). The reaction mix-
ture was stirred for 1 h at ꢁ40 ꢀC, quenched 5% NaHCO3 aq (10 ml)
and extracted AcOEt (10 ml). The organic layer was washed
5% NaHCO3 (10 ml) and brine (10 ml), dried over Na2SO4, and
concentrated in vacuo. The mixture was purified by a silica gel
column chromatography (CHCl3/MeOH 200:1/170:1/150:1) to
fied by
a silica gel column chromatography (CHCl3/MeOH
100:1/80:1/60:1) to yield to yield amide 6 (214 mg, 0.34 mmol,
82%) as a red amorphous solid; Mp 61e63 ꢀC; ½a D23
ꢃ
ꢁ38.5 (c 0.5, ac-
etone), IR (KBr) nmax 3416, 2925, 2853, and 1670 cmꢁ1
;
1H NMR
yield N-methyl-tetrahydro-b-carboline 15 (48 mg, 0.076 mmol,
(400 MHz, CDCl3) dH 8.07 (1H, br s), 7.79e6.65 (17H, m), 6.04 (1H, br
s), 4.84 (1H, t, J¼9.2 Hz), 4.63 (1H, br s), 4.49 (1H, m), 4.38 (1H, m),
4.14 (2H, m) 4.08 (1H, br s), 3.95 (1H, t, J¼7.9 Hz) 3.51 (2H, q,
J¼6.4 Hz), 3.33 (2H, q, J¼6.9 Hz), 3.06e2.82 (3H, m), 2.74 (3H, s), 2.68
(3H, s); 13C NMR(100 MHz, CDCl3) dC 171.22, 169.19, 157.14, 155.46,
143.98, 143.81, 143.66, 141.38, 141.35, 141.34, 137.31, 137.27, 137.14,
136.88, 129.05, 128.84, 128.66, 128.59, 127.93, 127.69, 127.58, 127.21,
127.18, 126.81, 126.59, 126.29, 126.20, 125.14, 124.97, 124.37, 124.04,
123.02, 122.81, 122.72, 122.67, 120.17, 120.09, 119.99, 119.92, 115.76,
115.66,114.35,114.23,112.89,112.81, 67.91, 66.68, 60.30, 59.13, 47.09,
95%) as a pale yellow amorphous solid; Mp 120e122 ꢀC; ½a D24
ꢃ þ50.5
(c 0.5, acetone), IR (film) nmax 3329, 3063, 3020,2928, 2850,
2801,1671 cmꢁ1 1H NMR (400 MHz, CDCl3) dH 9.07 (1H, br s),
;
7.80e7.09 (16H, m), 6.63 (1H, br s), 4.89 (1H, br s), 4.43 (1H, m), 4.27
(1H, br s), 3.94 (1H, br s), 3.18 (1H, m), 2.93 (1H, m), 2.65e2.49 (8H,
overlapping), 1.94 (1H, br s); 13C NMR (100 MHz, CDCl3) dC 156.03,
143.99, 141.25, 136.43, 128.74, 128.56, 128.37, 127.63, 126.95, 126.29,
126.18, 125.91, 125.06, 124.67, 122.16, 119.90, 119.21, 114.82, 113.89,
108.59, 67.13, 63.18, 60.07, 47.34, 47.12, 46.55, 42.26, 41.18, 38.66,
36.01, 35.53, 17.35; ESIMS m/z 620 and 622 ([MþH]þ, 1:1); HRMS

H. Ishiyama et al. / Tetrahedron 68 (2012) 6186e6192
6191
(ESIþ) C36H35O2N379Brþ ([MþH]þ) requires 620.1907; found
1.89 mmol, 76%) as a red solid; Mp 195e196 ꢀC; 1H NMR (500 MHz,
DMSO-d6) dH 12.3 (1H, br s), 8.38 (1H, d, J¼13.2 Hz), 8.26(1H, s), 8.22
(1H, d, J¼1.7 Hz), 7.47 (1H, d, J¼8.6 Hz), 7.38 (1H, dd, J¼8.6, 1.8 Hz).
620.1914.
4.2.9. Synthesis of eudistomidin G (1). To a solution of (1R)-N-
methyl-tetrahydro-
(2.5 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8
b
-carboline 15 (30 mg, 0.048 mmol) in CH2Cl2
l,
4.2.13. 5-Bromotryptamine (19). THF (2.7 ml) at 0 ꢀC was added
NaBH4 (61 mg, 1.61 mmol) and BF3$OEt2 (260 ml, 2.07 mmol) and
m
0.054 mmol) and stirred for 30 min at room temperature. The re-
action mixture was purified by a silica gel column chromatography
(CHCl3/MeOH 100:1/70:1/50:1) to yield eudistomidin G (1)
(13 mg, 0.033 mmol, 68%) as a pale yellow amorphous solid; Mp
stirred for 15 min at room temperature. The mixture was added
dropwise nitroolefin 18 (45 mg, 0.17 mmol) in THF (0.5 ml) and
reflux for 2 h. The reaction mixture was slowly quenched with ice,
acidified with 1 N HCl aq, and heated for 2 h at 85 ꢀC. The aqueous
layer was washed with Et2O (2ꢂ10 ml), made basic with 2 N NaOH
aq, added solid NaCl and extracted with Et2O (3ꢂ10 ml). The or-
ganic layer was dried over Na2SO4 and concentrated in vacuo to
yield amine 19 (33 mg, 0.14 mmol, 82%) as an amber oil; 1H NMR
(500 MHz, CDCl3) dH 8.16 (1H, br s), 7.73 (1H, s), 7.27 (2H, d,
J¼9.2 Hz), 7.23 (1H, d, J¼8.6 Hz), 7.05 (1H, s), 3.01 (2H, t, J¼6.9 Hz),
2.86 (2H, t, J¼6.3 Hz).
43e45 ꢀC; ½a 2D4
ꢃ
þ49.3 (c 0.2, MeOH), IR (film) nmax 3322, 3048,
2921,2852, and 1432 cmꢁ1; UV (MeOH) lmax 204 (
3
12,791), 230
(16,980), 286 (3657), 296 (3084), 364 (492) nm; CD (MeOH) lect 214
(D
3
ꢁ7.1), 231 (þ16.3) nm; 1H NMR (600 MHz, CDCl3); dH 11.12 (1H, s),
7.73 (1H), 7.71 (1H), 7.26 (1H), 7.24 (1H), 7.13 (1H), 7.05 (2H), 6.60
(2H), 5.05 (1H), 3.94 (1H), 3.24 (2H), 3.05 (1H), 2.89 (4H), 2.81 (3H),
2.43 (1H); 13C NMR (150 MHz, CDCl3) dC 137.59, 134.30, 128.85,
128.50,127.73, 123.89, 123.73, 122.10, 119.49, 117.48, 115.33, 106.00,
64.30, 63.87, 45.43, 39.73, 33.19, 32.64,15.03; ESIMS m/z 398 and 400
([MþH]þ, 1:1); HRMS (ESIþ) C21H25N379Brþ ([MþH]þ) requires
398.1226; found 398.1222.
4.2.14. Amidation of 5-bromotryptamine (19) and N-Fmoc-N-
methyl-Phe (8). To a solution of amine 19 (86 mg, 0.36 mmol) and
N-Fmoc-N-methyl-Phe 8 (144 mg, 0.43 mmol) in CH2Cl2 (3.9 ml) at
0 ꢀC was added HOBt$H2O (60 mg, 0.39 mmol) and EDC$HCl (74 mg,
0.39 mmol). The reaction mixture was stirred at room temperature
for 2 h. The mixture was concentrated in vacuo, diluted with CHCl3
(5 ml), and washed with 5% HCl aq (3ꢂ5 ml), 5% NaHCO3 aq (5 ml),
water (5 ml), and brine (5 ml). The organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. The mixture was pu-
4.2.10. Synthesis of eudistomidin H (2). To a solution of eudisto-
midin G (1) (13 mg, 0.033 mmol, 63%) in benzene (1 ml) was added
75% paraformaldehyde (2.3 mg) and refluxed for 1 h. The reaction
mixture was concentrated in vacuo and purified by a silica gel
column chromatography (n-hexane/AcOEt 10:1/8:1/5:1) to
yield eudistomidin H (2) (8.5 mg, 0.021 mmol, 65%) as a pale yellow
rified by
a silica gel column chromatography (CHCl3/MeOH
amorphous solid; Mp 53e55 ꢀC; ½a D24
ꢃ
þ61.3 (c 0.5, acetone), UV
100:1/80:1/60:1) to yield to yield amide 20 (165 mg, 0.27 mmol,
(MeOH) lmax 204 (
3
29,545), 237 (27,381), and 289 (7205) nm; CD
74%) as a yellow amorphous solid; Mp 49e52 ꢀC; ½a D23
ꢃ
ꢁ30.3 (c 0.5,
(MeOH) lect 218 (
D
3
ꢁ7.5), 243 (þ31.0), and 298 (ꢁ2.1) nm; IR (film)
acetone), IR (film) nmax 3318, 3015, 2931, and 1684 cmꢁ1 1H NMR
;
nmax 2940, 2847, 2784, and 1460 cmꢁ1; IR (film) vmax 2940, 2847,
2784 and 1460 cmꢁ1; 1H NMR (600 MHz, acetone-d6) dH 7.49 (1H, d,
J¼1.5), 7.34 (1H, d, J¼8.4 Hz), 7.23 (2H, d, J¼7.4 Hz), 7.19 (2H, m), 7.14
(1H, dd, J¼8.2,1.9 Hz), 7.11 (1H, m), 4.92 (1H, d, J¼10.8 Hz), 4.80 (1H,
d, J¼11.1 Hz), 3.65 (1H, m), 3.56 (1H, m), 3.10 (1H, dd, 11.5, 5.6 Hz),
2.85 (2H, overlapping), 2.69 (1H, s), 2.65 (1H, m), 2.56 (1H, m), 2.35
(1H, s), 2.17 (1H, dd, J¼15.3, 10.8 Hz); 13C NMR (150 MHz, acetone-
d6) dC 141.7, 139.0, 135.9, 130.1, 129.1, 128.5, 126.7, 123.4, 120.5, 114.4,
114.2, 108.3, 61.9, 61.6, 59.2, 55.3, 42.8, 42.8, 31.0, 22.4; ESIMS m/z
410 and 412 ([MþH]þ, 1:1); HRMS (ESIþ) C22H25N379Brþ ([MþH]þ)
requires 410.1226; found 410.1226.
(400 MHz, CDCl3) dH 8.13 (1H, br s), 7.81e6.65 (17H, m), 6.04 (1H,
m), 4.84 (1H, m), 4.58 (1H, m), 4.50 (1H, m), 4.34 (1H, m), 4.13 (2H,
m) 4.02 (1H, m), 3.91 (1H,m), 3.53 (2H, q, J¼6.4 Hz), 3.32 (2H, m),
3.06e2.70 (3H, m), 2.76 (3H, s), 2.67 (3H, s); 13C NMR (100 MHz,
CDCl3) dC 170.24, 169.19, 157.21, 155.53, 144.08, 144.03, 144.00,
143.81, 143.71, 141.44, 141.23, 137.38, 136.91, 135.13, 134.98, 130.57,
129.14, 128.99, 128.87, 128.80, 128.70, 128.62, 127.99, 127.84, 127.60,
127.27, 127.22, 126.83, 126.60, 125.23, 125.16, 125.07, 124.38, 123.99,
123.88, 123.40, 121.50, 121.34, 120.21, 120.17, 112.94, 112.87, 112.82,
112.78, 112.49, 112.42, 68.00, 66.74, 60.35, 58.97, 47.15, 39.61, 39.50,
34.28, 33.97, 30.52, 29.67, 25.06, 24.70; ESIMS m/z 644 and 646
([MþNa]þ, 1:1); HRMS (ESIþ) C35H32O3N379BrNaþ ([MþNa]þ) re-
quires 644.1519; found 644.1532.
4.2.11. 5-Bromoindole-3-carboxaldehyde (17). DMF (3 ml) at 0 ꢀC
was added POCl3 (440 m
l, 4.72 mmol) and stirred for 30 min at 0 ꢀC.
The mixture was added dropwise 5-bromoindole 16 (500 mg,
2.55 mmol) in DMF (2 ml) and stirred for 30 min at room tem-
perature, giving an orange paste. The reaction mixture was added
iceewater mixture (30 g), neutralized with 2 N NaOH aq, and
stirred for 2 h at room temperature. The mixture was extracted
with AcOEt (80 ml) and washed with water (80 ml) and brine
(80 ml). The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo to yield 5-bromo-3-carboxaldehyde 17
(562 mg, 2.51 mmol, 98%) as a yellow solid; Mp 207e208 ꢀC; 1H
NMR (400 MHz, acetone-d6) dH 11.3 (1H, br s), 10.0 (1H, s), 8.38 (1H,
d, J¼1.8 Hz), 8.27 (1H, d, J¼3.2 Hz), 7.53 (1H, d, J¼9.2 Hz), 7.41 (1H,
dd, J¼8.7, 1.8 Hz).
4.2.15. Cyclization of amide (20). To a solution of amide 20 (449 mg,
0.72 mmol) in benzene (18 ml) was added POCl3 (0.47 ml,
5.04 mmol) and refluxed for 2 h. The reaction mixture was diluted
with AcOEt (30 ml), washed with 5% NaHCO3 (30 ml), water (30 ml),
and brine (30 ml), dried over Na2SO4, filtered, and concentrated in
vacuo. The mixture was purified by a silica gel column chroma-
tography (CHCl3/AcOEt 50:1/40:1/30:1) to yield dihydro-b-car-
boline 21 (333 mg, 0.55 mmol, 76%) as a yellow amorphous solid;
Mp 52e54 ꢀC; ½a 2D1
ꢃ ꢁ0.76 (c 0.5, acetone), IR (KBr) nmax 3280, 3063,
3025, 2947, and 1669 cmꢁ1; 1H NMR (400 MHz, CDCl3) dH 9.98 (1H,
s), 7.74e7.16 (16H, m), 5.71 (1H, m), 4.57 (1H, m), 4.14 (3H, over-
lapping), 3.90 (1H, m), 3.31 (2H, m), 2.86 (2H, m), 2.80 (3H, s); 13C
NMR (100 MHz, CDCl3) dC 158.28, 157.57, 143.98, 143.35, 141.41,
141.30, 137.72, 135.16, 129.34, 129.01, 128.76, 128.71, 127.90, 127.85,
127.39, 127.20, 127.16, 126.85, 125.20, 124.91, 122.39, 120.13, 120.10,
115.92, 114.16, 113.34, 68.37, 56.89, 48.80, 47.18, 33.54, 28.39, 19.12;
ESIMS m/z 604 and 606 ([MþH]þ, 1:1); HRMS (ESIþ)
C35H31O2N379Brþ ([MþH]þ) requires 604.1594; found 604.1598.
4.2.12. 5-Bromo-3-(2-nitroethyl)indole (18). To a solution of 5-
bromoindole-3-carboxaldehyde 17 (560 mg, 2.51 mmol) and
AcONH4 (208 mg, 2.70 mmol) in nitromethane (6.7 ml) was
refluxed for 1.5 h. After cooling to room temperature, this solution
was added water (60 ml) and extracted with AcOEt (60 ml). The
organic layer was washed with water (2ꢂ60 ml) and brine (60 ml),
dried over Na2SO4, and concentrated in vacuo. The mixture was
recrystallized from MeOH to yield nitroolefin 18 (562 mg,
4.2.16. Reduction of 3,4-dihydro-b-carboline (21). To a solution of
dihydro- -carboline 21 (152 mg, 0.25 mmol) in DMF (2.5 ml) was
b

6192
H. Ishiyama et al. / Tetrahedron 68 (2012) 6186e6192
added HCO2H-Et3N (0.13 ml, 5:2 v/v), degassed with Ar gas, added
(S,S)-TsDPEN-Ru(II) (7.6 mg, 0.013 mmol, 5.0 mol %) and stirred for
18h. The reactionmixturewasadded5%NaHCO3 aq(20 ml), extracted
with AcOEt (20 ml) and washed H2O (2ꢂ20 ml) and brine (20 ml). The
organic layer was dried over Na2SO4, filtered, and concentrated in
vacuo. The mixture was purified by a silica gel column chromatogra-
phy (CHCl3/MeOH 200:1/150:1/100:1/80:1/60:1) to yield
paraformaldehyde (7.3 mg) and refluxed for 1 h. The reaction
mixture was concentrated in vacuo and purified by a silica gel
column chromatography (n-hexane/AcOEt 10:1/8:1/5:1) to
yield eudistomidin I (3) (42 mg, 0.10 mmol, 71%) as a pale yellow
amorphous solid; Mp 52e54 ꢀC; ½a D24
ꢃ ꢁ5.2 (c 0.5, acetone), UV
(MeOH) lmax 204 (
(MeOH) lect 224.0 (
3
29,545), 237 (27,381), and 289 (7205) nm; CD
D
3 ꢁ15.7), 246.0 (þ26.3), and 297.0 (-2.0) nm; IR
(1R)-tetrahydro-
b
-carboline 22 (124 mg, 0.20 mmol, 82%) as a red
(film) nmax 2940, 2847, 2784, and 1460 cmꢁ1; IR (film) nmax 2940,
2847, 2784 and 1460 cmꢁ1; 1H NMR (600 MHz, acetone-d6) dH 7.59
(1H, d, J¼1.8 Hz), 7.29 (1H, d, J¼8.8 Hz), 7.26 (2H, d, J¼3.3 Hz), 7.24
(2H, m), 7.20 (1H, dd, J¼8.5, 2.0 Hz), 7.14 (1H, m), 4.95 (1H, d,
J¼10.7 Hz), 4.81 (1H, d, J¼10.7 Hz), 3.69 (1H, m), 3.62 (1H, m), 3.14
(1H, dd, J¼11.5, 5.6 Hz), 2.89 (1H, overlapping), 2.88 (1H, over-
lapping), 2.73 (3H, s), 2.70 (1H, m), 2.60 (1H, m), 2.38 (3H, s), 2.18
(1H, dd, J¼15.2, 10.4 Hz); 13C NMR(150 MHz, acetone-d6) dC 141.6,
136.8, 136.5, 131.3, 130.0, 129.0, 126.6, 123.9, 121.5, 113.4, 112.8,
107.9, 61.9, 61.4, 59.2, 55.2, 42.7, 42.7, 30.9, 22.3; ESIMS m/z 410 and
412 ([MþH]þ, 1:1); HRMS (ESIþ) C22H25N379Brþ ([MþH]þ) requires
410.1226; found 410.1228.
amorphous solid; Mp 91e93 ꢀC; ½a D24
ꢃ
ꢁ9.6 (c 0.5, acetone), IR (film)
nmax 3328, 3063, 3023, 2925, and 1678 cmꢁ1
;
1H NMR (400 MHz,
CDCl3)dH 9.01(1H, brs), 7.73e7.13(16H, m), 4.99(1H, brs), 4.37(1H, br
s), 4.26 (1H, m), 4.09 (2H, m), 3.41 (1H, brd), 3.23(1H, m), 3.05(2H, m)
2.87 (3H, s), 2.68 (1H, overlapping), 2.45 (1H, m); 13C NMR (100 MHz,
CDCl3) dC 157.86, 143.88, 143.73, 141.30, 141.26, 137.83, 134.98, 134.81,
129.38, 128.87, 128.83, 127.74, 127.69, 127.08, 126.97, 125.07, 124.97,
124.30,120.65,119.99,112.66,112.54,109.93, 67.85, 57.47, 47.02, 43.82,
35.01, 22.28; ESIMS m/z 606 and 608 ([MþH]þ, 1:1); HRMS (ESIþ)
C35H33O2N379Brþ ([MþH]þ) requires 606.1751; found 606. 1763.
4.2.17. N-Methylation of (1R)-tetrahydro-b-carboline (22). To a so-
lution of (1R)-tetrahydro-b-carboline 22 (113 mg, 0.18 mmol) in
MeCN (3.8 ml) at ꢁ40 ꢀC was slowly added 37% HCHO (100
ml,
Acknowledgements
1.34 mmol) and NaBH3CN (96 mg,1.52 mmol). The reaction mixture
was stirred for 2 h at ꢁ40 ꢀC, quenched 5% NaHCO3 aq (20 ml) and
extracted AcOEt (20 ml). The organic layer was washed 5% NaHCO3
(20 ml), and brine (20 ml), dried over Na2SO4, and concentrated in
vacuo. The mixture was purified by a silica gel column chroma-
tography (CHCl3/MeOH 200:1/170:1/150:1) to yield N-methyl-
We thank S. Oka, Center for Instrumental Analysis, Hokkaido
University, for ESIMS measurements. This work was partly sup-
ported by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports, and Culture of Japan.
tetrahydro-b-carboline 23 (100 mg, 0.16 mmol, 87%) as a pale yel-
low amorphous solid; Mp 140e141 ꢀC; ½a D19
ꢃ ꢁ16.8 (c 0.5, CHCl3),
IR (film) nmax 3280, 3062, 3025,2925, 2851, and 1677 cmꢁ1; 1H NMR
(600 MHz, CDCl3) dH 9.08 (1H, br s), 7.79e7.08 (16H, m), 6.63 (1H, br
s), 4.89 (1H, br s), 4.43 (1H, m), 4.27 (1H, br s), 3.97 (1H, br s), 3.17
(1H, m), 2.95 (1H, m), 2.64e2.49 (8H, overlapping), 1.95 (1H, br s);
13C NMR(100 MHz, CDCl3) dC 156.27, 144.16, 141.48, 134.53,
129.01, 128.80, 128.62, 128.15, 127.88, 127.20, 126.54, 125.28, 124.99,
124.91, 124.67, 124.37, 121.15, 120.92, 120.14, 112.57, 112.44, 108.36,
67.37, 63.45, 60.34, 47.59, 47.34, 46.76, 42.50, 41.39, 41.34, 36.27,
35.77, 17.59; ESIMS m/z 620 and 622 ([MþH]þ, 1:1); HRMS (ESIþ)
C36H35O2N379Brþ ([MþH]þ) requires 620.1907; found 620.1914.
References and notes
1. Takahashi, Y.; Ishiyama, H.; Kubota, T.; Kobayashi, J. Bioorg. Med. Chem. Lett.
2010, 20, 4100e4103.
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as follows. The relative stereochemistry of compound 2 was assigned from
NOESY spectral data and 1H NMR coupling constant. Since the stereochemistry
at C-10 in 2 was S, the absolute stereochemistry at C-1 was deduced to be R
configuration.
7. Bischler, A.; Napieralski, B. Chem. Ber. 1893, 26, 1891e1903.
8. Liu, J.-J.; Hino, T.; Tsuruoka, A.; Harada, N.; Nakagawa, M. J. Chem. Soc., Perkin
Trans. 1 2000, 3487e3494.
4.2.18. Synthesis of eudistomidin B (4). To a solution of (1R)-N-
methyl-tetrahydro-
(8 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (24
b
-carboline 23 (95 mg, 0.15 mmol) in CH2Cl2
l,
m
0.16 mmol) and stirred for 30 min at room temperature. The re-
action mixture was purified by a silica gel column chromatography
(CHCl3/MeOH 100:1/70:1/50:1) to yield eudistomidin B (4)
(56 mg, 0.14 mmol, 87%) as a pale yellow amorphous solid. Spectral
data see Ref. 1.
9. Brogan, J. T.; Stoops, S. L.; Crew, B. C.; Marnett, L. J.; Linsley, C. W. ACS Chem.
Neurosci. 2011, 2, 633e639.
10. Freidinger, R. M.; Hinkle, J. S.; Perlow, D. S.; Arison, B. H. J. Org. Chem. 1983, 48,
77e81.
11. Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D.
J. J. Am. Chem. Soc. 2009, 131, 10796e10797.
12. Schumacher, R. W.; Davidson, B. S. Tetrahedron 1999, 55, 935e942.
13. Treatment of 18 with LiAlH4 provided complex mixture including tryptamine.
4.2.19. Synthesis of eudistomidin I (3). To a solution of eudistomidin
B (4) (57 mg, 0.14 mmol) in benzene (1 ml) was added 75%