Concise Total Syntheses of Pyrido[4,3-b]carbazole Alkaloids Using Copper-Mediated 6π-Electrocyclization

Article abstract of DOI:10.1002/ejoc.201600246

Concise syntheses of 9-methoxyellipticine, 3,4-dihydroellipticine (μ-alkaloid D), 1,2,3,4-tetrahydroellipticine, 2-methyl-1,2,3,4-tetrahydroellipticine, olivacine, 3,4-dihydroolivacine, (±)-guatambuine, and (±)-janetine were developed starting from hexatriene intermediates readily obtained by Pd-catalyzed tandem cyclization/cross-coupling reaction of indolylborates. The route enables the facile construction of pyrido[4,3-b]carbazoles by Cu-catalyzed 6π-electrocyclization and subsequent transformation of the pyridocarbazole intermediates into pyrido[4,3-b]carbazole alkaloids. Concise total syntheses of pyrido[4,3-b]carbazole alkaloids were accomplished using Cu-catalyzed 6π-electrocyclization of hexatriene as a key step.

Full text of DOI:10.1002/ejoc.201600246

DOI: 10.1002/ejoc.201600246
Full Paper
Alkaloid Synthesis
Concise Total Syntheses of Pyrido[4,3-b]carbazole Alkaloids
Using Copper-Mediated 6π-Electrocyclization
Tomoki Itoh,[a] Takumi Abe,[a] Tominari Choshi,[b] Takashi Nishiyama,[b] Reiko Yanada,[c] and
Minoru Ishikura*[a]
Abstract: Concise syntheses of 9-methoxyellipticine, 3,4-di- catalyzed tandem cyclization/cross-coupling reaction of indolyl-
hydroellipticine (μ-alkaloid D), 1,2,3,4-tetrahydroellipticine, 2- borates. The route enables the facile construction of pyrido-
methyl-1,2,3,4-tetrahydroellipticine, olivacine, 3,4-dihydro- [4,3-b]carbazoles by Cu-catalyzed 6π-electrocyclization and
olivacine, ( )-guatambuine, and ( )-janetine were developed subsequent transformation of the pyridocarbazole intermedi-
starting from hexatriene intermediates readily obtained by Pd- ates into pyrido[4,3-b]carbazole alkaloids.
Introduction
ties such as antitumor activity based on DNA intercalation and/
or topoisomerase II inhibition as well as antimalarial activity
(Figure 1).[4] Many structural analogues of 1 and 6 have recently
been synthesized and several have been found to display broad
spectrum anticancer activity.[5] The diverse biological activities
and structural intricacy of these alkaloids have elicited intense
synthetic interest.[6] In the course of our ongoing studies on the
synthetic use of indolylborate 11 generated in situ from indole
10,[7] we previously reported a total synthesis of ellipticine (1)[8]
and a formal synthesis of olivacine (6).[9] Both syntheses fea-
tured facile formation of pyridocarbazole 14 from triene 13 ob-
tained by the Pd-catalyzed tandem cyclization/cross-coupling
of 11 with bromide 12 in a one-pot reaction. Here, we report
the total syntheses of the pyrido[4,3-b]carbazole alkaloids 9-
methoxyellipticine (2), 3,4-dihydroellipticine (μ-alkaloid D) (3),
1,2,3,4-tetrahydroellipticine (4), 2-methyl-1,2,3,4-tetrahydroellip-
ticine (5), olivacine (6), 3,4-dihydroolivacine (7), ( )-janetine (8),
Alkaloids with a pyrido[4,3-b]carbazole framework, represented
by ellipticine (1)[1] and olivacine (6),[2] have been isolated from
various plants[3] and display a broad range of biological activi-
Figure 1. Pyrido[4,3-b]carbazole alkaloids.
[a] School of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan
E mail: ishikura@hoku-iryo-u.ac.jp
http://www.hoku-iryo-u.ac.jp./~iyaku/index.htm
[b] Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University,
Fukuyama, Hiroshima 729-0292, Japan
[c] Faculty of Pharmaceutical Sciences, Hiroshima International University,
5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600246.
Scheme 1. Synthetic scheme for generating pyrido[4,3-b]carbazole alkaloids.
Eur. J. Org. Chem. 2016, 2290–2299
2290
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
and ( )-gutambuine (9) using Cu-mediated 6π-electrocycliza- Entry 3). The catalytic protocol tolerated 16c[8] and 16d bearing
tion as the key step.
the N-Me and N-OMe groups, respectively, producing 18c[8] and
18d in 85 % and 80 % yields (Table 1, Entries 5 and 6). The
catalytic cyclization of 16e[9] bearing no Me group on the vinyl
carbon provided 18e[9] in 83 % yield, and the same treatment
of 16f[9] gave 18f[9] in 76 % yield, although a long reaction
time (16 h) was required (Table 1, Entries 7 and 8). Moreover,
increasing the catalyst loading to 30 mol-% gave 18f in 79 %
yield (Table 1, Entry 9).
Our synthetic approach is shown in Scheme 1. In our previ-
ous reports,[8,9] the conversion of triene 13 to pyridocarbazole
14 was accomplished by a photochemical 6π-electrocyclization,
but this reaction provided low yields and was compatible with
only small scale reactions. We recently developed a novel Cu-
catalyzed 6π-electrocyclization protocol[10] and envisioned that
14 could be successfully synthesized by this reaction. Further-
more, alkaloids 2–5 could be obtained from 14. In addition,
In addition, the cyclization of 19, with a bulky TMS group on
carbazole 14 could be transformed into carbazole 15, which the olefinic carbon, was examined (Scheme 2). Reacting 19a[11]
would serve as a diverging intermediate for construction of 6– under the catalytic conditions resulted in formation of 20a in
9.
55 % yield accompanied by spontaneous elimination of the
TMS group. Treating 19a with 1 equiv. of (CuOTf)2·toluene also
afforded 20a in 78 % yield. The catalytic cyclization of 19b hav-
ing the N-OMe group provided 20b in 75 % yield. Moreover,
cyclization of 21 lacking a Me group on the vinyl carbon under
the catalytic conditions provided carbazole 22 in 76 % yield,
and cyclization using 1 equiv. of (CuOTf)2·toluene led to 22 in
78 % yield. The TMS group of 22 was readily removed by treat-
ment with TBAF to give 23 (Scheme 2).
Results and Discussion
First, Cu-mediated cyclization of triene 16 was investigated
(Table 1). Initially, triene 16a[8] was added to a solution of (Cu-
OTf)2·toluene (1 equiv.) in CH2Cl2/MeCN (5:1; v/v) and the mix-
ture was stirred at room temperature in air for 1 h. This readily
produced pyridocarbazole 18a[8] in 85 % yield (Table 1, Entry
1). It is notable that the reversed addition of (CuOTf)2·toluene
(1 equiv.) to a solution of 16a in CH2Cl2/MeCN resulted in recov-
ery of 16a, although the reason for this is presently unclear.
Catalytic cyclization was examined next. Simple treatment of
16a with a catalytic amount of (CuOTf)2·toluene (10 mol-%)
required a long reaction time (16 h) to give 18a in 60 % yield
(Table 1, Entry 2). We were delighted to find that the addition
of PCC (1.2 equiv.) to accelerate the oxidation of diene interme-
diate 17 notably increased the yield of 18a to 84 % (Table 1,
Table 1. Cu-mediated cyclization of indole 16.
Scheme 2. Cu-promoted cyclization of trienes 19 and 21.
The cyclization of (E)-24[11] and (Z)-24,[11] derived from triene
19a, was carried out next (Scheme 3). From (E)-24, carbazole
20a was obtained in 45 % yield using the identified catalytic
conditions and the yield of 20a increased to 75 % by using
1 equiv. of (CuOTf)2·toluene. In contrast, attempted cyclization
of (Z)-24 provided no isolable products, likely due to the
twisted conformation of the hexatriene unit[8] (Scheme 3). Re-
pulsive interactions between the Me group on the vinyl carbon
and the indole ring of (E)-24 likely restricted the torsion of the
triene unit and was advantageous for the cyclization. A high
degree of conformational freedom in the twisted conformation
of (Z)-24 would hinder cyclization. Moreover, catalytic cycliza-
[a] Isolated yield. [b] (CuOTf)2·toluene (1 equiv.). [c] (CuOTf)2·toluene
(0.1 equiv.). [d] (CuOTf)2·toluene (0.1 equiv.), PCC (1.2 equiv.). [e] (CuOTf)2·tol-
uene (0.3 equiv.), PCC (1.2 equiv.).
Eur. J. Org. Chem. 2016, 2290–2299
www.eurjoc.org
2291
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
tion of 25, derived from 21 by removal of the TMS group, gave
23 in 55 % yield, along with recovery of 25 (20 %); 23 was ob-
tained in 78 % yield when 1 equiv. of (CuOTf)2·toluene was em-
ployed (Scheme 4). Even though 25 displays a high degree of
conformational flexibility, the less-substituted terminal olefin of
the triene unit appears to enable ring-closure.
Scheme 5. Synthesis of 9-methoxyellipticine (2).
amine 28, which was then treated with BBr3 in CH2Cl2 at –78 °C.
This sequence of transformations gave 1,2,3,4-tetrahydroellipti-
cine (4) in 65 % yield from 18a. Moreover, catalytic reduction
of carbazole 18d produced 4 in a one-pot reaction. Addition-
ally, amine 28 was oxidized with MnO2 in CH2Cl2 at room tem-
perature to give imine 29. Treatment of 29 with BBr3 in CH2Cl2
Scheme 3. Cu-promoted cyclization of triene 24.
Scheme 4. Cu-promoted cyclization of triene 25.
Having succeeded in achieving Cu-catalyzed cyclization of
16, transformation of carbazoles 18 into pyridocarbazole alka-
loids was undertaken next. Initially, 9-methoxyellipticine (2)[12]
was synthesized starting from carbazole 18b (Scheme 5). The
N-Cbz group was removed by catalytic hydrogenation, and re-
sulting amine 26 was subjected, without further purification, to
oxidation with MnO2 in dioxane at 100 °C, to afford 27 in 70 %
yield. Removal of the N-Boc group with BBr3 in CH2Cl2 at –78 °C
afforded 2 in 75 % yield.
Next, carbazole 18a was converted to 3,4-dihydroellipticine
(μ-alkaloid D) (3),[13] 1,2,3,4-tetrahydroellipticine (4)[14] and 2-
methyl-1,2,3,4-tetrahydroellipticine (5)[15] (Scheme 6) Removal
of the N-Cbz group of 18a by catalytic hydrogenation provided
Scheme 6. Synthesis of 4 and 5.
Eur. J. Org. Chem. 2016, 2290–2299
www.eurjoc.org
2292
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
at –78 °C provided 3,4-dihydroellipticine (3) in 75 % yield. The 7.04 ppm) had distinctly different chemical shifts, although the
N-Cbz group of 18a was readily reduced to the N-Me group 1H NMR spectrum of 9a closely resembled that of 9.
with DIBAL in THF at room temperature, leading to compound
30 in 75 % yield. The N-Boc group was then removed with BBr3
in CH2Cl2 at –78 °C to give 2-methyl-1,2,3,4-tetrahydroellipticine
(5).
The structure of natural (+)-9 was unequivocally confirmed
by X-ray crystal structure analysis, which showed that the D ring
is in a half-chair conformation and that the C1-Me is axial.[20]
The NOE effect between the C1-Me (δ = 1.50 ppm) and the C3-
The total syntheses of olivacine (6),[16] 3,4-dihydroolivacine Ha (δ = 3.20 ppm) was present in synthetic ( )-9 (Figure 2). On
(7),[17] ( )-janetine (8),[18,17a] and ( )-gutambuine (9)[19] were the other hand, irradiation of the C1-H resonance (δ =
undertaken starting from carbazole 18f. To transform 18f into 3.90 ppm) for 9a produced NOE effects on the peaks represent-
carbazole 15, the N-Cbz group of 18f was removed by catalytic ative of the C1-Me, N2-Me, C3-Hb, and C11-H moieties. Addi-
hydrogenation, and resulting amine 31 was subjected, without tionally, irradiation of the N2-Me resonance produced distinct
purification, to oxidation with MnO2 in CH2Cl2 at room tempera- enhancements in the NOE effects noted for C1-Me, C1-H, C3-
ture, to yield 32 in 70 % yield from 18f. Next, the Me group Ha, and C3-Hb signals. Taken together, these results suggest that
was introduced into the C-1 position of 32. Treatment of 32 the C1-Me group in 9 switched from its axial placement to be-
with ClCO2Bn in THF at room temperature, followed by the ad- ing equatorial in 9a; this appears to result from a conforma-
dition of MeMgBr, readily provided 15 in 80 % yield.
tional inversion of the D-ring, accompanied by inversion of the
nitrogen at the 2-position.
Conversion of 15 to ( )-guatambuine (9) was carried out
(Scheme 7) by first converting the N-Cbz group of 15 to its N-
Me congener with DIBAL in THF at room temperature; 33 was
generated in 80 % yield. Removal of the N-Boc group in 33 was
effected with BBr3 in CH2Cl2 at –78 °C to provide ( )-guatam-
buine (9) in 60 % yield. The NMR spectroscopic data of 9 were
in good agreement with previously reported data.[19c] Addition-
ally, the N-Boc group in 33 was cleaved by treatment with
Cs2CO3 in refluxing MeOH/THF to render 9a. Importantly, some
aspects of the NMR spectroscopic data of 9a were not consist-
1
ent with those of 9. Notably, the H NMR spectroscopic data of
9 and 9a show that the signals of the C5-Me (9, δ = 2.40 ppm;
9a, δ = 2.76 ppm) and the C11-H (9, δ = 7.69 ppm; 9a, δ =
Figure 2. Conformation of 9 and 9a.
Next, 15 was converted to ( )-janetine (8) (Scheme 8) by
removal of the N-Cbz group using catalytic hydrogenation. Re-
sulting amine 34 was subjected, without purification, to reac-
tion with BBr3 in CH2Cl2 at –78 °C to produce ( )-janetine (8)[17b]
in 50 % yield. Additionally, amine 34 was oxidized with a five-
fold excess of MnO2, with respect to 15 (w/w), in THF at room
temperature for 4 d. This oxidation provided imine 35 in 70 %
yield and 36 in 5 % yield from 15. A 20-fold excess of MnO2
and prolonged reaction time (7 d) sufficed for the oxidation of
34 at room temperature, affording 36 in 72 % yield from 15.
Removal of the N-Boc group in 36 with BBr3 at –78 °C provided
olivacine (6) in 60 % yield; the NMR spectroscopic data of this
synthetic material were in good agreement with those of natu-
ral 6.[16a] On the other hand, 3,4-dihydroolivacine (7) was gener-
ated by treatment of 35 with BBr3 at –78 °C. The 1H NMR spec-
Scheme 7. Synthesis of ( )-9.
Eur. J. Org. Chem. 2016, 2290–2299
www.eurjoc.org
2293
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
luted with AcOEt (500 mL), washed with brine, and dried with
MgSO4. The solvent was removed and the residue was separated
by flash column chromatography (AcOEt/hexane, 1:7) to give 16b
troscopic data of synthetic 7 in [D6]acetone approximately coin-
cided with the 1H NMR spectroscopic data for 7 in CDCl3 re-
ported in the literature.[17b] Here, synthetic 7 was dissolved in
[D6]acetone because it was insoluble in CDCl3.
(1.3 g, 63 %) as an oil. IR (neat): ν = 1726, 1699 cm–1 1H NMR
.
˜
(500 MHz, CDCl3): δ = 1.34–1.46 (m, 3 H), 1.59 (s, 9 H), 1.88 (s, 3 H),
2.24–2.36 (m, 1 H), 2.59–2.70 (m, 1 H), 3.50–3.89 (m, 3 H), 3.83 (s, 3
H), 4.46, 4.49 (two s, 1 H), 5.16 (s, 2 H), 5.12–5.23 (m, 1 H), 5.97, 6.01
(two s, 1 H), 6.84 (dd, J = 2.5, 9.0 Hz, 1 H, 1 H), 6.88 (br. s, 1 H),
7.29–7.44 (m, 5 H), 8.01 (d, J = 9.0 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 13.5, 20.4, 28.1, 30.3, 42.9, 45.6, 55.7, 67.2, 83.3, 103.0,
106.3, 111.9, 116.1, 123.9, 124.3, 125.3, 127.9, 128.0, 128.5, 130.5,
131.2, 133.7, 135.0, 135.2, 136.9, 143.5, 149.9, 155.5, 155.8 ppm.
HRMS (ESI): calcd. for C31H36N2NaO5 [M + Na]+ 539.2521, found
539.2523.
Benzyl (3E/Z,4Z)-3-Ethylidene-4-[1-(1-methoxy-1H-indol-2-yl)-
ethylidene]piperidine-1-carboxylate (16d): nBuLi (1.6
M solution
in hexane, 6 mL, 9.6 mmol) was added to a solution of 1-methoxyin-
dole (1.17 g, 8 mmol) in THF (100 mL) at –20 °C under an argon
atmosphere, and the mixture was stirred for 0.5 h. Then, BEt3 (1
M
solution in hexane, 9.6 mL, 9.6 mmol) was added, and the whole
mixture was gradually warmed to room temperature over 1 h. Then,
PdCl2(PPh3)2 (140 mg, 0.2 mmol) and bromide 12 (R = Me, 1.34 g,
4 mmol) were added, and the mixture was heated at 60 °C for 1 h.
The mixture was cooled to 0 °C, and 10 % aqueous NaOH solution
(20 mL) and 30 % aqueous H2O2 solution (10 mL) were added. After
stirring for 20 min, the mixture was diluted with AcOEt (500 mL),
washed with brine, and dried with MgSO4. The solvent was re-
moved and the residue was separated by flash column chromatog-
raphy (AcOEt/hexane, 1:7) to give 16d (1.08 g, 65 %) as an oil. IR
1
(neat): ν = 1693 cm–1. H NMR (500 MHz, CDCl3): δ = 1.32–1.45 (m,
˜
3 H), 2.08 (s, 3 H), 2.54–2.64 (m, 2 H), 3.60–3.69 (m, 2 H), 3.76 (s, 3
H), 4.24 (br. s, 2 H), 5.02–5.14 (m, 1 H), 5.14 (s, 2 H), 6.14 (s, 1 H),
7.04 (t, J = 8.0 Hz, 1 H), 7.10 (t, J = 8.5 Hz, 1 H), 7.29–7.40 (m, 6 H),
7.48 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.4,
20.2, 31.1, 31.2, 43.0, 45.2, 45.5, 64.6, 67.1, 97.6, 108.1, 119.4, 119.8,
120.3, 121.7, 123.8, 124.2, 124.6, 128.0, 128.1, 128.6, 132.0, 133.9,
137.0, 138.4, 155.5 ppm. HRMS (ESI): calcd. for C26H28N2NaO3 [M +
Na]+ 439.1998, found 439.1998.
Scheme 8. Synthesis of 6, 7, and ( )-8.
Conclusions
General Procedure for the Cyclization of Triene 16 Using (Cu-
OTf)2·toluene (1.0 equiv.): A solution of 16 (0.5 mmol) in CH2Cl2/
MeCN (5:1; v/v) (5 mL) was added to a stirred solution of (Cu-
OTf)2·toluene (259 mg, 0.5 mmol) in CH2Cl2/MeCN (5:1; v/v) (20 mL)
at room temperature in air, and the mixture was stirred (see Table 1
for the reaction time). Then, the mixture was concentrated, and
In conclusion, total syntheses of 9-methoxyellipticine (2), 3,4-
dihydroellipticine (3), 1,2,3,4-tetrahydroellipticine (4), 2-methyl-
1,2,3,4-tetrahydroellipticine (5), olivacine (6), 3,4-dihydrooliva-
cine (7), ( )-janetine (8), and ( )-guatambuine (9) were
achieved using triene 16 as a key intermediate. Most impor-
tantly, the cyclization of triene 16 to pyridocarbazole 18 was the residue was separated by flash column chromatography with
hexane/AcOEt to give pyridocarbazole 18.
successfully performed by taking advantage of Cu-mediated
6π-electrocyclization, enabling a gram-scale reaction.
General Procedure for the Catalytic Cyclization of Triene 16 Us-
ing (CuOTf)2·toluene (0.1 equiv.) and PCC (1.2 equiv.): To a
stirred mixture of (CuOTf)2·toluene (25.9 mg, 0.05 mmol) and PCC
(129 mg, 60 mmol) in CH2Cl2/MeCN (5:1; v/v) (20 mL), triene 16
(0.5 mmol) was added, and the mixture was stirred at room temper-
ature in air (see Table 1 for the reaction time). Then, the mixture
was concentrated, and the residue was separated by flash column
chromatography with hexane/AcOEt to give pyridocarbazole 18.
Experimental Section
tert-Butyl 2-((1Z)-1-{(3E,Z)-1-[(Benzyloxy)carbonyl]-3-ethyliden-
epiperidin-4-ylidene}ethyl)-5-methoxy-1H-indole-1-carboxylate
(16b): tBuLi (1.6
M solution in pentane, 6 mL, 9.6 mmol) was added
to a solution of indole 10 (X = OMe, 1.98 g, 8 mmol) in THF (100 mL)
at –78 °C under an argon atmosphere, and the mixture was stirred
2-Benzyl 6-tert-Butyl 9-Methoxy-5,11-dimethyl-3,4-dihydro-1H-
pyrido[4,3-b]carbazole-2,6-dicarboxylate (18b): Colorless crys-
for 1 h. Then, BEt3 (1
M solution in hexane, 9.6 mL, 9.6 mmol) was
added, and the whole mixture was gradually warmed to room tem- tals, m.p. 102–103 °C. IR (CHCl3): ν = 1722, 1659 cm–1 1H NMR
.
˜
perature over 1 h. Then, PdCl2(PPh3)2 (140 mg, 0.2 mmol) and brom- (500 MHz, CDCl3): δ = 1.65 (s, 9 H), 2.29 (s, 3 H), 2.65 (s, 3 H), 2.90–
ide 12 (R = Me, 1.34 g, 4 mmol) were added, and the mixture was
heated at 60 °C for 3 h. The mixture was cooled to 0 °C, and 10 %
aqueous NaOH solution (20 mL) and 30 % aqueous H2O2 solution
3.00 (m, 2 H), 3.73–3.80 (m, 2 H), 3.91 (s, 3 H), 4.72, 4.77 (two s, 2
H), 5.20 (s, 2 H), 7.05 (d, J = 9.0 Hz, 1 H), 7.30–7.44 (m, 5 H), 7.62 (s,
1 H), 7.98 (d, J = 9.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
(10 mL) were added. After stirring for 20 min, the mixture was di- 15.1, 15.5, 16.6, 17.3, 26.5, 26.8, 27.1, 27.4, 28.2, 41.1, 41.3, 41.5, 44.6,
Eur. J. Org. Chem. 2016, 2290–2299
www.eurjoc.org
2294 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
45.0, 55.9, 67.2, 83.6, 107.6, 112.5, 115.8, 120.4, 120.8, 122.1, 122.3,
(CHCl3): ν = 1718, 1683 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.51
˜
124.4, 124.6, 128.0, 128.1, 128.4, 128.6, 131.3, 131.7, 132.9, 133.2, (s, 9 H), 1.75 (s, 9 H), 2.71 (s, 3 H), 3.01 (t, J = 5.7 Hz, 2 H), 3.67 (t,
135.4, 135.5, 136.9, 138.6, 138.8, 151.5, 151.6, 155.5, 156.0 ppm. J = 5.7 Hz, 2 H), 4.71 (s, 2 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.43 (t, J =
HRMS (ESI): calcd. for C31H34NaN2O5 [M + Na]+ 537.2365, found
537.2349.
7.5 Hz, 1 H), 8.07 (s, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.31 (d, J = 8.0 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 15.4, 28.5, 28.6, 30.7, 40.5,
42.1, 43.8, 44.6, 79.9, 84.0, 113.7, 116.1, 122.4, 122.9, 123.0, 126.2,
126.6, 1217.0, 129.5, 134.0, 137.5, 151.2, 155.1 ppm. HRMS (ESI):
calcd. for C26H32N2NaO4 [M + Na]+ 459.2260, found 459.2264.
Benzyl
6-Methoxy-5,11-dimethyl-1,3,4,6-tetrahydro-2H-pyr-
ido[4,3-b]carbazole-2-carboxylate (18d): Oil. IR (CHCl3): ν =
˜
1693 cm–1 1H NMR (500 MHz, CDCl3): δ = 2.64 (s, 3 H), 2.65–2.75
.
(m, 3 H), 2.92–3.00 (m, 2 H), 3.75–3.82 (m, 2 H), 3.81 (s, 3 H), 4.79
(s, 2 H), 5.20 (s, 2 H), 7.25 (t, J = 8.0 Hz, 1 H), 7.29–7.42 (m, 5 H),
7.48 (t, J = 8.0 Hz, 1 H), 7.52 (d, J = 8.0 Hz, 1 H), 8.14 (d, J = 8.0 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 12.4, 15.3, 26.8, 27.0, 41.3,
41.5, 44.6, 61.8, 67.2, 109.4, 116.8, 117.0, 119.4, 120.9, 121.8, 122.9,
124.8, 125.2, 125.6, 127.1, 127.5, 128.0, 128.4, 132.1, 132.3, 135.9,
137.0, 139.9 155.5 ppm. HRMS (ESI): calcd. for C26H26N2NaO3 [M +
Na]+ 437.1841, found 437.1844.
tert-Butyl 6-Methoxy-11-methyl-1,3,4,6-tetrahydro-2H-pyrido-
[4,3-b]carbazole-2-carboxylate (20b): Colorless crystals, m.p. 178–
1
179 °C. IR (KBr): ν = 1701 cm–1. H NMR (500 MHz, CDCl3): δ = 1.51
˜
(s, 9 H), 2.74 (s, 3 H), 3.04 (s, 2 H), 3.68 (s, 2 H), 4.08 (s, 3 H), 4.72 (s,
2 H), 7.16 (s, 1 H), 7.24 (t, J = 7.4 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 1 H),
7.50 (d, J = 8.0 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 15.5, 28.5, 30.6, 40.7, 41.9, 43.6, 44.3, 63.2,
79.8, 105.5, 108.2, 117.7, 120.1, 120.7, 122.7, 124.1, 125.4, 129.9,
130.3, 133.6, 136.7, 138.1, 155.2 ppm. HRMS (ESI): calcd. for
C22H26N2NaO3 [M + Na]+ 389.1841, found 389.1841.
tert-Butyl (3E/Z,4E)-3-Ethylidene-4-[(1-methoxy-1H-indol-2-yl)-
(trimethylsilyl)methylidene]-piperidine-1-carboxylate (19b): Oil.
1
IR (neat): ν = 1693 cm–1. H NMR (500 MHz, CDCl3): δ = 0.13, 0.21
˜
tert-Butyl 6-Methoxy-5-(trimethylsilyl)-1,3,4,6-tetrahydro-2H-
(two s, 9 H), 1.18, 1.40 (two d, J = 7.5 Hz, 3 H), 1.45, 1.46 (two s, 9
H), 2.40–2.82 (m, 2 H), 3.48–3.73 (m, 2 H), 3.86, 3.92 (two s, 3 H),
4.15, 4.18 (two s, 1 H), 5.11–5.19 (m, 1 H), 5.21–5.30 (m, 1 H), 5.83,
5.94 (two s, 1 H), 7.03 (t, J = 7.5 Hz, 1 H), 7.10–7.14 (m, 1 H), 7.30
(d, J = 8.0 Hz, 1 H), 7.45 (dd, J = 2.3, 7.5 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 0.68, 1.35, 13.4, 15.8, 28.5, 35.0, 36.2, 44.6,
45.5, 53.5, 64.5, 65.0, 79.7, 96.7, 97.0, 107.7, 107.8, 119.5, 119.9,
120.0, 120.7, 121.0, 121.7, 123.6, 123.9, 126.9, 131.4, 131.6, 136.4,
137.4, 138.3, 154.5, 154.8 ppm. HRMS (ESI): calcd. for
pyrido[4,3-b]carbazole-2-carboxylate (22): Oil. IR (CHCl3): ν =
˜
1683 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.49 (s, 9 H), 1.47–1.54
(m, 9 H), 3.09 (t, J = 6.2 Hz, 2 H), 3.32 (s, 3 H), 3.53–3.65 (m, 2 H),
4.66 (s, 2 H), 7.25 (dt, J = 1.2, 7.5 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 1 H),
7.49 (d, J = 8.0 Hz, 1 H), 7.70–7.76 (m, 1 H), 7.91 (d, J = 7.3 Hz, 1
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 1.49, 1.89, 28.6, 32.1, 32.4,
41.5, 42.6, 45.5, 46.6, 57.8, 63.4, 79.7, 79.8, 108.5, 112.1, 119.5, 119.8,
120.2, 120.4, 122.0, 122.2, 123.8, 126.1, 126.4, 128.5, 129.2, 134.0,
137.0, 138.2, 141.1, 141.9, 142.1, 144.7, 155.0, 155.1 ppm. HRMS
25H36N2NaO3Si [M + Na]+ 463.1393, found 463.2389.
(ESI): calcd. for
447.2082.
C
24H32N2NaO3Si: [M + Na]+ 447.2080, found
C
tert-Butyl (4E)-4-[(1-Methoxy-1H-indol-2-yl)(trimethylsilyl)-
methylidene]-3-methylidenepiperidine-1-carboxylate (21): Oil.
IR (neat): ν = 1693 cm–1 1H NMR (500 MHz, CDCl3): δ = 0.15 (s, 9
tert-Butyl 6-Methoxy-1,3,4,6-tetrahydro-2H-pyrido[4,3-b]carb-
azole-2-carboxylate (23): TBAF (1 solution in THF, 1 mL, 1 mmol)
.
˜
M
H), 1.48 (s, 9 H), 2.59–2.65 (m, 1 H), 2.66–2.74 (m, 1 H), 3.50–3.57
(m, 1 H), 3.68–3.74 (m, 1 H), 3.95 (s, 3 H), 3.92–4.02 (m, 2 H), 4.64,
4.80 (two s, 2 H), 5.86 (s, 1 H), 7.04 (t, J = 7.5 Hz, 1 H), 7.13 (t, J =
7.5 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 7.46 (d, J = 7.5 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 0.53, 28.5, 34.9, 44.2, 52.0, 65.1,
79.9, 96.5, 107.8, 114.7, 119.7, 120.0, 120.9, 123.9, 127.4, 131.8, 138.0,
142.5, 153.5, 154.7 ppm. HRMS (ESI): calcd. for C24H34N2NaO3Si [M
+ Na]+ 449.2236, found 449.2238.
was added to a solution of 22 (212 mg, 0.5 mmol) in THF (20 mL)
at room temperature under an argon atmosphere, 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 separated by flash column chro-
matography (AcOEt/hexane, 1:10) to give 23 (158 mg, 90 % yield)
1
as an oil. IR (CHCl3): ν = 1681 cm–1. H NMR (500 MHz, CDCl3): δ =
˜
1.51 (s, 9 H), 3.04 (t, J = 6.0 Hz, 2 H), 3.69 (t, J = 6.0 Hz, 2 H), 4.10
(s, 3 H), 4.73 (s, 2 H), 7.22 (dt, J = 1.1, 7.5 Hz, 1 H), 7.28 (s, 1 H), 7.44
(dt, J = 1.1, 8.0 Hz, 1 H), 7.48 (d, J = 7.9 Hz, 1 H), 7.77 (s, 1 H), 7.97
(d, J = 7.4 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 28.6, 30.1,
30.4, 63.4, 79.8, 107.7, 108.5, 118.1, 118.9, 119.9, 120.2, 120.4, 125.6,
126.1, 134.0, 135.8, 137.0, 138.2, 155.1 ppm. HRMS (ESI): calcd. for
C21H24N2NaO3 [M + Na]+ 375.1685, found 375.1684.
tert-Butyl
(4Z)-4-[(1-Methoxy-1H-indol-2-yl)methylidene]-3-
solution in
methylidenepiperidine-1-carboxylate (25): TBAF (1
M
THF, 2 mL, 2 mmol) was added to a solution of 21 (500 mg,
1.1 mmol) in THF (50 mL) at room temperature under an argon
atmosphere, and the mixture was stirred for 30 min. The mixture
was diluted with AcOEt (200 mL), washed with brine, and dried with
MgSO4. The solvent was removed, and the residue was separated
by flash column chromatography (AcOEt/hexane, 10:1) to give 20
tert-Butyl 9-Methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole-
6-carboxylate (27): A solution of 18b (500 mg, 0.97 mmol) was
stirred in the presence of 20 % Pd(OH)2/C (500 mg) in THF under
atmospheric pressure of hydrogen for 1 h, the catalyst and the sol-
vent were removed. The residue 26 and MnO2 (5 g) were heated in
dioxane (100 mL) at 100 °C for 12 h. After cooling, the insoluble
materials were removed by filtration, and the filtrate was concen-
trated and separated by flash column chromatography with AcOEt/
(350 mg, 90 % yield) as an oil. IR (neat): ν = 1693 cm–1 1H NMR
.
˜
(500 MHz, CDCl3): δ = 1.49 (s, 9 H), 2.48 (br. s, 1 H), 2.80, 2.89 (two
t, J = 5.5 Hz, 1 H), 3.55, 3.61 (two t, J = 6.3 Hz, 2 H), 4.00, 4.02 (two
s, 3 H), 4.09, 4.14 (two s, 2 H), 4.99, 5.24, 5.27, 5.29, 5.34 (five s, 2
H), 6.35, 6.37 (two s, 1 H), 6.62, 6.83 (two s, 1 H), 7.05, 7.09 (two t,
J = 7.8 Hz, 1 H), 7.17, 7.22 (two t, J = 7.8 Hz, 1 H), 7.36, 7.39 (two d,
J = 8.0 Hz, 1 H), 7.46, 7.55 (two d, J = 8.0 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 28.5, 38.1, 44.8, 45.5, 51.2, 52.2, 65.2, 80.0,
97.5, 108.0, 111.5, 114.3, 114.7, 120.4, 120.6, 122.3, 123.8, 131.6,
132.0, 141.2, 154.7 ppm. HRMS (ESI): calcd. for C21H26N2NaO3 [M +
Na]+ 377.1841, found 377.1843.
hexane (1:1) to give 27 (537 mg, 70 %) as colorless crystals, m.p.
1
155–156 °C. IR (CHCl3): ν = 1724 cm–1. H NMR (CDCl3): δ = 1.69 (s,
˜
9 H), 2.83 (s, 3 H), 3.09 (s, 3 H), 3.95 (s, 3 H), 7.14 (dd, J = 2.9, 9.1 Hz,
1 H), 7.80 (d, J = 2.9 Hz, 1 H), 8.04 (d, J = 6.3 Hz, 1 H), 8.07 (d, J =
9.1 Hz, 1 H), 8.56 (d, J = 6.3 Hz, 1 H), 9.63 (s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 14.6, 16.8, 28.2, 56.0, 83.9, 109.2, 114.5, 116.3,
116.8, 119.6, 125.3, 127.5, 127.8, 129.4, 132.7, 137.3, 138.2, 141.1,
Di-tert-Butyl 11-Methyl-3,4-dihydro-1H-pyrido[4,3-b]carbazole-
2,6-dicarboxylate (20a): Colorless crystals, m.p. 180–181 °C. IR
Eur. J. Org. Chem. 2016, 2290–2299
www.eurjoc.org
2295
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
149.8, 151.4, 156.2 ppm. HRMS (ESI): calcd. for C23H24N2NaO3 [M +
Na]+ 399.1685, found 399.1687.
1,2,3,4-Tetrahydroellipticine (4): A solution of 18a (500 mg,
1.03 mmol) was stirred in the presence of 20 % Pd(OH)2/C (500 mg)
in THF under atmospheric pressure of hydrogen for 1 h, the catalyst
9-Methoxyellipticine (2): To a solution of 27 (100 mg, 0.26 mmol)
and the solvent were removed. BBr3 (1
M solution in CH2Cl2, 2 mL)
in CH2Cl2 at –78 °C under an argon atmosphere, BBr3 (1
M solution
was added to a solution of the residue 28 in CH2Cl2 at –78 °C under
an argon atmosphere. After the mixture was stirred for 30 min, 10 %
aqueous NaOH solution (2 mL) was added. The mixture was diluted
with CH2Cl2, washed with brine, and dried with Na2SO4. The solvent
was removed, and the residue was separated by flash column chro-
matography with AcOEt/MeOH (50:1) to give 4 (167 mg, 65 %) as
colorless crystals, m.p. 154–157 °C dec. (ref.[14b] 163–165 °C dec). IR
in CH2Cl2, 0.3 mL) was added. After stirring for 30 min, the reaction
was quenched with 10 % aqueous NaOH solution (2 mL). The mix-
ture was extracted with CH2Cl2 (100 mL), and the extract was dried
with Na2SO4. The solvent was removed, and the residue was sepa-
rated by alumina column chromatography with AcOEt to give 2
(68 mg, 70 %) as pale orange colored crystals, m.p. 277–278 °C
(ref.[12a] m.p. 276.3–278.5 °C). IR (KBr): ν = 3437, 3155 cm–1. 1H NMR
˜
(CHCl3): ν = 3308 cm–1 1H NMR (500 MHz, CD3OD): δ = 2.40 (s, 3
.
˜
(500 MHz, [D6]acetone): δ = 2.78 (s, 3 H), 3.31 (s, 3 H), 7.15 (dd, J =
2.3, 8.6 Hz, 1 H), 7.46 (d, J = 8.6 Hz, 1 H), 7.87 (d, J = 5.7 Hz, 1 H),
7.93 (d, J = 2.3 Hz, 1 H), 8.39 (d, J = 5.7 Hz, 1 H), 9.67 (s, 1 H), 10.20
(br. s, 1 H) ppm. 13C NMR (125 MHz, [D8]THF): δ = 10.9, 13.6, 55.2,
107.5, 107.8, 110.5, 114.7, 123.9, 124.5, 128.1, 132.9, 137.7, 140.8,
141.6, 149.6, 153.9 ppm. HRMS (ESI): calcd. for C18H17N2O [M + H]+
277.1341, found 277.1344.
H), 2.66 (s, 3 H), 2.91 (t, J = 6.3 Hz, 2 H), 3.14 (t, J = 6.3 Hz, 2 H),
4.13 (s, 2 H), 7.09 (t, J = 7.5 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.43
(d, J = 8.0 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz,
CD3OD): δ = 11.3, 13.8, 26.8, 43.0, 46.0, 110.1, 114.7, 118.0, 119.6,
121.9, 123.2, 124.0, 124.1, 125.9, 129.7, 138.4, 140.6 ppm. HRMS (EI):
calcd. for C17H18N2 [M]+ 250.1469, found 250.1455.
Preparation of 4 from 18d: A solution of 18d (100 mg, 0.24 mmol)
was stirred in the presence of 20 % Pd(OH)2/C (70 mg) in THF under
atmospheric pressure of hydrogen for 1 h, and the solvent and the
catalyst was removed to give 4 (48 mg, 80 %).
tert-Butyl 5,11-Dimethyl-3,4-dihydro-6H-pyrido[4,3-b]carbaz-
ole-6-carboxylate (29): A solution of 18a (1.1 g, 2.3 mmol) was
stirred in the presence of 20 % Pd(OH)2/C (500 mg) in THF under
atmospheric pressure of hydrogen for 1 h, the catalyst and the sol-
vent were removed. The residue 28 and MnO2 (5 g) were stirred in
CH2Cl2 at room temperature for 3 d. The insoluble materials were
removed by filtration, and the filtrate was concentrated and sepa-
rated by alumina column chromatography with hexane/AcOEt (1:1)
to give 29 as a pair of conformers (537 mg, 70 %).
tert-Butyl 2,5,11-Trimethyl-1,2,3,4-tetrahydro-6H-pyrido[4,3-b]-
carbazole-6-carboxylate (30): To a solution of 18a (200 mg,
0.41 mmol) in THF (30 mL) at room temperature under an argon
atmosphere, DIBAL (1
M solution in toluene, 2 mL, 2 mmol) was
added. After stirring for 1 h, 10 % aqueous NaOH solution (2 mL)
was added to the reaction mixture, and the mixture was diluted
with AcOEt (100 mL) and washed with brine. The solvent was re-
moved, and the residue was separated by alumina column chroma-
tography with AcOEt/hexane (1:2) to give 30 (160 mg, 75 %) as
Early-Eluting Fraction 29a: Colorless crystals, m.p. 161–162 °C. IR
1
(CHCl3): ν = 1726 cm–1. H NMR (500 MHz, CDCl3): δ = 1.68 (s, 9 H),
˜
2.57 (s, 3 H), 2.73 (s, 3 H), 2.83 (t, J = 8.0 Hz, 2 H), 3.76 (t, J = 8.0 Hz,
2 H), 7.35 (t, J = 7.5 Hz, 1 H), 7.47 (t, J = 7.5 Hz, 1 H), 8.10 (d, J =
8.0 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.80 (s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 15.4, 16.5, 22.8, 28.2, 47.1, 82.4, 115.0, 122.4,
123.1, 123.2, 125.6, 126.9, 127.0, 127.1, 128.4, 131.1, 137.9, 141.5,
151.1, 159.1 ppm. HRMS (ESI): calcd. for C22H25N2O2 [M + H]+
349.1916, found 349.1915.
colorless crystals, m.p. 158–159 °C. IR (CHCl3): ν = 1728 cm–1 1H
.
˜
NMR (500 MHz, CDCl3): δ = 1.65 (s, 9 H), 2.26, 2.29 (two s, 3 H), 2.56,
2.57 (two s, 3 H), 2.64, 2.68 (two s, 3 H), 2.79 (t, J = 6.0 Hz, 2 H),
2.97, 3.01 (two t, J = 6.0 Hz, 2 H), 3.68, 3.74 (two s, 2 H), 7.31 (t, J =
7.5 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 8.10,
8.11 (two d, J = 7.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
15.1, 15.5, 16.4, 17.1, 27.5, 28.2, 46.1, 52.4, 52.6, 56.6, 57.0, 83.6,
115.0, 119.9, 121.7, 122.4, 122.5, 122.9, 124.0, 124.3, 125.9, 126.3,
127.6, 127.8, 128.1, 132.1, 132.4, 137.6, 137.9, 140.9, 141.0, 151.5,
151.6 ppm. HRMS (ESI): calcd. for C23H29N2O2 [M + H]+ 365.2229,
found 365.2231.
Later-Eluting Fraction 29b: Colorless crystals, m.p. 166–167 °C. IR
1
(CHCl3): ν = 1730 cm–1. H NMR (500 MHz, CDCl3): δ = 1.70 (s, 9 H),
˜
2.33 (s, 3 H), 2.85–2.89 (m, 2 H), 2.94 (s, 3 H), 3.74–3.80 (m, 2 H),
7.38 (t, J = 7.5 Hz, 1 H), 7.47 (t, J = 7.5 Hz, 1 H), 8.07 (d, J = 8.0 Hz,
1 H), 8.14 (d, J = 8.0 Hz, 1 H), 8.92 (s, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 15.0, 16.9, 23.8, 28.2, 46.6, 84.4, 114.7, 120.7, 122.6,
122.9, 123.3, 124.4, 126.4, 127.0, 129.4, 135.9, 140.5, 140.8, 151.0,
158.4 ppm. HRMS (ESI): calcd. for C22H25N2O2: [M + H]+ 349.1916,
found 349.1914.
2-Methyl-1,2,3,4-tetrahydroellipticine (5): To a solution of 30
(100 mg, 0.27 mmol) in CH2Cl2 at –78 °C under an argon atmos-
phere, BBr3 (1
M solution in CH2Cl2, 0.4 mL) was added. After stirring
3,4-Dihydroellipticine (μ-Alkaloid D) (3): BBr3 (1
M
solution in
for 30 min, the reaction was quenched with 10 % aqueous NaOH
solution (2 mL). The mixture was extracted with CH2Cl2 (100 mL),
and the extract was dried with Na2SO4. The solvent was removed,
and the residue was separated by alumina column chromatography
with AcOEt/hexane (3:1) to give 5 (46 mg, 65 %) as colorless crystals,
CH2Cl2, 0.4 mL) was added to a solution of 29 (100 mg, 0.287 mmol)
in CH2Cl2 (10 mL) at –78 °C, and the mixture was stirred for 0.5 h.
To the reaction mixture, 10 % aqueous NaOH solution (2 mL) was
added, and the mixture was extracte with CH2Cl2. The organic layer
was washed with brine and dried with Na2SO4. The solvent was m.p. 221–225 °C (ref.[15] m.p. 218–223 °C). IR (CHCl3): ν = 3474 cm–1
.
˜
removed, and the residue was separated by alumina column chro-
matography with AcOEt/MeOH (100:1) to give 3 (53 mg, 75 %) as H), 2.76 (t, J = 6.3 Hz, 2 H), 2.99 (t, J = 6.3 Hz, 2 H), 3.73 (s, 2 H),
colorless crystals, m.p. 276–280 °C dec. (ref.[13a] 281–283 °C dec). IR
7.19 (t, J = 7.5 Hz, 1 H), 7.36 (t, J = 7.5 Hz, 1 H), 7.43 (d, J = 8.0 Hz,
(CHCl3): ν = 3650, 1603, 1572 cm–1. 1H NMR (500 MHz, CD3OD): δ = 1 H), 7.97 (br. s, 1 H), 8.18 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR
1H NMR (500 MHz, CDCl3): δ = 2.36 (s, 3 H), 2.57 (s, 3 H), 2.66 (s, 3
˜
2.68 (s, 3 H), 2.75 (s, 3 H), 2.88 (t, J = 7.5 Hz, 2 H), 3.67 (dt, J = 1.7,
7.5 Hz, 2 H), 7.16 (t, J = 7.5 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 1 H), 7.50
(d, J = 8.0 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 8.77 (s, 1 H) ppm. 13C
NMR (125 MHz, CD3OD): δ = 10.6, 14.2, 22.3, 46.6, 110.6, 117.3,
(125 MHz, CDCl3): δ = 12.7, 15.1, 28.2, 46.6, 52.8, 57.0, 110.4, 114.3,
1
119.1, 120.0, 122.6, 124.6, 124.7, 126.6, 130.0, 137.8, 139.9 ppm. H
NMR (500 MHz, CD3OD): δ = 2.37 (s, 3 H), 2.52 (s, 3 H), 2.64 (s, 3 H),
2.77 (t, J = 6.3 Hz, 2 H), 2.98 (t, J = 6.3 Hz, 2 H), 3.73 (s, 2 H), 7.08
118.7, 122.6, 122.8, 123.4, 124.1, 125.1, 125.5, 126.6, 137.9, 141.5, (t, J = 7.5 Hz, 1 H), 7.28 (t, J = 7.5 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H),
159.8 ppm. HRMS (ESI): calcd. for C17H17N2 [M + H]+ 249.1392, found
249.1379.
8.11 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CD3OD): δ = 11.4,
13.9, 27.2, 44.9, 52.3, 56.2, 110.7, 114.5, 118.0, 119.7, 121.9, 122.3,
Eur. J. Org. Chem. 2016, 2290–2299
www.eurjoc.org
2296
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
123.9, 124.1, 125.8, 128.6, 138.4, 140.7 ppm. HRMS (ESI): calcd. for
C18H21N2 [M + H]+ 265.1705; found 265.1677.
Na2SO4. The solvent was removed, and the residue was separated
on TLC plate (Aluminium oxide 60 F254 basic, Merck) with hexane/
AcOEt (2:1) to give ( )-9 (20 mg, 60 %) as colorless crystals, m.p.
tert-Butyl 5-Methyl-3,4-dihydro-6H-pyrido[4,3-b]carbazole-6-
carboxylate (32): A solution of 18f (1.1 g, 2.3 mmol) was stirred in
the presence of 20 % Pd(OH)2/C (500 mg) in THF under atmospheric
pressure of hydrogen for 1 h, the catalyst and the solvent were
removed. The residue 31 and MnO2 (5 g) were stirred in dioxane at
room temperature for 3 d. The insoluble materials were removed
by filtration, and the filtrate was concentrated and separated by
flash column chromatography with AcOEt/hexane (1:1) to give
32[13] (537 mg, 70 %).
248–250 °C (ref.[19a] m.p. 245–248 °C). IR (KBr): ν = 3136, 1600 cm–1
.
˜
1H NMR (500 MHz, CDCl3): δ = 1.50 (d, J = 6.9 Hz, 3 H), 2.40 (s, 3 H),
2.52 (s, 3 H), 2.72–2.80 (m, 1 H), 2.88–2.98 (m, 2 H), 3.12–3.20 (m, 1
H), 3.86 (q, J = 6.9 Hz, 1 H), 7.18 (t, J = 7.5 Hz, 1 H), 7.36 (t, J =
7.5 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), 7.69
(s, 1 H), 7.81 (s, 1 H), 8.00 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 13.0, 20.5, 25.9, 42.8, 48.6, 59.7, 110.6, 116.0,
116.7, 119.3, 120.2, 121.2, 123.9, 125.5, 130.0, 131.7, 137.9,
139.8 ppm. 1H NMR (500 MHz, CD3OD): δ = 1.48 (d, J = 6.9 Hz, 3
H), 2.42 (s, 3 H), 2.48 (s, 3 H), 2.74–2.80 (m, 1 H), 2.90–3.00 (m, 2 H),
3.14–3.20 (m, 1 H), 3.89 (q, J = 6.5 Hz, 1 H), 7.07 (t, J = 7.5 Hz, 1 H),
7.28 (t, J = 7.5 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.68 (s, 1 H), 7.94
(d, J = 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CD3OD): δ = 11.6, 18.5,
22.8, 39.4, 47.3, 60.1, 110.5, 115.7, 117.5, 118.5, 119.5, 121.7, 123.0,
125.3, 125.4, 125.8, 139.1, 140.8 ppm. HRMS (ESI): calcd. for C18H21N2
[M + H]+ 265.1705, found 265.1705.
2-Benzyl 6-tert-Butyl
1,5-Dimethyl-3,4-dihydro-1H-pyrido-
[4,3-b]carbazole-2,6-dicarboxylate (15): Benzyl chloroformate
(0.33 mL, 2.3 mmol) was added to a solution of 32 (600 mg,
1.8 mmol) in THF (50 mL) at 0 °C under an argon atmosphere, and
the mixture was stirred for 30 min at 0 °C. Then, MeMgBr (1.4
M
solution in THF, 1.6 mL) was added to the mixture at 0 °C, and the
whole mixture was stirred at 0 °C for 30 min. Then, ice-cold water
was (20 mL) added, and the mixture was extracted with AcOEt
(200 mL). The organic layer was washed with brine, and dried with
MgSO4. The solvent was removed, and the residue was separated
by flash column chromatography with hexane/AcOEt (1:1) to give
Conformer 9a: A mixture of 33 (50 mg) and Cs2CO3 (100 mg) in
MeOH (10 mL) and THF (10 mL) was heated under reflux for 3 h,
and then, the solvent was removed. The residue was diluted with
CH2Cl2 (100 mL), washed with brine, and dried with Na2SO4. The
solvent was removed, and the residue was separated on TLC plate
(Aluminium oxide 60 F254 basic, Merck) with hexane/AcOEt (2:1) to
give 9a (22 mg, 61 %) as colorless crystals, m.p. 240–241 °C. IR (KBr):
15 (700 mg, 80 %) as an oil. IR (neat): ν = 1722, 1697 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 1.52–1.60 (m, 3 H), 1.68, 1.75 (two s, 9 H),
2.32, 2.72 (two s, 3 H), 2.82–3.04 (m, 2 H), 3.30–3.49 (m, 1 H), 4.15–
4.39 (m, 1 H), 5.12–5.28 (m, 2 H), 5.38–5.50 (m, 1 H), 7.29–7.46 (m,
7 H), 7.53–7.59, 7.86–7.91 (two m, 0.6 H), 8.00, 8.01 (two s, 0.4 H),
8.03–8.08, 8.27–8.32 (two m, 1 H), 8.13–8.18, 8.36–8.41 (two m, 1
H) ppm. 13C NMR (500 MHz, CDCl3): δ = 16.0, 17.5, 22.6, 23.0, 23.2,
26.2, 26.3, 27.0, 27.1, 28.3, 28.5, 37.4, 37.8, 38.2, 51.1, 51.7, 67.1, 67.2,
83.8, 84.0, 112.2, 112.4, 115.5, 116.1, 119.6, 119.7, 122.5, 122.9, 123.1,
123.2, 124.7, 124.9, 125.8, 126.3, 126.5, 126.9, 127.1, 127.4, 127.9,
128.0, 128.6, 130.7, 130.9, 132.3, 132.6, 134.3, 134.7, 137.0, 137.2,
137.3, 137.4, 137.7, 138.0, 138.9, 139.1, 140.8, 151.1, 151.4, 154.9,
155.2 ppm. HRMS (ESI): calcd. for C30H32N2O4Na [M + Na]+ 507.2260,
found 507.2261.
ν = 3138, 1610 cm–1 1H NMR (500 MHz, CDCl3): δ = 1.48 (d, J =
.
˜
6.3 Hz, 3 H), 2.52 (s, 3 H), 2.76 (s, 3 H), 2.74–2.84 (m, 1 H), 2.90–3.00
(m, 2 H), 3.06–3.24 (m, 1 H), 3.83 (q, J = 6.3 Hz, 1 H), 7.04 (s, 1 H),
7.20 (dt, J = 1.1, 7.5 Hz, 1 H), 7.37 (dt, J = 1.1, 7.5 Hz, 1 H), 7.40 (d,
J = 8.0 Hz, 1 H), 7.94 (br. s, 1 H), 8.20 (d, J = 7.5 Hz, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 15.9, 20.5, 25.3, 42.8, 49.2, 60.1, 106.2,
1
110.3, 119.2, 121.2, 122.7, 124.0, 125.1, 131.1, 138.2, 140.1 ppm. H
NMR (500 MHz, CD3OD): δ = 1.51 (d, J = 6.3 Hz, 3 H), 2.55 (s, 3 H),
2.73 (s, 3 H), 2.84–2.92 (m, 1 H), 2.96–3.04 (m, 2 H), 3.24–3.30 (m, 1
H), 3.98 (q, J = 6.5 Hz, 1 H), 7.09 (s, 1 H), 7.11 (t, J = 7.5 Hz, 1 H),
7.31 (t, J = 7.5 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 8.15 (d, J = 8.0 Hz,
1 H) ppm. 13C NMR (125 MHz, CD3OD): δ = 14.6, 18.5, 24.2, 41.1,
58.5, 106.0, 110.0, 118.0, 120.7, 121.2, 122.0, 123.4, 124.4, 130.2,
136.4, 138.9, 140.8 ppm. HRMS (ESI): calcd. for C18H21N2 [M + H]+
265.1705, found 265.1700.
tert-Butyl 1,2,5-Trimethyl-1,2,3,4-tetrahydro-6H-pyrido[4,3-b]-
carbazole-6-carboxylate (33): To a solution of 15 (190 mg,
0.39 mmol) in THF (30 mL), DIBAL (1
M solution in toluene, 5 mL)
was added at 0 °C, and then stirred at room temperature for 3 h.
Ice-cold water (10 mL) was added to the mixture, and the mixture
was extracted with AcOEt (100 mL). The organic layer was washed
with brine and dried with MgSO4. The solvent was removed, and
the residue was separated by flash column chromatography with
( )-Janetine (8): A solution of 15 (100 mg, 0.2 mmol) was stirred in
the presence of 20 % Pd(OH)2/C (100 mg) in THF under atmospheric
pressure of hydrogen for 1 h, the catalyst and the solvent were
removed. The residue 34 was dissolved in CH2Cl2, and cooled to
hexane/AcOEt (1:1) to give 33 (114 mg, 80 %) as an oil. IR (CHCl3):
–78 °C under an argon atmosphere. Then, BBr3 (1
M solution in
1
ν = 1716 cm–1. H NMR (500 MHz, CDCl3): δ = 1.49 (d, J = 6.9 Hz, 3
˜
CH2Cl2, 0.26 mL) was added. After stirring for 30 min, the reaction
was quenched with 10 % aqueous NaOH solution (2 mL). The mix-
ture was extracted with CH2Cl2 (100 mL), and the extract was dried
with Na2SO4. The solvent was removed, and the residue was sepa-
rated on TLC plate (Aluminium oxide 60 F254 basic, Merck) with
hexane/AcOEt (1:1) to give ( )-8 (25 mg, 50 %) as colorless crystals,
H), 1.75 (s, 9 H), 2.52 (s, 3 H), 2.71 (s, 3 H), 2.74–2.80 (m, 1 H), 2.86–
3.00 (m, 2 H), 3.14–3.22 (m, 1 H), 3.84 (q, J = 6.9 Hz, 1 H), 7.33 (t,
J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 1 H), 8.05 (s, 1 H), 8.15 (d, J =
8.0 Hz, 1 H), 8.34 (d, J = 8.6 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 15.9, 17.3, 20.0, 20.4, 25.5, 26.3, 28.3, 28.5, 42.9, 48.4,
48.7, 59.6, 60.3, 83.6, 83.7, 112.3, 115.3, 115.5, 116.1, 119.4, 122.3,
122.7, 122.8, 123.0, 124.4, 125.5, 126.1, 126.7, 126.8, 127.3, 130.5,
132.6, 135.8, 137.2, 137.7, 139.0, 139.1, 140.8, 151.2, 151.5 ppm.
HRMS (ESI): calcd. for C23H29N2O2 [M + H]+ 365.2229, found
365.2243.
m.p. > 300 °C. (ref.[17a] 290–295 °C). IR (KBr): ν = 3431, 3286,
˜
1606 cm–1. 1H NMR (500 MHz, CD3OD): δ = 1.77 (d, J = 6.8 Hz, 3 H),
2.48 (s, 3 H), 3.09–3.24 (m, 2 H), 3.40–3.48 (m, 1 H), 3.57–3.63 (m, 1
H), 4.70 (q, J = 6.8 Hz, 1 H), 7.12 (dt, J = 1.2, 7.5 Hz, 1 H), 7.34 (dt,
J = 1.2, 7.5 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.84 (s, 1 H), 8.00 (d,
J = 7.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CD3OD): δ = 11.8, 19.0,
23.3, 39.4, 52.0, 110.6, 114.8, 117.7, 118.6, 119.6, 121.8, 122.9, 124.1,
125.5, 126.2, 139.3, 140.8 ppm. HRMS (ESI): calcd. for C17H19N2 [M
+ H]+ 251.1548, found 251.1554.
( )-Guatambuine (9): To a solution of 33 (50 mg, 0.13 mmol) in
CH2Cl2 (15 mL) at –78 °C under an argon atmosphere, BBr3 (1
M
solution in CH2Cl2, 0.26 mL) was added. Then, the whole mixture
was stirred at –78 °C for 30 min, and the reaction was quenched
with 10 % aqueous NaOH solution (2 mL). The mixture was ex- tert-Butyl 1,5-Dimethyl-6H-pyrido[4,3-b]carbazole-6-carboxyl-
tracted with CH2Cl2 (100 mL), and the extract was dried with ate (36): A solution of 24 (300 mg, 0.62 mmol) was stirred in the
Eur. J. Org. Chem. 2016, 2290–2299
www.eurjoc.org
2297
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
presence of 20 % Pd(OH)2/C (300 mg) in THF under atmospheric
pressure of hydrogen for 1 h, and then, the catalyst and the solvent
were removed. The residue 34 was stirred with MnO2 (6 g) in CH2Cl2
(100 mL) at room temperature for 7 d. The insoluble materials were
removed by filtration, and the filtrate was concentrated and sepa-
rated by flash column chromatography with AcOEt to give 36
J = 1.1, 7.5 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1
H), 7.87 (d, J = 6.3 Hz, 1 H), 8.15 (d, J = 6.3 Hz, 1 H), 8.26 (d, J =
7.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CD3OD): δ = 11.0, 21.0, 110.5,
111.2, 114.6, 115.2, 119.2, 120.7, 127.3, 123.1, 125.8, 127.5, 133.0,
137.6, 141.6, 143.2 ppm. HRMS (ESI): calcd. for C17H15N2 [M + H]+
247.1235, found 247.1233.
(154 mg, 72 %) as colorless crystals, m.p. 183–184 °C. IR (CHCl3): ν =
˜
1732 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.71, 1.83 (two s, 9 H),
Acknowledgments
2.75, 3.16 (two s, 6 H), 7.40–7.49 (m, 1 H), 7.54, 7.60 (two dt, J = 1.1,
7.5 Hz, 1 H), 7.89, 7.98 (two d, J = 6.3 Hz, 1 H), 8.10, 8.48 (two d, J =
8.5 Hz, 1 H), 8.12, 8.36 (two d, J = 7.9 Hz, 1 H), 8.40 (d, J = 6.3 Hz,
1 H), 8.58, 9.00 (two s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
15.2, 17.3, 22.8, 23.0, 28.2, 28.5, 84.3, 84.4, 109.2, 113.9, 115.4, 115.6,
116.1, 116.3, 120.2, 120.5, 123.4, 123.7, 123.9, 124.9, 125.6, 126.0,
126.5, 127.5, 128.1, 128.4, 128.5, 128.6, 131.4, 135.6, 137.3, 139.0,
139.7, 140.2, 140.9, 142.2, 151.0, 151.1, 158.8, 159.0 ppm. HRMS
(ESI): calcd. for C22H23N2O2 [M + H]+ 347.1760, found 347.1766.
This work was supported in part by the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan through
a Grant-in-Aid for Scientific Research (grant number 26460012),
and by the Akiyama Foundation.
Keywords: Total synthesis · Natural products · Alkaloids ·
Nitrogen heterocycles · Electrocyclization · Copper
tert-Butyl 1,5-Dimethyl-3,4-dihydro-6H-pyrido[4,3-b]carbazole-
6-carboxylate (35): A solution of 15 (300 mg, 0.62 mmol) was
stirred in the presence of 20 % Pd(OH)2/C (300 mg) in THF (30 mL)
under atmospheric pressure of hydrogen for 1 h, and then, the
catalyst and the solvent were removed. The residue 34 was stirred
with MnO2 (1.5 g) in THF (50 mL) at room temperature for 4 d. The
insoluble materials were removed by filtration, and the filtrate was
concentrated and separated by flash column chromatography with
[1] S. Goodwin, A. F. Smith, E. C. Horning, J. Am. Chem. Soc. 1959, 81, 1903–
1908.
[2] J. Schmutz, F. Hunzicker, Pharm. Acta Helv. 1958, 33, 341–347.
[3] a) A. R. Carroll, R. Addepalli, G. Fechner, J. Smith, G. P. Guymer, P. I. Forster,
R. J. Quinn, J. Nat. Prod. 2008, 71, 1063–1065; b) J. J. de Souza, L. Mathias,
R. Braz-Filho, I. J. C. Vieira, Helv. Chim. Acta 2010, 93, 422–429; c) A. K. L.
Santos, L. L. Machado, A. M. C. Bizerra, F. J. Q. Monte, G. M. P. Santiago,
R. Braz-Filho, T. L. G. Lemos, Nat. Prod. Commun. 2012, 7, 729–730; d)
Z. E. dos Santos Torres, E. R. Silveira, L. F. R. de Silva, E. S. Lima, M. C.
de Vasconcello, D. E. de Andrade Uchoa, R. B. Filho, A. M. Pohlit, Molecules
2013, 18, 6281–6297.
[4] a) M. Stiborová, J. Sejbal, L. Bořek-Dohalská, D. Aimová, J. Poljaková, K.
Forsterová, M. Rupertová, J. Wiesner, J. Hudecek, M. Wiessler, E. Frei, Can-
cer Res. 2004, 64, 8374–8380; b) R. Jasztold-Howorko, M. Pelczynska, A.
Nasulewicz, J. Wietrzyk, A. Opolski, Arch. Pharm. Chem. Sci. Ed. 2005, 338,
556–561; c) M. Ohashi, T. Oki, Expert. Opin. Ther. Pat. 1996, 6, 1285–1294;
d) F. M. Deane, E. C. O'Sullivan, A. R. Maguire, J. Gilbert, J. A. Sakoff, A.
McCluskey, F. O. McCarthy, Org. Biomol. Chem. 2013, 11, 1334–1344; e)
T. P. Chierrito, A. C. C. Aguiar, I. M. de Andrade, I. P. Ceravolo, R. A. C.
Gonçalves, A. J. B. de Oliveira, A. U. Krettli, Malar. J. 2014, 13:142; f) A.
Montoia, L. F. R. e. Silva, Z. E. Torres, D. S. Costa, M. C. Henrique, E. S.
Lima, M. C. Vasconcellos, R. C. Souza, M. R. F. Costa, A. Grafov, I. Grafova,
M. N. Eberlin, W. P. Tadei, R. C. N. Amorim, A. M. Pohlit, Bioorg. Med.
Chem. Lett. 2014, 24, 2631–2634.
[5] a) B. Tylińska, R. Jasztold-Howorko, H. Mastalarz, D. Kłopotowska, B. Filip,
J. Wietrzyk, Acta Pol. Pharm. Drug Res. 2010, 67, 495–502; b) R. Jasztold-
Howorko, B. Tylińska, B. Biaduń, T. Gebarowski, K. Gasiorowski, Acta Pol.
Pharm. Drug Res. 2013, 70, 823–832.
[6] a) M. Álvarez, J. A. Joule, Heterocyclic Compounds, Supplement to vol. 25:
The Uleine-Ellipticine-Vallesamine-Ngouniensine group (Ed.: J. E. Saxton),
John Wiley & Sons, Chichester, UK, 1994, p. 261–278; b) M. Álvarez, J. A.
Joule, The Alkaloids, vol. 57: Ellipticine, Uleine, Apparicine, and Related
Alkaloids (Ed., G. A. Cordell), Academic Press, Amsterdam, 2001, p. 235–
272; c) H.-J. Knölker, K. R. Reddy, Chem. Rev. 2002, 102, 4303–4427; d)
A. W. Schmidt, K. R. Reddy, H.-J. Knölker, Chem. Rev. 2012, 112, 3193–
3328; e) I. Bauer, H.-J. Knölker, Top. Curr. Chem. 2012, 309, 203–253; f) J.
Roy, A. K. Jana, D. Mal, Tetrahedron 2012, 68, 6099–6121.
AcOEt to give 35 (151 mg, 70 %) as an oil and 36 (10 mg, 5 %). IR
1
(CHCl3): ν = 1722 cm–1. H NMR (500 MHz, CDCl3): δ = 1.79 (s, 9 H),
˜
2.61 (s, 3 H), 2.79 (s, 3 H), 2.90–2.97, 3.09–3.14 (two m, 2 H), 3.76–
3.80, 4.08–4.14 (two m, 2 H), 7.37, 7.39 (two t, J = 7.5 Hz, 1 H), 7.48,
7.52 (two t, J = 7.5 Hz, 1 H), 8.16, 8.22 (two d, J = 7.9 Hz, 1 H), 8.39,
8.42 (two d, J = 7.5 Hz, 1 H), 8.53, 8.58 (two s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 16.0, 22.7, 23.3, 28.5, 46.1, 84.4, 112.6, 116.3,
123.0, 123.1, 123.3, 125.9, 127.3, 127.6, 129.7, 130.5, 137.0, 139.8,
150.9 ppm. HRMS (ESI): calcd. for C22H25N2O2 [M + H]+ 349.1916,
found 349.1919.
3,4-Dihydroolivacine (7): To a solution of 35 (100 mg, 0.26 mmol)
in CH2Cl2 (20 mL) at –78 °C under an argon atmosphere, BBr3 (1
M
solution in CH2Cl2, 0.5 mL) was added. Then, the whole mixture was
stirred at –78 °C for 30 min, and the reaction was quenched with
10 % aqueous NaOH solution (2 mL). The mixture was extracted
with CH2Cl2 (100 mL), and the extract was dried with Na2SO4. The
solvent was removed, and the residue was separated on TLC plate
(aluminum oxide 60 F254 basic, Merck) with hexane/AcOEt (2:1) to
give 7 (42 mg, 60 %) as pale yellow crystals, m.p. > 300 °C. (ref.[17a]
307–318 °C). IR (KBr): ν = 3300, 1627 cm–1 1H NMR (500 MHz,
.
˜
[D6]acetone): δ = 2.42 (s, 3 H), 2.52 (s, 3 H), 2.75–2.85 (m, 2 H), 3.56
(t, J = 7.5 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 7.35 (t, J = 7.5 Hz, 1 H),
7.49 (d, J = 8.0 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.24 (s, 1 H), 10.4
(br. s, 1 H) ppm. 13C NMR (125 MHz, [D6]acetone): δ = 12.0, 23.2,
23.4, 46.9, 111.1, 115.7, 116.3, 119.3, 120.0, 120.5, 122.4, 124.0, 125.5,
133.4, 140.4, 140.9, 163.9 ppm. HRMS (ESI): calcd. for C17H17N2 [M
+ H]+ 249.1392, found 249.1398.
[7] M. Ishikura, Heterocycles 2011, 83, 247–273.
Olivacine (6): To a solution of 36 (50 mg, 0.13 mmol) in CH2Cl2
[8] M. Ishikura, A. Hino, T. Yaginuma, I. Agata, N. Katagiri, Tetrahedron 2000,
56, 193–207.
[9] M. Ishikura, N. Takahashi, K. Yamada, T. Abe, R. Yanada, Helv. Chim. Acta
2008, 91, 1828–1837.
[10] T. Abe, T. Ikeda, R. Yanada, M. Ishikura, Org. Lett. 2011, 13, 3356–3359.
[11] M. Ishikura, N. Takahashi, K. Yamada, T. Abe, Heterocycles 2008, 75, 107–
118.
[12] a) C.-Y. Liu, P. Knochel, J. Org. Chem. 2007, 72, 7106–7115; b) F. M. Deane,
C. M. Millaer, A. R. Maguire, F. O. MaCarthy, J. Heterocycl. Chem. 2011, 48,
814–823; c) N. Ramkumar, M. S. Raghavendra, R. Nagarajan, Synlett 2014,
25, 2791–2793.
(15 mL) at –78 °C under an argon atmosphere, BBr3 (1
M solution
in CH2Cl2, 0.26 mL) was added. Then, the whole mixture was stirred
at –78 °C for 30 min, and the reaction was quenched with 10 %
aqueous NaOH solution (2 mL). The mixture was extracted with
CH2Cl2 (100 mL), and the extract was dried with Na2SO4. The solvent
was removed, and the residue was separated on TLC plate (alumi-
num oxide 60 F254 basic, Merck) with hexane/AcOEt (2:1) to give 6
(20 mg, 60 %) as colorless crystals, m.p. > 300 °C (ref.[16a] > 300 °C).
1H NMR (500 MHz, CD3OD): δ = 2.82 (s, 3 H), 3.06 (s, 3 H), 7.23 (dt,
Eur. J. Org. Chem. 2016, 2290–2299
www.eurjoc.org
2298
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[13] a) G. Büchi, D. W. Mayo, F. A. Hochstein, Tetrahedron 1961, 15, 167–172;
b) H. Lehner, J. Schmutz, Helv. Chim. Acta 1961, 44, 444–446.
[14] a) A. M. Morfaux, T. Mulamba, B. Richard, C. Delaude, G. Massiot, L. L.
Men-Oliver, Phytochemistry 1982, 21, 1767–1769; b) F. L. Goffic, A. Gouy-
ette, A. Ahond, Tetrahedron 1973, 29, 3357–3362.
[18] C. G. Gonzalez, S. C. Rodriguez, Rev. Cubana Farm. 1978, 12, 177–183.
[19] a) M. A. Ondetti, V. Deulofeu, Tetrahedron 1961, 15, 160–166; b) R. Besse-
lièvre, H.-P. Husson, Tetrahedron 1981, 37, 241–246; c) M.-L. Bennasar, T.
Roca, F. Ferrando, J. Org. Chem. 2006, 71, 1746–1749.
[20] C. A. De Simone, V. R. S. Malta, G. S. Lamenha, M. M. S. Humberto, K. R. A.
Porto, A. E. G. Sant'Ana, Z. Kristallogr. New Cryst. Struct. 2006, 221, 233–
234.
[15] M. C. Henrique, S. M. Nunomura, A. M. Pohlit, Quim. Nova 2010, 33, 284–
287.
[16] a) N. Ramkumar, R. Nagarajan, J. Org. Chem. 2014, 79, 736–741; b) X.
Zheng, L. Lv, S. Lu, W. Wang, Z. Li, Org. Lett. 2014, 16, 5156–5159.
[17] a) J. Schumz, H. Wittwer, Helv. Chim. Acta 1960, 43, 793–799; b) M.
Azoug, A. Loukaci, B. Richard, J.-M. Nuzillard, C. Moreti, M. Zeches-Hanrot,
L. L. Men-Oliver, Phytochemistry 1995, 39, 1223–1228.
Received: March 3, 2016
Published Online: April 13, 2016
Eur. J. Org. Chem. 2016, 2290–2299
www.eurjoc.org
2299
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim