Concise synthesis of (±)-aurantioclavine through a base-promoted Pictet-Spengler reaction

Article abstract of DOI:10.1002/ejoc.200900742

A concise total synthesis of (±)-aurantioclavine (1) was completed in three steps through the base-promoted Pictet-Spengler reaction of N _b-benzylserotonin with 3-methylbut2-enal.

Full text of DOI:10.1002/ejoc.200900742

FULL PAPER
DOI: 10.1002/ejoc.200900742
Concise Synthesis of (؎)-Aurantioclavine through a Base-Promoted
Pictet–Spengler Reaction
Koji Yamada,[a] Yuichi Namerikawa,[a] Tomohiro Haruyama,[a] Yoshihisa Miwa,[b]
Reiko Yanada,[b] and Minoru Ishikura*[a]
Keywords: Alkaloids / Natural products / Nitrogen heterocycles / Cyclization
A concise total synthesis of (Ϯ)-aurantioclavine (1) was com-
pleted in three steps through the base-promoted Pictet–
Spengler reaction of Nb-benzylserotonin with 3-methylbut-
2-enal.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
us to devise a straightforward strategy for the synthesis of
azepinoindole alkaloids (Scheme 1). Our synthetic route to
(Ϯ)-1 involves the one-pot assembly of azepinoindole 6a
from 4 and 3-methylbut-2-enal (5) as the key step and the
subsequent removal of the OH group at the 7-position and
the Nb-benzyl (Bn) group at the 5-position (Scheme 1). This
paper describes a novel and concise total synthesis of (Ϯ)-
aurantioclavine (1) and expands upon our previous com-
munication.[7]
Introduction
Aurantioclavine (1),[1] clavicipitic acid (2),[2] and hyrti-
azepine (3)[3] (Figure 1) are members of a unique class of
indole alkaloids characterized by a novel azepino[5,4,3-cd]-
indole ring system. (–)-Aurantioclavine (1) was first isolated
in 1981 from Penicillium aurantiovirens,[1] and the absolute
configuration was confirmed to be (R) in 2008.[4]
Figure 1. Azepinoindole alkaloids.
Previously, two racemic[5] syntheses and one enantiose-
lective[4] synthesis of 1 were achieved in multiple steps
through the preparation of properly functionalized 3,4-di-
substituted indoles, with subsequent ring closure to form
the azepane ring. In the context of our interest in indole
alkaloid synthesis,[6] we developed a novel one-pot pro-
cedure for the assembly of the azepino[5,4,3-cd]indole ring
system through the base-promoted Pictet–Spengler reaction
of Nb-benzylserotonin (4) with aldehydes.[7] This prompted
Scheme 1.
Results and Discussion
Although the Pictet–Spengler reaction has been exten-
sively investigated,[8] the one-pot construction of the azepi-
noindole moiety is a remarkable finding for this reaction.
The study was initially undertaken to probe the conditions
for the reaction of 4 with various α,β-unsaturated alde-
hydes. Initial treatment of 4 with acrolein (7a; 3 equiv.) in
the presence of Et3N in MeOH at room temperature for
24 h under a nitrogen atmosphere resulted in the addition
of MeOH to afford azepinoindole 8a in 41% yield
[a] Faculty of Pharmaceutical Sciences, Health Sciences University
of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan
Fax: +81-133-23-1245
E-mail: ishikura@hoku-iryo-u.ac.jp
[b] Faculty of Pharmaceutical Sciences, Hiroshima International
University,
5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
5752
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5752–5759

Alkaloid Synthesis through a Base-Promoted Pictet–Spengler Reaction
(Scheme 2). The yield was increased slightly to 55% by 12b in 53% yield along with pyranoindole 13 in 14% yield.
heating the reaction mixture at reflux for 3 h. The reaction Under reflux for 20 min, the reaction afforded 12b in 69%
proceeded similarly in the case of crotonaldehyde (7b) at yield and 13 in 11% yield (Scheme 3).
room temperature for 24 h, and MeOH adduct 8b was ob-
Azepinoindoles 12 were likely precursors of 13 and 14.
tained as a separable mixture of two diastereomers in 75% A series of ring-opening and ring-closing sequences trig-
yield. The production of 8 can conceivably occur through gered by the unprotected OH group in 12b likely account
the addition of MeOH to 7 and/or to iminium ion 9 fol- for the generation of 13 (Scheme 4). It is also possible that,
lowed by the cyclization of 10.
in boiling MeOH, 12a underwent this series of transforma-
tions accompanied by the Pictet–Spengler reaction with
11a, leading to 14.
Scheme 4.
Serious retardation of the reaction was observed in the
reaction with α-methyl-substituted aldehydes 15. Running
the reaction with methacrolein (15a) at room temperature
for 7 d resulted in the isolation of 16 in 10% yield and 17
in 16% yield along with the recovery of unreacted 4 in 30%
yield (Scheme 5). The formation of 17 can be explained by
the reaction of 4 with propionaldehyde generated from 15a
and H2O in situ. Heating 4 at reflux with 2-methyl-2-but-
enal (15b) and α-methylcinnamaldehyde (15c) for 5 d re-
sulted in the isolation of 18a and 18b in 22 and 50% yield,
respectively.
Scheme 2.
Under the same conditions, carrying out the reaction
The successful formation of azepinoindoles in one pot
with cinnamaldehyde (11a) at room temperature for 6 h prompted us to extend the reaction to the synthesis of (Ϯ)-
provided 12a in 84% yield without the formation of MeOH aurantioclavine (1). Similarly, the reaction of 4 with 3-meth-
adduct, whereas pyranocarboline 14 was obtained as an in- ylbut-2-enal (5) (3 equiv.) was first conducted in the pres-
separable mixture of two diastereomers in 80% yield by re- ence of Et3N in MeOH at room temperature for 10 h
fluxing for 24 h. On the other hand, the reaction with 4- (Scheme 6). The separation of the reaction mixture by silica
nitrocinnamaldehyde (11b) was more facile; the reaction gel column chromatography resulted in the isolation of two
was complete within 1 h at room temperature, producing products, azepinoindole 6a and pyranoindole 19, in an al-
Scheme 3.
Eur. J. Org. Chem. 2009, 5752–5759
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M. Ishikura et al.
FULL PAPER
Table 1. Reaction of 4 with 5 in Et3N/MeOH (1:1).[a]
Entry Conditions
Yield [%][b]
6
19
1
2
3
4
r.t./10 h
reflux/0.5 h
34 (6a: R = H) 35
–
62
–
r.t./10 h, then AcCl/Et3N/DMAP/CH2Cl2 58 (6b: R = Ac)
r.t./10 h, then Tf2O/Et3N/CH2Cl2 60 (6c: R = Tf)
–
[a] Compounds 4 and 5 (3 equiv.) in Et3N/MeOH (1:1). [b] Isolated
yield based on 4.
Scheme 5.
Scheme 7.
most 1:1 ratio (Table 1, Entry 1). Because the TLC of the
reaction mixture showed only a single spot that was attrib-
utable to 6a, 19 was possibly formed from 6a during silica
gel chromatography. When conducting the reaction in re-
fluxing MeOH, 6a was not formed and only 19 was ob-
served on the TLC plate of the reaction mixture; 19 was
then isolated in 62% yield after column chromatography
(Table 1, Entry 2). After conducting the reaction at room
temperature for 10 h, the mixture was immediately evapo-
rated under reduced pressure and then treated with AcCl/
Et3N in CH2Cl2 or Tf2O/Et3N in CH2Cl2, giving rise to the
isolation of 6b and 6c in 58 and 60% yield, respectively,
without the formation of 19 (Table 1, Entries 3 and 4).[7]
To evaluate the feasibility of the process, the reaction was
carried out with the use of dibenzylamine and 5 (3 equiv.)
under the same conditions, leading to the isolation of 22 in
51% yield (Scheme 8).
Scheme 8.
1
The structure of 21 was determined on the basis of H
NMR NOESY experiments, in which no NOE correlation
between Ha (δ = 2.17 ppm) and Hb (δ = 3.88 ppm) was ob-
served. The assignment was further confirmed by compari-
son with 22 (Figure 2). Moreover, conversion of 22 into hy-
drazone 23 permitted the unequivocal structural confirm-
ation of 23 by X-ray crystal structure analysis,[9] whereas
Scheme 6.
In contrast, an alternative reaction outcome was the re- formation of hydrazone of 21 was not successful due to its
sult of using pyridine as the base; treatment of 4 with 5 instability under acidic conditions.
(3 equiv.) in pyridine/MeOH (1:1) at room temperature for
With azepinoindole 6c in hand, attention was then
10 h produced 21 in 80% yield (Scheme 7). The reaction shifted to selective removal of the OTf and N-Bn groups of
path accounting for the formation of 21 possibly involved 6c. Preliminary experiments revealed that a catalytic re-
a [4π+2π] cycloaddition between 5 and dienamine 20.
duction of 24 (derived from 4 and 3-methylbutanal followed
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Eur. J. Org. Chem. 2009, 5752–5759

Alkaloid Synthesis through a Base-Promoted Pictet–Spengler Reaction
Scheme 9.
phosphanylpropane (dppp) was performed,[12] producing 27
in low yield (Table 2, Entry 2). After several experiments,
(Ϯ)-aurantioclavine (1) was obtained in 35% yield by the
reduction of 6c with the use of HCO2NH4 (4 equiv.) in the
presence of 10% Pd-C[10] in MeOH at room temperature
for 30 min, along with 26 and 28 (Table 2, Entry 4).[13] Con-
version of 26 into 1 was also accomplished by heating with
formic acid in the presence of PdCl2(PPh3)2, dppp, and
Et3N in DMF at 100 °C for 2 h, giving (Ϯ)-1 in 43% yield.
Figure 2. Diagnostic NOE correlations of 21, 22, and 23.
by treatment with Tf2O in 69% yield) with 10% Pd-C[10] in
MeOH under atmospheric pressure of hydrogen was suc-
cessful in producing dihydroaurantioclavine 25 in 80% yield
(Scheme 9).[11]
Nevertheless, attempted reduction of 6c under similar
conditions proved to be problematic due to the suscep-
Conclusions
In summary, a concise total synthesis of (Ϯ)-aurantiocla-
tibility of the isobutenylamine moiety to the reduction con- vine (1) was completed in three steps from Nb-benzylseroto-
ditions (Scheme 10). This susceptibility resulted in the gen- nin (4). A base-promoted Pictet–Spengler reaction was the
eration of over-reduced product 28 (Table 2, Entry 1). Thus, key step of the synthesis. Further studies directed to the
Pd-catalyzed hydrogenolysis of 6c with HCO2H as a hy- synthesis of other azepinoindole alkaloids with the use of
dride source in the presence of PdCl2(PPh3)2 with diphenyl- this methodology are in progress.
Scheme 10.
Table 2. Conversion of 6c into (Ϯ)-aurantioclavine (1).
Entry
Conditions
Yield [%][a]
1
26
27
28
1
2
3
4
10% Pd-C[b]/H2 (1 atm)/MeOH/0.5 h
PdCl2(PPh3)2/dppp/HCO2H/Et3N/DMF/100 °C/7 h
10% Pd-C/HCO2NH4 (2 equiv.)/MeOH/r.t./0.5 h
10% Pd-C/HCO2NH4 (4 equiv.)/MeOH/r.t./0.5 h
–
–
9
–
–
21
18
–
22
–
90
–
2
35
–
28
[a] Isolated yield based on 6c. [b] 10% Pd-C (K-type) purchased from N.E. CHEMCAT Inc., Japan.
Eur. J. Org. Chem. 2009, 5752–5759
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M. Ishikura et al.
FULL PAPER
5-Benzyl-6-[(E)-2-phenylethenyl]-3,4,5,6-tetrahydro-1H-azepino-
[5,4,3-cd]indol-7-ol (12a): Yield: 128 mg (84%); pale-yellow oil. IR
Experimental Section
(CHCl ): ν = 3484 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.56
General: Melting points were recorded with a Yamato MP21 and
are uncorrected. MS and HRMS spectra were recorded with a
Micromass AutoSpec 3100 mass spectrometer. IR spectra were
measured with a Hitachi Model 270–30 spectrometer. The NMR
experiments were performed with a Jeol JNM-ECA500 (500 MHz)
spectrometer, and chemical shifts are expressed in ppm (δ) with
TMS as an internal reference. Column chromatography was per-
formed on silica gel (Silica Gel 60N, Kanto Chemical Co., Ltd.).
˜
3
(br. s, 1 H), 2.85 (dt, J = 16.6, 2.4 Hz, 1 H), 3.07 (ddd, J = 13.7,
3.2, 2.4 Hz, 1 H), 3.20 (ddd, J = 16.6, 13.7, 3.2 Hz, 1 H), 3.59 (td,
J = 13.7, 3.2 Hz, 1 H), 3.94 (d, J = 13.7 Hz, 1 H), 4.10 (d, J =
13.7 Hz, 1 H), 5.18 (d, J = 5.7 Hz, 1 H), 6.16 (d, J = 16.0 Hz, 1
H), 6.58 (dd, J = 16.0, 5.2 Hz, 1 H), 6.78 (d, J = 8.6 Hz, 1 H), 6.98
(s, 1 H), 7.19 (d, J = 8.6 Hz, 1 H), 7.24–7.27 (m, 5 H), 7.30–7.34
(m, 3 H), 7.41 (d, J = 7.4 Hz, 2 H), 7.96 (s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 26.4, 46.2, 56.6, 63.3, 110.2, 113.0, 115.5,
119.9, 121.9, 126.6, 126.9, 127.4, 128.3, 128.4, 128.8, 130.5, 131.6,
132.4, 136.9, 140.0, 146.3 ppm. HRMS (EI): calcd. for C26H24N2O
[M]+ 380.1889; found 380.1890.
General Procedure for the Reaction of Nb-Benzylserotonin 4 with
Aldehydes 7, 11, and 15 in the Presence of Et3N in MeOH: To a
solution of 4 (0.4 mmol) in Et3N (5 mL) and MeOH (5 mL) was
added aldehyde (7, 11, or 15; 1.2 mmol), and the mixture was
stirred at room temperature or heated under reflux. The mixture
was concentrated under reduced pressure, and the residue was sepa-
rated by column chromatography on SiO2 to give 8, 12, 16, 17, and
18 with AcOEt/hexane, 1:3; 14 with AcOEt/hexane, 1:9; or 13 with
CHCl3/MeOH/28% NH4OH, 46:3:0.3.
5-Benzyl-6-[(E)-2-(4-nitrophenyl)ethenyl]-3,4,5,6-tetrahydro-1H-azep-
ino[5,4,3-cd]indol-7-ol (12b): Yield: 90 mg (53%), after treatment at
room temperature for 1 h; 117 mg (69%), after heating under reflux
1
for 20 min; pale-yellow oil. IR (CHCl ): ν = 3484 cm–1. H NMR
˜
3
(500 MHz, CDCl3): δ = 1.56 (br. s, 1 H), 2.87 (dt, J = 15.0, 2.9 Hz,
1 H), 3.17 (dt, J = 14.2, 2.9 Hz, 1 H), 3.25 (ddd, J = 15.0, 14.2,
2.9 Hz, 1 H), 3.54 (td, J = 14.2, 2.9 Hz, 1 H), 3.94 (d, J = 13.6 Hz,
1 H), 4.09 (d, J = 13.6 Hz, 1 H), 4.27 (s, 1 H), 5.28 (d, J = 4.0 Hz,
1 H), 6.11 (d, J = 16.4 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H), 6.79
(dd, J = 16.4, 4.0 Hz, 1 H), 7.01 (s, 1 H), 7.21 (d, J = 8.5 Hz, 1 H),
7.34 (t, J = 7.1 Hz, 2 H), 7.39–7.43 (m, 4 H), 8.01 (s, 1 H), 8.10 (d,
J = 8.5 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 26.1,
46.8, 56.1, 62.8, 110.6, 112.6, 115.5, 119.2, 122.4, 123.9, 126.9,
127.1, 127.2, 128.5, 128.9, 129.1, 132.4, 137.2, 139.9, 143.9, 146.2,
146.7 ppm. HRMS (EI): calcd. for C26H23N3O3 [M]+ 425.1739;
found 425.1806.
5-Benzyl-6-(2-methoxyethyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]-
indol-7-ol (8a): Yield: 55 mg (41%), after treatment at room tem-
perature for 24 h; 74 mg (55%), after heating under reflux for 3 h;
yellow oil. IR (CHCl ): ν = 3480 cm–1 1H NMR (500 MHz,
.
˜
3
CDCl3): δ = 1.85 (m, 1 H), 2.33 (m, 1 H), 2.89 (dt, J = 16.0, 3.0 Hz,
1 H), 3.15 (m, 1 H), 3.27 (td, J = 14.4, 6.0 Hz, 1 H), 3.28 (s, 3 H),
3.43–3.50 (m, 2 H), 3.60 (ddd, J = 14.4, 11.8, 3.0 Hz, 1 H), 3.82
(d, J = 13.7 Hz, 1 H), 3.98 (d, J = 13.7 Hz, 1 H), 4.49 (t, J =
6.3 Hz, 1 H), 6.40 (s, 1 H), 6.78 (d, J = 8.6 Hz, 1 H), 6.93 (s, 1 H),
7.10 (d, J = 8.6 Hz, 1 H), 7.24 (t, J = 7.4 Hz, 1 H), 7.31 (t, J =
7.4 Hz, 2 H), 7.33 (d, J = 7.4 Hz, 2 H), 7.89 (s, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 25.3, 35.2, 45.0, 56.2, 57.1, 58.6,
70.6, 109.9, 113.4, 115.0, 121.5, 122.0, 125.8, 126.8, 128.1, 128.9,
131.8, 140.2, 147.0 ppm. HRMS (EI): calcd. for C21H24N2O2 [M]+
336.1838; found 336.1824.
N-Benzyl-2-[7-(4-nitrophenyl)-3,7-dihydropyrano[3,2-e]indol-1-yl]-
ethanamine (13): Yield: 23.8 mg (14 %), after treatment at room
temperature for 1 h; 18.7 mg (11%), after heating under reflux for
20 min; pale-yellow oil. IR (CHCl ): ν = 3485 cm–1 1H NMR
.
˜
3
5-Benzyl-6-(2-methoxypropyl)-3,4,5,6-tetrahydro-1H-azepino-
[5,4,3-cd]indol-7-ol (8b, Less Polar): Yield: 52.5 mg (37.5%); pale-
(500 MHz, CDCl3): δ = 1.89 (s, 1 H), 2.98 (t, J = 7.1 Hz, 2 H),
3.09 (t, J = 7.1 Hz, 2 H), 3.84 (s, 2 H), 5.83 (dd, J = 9.6, 4.0 Hz, 1
H), 5.89 (d, J = 4.0 Hz, 1 H), 6.77 (d, J = 8.5 Hz, 1 H), 7.00 (d, J
= 1.7 Hz, 1 H), 7.13 (d, J = 8.5b Hz, 1 H), 7.19 (d, J = 9.6 Hz, 1
H), 7.24 (m, 1 H), 7.30–7.35 (m, 4 H), 7.64 (d, J = 8.5 Hz, 2 H),
7.93 (s, 1 H), 8.19 (d, J = 8.5 Hz, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 27.7, 49.6, 53.9, 74.9, 112.2, 112.3, 113.4, 114.0, 122.2,
123.1, 123.4, 123.8, 124.2, 127.2, 127.6, 128.3, 128.5, 132.9, 146.9,
147.4, 147.7, 148.4 ppm. HRMS (EI): calcd. for C26H23N3O3 [M]+
425.1739; found 425.1740.
yellow oil. IR (CHCl ): ν = 3484 cm–1 1H NMR (500 MHz,
.
˜
3
CDCl3): δ = 1.10 (d, J = 5.7 Hz, 3 H), 1.41 (dd, J = 15.5, 10.9 Hz,
1 H), 2.24 (dd, J = 15.5, 8.6 Hz, 1 H), 2.92 (d, J = 16.6 Hz, 1 H),
3.03 (s, 3 H), 3.41–3.26 (m, 3 H), 3.68 (td, J = 13.7, 3.0 Hz, 1 H),
3.82 (d, J = 13.2 Hz, 1 H), 4.00 (d, J = 13.2 Hz, 1 H), 4.33 (d, J =
8.6 Hz, 1 H), 6.79 (d, J = 8.6 Hz, 1 H), 6.92 (br. s, 1 H), 7.05 (br.
s, 1 H), 7.10 (d, J = 8.6 Hz, 1 H), 7.24 (m, 1 H), 7.30–7.34 (m, 4
H), 7.87 (br. s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 18.6,
25.5, 43.8, 46.4, 55.7, 56.3, 56.7, 76.2, 109.7, 113.5, 114.9, 121.1,
122.4, 125.4, 126.9, 128.1, 129.4, 131.4, 140.4, 147.0 ppm. HRMS
(EI): calcd. for C22H26N2O2 [M]+ 350.1994; found 350.1973.
9-Benzyl-3-phenyl-8-[(E)-2-phenylethenyl]-3,7,8,9,10,11-hexahydro-
pyrano[3,2-e]pyrido[3,4-b]indole (14): Yield: 158 mg (80%); pale-yel-
low oil. IR (CHCl ): ν = 3464 cm–1. 1H NMR (500 MHz, CDCl ):
˜
3
3
5-Benzyl-6-(2-methoxypropyl)-3,4,5,6-tetrahydro-1H-azepino-
[5,4,3-cd]indol-7-ol (8b, More Polar): Yield: 52.5 mg (37.5%); color-
δ = 2.62 (dt, J = 19.5, 6.2 Hz, 1 H), 2.93–3.02 (m, 2 H), 3.20 (m,
1 H), 3.49 (dd, J = 13.7, 8.0 Hz, 1 H), 4.16 (dd, J = 13.7, 8.0 Hz,
1 H), 4.28 (d, J = 8.6 Hz, 1 H), 5.80–5.85 (m, 2 H), 6.35 (ddd, J =
15.8, 8.6, 2.0 Hz, 1 H), 6.68 (dd, J = 8.6, 1.7 Hz, 2 H), 6.72 (dd, J
= 15.8, 10.6 Hz, 2 H), 6.99 (dd, J = 8.6, 2.9 Hz, 1 H), 7.07 (d, J =
8.0 Hz, 1 H), 7.25–7.36 (m, 7 H), 7.42 (dd, J = 12.9, 7.7 Hz, 4 H),
7.50 (d, J = 7.4 Hz, 2 H), 7.56 (d, J = 3.4 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 23.6, 48.2, 58.6, 63.0, 76.4, 76.7, 108.32,
111.2, 111.5, 113.3, 122.1, 122.4, 123.5, 123.6, 123.7, 126.6, 127.0,
127.1, 128.1, 128.3, 128.5128.7, 129.7, 131.9, 133.9, 134.8, 136.1,
139.1, 141.1, 147.2 ppm. HRMS (EI): calcd. for C35H30N2O [M]+
494.2350; found 494.2358.
less crystals. M.p. 185–187 °C (CHCl /hexane). IR (CHCl ): ν =
˜
3
3
1
3484 cm–1. H NMR (500 MHz, CDCl3): δ = 1.21 (d, J = 5.7 Hz,
3 H), 1.84 (ddd, J = 14.0, 7.0, 6.7 Hz, 1 H), 2.27 (ddd, J = 14.0,
7.4, 6.0 Hz, 1 H), 2.87 (dt, J = 16.6, 2.9 Hz, 1 H), 3.09 (ddd, J =
14.9, 5.1, 2.9 Hz, 1 H), 3.22 (ddd, J = 16.6, 11.5, 4.6 Hz, 1 H), 3.32
(s, 3 H), 3.54–3.62 (m, 2 H), 3.79 (d, J = 13.7 Hz, 1 H), 3.96 (d, J
= 13.7 Hz, 1 H), 4.59 (dd, J = 7.4, 7.0 Hz, 1 H), 6.74 (d, J = 8.6 Hz,
1 H), 6.93 (s, 1 H), 7.09 (d, J = 8.6 Hz, 1 H), 7.23 (m, 1 H), 7.28–
7.32 (m, 4 H), 8.53 (br. s, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 18.0, 24.8, 40.0, 43.9, 54.6, 56.0, 57.4, 74.6, 109.6, 112.8, 114.4,
121.6, 122.1, 125.9, 126.7, 128.0, 128.8, 131.8, 139.7, 146.4 ppm.
HRMS (EI): calcd. for C22H26N2O2 [M]+ 350.1994; found
350.1974. C22H26N2O2 (350.46): calcd. C 75.39, H 7.47, N 7.99;
found C 75.25, H 7.56, N 7.97.
5-Benzyl-6-(1-methoxypropan-2-yl)-3,4,5,6-tetrahydro-1H-azepino-
[5,4,3-cd]indol-7-ol (16): Yield: 14 mg (10 %); pale-yellow oil. IR
(CHCl ): ν = 3484 cm–1. 1H NMR (500 MHz, CDCl ): δ = 0.63 (d,
˜
3
3
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Alkaloid Synthesis through a Base-Promoted Pictet–Spengler Reaction
J = 7.4 Hz, 3 H), 2.40 (m, 1 H), 2.94 (dt, J = 16.4, 3.6 Hz, 1 H),
3 H), 2.86 (dt, J = 16.1, 2.7 Hz, 1 H), 3.01 (m, 1 H), 3.17 (m, 1 H),
3.17 (dt, J = 14.0, 3.5 Hz, 1 H), 3.25 (m, 1 H), 3.29 (s, 3 H), 3.50 3.55 (td, J = 13.6, 2.7 Hz, 1 H), 3.84 (d, J = 13.2 Hz, 1 H), 4.00
(d, J = 2.8 Hz, 2 H), 3.56 (m, 1 H), 3.79 (d, J = 13.2 Hz, 1 H), 3.93
(d, J = 13.2 Hz, 1 H), 4.36 (d, J = 5.7 Hz, 1 H), 6.78 (d, J = 8.5 Hz,
1 H), 6.92 (s, 1 H), 6.93 (s, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.24 (t,
J = 7.0 Hz, 1 H), 7.30–7.35 (m, 4 H), 7.89 (s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 14.6, 25.5, 38.5, 46.1, 56.2, 58.9, 61.6, 77.6,
110.0, 113.5, 115.2, 119.9, 121.2, 126.6, 126.7, 128.1, 128.9, 131.6,
140.3, 147.9 ppm. HRMS (EI): calcd. for C22H26N2O2 [M]+
350.1994; found 350.1992.
(d, J = 13.2 Hz, 1 H), 4.39 (br. s, 1 H), 5.03 (d, J = 9.2 Hz, 1 H),
5.44 (dd, J = 9.2, 1.1 Hz, 1 H), 6.77 (d, J = 8.6 Hz, 1 H), 6.96 (s,
1 H), 7.12 (d, J = 8.6 Hz, 1 H), 7.24 (t, J = 8.3 Hz, 1 H), 7.30 (t,
J = 7.4 Hz, 2 H), 7.38 (d, J = 7.4 Hz, 2 H), 7.93 (s, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 18.2, 26.1, 26.8, 46.1, 57.1, 59.3,
109.7, 113.2, 115.5, 121.8, 122.5, 124.2, 125.8, 126.9, 128.2, 129.0,
132.4, 137.3, 140.1, 146.3 ppm. HRMS (EI): calcd. for C22H24N2O
[M]+ 332.18898; found 332.1887.
5-Benzyl-6-ethyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-7-ol
N-Benzyl-2-(7,7-dimethyl-3,7-dihydropyrano[3,2-e]indol-1-yl)ethan-
amine (19): Colorless crystals. M.p. 120–123 °C (AcOEt/hexane).
(17): Yield: 19.5 mg (16%); pale-yellow oil. IR (CHCl ): ν = 3600,
˜
3
3480 cm–1. H NMR (500 MHz, CDCl3): δ = 1.10 (t, J = 7.4 Hz,
1
IR (CHCl ): ν = 3480 cm–1. 1H NMR (500 MHz, CDCl ): δ = 1.43
˜
3
3
3 H), 1.77–1.86 (m, 2 H), 2.85 (dt, J = 16.4, 2.3 Hz, 1 H), 3.10
(ddd, J = 14.0, 4.2, 2.3 Hz, 1 H), 3.26 (ddd, J = 16.4, 14.0, 4.4 Hz,
1 H), 3.51 (td, J = 14.0, 4.2 Hz, 1 H), 3.84 (d, J = 14.2 Hz, 1 H),
4.04 (d, J = 14.2 Hz, 1 H), 4.21 (br. s, 1 H), 4.34 (dd, J = 10.2,
5.1 Hz, 1 H), 6.66 (d, J = 8.5 Hz, 1 H), 6.95 (s, 1 H), 7.07 (d, J =
8.5 Hz, 1 H), 7.24 (t, J = 7.4 Hz, 1 H), 7.31 (t, J = 7.4 Hz, 2 H),
7.38 (d, J = 7.4 Hz, 2 H), 7.89 (s, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 12.0, 25.0, 26.8, 42.9, 55.6, 62.5, 109.2, 112.4, 115.6,
122.0, 124.7, 126.2, 126.7, 128.2, 128.7, 132.2, 140.7, 145.5 ppm.
HRMS (EI): calcd. for C20H22N2O [M]+ 306.1732; found 306.1732.
(2ϫs, 6 H), 1.60 (br. s, 1 H), 2.97 (t, J = 6.9 Hz, 2 H), 3.07 (t, J =
6.9 Hz, 2 H), 3.83 (s, 2 H), 5.60 (d, J = 9.7 Hz, 1 H), 6.71 (d, J =
8.6 Hz, 1 H), 6.92 (d, J = 9.7 Hz, 1 H), 6.95 (d, J = 2.3 Hz, 1 H),
7.08 (d, J = 8.6 Hz, 1 H), 7.23 (m, 1 H), 7.28–7.31 (m, 4 H), 7.86
(m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 27.2, 27.8, 49.7,
54.0, 74.8, 111.1, 112.9, 113.1, 113.9, 120.2, 122.8, 123.5, 126.9,
128.1, 128.4, 129.6, 132.5, 140.4, 146.8 ppm. HRMS (EI): calcd. for
C22H24N2O [M]+ 332.1889; found 332.1885. C22H24N2O (332.44):
calcd. C 79.48, H 7.27, N 8.42; found C 79.65, H 7.20, N 8.45.
5-Benzyl-6-(2-methylprop-1-en-1-yl)-3,4,5,6-tetrahydro-1H-azepino-
[5,4,3-cd]indol-7-yl Acetate (6b): To a solution of 4 (106 mg,
0.4 mmol) in Et3N (5 mL) and MeOH (5 mL) was added 5
(0.12 mL, 1.3 mmol), and the mixture was stirred at room tempera-
ture for 10 h under a nitrogen atmosphere. After evaporation of the
solvent, CH2Cl2 (10 mL), Et3N (0.16 mL, 1.2 mmol), and DMAP
(10 mg, 0.08 mmol) were added to the residue. Then, AcCl (55 mg,
0.7 mmol) was added to the mixture under ice-cooling. After stir-
ring for 1 h, the mixture was diluted with AcOEt (100 mL) and
washed with brine, and the organic layer was dried with MgSO4.
The solvent was removed, and the residue was separated by column
chromatography on SiO2 (AcOEt/hexane, 1:2) to give 6b (87 mg,
5-Benzyl-6-[(2E)-but-2-en-2-yl]-3,4,5,6-tetrahydro-1H-azepino-
[5,4,3-cd]indol-7-ol (18a): Yield: 29.2 mg (22%); pale-yellow oil. IR
(CHCl ): ν = 3480 cm–1. 1H NMR (500 MHz, CDCl ): δ = 1.56 (d,
˜
3
3
J = 6.8 Hz, 3 H), 1.91 (s, 3 H), 2.81 (dt, J = 15.9, 2.0 Hz, 1 H),
3.01 (ddd, J = 13.7, 3.8, 2.0 Hz, 1 H), 3.24 (td, J = 15.9, 3.8 Hz, 1
H), 3.37 (td, J = 13.7, 3.8 Hz, 1 H), 3.85 (d, J = 14.2 Hz, 1 H),
4.06 (d, J = 14.2 Hz, 1 H), 4.27 (br. s, 1 H), 4.77 (s, 1 H), 4.93 (q,
J = 6.8 Hz, 1 H), 6.80 (d, J = 8.5 Hz, 1 H), 6.96 (s, 1 H), 7.17 (d,
J = 8.5 Hz, 1 H), 7.24 (t, J = 7.4 Hz, 1 H), 7.31 (t, J = 7.4 Hz, 2
H), 7.37 (d, J = 7.4 Hz, 2 H), 7.95 (s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 13.6, 16.0, 25.0, 43.3, 55.3, 68.8, 110.0,
113.2, 115.2, 120.8, 122.0, 122.2, 126.8, 126.9, 128.2, 128.8, 132.3,
136.4, 140.5, 146.5 ppm. HRMS (EI): calcd. for C22H24N2O [M]+
332.1889; found 332.1880.
58%) as a pale yellow oil. IR (CHCl ): ν = 3480, 1742 cm–1. 1H
˜
3
NMR (500 MHz, CDCl3): δ = 1.66 (s, 3 H), 1.67 (s, 3 H), 2.08 (s,
3 H), 2.88 (dt, J = 16.0, 3.4 Hz, 1 H), 3.06 (dd, J = 13.2, 3.4 Hz, 1
H), 3.22 (ddd, J = 16.0, 13.2, 3.4 Hz, 1 H), 3.61 (td, J = 13.2,
3.4 Hz, 1 H), 3.79 (d, J = 13.2 Hz, 1 H), 3.93 (d, J = 13.2 Hz, 1
H), 4.99 (d, J = 8.6 Hz, 1 H), 5.22 (d, J = 8.6 Hz, 1 H), 6.80 (d, J
= 8.6 Hz, 1 H), 6.94 (s, 1 H), 7.14 (d, J = 8.6 Hz, 1 H), 7.24 (t, J
= 7.4 Hz, 1 H), 7.29 (t, J = 7.4 Hz, 2 H), 7.34 (d, J = 7.4 Hz, 2 H),
8.11 (br. s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 18.3, 21.0,
25.8, 45.8, 55.9, 58.7, 109.6, 116.5, 117.2, 122.2, 125.6, 125.9, 126.9,
128.2, 129.3, 129.5, 134.7, 134.8, 140.0, 141.3, 170.3 ppm. HRMS
(EI): calcd. for C24H26N2O2 [M]+ 374.1994; found 374.1990.
5-Benzyl-6-[(1E)-1-phenylprop-1-en-2-yl]-3,4,5,6-tetrahydro-1H-azep-
ino[5,4,3-cd]indol-7-ol (18b): Yield: 78.8 mg (50%); pale-yellow oil.
IR (CHCl ): ν = 3484 cm–1. 1H NMR (500 MHz, CDCl ): δ = 2.17
˜
3
3
(s, 3 H), 2.85 (d, J = 16.4 Hz, 1 H), 3.08 (ddd, J = 14.4, 4.5, 2.3 Hz,
1 H), 3.28 (ddd, J = 16.4, 14.4, 4.5 Hz, 1 H), 3.49 (td, J = 14.4,
4.5 Hz, 1 H), 3.90 (d, J = 13.6 Hz, 1 H), 4.10 (d, J = 13.6 Hz, 1
H), 4.25 (s, 1 H), 4.95 (s, 1 H), 5.88 (s, 1 H), 6.81 (d, J = 8.5 Hz,
1 H), 6.98 (s, 1 H), 7.15 (d, J = 7.4 Hz, 2 H), 7.20 (d, J = 8.5 Hz,
1 H), 7.23–7.27 (m, 4 H), 7.33 (t, J = 7.4 Hz, 2 H), 7.40 (d, J =
6.8 Hz, 2 H), 7.96 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 18.2, 25.0, 43.8, 55.5, 69.2, 110.3, 113.1, 115.3, 120.4, 122.1,
126.3, 126.9, 127.1, 127.4, 128.0, 128.3, 128.8, 129.1, 132.3, 138.1,
139.4, 140.3, 146.6 ppm. HRMS (EI): calcd. for C27H26N2O [M]+
394.2045; found 394.2038.
5-Benzyl-6-(2-methylprop-1-en-1-yl)-3,4,5,6-tetrahydro-1H-azepino-
[5,4,3-cd]indol-7-yl Trifluoromethanesulfonate (6c): To a solution of
4 (300 mg, 1.1 mmol) in Et3N (15 mL) and MeOH (15 mL) was
added 5 (0.32 mL, 3.3 mmol), and the mixture was stirred at room
temperature for 10 h under a nitrogen atmosphere. After evapora-
tion of the solvent, CH2Cl2 (30 mL) and Et3N (0.78 mL, 5.6 mmol)
were added to the residue. Then, Tf2O (0.28 mL, 1.7 mmol) was
added to the solution under ice-cooling, and the mixture was
stirred for 30 min. The mixture was diluted with AcOEt (200 mL)
and washed with brine, and the organic layer was dried with
MgSO4. The solvent was removed, and the residue was separated
by column chromatography on SiO2 (AcOEt/hexane, 1:5) to give
6c (306 mg, 60%) as colorless crystals. M.p. 127–128 °C (AcOEt/
Reaction of 4 with 3-Methylbut-2-enal (5): To a solution of 4
(53 mg, 0.2 mmol) in Et3N (5 mL) and MeOH (5 mL) was added
5 (0.05 mL, 0.6 mmol), and the mixture was stirred at room tem-
perature for 10 h. The mixture was concentrated under reduced
pressure, and the residue was separated by column chromatography
on SiO2. The first elution (AcOEt/hexane, 1:2) gave 6a (45 mg,
34 %) and the second elution (CHCl3/MeOH/28 % NH4OH,
46:3:0.3) gave 19 (46 mg, 35%).
5-Benzyl-6-(2-methylprop-1-en-1-yl)-3,4,5,6-tetrahydro-1H-azepino-
hexane). IR (CHCl ): ν = 3480 cm–1. 1H NMR (500 MHz, CDCl ):
˜
3
3
[5,4,3-cd]indol-7-ol (6a): Pale-yellow oil. IR (CHCl ): ν =
δ = 1.71 (s, 3 H), 1.82 (s, 3 H), 2.85 (d, J = 16.6 Hz, 1 H), 2.97
˜
3
3480 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.77 (s, 3 H), 1.79 (s, (dd, J = 3.6, 14.2 Hz, 1 H), 3.21 (ddd, J = 3.6, 14.2, 16.6 Hz, 1 H),
Eur. J. Org. Chem. 2009, 5752–5759
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5757

M. Ishikura et al.
FULL PAPER
3.57 (dt, J = 3.6, 14.2 Hz, 1 H), 3.88 (1d, J = 13.7 Hz, 1 H), 3.95
(d, J = 13.7 Hz, 2 H), 5.17 (d, J = 8.0 Hz, 1 H), 5.28 (d, J = 8.0 Hz,
1 H), 7.04 (s, 1 H), 7.04 (d, J = 9.0 Hz, 1 H), 7.20 (d, J = 9.0 Hz,
1 H), 7.24 (t, J = 7.4 Hz, 1 H), 7.31 (t, J = 7.4 Hz, 2 H), 7.37 (d,
J = 7.4 Hz, 2 H), 8.21 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 18.5, 25.3, 25.8, 44.2, 55.6, 60.6, 110.1, 114.8, 115.2, 117.3,
117.4, 120.0, 122.5, 123.3, 124.4, 126.1, 127.0, 128.3, 128.9, 132.2,
135.4, 137.2, 139.6, 140.8 ppm. MS (EI): m/z = 464 [M+].
C23H23F3N2O3S (464.50): calcd. C 59.47, H 4.99, N 6.03; found C
59.60, H 4.85, N 6.00.
CDCl3): δ = 21.2, 23.7, 30.0, 34.1, 45.9, 50.7, 54.5, 55.8, 116.6,
117.3, 123.7, 127.1, 128.0, 128.7, 128.9, 130.0, 136.3, 137.7, 140.3,
145.1, 155.5 ppm. HRMS (EI): calcd. for C30H33N5O4 [M]+
527.2533; found 527.2541. C30H33N5O4 (527.62): calcd. C 68.29, H
6.30, N 13.27; found C 68.36, H 6.15, N 1311.
5-Benzyl-6-(2-methylpropyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]-
indol-7-yl Trifluoromethanesulfonate (24): To a solution of 4
(106 mg, 0.4 mmol) in Et3N (5 mL) and MeOH (5 mL) was added
3-methylbutanal (1.3 mL, 1.2 mmol), and the mixture was stirred
at room temperature for 5 h under a nitrogen atmosphere. After
the mixture was concentrated under reduced pressure, CH2Cl2
(10 mL) and Et3N (0.3 mL, 2.0 mmol) were added to the residue.
Then, Tf2O (0.08 mL, 0.5 mmol) was added to the mixture under
ice-cooling, and the mixture was stirred for 30 min. The mixture
was diluted with AcOEt (100 mL), washed with brine, and dried
with MgSO4. The solvent was removed, and the residue was sepa-
rated by column chromatography on SiO2 (hexane/AcOEt, 5:1) to
give 24 (124 mg, 69 %) as a colorless solid. M.p. 113–114 °C
(CHCl /hexane). IR (KBr): ν = 3440 cm–1. 1H NMR (500 MHz,
rel-(1S,2S)-2-{Benzyl[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino}-
4,6,6-trimethylcyclohex-3-ene-1-carbaldehyde (21): To a solution of
4 (51 mg, 0.2 mmol) in pyridine (5 mL) and MeOH (5 mL) was
added 5 (0.06 mL, 0.6 mmol), and the mixture was then stirred at
room temperature for 10 h under a nitrogen atmosphere. The mix-
ture was concentrated under reduced pressure, and the residue was
separated by column chromatography on SiO2 (hexane/AcOEt, 3:1)
to give 21 (64 mg, 80 %) as a pale-yellow oil. IR (CHCl ): ν =
˜
3
1706 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.91 (s, 3 H), 0.96 (s,
3 H), 1.53 (d, J = 17.8 Hz, 1 H), 1.68 (s, 3 H), 1.70 (br. s, 1 H),
1.93 (d, J = 17.8 Hz, 1 H), 2.17 (dd, J = 5.2, 10.9 Hz, 1 H, 1 H),
2.87–2.64 (m, 4 H), 3.53 (d, J = 13.7 Hz, 1 H), 3.84 (d, J = 13.7 Hz,
1 H), 3.88 (d, J = 10.9 Hz, 1 H), 5.56 (s, 1 H), 6.67 (d, J = 2.3 Hz,
1 H), 6.73 (dd, J = 2.3, 8.6 Hz, 1 H), 6.87 (d, J = 2.3 Hz, 1 H),
7.15 (d, J = 8.6 Hz, 1 H), 7.24 (t, J = 8.2 Hz, 1 H), 7.33–7.29 (m,
4 H), 7.77 (s, 1 H), 9.43 (d, J = 5.2 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 21.7, 23.4, 25.4, 29.4, 34.3, 46.6, 51.1, 55.4,
55.9, 58.9, 103.2, 111.6, 111.7, 113.6, 117.6, 122.7, 126.8, 128.1,
128.2, 129.0, 131.4, 136.1, 140.4, 149.4, 208.1 ppm. HRMS (EI):
calcd. for C27H32N2O2 [M]+ 416.2464; found 416.2453.
3
˜
CDCl3): δ = 0.92 (d, J = 6.9 Hz, 3 H), 1.01 (d, J = 6.9 Hz, 3 H),
1.29 (ddd, J = 14.2, 11.0, 4.3 Hz, 1 H), 1.92 (ddd, J = 14.2, 11.7,
2.9 Hz, 1 H), 1.97–2.05 (m, 1 H), 2.80 (ddd, J = 16.6, 3.4, 2.2 Hz,
1 H), 3.02 (ddd, J = 14.3, 4.6, 2.2 Hz, 1 H), 3.25 (ddd, J = 16.6,
14.3, 4.6 Hz, 1 H), 3.41 (td, J = 14.3, 3.4 Hz, 1 H), 3.89 (d, J =
14.0 Hz, 1 H), 4.04 (d, J = 14.0 Hz, 1 H), 4.67 (dd, J = 11.7, 4.3 Hz,
1 H), 7.04 (s, 1 H), 7.06 (d, J = 8.8 Hz, 1 H), 7.20 (d, J = 8.8 Hz,
1 H), 7.24 (t, J = 7.4 Hz, 1 H), 7.31 (t, J = 7.4 Hz, 2 H), 7.36 (d,
J = 7.4 Hz, 2 H), 8.17 (br. s, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 20.4, 23.7, 24.3, 24.6, 41.7, 43.4, 55.4, 60.6, 109.8,
114.8, 115.3, 116.8, 117.3, 119.9, 122.0, 123.1, 126.0, 126.8, 128.2,
128.6, 133.6, 135.3, 139.6, 139.7 ppm. HRMS (EI): calcd. for
C23H25F3N2O2S [M]+ 466.1538; found 466.1492. C23H25F3N2O2S
(450.52): calcd. C 61.32, H 5.59, N 6.22; found C 61.22, H 5.70, N
6.32.
rel-(1S,2S)-2-(Dibenzylamino)-4,6,6-trimethylcyclohex-3-ene-1-carb-
aldehyde (22): To a solution of dibenzylamine (260 mg, 1.3 mmol)
in pyridine (1 mL) and MeOH (5 mL) was added 5 (0.28 mL,
2.9 mmol), and the mixture was then stirred at room temperature
for 10 h under a nitrogen atmosphere. The mixture was concen-
trated under reduced pressure, and the residue was separated by
column chromatography on SiO2 (hexane/AcOEt, 10:1) to give 22
6-(2-Methylpropyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-7-
ol (25): A mixture of 24 (75 mg, 0.16 mmol) and 10% Pd-C[10]
(35 mg) in MeOH (5 mL) was stirred at room temperature under
atmospheric pressure of hydrogen for 5 h. The catalyst and solvent
were removed, and the residue was separated by column
chromatography on SiO2 (CHCl3/MeOH/28% NH4OH, 46:2:0.2)
(232 mg, 51%) as a pale-yellow oil. IR (CHCl ): ν = 1712 cm–1. 1H
˜
3
NMR (500 MHz, CDCl3): δ = 0.82 (s, 3 H), 0.94 (s, 3 H), 1.54 (d,
J = 17.0 Hz, 1 H), 1.73 (s, 3 H), 1.96 (d, J = 17.0 Hz, 1 H), 2.19
(dd, J = 5.1, 10.8 Hz, 1 H), 3.42 (d, J = 13.8 Hz, 2 H), 3.71 (d, J
= 13.8 Hz, 2 H), 3.80 (d, J = 10.8 Hz, 1 H), 5.66 (s, 1 H), 7.22–
7.18 (m, 2 H), 7.24–7.29 (m, 8 H), 9.17 (d, J = 5.1 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 21.6, 23.6, 29.4, 34.2, 46.6, 53.8,
54.2, 58.7, 116.8, 127.0, 128.2, 129.0, 136.4, 139.7, 207.3 ppm.
HRMS (EI): calcd. for C24H29NO [M]+ 347.2249; found 347.2250.
to give 25 (29 mg, 80%) as a colorless solid. M.p. 121–123 °C (hex-
1
ane/CHCl ). IR (KBr): ν = 3136, 3088 cm–1. H NMR (500 MHz,
˜
3
CDCl3): δ = 0.98 (d, J = 6.3 Hz, 3 H), 1.03 (d, J = 6.3 Hz, 3 H),
1.57 (ddd, J = 14.6, 10.3, 4.5 Hz, 1 H), 1.83–1.91 (m, 2 H), 2.46
(br. s, 1 H), 2.98–3.16 (m, 3 H), 3.35 (ddd, J = 13.0, 9.2, 3.4 Hz, 1
H), 4.40 (dd, J = 10.3, 4.5 Hz, 1 H), 6.85 (d, J = 7.8 Hz, 1 H), 6.94
(s, 1 H), 7.09 (t, J = 7.8 Hz, 1 H), 7.17 (d, J = 7.8 Hz, 1 H), 8.17
(br. s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.6, 23.7,
25.0, 30.7, 43.8, 45.2, 59.4, 108.8, 115.2, 116.9, 120.9, 121.5, 125.2,
137.1, 140.6 ppm. HRMS (EI): calcd. for C15H20N2 [M]+ 228.1626;
found 228.1658. C15H20N2 (228.34): calcd. C 78.90, H 8.83, N
12.27; found C 78.77, H 8.90, N 12.31.
rel-(1S,2S)-N,N-Dibenzyl-6-{(E)-[2-(2,4-dinitrophenyl)hydraz-
inylidene]methyl}-3,5,5-trimethylcyclohex-2-en-1-amine (23):[9] To a
solution of 22 (232 mg, 0.7 mmol) in AcOH (1 mL) and MeOH
(5 mL) was added 2,4-dinitrophenylhydrazine (159 mg, 0.8 mmol),
and the mixture was heated under reflux for 2 h under a nitrogen
atmosphere. The mixture was concentrated under reduced pressure,
and the residue was separated by column chromatography on SiO2
(hexane/AcOEt, 10:1) to give 23 (276 mg, 78%) as red prisms. M.p.
Conversion of 6c into (؎)-Aurantioclavine (1): A mixture of 6c
(100 mg, 0.2 mmol), HCO2NH4 (55.1 mg, 0.9 mmol), and 10% Pd-
C[10] (200 mg) in MeOH (5 mL) was stirred for 30 min under a
nitrogen atmosphere. The resulting suspension was passed over
SiO2 and washed with CHCl3/MeOH/28% NH4OH (46:5:0.5). The
filtrate was evaporated, and the residue was separated by column
chromatography on SiO2 (CHCl3/MeOH/28% NH4OH, 46:3:0.3)
to give (Ϯ)-1 (16 mg, 35%), 26 (13 mg, 18%), and 28 (13 mg, 28%).
190–191 °C (decomp.) (CHCl /MeOH). IR (CHCl ): ν =
˜
3
3
1614 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.77 (s, 3 H), 0.92 (s,
3 H), 1.64 (d, J = 17.3 Hz, 1 H), 1.77 (s, 3 H), 2.02 (d, J = 17.3 Hz,
1 H), 2.43 (dd, J = 7.9, 10.8 Hz, 1 H), 3.33 (d, J = 10.8 Hz, 1 H),
3.44 (d, J = 13.6 Hz, 2 H), 3.73 (d, J = 13.6 Hz, 2 H), 5.66 (s, 1
H), 6.69 (d, J = 7.9 Hz, 1 H), 7.19–7.22 (m, 6 H), 7.25–7.28 (m, 4
H), 8.06 (d, J = 9.6 Hz, 1 H), 8.34 (dd, J = 2.8, 9.6 Hz, 1 H), 9.20 (؎)-Aurantioclavine (1): M.p. 186–188 °C (CHCl3) (ref.[1] m.p. 188–
(d, J = 2.8 Hz, 1 H), 10.96 (s, 1 H) ppm. 13C NMR (125 MHz,
189 °C). IR (CHCl ): ν = 3480 cm–1. 1H NMR (500 MHz, CDCl ):
˜
3
3
5758
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5752–5759

Alkaloid Synthesis through a Base-Promoted Pictet–Spengler Reaction
δ = 1.78 (br. s, 1 H), 1.84 (s, 3 H), 1.85 (s, 3 H), 3.00–3.14 (m, 3 H), 6.99 (s, 1 H), 7.09 (t, J = 7.4 Hz, 1 H), 7.22 (d, J = 7.4 Hz, 1
H), 3.54–3.58 (m, 1 H), 4.89 (d, J = 9.1 Hz, 1 H), 5.46 (dd, J = H), 7.24 (t, J = 7.4 Hz, 1 H), 7.30 (t, J = 7.4 Hz, 2 H), 7.38 (d, J
9.1, 1.1 Hz, 1 H), 6.84 (dd, J = 7.6, 1.1 Hz, 1 H), 7.01 (s, 1 H), 7.09
(t, J = 7.6 Hz, 1 H), 7.22 (d, J = 7.6 Hz, 1 H), 8.11 (br. s, 1 H) ppm. δ = 18.4, 25.9, 26.1, 46.9, 55.5, 64.9, 108.9, 115.8, 118.7, 120.8,
13C NMR (125 MHz, CDCl3): δ = 18.3, 25.9, 31.0, 48.9, 62.6,
121.9, 125.4, 126.4, 126.7, 128.1, 128.9, 133.4, 136.8, 138.9,
= 7.4 Hz, 2 H), 8.04 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
109.1, 115.8, 117.8, 120.9, 121.5, 125.3, 127.7, 133.1, 137.0, 140.3 ppm. HRMS (EI): calcd. for C22H24N2 [M]+ 316.1939; found
138.5 ppm. HRMS (EI): calcd. for C15H18N2 [M]+ 226.1470; found
226.1471.
316.1954.
6-(2-Methylprop-1-en-1-yl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]-
indol-7-yl Trifluoromethanesulfonate (26): Colorless crystals. M.p.
Acknowledgments
124–126 °C (AcOEt/hexane). IR (CHCl ): ν = 3480 cm–1. 1H NMR
This work was supported in part by the Ministry of Education,
Culture, Sports, Science and Technology of Japan through a Grant-
in Aid for High Technology Research and through a Grant-in Aid
˜
3
(500 MHz, CDCl3): δ = 1.73 (d, J = 1.1 Hz, 3 H), 1.86 (d, J =
1.1 Hz, 3 H), 1.91 (br. s, 1 H), 2.96 (m, 1 H), 3.07–3.15 (m, 2 H),
3.40 (m, 1 H), 5.32 (dtt, J = 9.6, 1.1, 1.1 Hz, 1 H), 5.41 (d, J = for Scientific Research (No. 18590011). This work was also sup-
8.5 Hz, 1 H), 7.02 (d, J = 9.1 Hz, 1 H), 7.07 (br. s, 1 H), 7.19 (d, J =
ported by the Research Institute of Personalized Health Sciences,
9.1 Hz, 1 H), 8.30 (br. s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ Health Sciences University of Hokkaido through a Grant-in-aid
= 18.1, 25.7, 31.2, 42.7, 55.4, 109.9, 114.9, 117.2, 118.6, 123.2,
125.0, 125.8, 132.6, 135.7, 136.1, 140.0 ppm. HRMS (EI): calcd. for
C16H17F3N2O3S [M]+ 374.0912; found 374.0912. C16H17F3N2O3S
(374.38): calcd. C 51.33, H 4.58, N 7.48; found C 51.00, H 4.46, N
7.42.
for a 2009–2010 Research Project.
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Adanin, Dokl. Akad. Nauk SSSR 1981, 260, 230–233.
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104, 2311–2352.
[9] CCDC-711874 (for 23) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[10] The reduction was performed by using 10% Pd-C (K-type)
purchased from N.E. CHEMCAT Inc., Japan.
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Received: July 6, 2009
2-[4-(3-Methylbutyl)-1H-indol-3-yl]ethanamine (28): Colorless crys-
tals. M.p. 84–86 °C (CHCl ). IR (CHCl ): ν = 3480 cm–1. 1H NMR
˜
3
3
(500 MHz, CDCl3): δ = 0.98 (2ϫd, J = 6.2 Hz, 6 H), 1.42 (br. s, 2
H), 1.56–1.61 (m, 2 H), 1.65–1.75 (m, 1 H), 2.95–2.98 (m, 2 H),
3.01 (s, 4 H), 6.87 (d, J = 7.4 Hz, 1 H), 6.96 (s, 1 H), 7.08 (t, J =
7.4 Hz, 1 H), 7.17 (d, J = 7.4 Hz, 1 H), 8.20 (s, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 22.7, 28.3, 31.4, 31.5, 41.6, 43.0,
109.0, 113.8, 120.0, 122.0, 122.3, 125.0, 136.3, 137.2 ppm. HRMS
(EI): calcd. for C15H22N2 [M]+ 230.1783; found 230.1793.
C15H22N2 (230.35): calcd. C 78.21, H 9.62, N 12.16; found C 78.35,
H 9.76, N 12.22.
Conversion of 26 into (؎)-Aurantioclavine (1): A mixture of 26
(90.4 mg, 0.2 mmol), PdCl2(PPh3)2 (33.9 mg, 0.05 mmol), dppp
(40.4 mg, 0.1 mmol), Et3N (0.17 mL, 1.2 mmol), and formic acid
(0.02 mL, 0.5 mmol) in DMF (2 mL) was heated at 100 °C for 2 h
under an argon atmosphere. The solvent was removed, and the resi-
due was separated by column chromatography on SiO2 (CHCl3/
MeOH/28% NH4OH, 23:1:0.1) to give 1 (23.4 mg, 43%).
5-Benzyl-6-(2-methylprop-1-en-1-yl)-3,4,5,6-tetrahydro-1H-azepino-
[5,4,3-cd]indole (27):
A mixture of 6c (101 mg, 0.22 mmol),
PdCl2(PPh3)2 (31 mg, 0.04 mmol), dppp (36 mg, 0.09 mmol), Et3N
(0.26 mL, 1.1 mmol), and formic acid (0.02 mL, 0.44 mmol) in
DMF (3 mL) was heated at 100 °C for 7 h under an argon atmo-
sphere. The solvent was removed, and the residue was separated by
column chromatography on SiO2 (hexane/AcOEt, 4:1) to give 27
1
(15 mg, 22%) as a pale-yellow oil. IR (CHCl ): ν = 3480 cm–1. H
˜
3
NMR (500 MHz, CDCl3): δ = 1.73 (s, 3 H), 1.74 (s, 3 H), 2.95 (dt,
J = 16.4, 4.0 Hz, 1 H), 3.06 (dt, J = 14.5, 4.0 Hz, 1 H), 3.16 (ddd,
J = 16.4, 11.0, 4.0 Hz, 1 H), 3.60 (ddd, J = 14.5, 11.0, 4.0 Hz, 1
H), 3.82 (d, J = 13.6 Hz, 1 H), 3.94 (d, J = 13.6 Hz, 1 H), 4.96 (d,
J = 8.5 Hz, 1 H), 5.46 (d, J = 8.5 Hz, 1 H), 6.75 (d, J = 7.4 Hz, 1
Published Online: September 25, 2009
Eur. J. Org. Chem. 2009, 5752–5759
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5759