Total synthesis of calothrixins A and B by palladium-catalyzed tandem cyclization/cross-coupling reaction of indolylborate

Article abstract of DOI:10.1002/ejoc.201200657

The palladium-catalyzed tandem cyclization/cross-coupling reaction of triethyl(indol-2-yl)borate with vinyl bromide was successfully used in the concise total synthesis of the indolophenanthridine alkaloids, calothrixins A and B. Palladium-catalyzed cross

Full text of DOI:10.1002/ejoc.201200657

Job/Unit: O20657
/KAP1
Date: 25-07-12 16:02:51
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201200657
Total Synthesis of Calothrixins A and B by Palladium-Catalyzed Tandem
Cyclization/Cross-Coupling Reaction of Indolylborate
Takumi Abe,[a] Toshiaki Ikeda,[a] Tominari Choshi,[b] Satoshi Hibino,[b] Noriyuki Hatae,[a]
Eiko Toyata,[a] Reiko Yanada,[c] and Minoru Ishikura*[a]
Keywords: Cross-coupling / Total synthesis / Palladium / Copper / Electrocyclic reactions
The palladium-catalyzed tandem cyclization/cross-coupling
reaction of triethyl(indol-2-yl)borate with vinyl bromide was
successfully used in the concise total synthesis of the indolo-
phenanthridine alkaloids, calothrixins A and B.
tic total synthesis of 2 via a common indolo[2,3-a]carbazole
intermediate was accomplished by Hibino[6] and Moody,[7]
independently.
Introduction
Calothrixins A (1) and B (2) were originally isolated in
1999 from lyophilized extracts of Calothrix cyanobacteria,
which were collected in the Australian Capital Territory
(Figure 1).[1] The structures have an unusual pentacyclic
indolo[3,2-j]phenanthridine system, incorporating indole,
quinone, and quinoline moieties, that was identified by
spectroscopic and single-crystal X-ray analyses. Both 1 and
2 were found to inhibit the growth of human HeLa cancer
cells and of a chloroquine-resistant strain of the human ma-
laria parasite Plasmodium falciparum.[2] Recently, 1 and 2
were shown to act as human topoisomerase I poisons; both
compounds reversibly stabilize the topoisomerase–DNA bi-
nary complex, leading to cell death.[3] The total synthesis
of calothrixins A (1) and B (2) was first completed in 2000
by Kelly and co-workers, who twice used o-lithiation to
construct the indolophenanthridine core of 2, and then per-
formed N-oxidation of 2 with m-CPBA (meta-chloroper-
benzoic acid) to obtain 1.[4] Since then, several methods for
synthesizing 1 and 2 have been developed:[5] the core struc-
ture has been assembled by cyclization of 2-indolylacyl rad-
ical onto the quinoline ring, by Friedel–Crafts acylation
and metalation strategies, by hetero-Diels–Alder reaction
between 2-azadiene and 3-bromo-9H-carbazole, and by all-
ene-mediated electrocyclization.[5] Moreover, the biomime-
Figure 1. Calothrixins A (1) and B (2).
Recent studies have highlighted the palladium-catalyzed
cross-coupling reaction using organoboron compounds
(Suzuki–Miyaura coupling) as
a promising synthetic
method.[8] However, tetracoordinate organoboron com-
pounds (ate complexes) have proved impractical for palla-
dium-catalyzed cross-coupling,[9] although a method using
heteroaryltrifluoroborates has recently been developed.[10]
In connection with our continuing interest in the chemical
reactivity and synthetic applications of trialkyl(indol-2-yl)-
borates (indolylborates),[11] we found that indolylborate 4,
a tetracoordinate complex, showed high reactivity in palla-
dium-catalyzed cross-coupling. Accordingly, we set out to
develop the cross-coupling reaction of indolylborates as a
synthetic tool for the synthesis of indole derivatives. In this
paper, we report the full details of our approach to cal-
othrixins A (1) and B (2) using palladium-catalyzed tandem
cyclization/cross-coupling reactions of indolylborates.[12]
Our synthetic approach is outlined in Scheme 1. Triene 6
was envisioned to be accessible by a one-pot cross-coupling
reaction of indolylborate 4 (generated in situ from indole 3)
with bromide 5. Subsequent 6π-electrocyclization of triene
6 would then produce indolophenanthridine 7, which in
turn could be converted into the target calothrixins.
[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
Homepage: 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,
Hirokoshingai, Kure, Hiroshima 737-0112, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200657.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20657
/KAP1
Date: 25-07-12 16:02:51
Pages: 11
M. Ishikura et al.
FULL PAPER
Scheme 1. Synthetic strategy.
Scheme 3. Reagents and conditions: (a) nBuLi or tBuLi, THF, then
BEt3; (b) see Table 1.
Results and Discussion
Bromide 5 was readily prepared by the reaction sequence
outlined in Scheme 2. Sonogashira coupling of 2-iodo-
aniline with 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran in
the presence of PdCl2(PPh3)2 (3 mol-%) and CuI (10 mol-
%) in Et2NH at room temperature for 1 h smoothly pro-
duced phenylacetylene 8 in 80% yield.[13] Treatment of 8
with acetyl chloride in the presence of Et3N in CH2Cl2 gave
acetoamide 9 in 85% yield. Finally, bromide 5 was obtained
in 80% yield by treating 9 with NaH and 2,3-dibromo-
propene in THF.
Table 1. Cross-coupling reactions of 4 with 5.[a]
Entry
4
Conditions
Yield [%] (product)[b]
1
2
3
4
4a PdCl2(MeCN)2,[c] 0.5 h
4a Pd(OAc)2,[c] 0.5 h
48 (6a)
45 (6a)
52 (6a)
23 (6a)
25 (6a)
25 (6a)
55 (6a)
53 (6a)
72 (6a)
42 (6b)
50 (6b)
20 (6b)
18 (6b)
55 (6b)
60 (6b)
68 (6b)
5 (10a)
8 (10a)
7 (10a)
7 (10a)
8 (10a)
8 (10a)
5 (10a)
6 (10a)
4 (10a)
5 (10b)
6 (10b)
7 (10b)
7 (10b)
8 (10b)
8 (10b)
5 (10b)
4a Pd2(dba)3·CHCl3,[d] 0.5 h
4a Pd(OAc)2,[c] PPh3,[e] 2 h
4a PdCl2(PPh3)2,[c] 2 h
5
6
7
8
9
10
11
12
13
14
15
16
4a Pd2(dba)3·CHCl3,[d] PPh3,[e] 2 h
4a PdCl2[P(oTol)3]2,[c] 0.5 h
4a Pd(OAc)2,[c] P(oTol)3,[e] 0.5 h
4a Pd2(dba)3·CHCl3,[d] P(oTol)3,[e] 0.5 h
4b Pd(OAc)2,[c] 0.5 h
4b Pd2(dba)3·CHCl3,[d] 0.5 h
4b PdCl2(PPh3)2,[c] 2 h
4b Pd2(dba)3·CHCl3,[d] PPh3,[e] 2 h
4b Pd(OAc)2,[c] P(oTol)3,[e] 0.5 h
4b PdCl2[P(oTol)3]2,[c] 0.5 h
4b Pd2(dba)3·CHCl3,[c] P(oTol)3,[d] 0.5 h
[a] The reaction of 4 (2 equiv.) with 5 was performed in the presence
of a catalytic amount of a palladium complex in THF at 60 °C
under an argon atmosphere. [b] Yield [%] based on 5. [c] 5 mol-%.
[d] 2.5 mol-%. [e] 10 mol-%.
Scheme 2. Reagents and conditions: (a) PdCl2(PPh3)2, Et2NH, CuI,
r.t., 80%; (b) AcCl, Et3N, CH2Cl2, 85%; (c) 2,3-dibromopropene,
NaH, THF, 80%.
The cross-coupling reaction was first attempted by heat- (2.5 mol-%) in conjunction with P(oTol)3 (10 mol-%) re-
ing 4 (generated in situ from indole 3 and tBuLi or nBuLi, sulted in the highest yield of 6. The yield of 10 was invaria-
followed by treatment with BEt3) together with bromide 5 bly low, regardless of the palladium complex used. The out-
in the presence of a catalytic amount of a palladium com- come of the cross-coupling reaction can be understood in
plex in THF under an argon atmosphere at 60 °C. The reac- terms of a common mechanism (Scheme 4).[14] The catalyti-
tion produced triene 6 together with a small amount of 2- cally active Pd0 species underwent oxidative addition with
vinylindole 10 (Scheme 3). The results are summarized in bromide 5 to produce vinylpalladium complex A. Although
Table 1.
transmetallation between 4 and complex A followed by re-
In the reaction using a Pd complex without PPh3 as a ductive elimination of Pd0Ln from complex E produced 10,
ligand, bromide 5 was consumed within 0.5 h, and 6 was intramolecular cyclization of complex A (carbopallad-
obtained in moderate yield (Table 1, entries 1–3, 10 and 11). ation), leading to formation of complex B or C, occurred
The presence of PPh3 reduced the yield of 6 and necessi- more rapidly than the transmetallation step. PPh3 might
tated a longer heating time (Table 1, entries 4–6 and 12–13). stabilize tetracoordinate complex B and suppress the trans-
The combination of a P(oTol)3 ligand with the Pd complex, fer of the indole ring from 4 in the transmetallation step,
on the other hand, increased the yield of 6 (Table 1, en- thus providing the opportunity for side-reactions to occur.
tries 7–9 and 14–16). The reaction using Pd2(dba)3·CHCl3 In contrast, coordination of bulky P(oTol)3 shifted the equi-
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20657
/KAP1
Date: 25-07-12 16:02:51
Pages: 11
Total Synthesis of Calothrixins A and B
librium between B and C towards the less crowded tricoord- Table 2. Lewis acid promoted cyclization of 6a.[a]
inate complex C, thus promoting the transfer of the indole
Entry Conditions
Yield [%] (product)
ring from 4, and leading to formation of complex D. Re-
1
2
3
4
5
6
7
8
InCl3,[b] DMF, 120 °C, 1 h
no reaction
20 (7a)
no reaction
51 (7a)
No reaction
70 (7a)
no reaction
no reaction
no reaction
74 (7c) + 13 (6c)
complex mixture
47 (7c)
ductive elimination of Pd0Ln from complex D gave triene 6.
In(OTf)3,[b] DMF, 120 °C, 2 h
In(OTf)3,[b] MeCN, r.t., 4 h
Cp2ZrCl2,[c] MeCN, r.t., 4 h
Cp2ZrCl2,[c] MeCN, r.t., 4 h
[Cp*IrCl2]2,[c][e] MeCN, r.t., 4 h
[Cp*IrCl2]2,[d][e] MeCN, r.t., 4 h
Cu(OTf)2,[c] MeCN, r.t., 1 h
9
CuOTf,[c] MeCN, r.t., 1 h
10
11
12
13
(CuOTf)2·toluene,[c] MeCN, r.t., 1 h
(CuOTf)2·toluene,[d] MeCN, reflux, 16 h[f]
(CuOTf)2·toluene,[d] MeCN, reflux, 16 h[g]
(CuOTf)2·toluene,[d] MeCN, reflux, 16 h[h]
65 (7c) + 10 (6c)
[a] All reactions were performed in air. [b] 2 equiv. [c] 1 equiv.
[d] 0.1 equiv. [e] Cp* = 1,2,3,4,5-pentamethylcyclopedienyl. [f] A
mixture of (CuOTf)2·toluene and 6a in MeCN was heated under
reflux. [g] A solution of (CuOTf)2·toluene in MeCN was added
dropwise to a refluxing solution of 6a in MeCN. [h] A solution of
6a in MeCN was added dropwise to a refluxing solution of (Cu-
OTf)2·toluene in MeCN.
Heating 6a with In(OTf)3 in DMF at 120 °C produced
7a in 20% yield, whereas InCl3 was completely ineffective
(Table 2, entries 1 and 2). Treatment of 6a with Zr and Ir
complexes in MeCN at room temperature gave 7a in 51 and
70% yields, respectively (Table 2, entries 4 and 6). More-
over, performing the reaction using (CuOTf)2·toluene com-
plex (1 equiv.) at room temperature led to the formation of
7c (74%) and 6c (13%), in which the O-THP group had
been removed (Table 2, entry 10). However, other Cu com-
plexes [CuOTf and Cu(OTf)2] were completely ineffective.
Further evaluation revealed that the reaction could be cata-
lyzed by (CuOTf)2·toluene (10 mol-%); dropwise addition
of a MeCN solution of 6a to a refluxing MeCN solution
of (CuOTf)2·toluene (10 mol-%) provided 7c (65%) and 6c
(10%) (Table 2, entry 13). In contrast, simply heating a mix-
ture of 6a and (CuOTf)2·toluene (10 mol-%) in MeCN re-
sulted in the formation of a complex mixture of products,
and dropwise addition of a MeCN solution of (CuOTf)2·
toluene (10 mol-%) to a refluxing MeCN solution of 6a
Scheme 4. A possible reaction pathway.
Next, we turned our attention to assembling the indol- provided 7c in 47% yield (Table 2, entries 11 and 12). When
ophenanthridine ring-system of 7 by 6π-electrocyclization (CuOTf)2·toluene was used in the cyclization reaction of 6a,
of triene 6. There are a number of studies on the 6π-electro- uncyclized alcohol 6c was formed along with cyclized com-
cyclization process, which has become a powerful and im- pound 7c, presumably with faster cleavage of the O-THP
portant synthetic tool often used in natural product synthe- group preceding the cyclization step. The cyclization reac-
sis.[15] We have previously reported that photochemical and tion was therefore carried out using 6c (Scheme 4). The O-
TiCl4-promoted 6π-electrocyclization processes were effec- THP group of 6a was removed with a catalytic amount of
tive for constructing pyridocarbazoles.[16] First, photochem- camphorsulfonic acid (CSA) in MeOH/CH2Cl2 (5:1) at
ical cyclization of 6a was attempted: using a high-pressure room temperature to give 6c in 90% yield. Then, treating
mercury lamp to irradiate of 6a in benzene cooled in an ice- 6c with 1 equiv. of (CuOTf)2·toluene in MeCN at room
water bath resulted only in a complex mixture, without any temperature for 1 h provided 7c in 82% yield. Compound
isolable products. In contrast, treatment of 6a with TiCl4 in 7c was also obtained in 71% yield from the catalyzed reac-
CH2Cl2 at –78 °C under an argon atmosphere gave alcohol tion of 6c with 0.1 equiv. of (CuOTf)2·toluene in MeCN
6c without any cyclization products. Because Lewis acids under reflux for 16 h (Scheme 5). Only a few examples of
are known to lower the activation energy of some pericyclic Lewis-acid-mediated 6π-electrocyclization are known,[15]
reactions by complexation with unsaturated systems,[15] and the reaction described here is, to the best of our knowl-
various Lewis acids were screened for the 6π-electrocycliza- edge, the first example of Cu-catalyzed 6π-electrocycliza-
tion of 6a (Table 2).
tion.[17] The (CuOTf)2·toluene complex, the color of which
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20657
/KAP1
Date: 25-07-12 16:02:51
Pages: 11
M. Ishikura et al.
FULL PAPER
gradually changed from an initial pale-green after the bottle
was newly opened to gray, was effective in promoting the
reaction.
Scheme 6. Reagents and conditions: (a) (PhSe)2 (0.1 equiv.), 30%
aq. H2O2, CH2Cl2, r.t., then 10% aq. NaOH, O2, r.t., 50% (15a),
15% (16a); (b) (PhSe)2 (0.3 equiv.), 30% aq. H2O2, CH2Cl2, r.t.,
then 10% aq. NaOH, O2, r.t., 60%; (c) OXONE®, K2CO3, acetone/
H2O (1:1), 63%.
Scheme 5. Reagents and conditions: (a) CSA, MeOH/CH2Cl2 (5:1),
r.t., 90%; (b) 6c, (CuOTf)2·toluene (1 equiv.), MeCN, r.t., 82% (7c);
6c, (CuOTf)2·toluene (0.1 equiv.), MeCN, reflux, 71% (7c); (c) 7c,
PCC, CH2Cl2, r.t., 80%; (d) (PhSe)2 (0.1 equiv.), 30% aq. H2O2,
CH2Cl2, room temp., 70%; (e) MeOH, NaOMe, 90%.
% (CuOTf)2·toluene complex for 16 h produced 7d in 72%
yield. In addition, 7d was found to be obtained in good
yield (79%) by treating 6d with 0.2 equiv. (CuOTf)2·toluene
Having found conditions for obtaining indolophen-
anthridine 7c in high yield, we next examined the transfor-
mation of 7c to quinone 14. Oxidation of 7c with pyridin-
ium chlorochromate (PCC) in CH2Cl2 gave aldehyde 11a
in 80% yield. Subjecting 11a to Dakin oxidation with
[18]
(PhSe)2 and 30% H2O2 in CH2Cl2 produced formate 12,
and then methanolysis of 12 with NaOMe in MeOH pro-
vided phenol 13. However, all attempts to oxidize 13 into
quinone 14 using 10% NaOH with O2, MnO2, DDQ (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone), CAN [cerium(IV)
ammonium nitrate], or PhI(OAc)2 as oxidant were unsuc-
cessful, and resulted either in complex mixtures of products
or in the recovery of 13 (Scheme 5).
From a search for suitable reaction conditions, oxidation
of 11a with (PhSe)2 and 30% H2O2 at room temperature
for 24 h, followed by treatment with 10% NaOH under an
oxygen atmosphere for 24 h was found to produce N-meth-
ylcalothrixin B (15a) in 50% yield, along with aldehyde 16a
in 15% yield. Aldehyde 16a was converted to 15a by Dakin
oxidation with (PhSe)2 and 30% aqueous H2O2 solution in
60% yield. Moreover, oxidation of 15a with OXONE® in
50% aqueous acetone in the presence of K2CO3 gave N-
methylcalothrixin A (17) in 63% yield (Scheme 6).
Having completed the synthesis of N-methylcalothrix-
ins A (17) and B (15a) from N-methylindole (3a), we next
investigated the total synthesis of calothrixins A (1) and B
(2) using triene 6b (Scheme 7). First, the O-THP group of
6b was removed by treatment with CSA to give 6d in 90%
yield. The Cu-mediated 6π-electrocyclization of 6d success-
fully produced phenanthridine 7d. Reaction of 6d with
1 equiv. (CuOTf)2·toluene complex at room temperature for
Scheme 7. Reagents and conditions: (a) CSA, MeOH/CH2Cl2 (5:1),
r.t., 90%; (b) (CuOTf)2·toluene (1 equiv.), MeCN, r.t., 1 h, 83%;
(CuOTf)2·toluene (0.1 equiv.), MeCN, reflux, 16 h, 72%; (CuOTf)
2·toluene (0.2 equiv.), MeCN/CH2Cl2 (1:1), r.t., 24 h, 79%;
(c) PCC, CH2Cl2, r.t., 80%; (d) (CuOTf)2·toluene (0.2 equiv.), PCC
(3 equiv.), MeCN/CH2Cl2 (1:1), 50 °C, 3 h, 70%; (e) (PhSe)2
(0.1 equiv.), 30% aq. H2O2, CH2Cl2, r.t., then 10% aq. NaOH, O2,
53% (15b), 18% (16b); Cu(OAc)2 (1 equiv.), PCC (3 equiv.),
CH2Cl2, reflux, 10 h, 60%; (f) 10% Pd/C, H2, THF, 85%;
1 h gave 7d in 83% yield; heating 6d at reflux with 10 mol- (g) OXONE®, K2CO3, acetone/H2O (1:1), 70%.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20657
/KAP1
Date: 25-07-12 16:02:51
Pages: 11
Total Synthesis of Calothrixins A and B
The solvent was removed, and the residue was separated by column
complex in MeCN/CH2Cl2 at room temperature for 24 h.
PCC oxidation of alcohol 7d produced aldehyde 11b in 80%
yield. We also attempted the one-pot conversion of 6d to
11b; a mixture of 6d, (CuOTf)2·toluene complex (0.2 equiv.)
and PCC (3 equiv.) in CH2Cl2/CH3CN (1:1) was heated at
50 °C for 3 h. This provided 11b in 70% yield in one pot.
Next, Dakin oxidation of aldehyde 11b with (PhSe)2
(0.1 equiv.) and 30% aqueous H2O2 solution in CH2Cl2, fol-
lowed by treatment with 10% aqueous NaOH solution un-
chromatography on SiO2 (hexane/EtOAc, 3:1) to give 8 (1.68 g,
80%) as a pale yellow oil. IR (neat): ν = 3360, 1614 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 1.50–1.69 (m, 4 H), 1.72–1.80 (m, 1 H),
1.80–1.89 (m, 1 H), 3.53–3.60 (m, 1 H), 3.86–3.92 (m, 1 H), 4.22
(br. s, 2 H), 4.52 (d, J = 15.9 Hz, 1 H), 4.56 (d, J = 15.9 Hz, 1 H),
4.91 (t, J = 3.4 Hz, 1 H), 6.64–6.69 (m, 2 H), 7.10 (dt, J = 1.7,
7.5 Hz, 1 H), 7.28 (dd, J = 3.5, 8.0 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 19.1, 25.4, 30.4, 55.1, 62.2, 82.6, 90.5, 97.0,
107.4, 114.3, 117.8, 129.9, 132.5, 148.3 ppm. HRMS (ESI): calcd.
der an O2 atmosphere gave quinone 15b in 53% yield, along for C14H17NO2Na [M + Na]+ 254.1157; found 254.1122.
with aldehyde 16b in 18% yield, but the oxidation was
sometimes poorly reproducible. Therefore, we sought to de-
velop a more efficient oxidation of 11b to form 15b. After
evaluating the oxidation conditions, pre-mixed Cu(OAc)2
with PCC was found to be suitable as an oxidant;[19] heating
N-{2-[3-(Tetrahydro-2H-pyran-2-yloxy)prop-1-yn-1-yl]phenyl}-
acetamide (9): Acetyl chloride (1.35 g, 17.2 mmol) was added slowly
to a solution of 8 (2 g, 8.6 mmol) and Et3N (2.6 mL, 25.8 mmol)
in CH2Cl2 (100 mL) under ice-cooling. The mixture was then al-
lowed to warm gradually to room temperature and stirred for an
a mixture of pre-mixed Cu(OAc)2 (1 equiv.) and PCC additional 2 h. The mixture was concentrated on a rotary evapora-
tor, and the residue was diluted with EtOAc (200 mL). The organic
phase was washed with brine, and dried with MgSO4. The solvent
was removed, and the residue was separated by column chromatog-
raphy on SiO2 (hexane/EtOAc, 1:5) to give 9 (1.99 g, 85%) as a
(4 equiv.) with 11b in CH2Cl2 under reflux for 10 h pro-
duced 15b in 60% yield. Finally, the N-OMe group of 15b
was removed by catalytic hydrogenation using 10% Pd/C in
THF to give calothrixin B (2) in 85% yield. The N-oxi-
dation of 2 with OXONE® in aqueous acetone in the pres-
ence of K2CO3 provided calothrixin A (1) in 70% yield.
colorless solid. M.p. 56–58 °C (hexane/EtOAc). IR (CHCl ): ν =
˜
3
3402, 1695 cm–1. H NMR (500 MHz, CDCl3): δ = 1.50–1.70 (m,
1
4 H), 1.72–1.89 (m, 2 H), 2.21 (s, 3 H), 3.54–3.60 (m, 1 H), 3.86–
3.93 (m, 1 H), 4.53 (d, J = 16.6 Hz, 1 H), 4.57 (d, J = 16.6 Hz, 1
H), 4.91 (t, J = 3.4 Hz, 1 H), 7.00 (t, J = 7.5 Hz, 1 H), 7.31 (dt, J
= 1.7, 7.4 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 8.02 (br. s, 1 H),
8.37 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
19.0, 24.9, 25.4, 30.4, 55.3, 62.1, 81.3, 92.7, 97.6, 129.9, 131.8,
139.5, 168.5 ppm. HRMS (ESI): calcd. for C16H19NO3Na [M +
Na]+ 296.1262; found 296.1235.
Conclusions
In summary, we have developed a concise total synthesis
of calothrixins A (1) and B (2) and their respective N-
methyl derivatives 17 and 15a. The key features of the syn-
thesis are one-pot generation of key intermediate 6 through
the palladium-catalyzed tandem cyclization/cross-coupling
reaction of indolylborate 4 with bromide 5. We have also
developed a new protocol for 6π-electrocyclization using
(CuOTf)2·toluene complex, which is unprecedented to the
best of our knowledge. We are currently investigating fur-
ther application of this cross-coupling methodology using
indolylborate 4 in the synthesis of other indole alkaloids.
N-(2-Bromoprop-2-en-1-yl)-N-{2-[3-(tetrahydro-2H-pyran-2-yloxy)-
prop-1-yn-1-yl]phenyl}acetamide (5): Compound 9 (2.73 g,
10 mmol) was added slowly to a suspension of NaH (55% disper-
sion in mineral oil, 872 mg, 20 mmol) in THF (100 mL) at 0 °C.
The mixture was stirred for 30 min, after which time 2,3-dibro-
mopropene (3 g, 15 mmol) was added dropwise. The mixture was
allowed to warm gradually to room temperature and stirred for
2 h. The mixture was concentrated on a rotary evaporator, and the
residue was diluted with EtOAc (300 mL). The organic phase was
washed with brine and dried with MgSO4. The solvent was re-
moved, and the residue was separated by silica gel column
chromatography (hexane/EtOAc, 4:1) to give 5 (3.1 g, 80%) as a
pale yellow oil. IR (neat): ν = 1672 cm–1. 1H NMR (500 MHz,
˜
Experimental Section
CDCl3): δ = 1.50–1.65 (m, 4 H), 1.72–1.86 (m, 2 H), 1.85 (s, 3 H),
3.51–3.59 (m, 1 H), 3.82–3.89 (m, 1 H), 3.93 (d, J = 15.3 Hz, 1 H),
4.45 (d, J = 16.4 Hz, 1 H), 4.49 (d, J = 16.4 Hz, 1 H), 4.81 (t, J =
3.0 Hz, 1 H), 5.26 (d, J = 15.3 Hz, 1 H), 5.48 (s, 1 H), 5.65 (s, 1
H), 7.29–7.38 (m, 3 H), 7.53 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 19.2, 22.5, 25.4, 30.3, 54.6, 55.2, 62.3, 81.5,
91.4, 97.0, 120.0, 122.2, 128.4, 128.7, 129.5, 129.6, 129.7, 129.8,
133.7, 143.3, 170.5 ppm. HRMS (ESI): calcd. for C19H22BrNO3Na
[M + Na]+ 414.0680, 416.0660; found 414.0656, 416.0637.
General Methods: Melting points were recorded with a Yamato
MP21 apparatus. HRMS (ESI) spectra were recorded with a JEOL
JMS-T100LP mass spectrometer. IR spectra were measured with a
Shimadzu IRAffinity-1 FTIR spectrophotometer. 1H NMR and
13C NMR spectra were recorded 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 performed on silica gel (Silica Gel 60N, Kanto Chemical Co.,
Ltd.).
Palladium-Catalyzed Cross-Coupling Reaction of 4a with 5: tBuLi
(1.6 m in pentane, 8.25 mL, 13.2 mmol) was added to a solution of
N-methylindole (3a; 1.44 g, 11 mmol) in THF (100 mL) at 0 °C un-
der an argon atmosphere, and the mixture was allowed to warm to
room temperature. After the mixture was stirred for 1 h, BEt3 (1 m
in hexane, 13.2 mL, 13.2 mmol) was added, and the mixture was
stirred for a further 1 h. Then, 5 (2.15 g, 5.5 mmol) and a catalytic
amount of palladium complex (see Table 1 for catalyst structures
and quantities) were added. After stirring at room temperature for
2-[3-(Tetrahydro-2H-pyran-2-yloxy)prop-1-yn-1-yl]aniline (8):
A
mixture of 2-iodoaniline (2 g, 9.1 mmol), 2-(prop-2-yn-1-yloxy)-
tetrahydro-2H-pyran (1.96 g, 14 mmol), PdCl2(PPh3)2 (191 mg,
0.273 mmol), and CuI (173 mg, 0.91 mmol) in diethylamine
(40 mL) was stirred at room temperature for 1 h under an argon
atmosphere. This was an exothermic reaction. After this time, the
mixture was concentrated in vacuo, and the residue was diluted
with EtOAc (200 mL), washed with brine, and dried with MgSO4.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20657
/KAP1
Date: 25-07-12 16:02:51
Pages: 11
M. Ishikura et al.
FULL PAPER
10 min, the mixture was heated at 60 °C (see Table 1 for reaction
times). The mixture was then cooled to 0 °C, and 10% aqueous
NaOH solution (20 mL) and 30% aqueous H2O2 solution (10 mL).
After stirring for 20 min, the mixture was diluted with EtOAc
(500 mL), washed with brine, and dried with MgSO4. The solvent
was removed, and the residue was separated by column chromatog-
raphy on SiO2 (hexane/EtOAc, 1.5:1) to give 6a as a pale yellow
solid and 10a as a pale yellow oil (see Table 1 for yields of 6a and
10a).
2.19 (s, 3 H), 3.37–3.46 (m, 1 H), 3.65–3.73 (m, 1 H), 3.81 (s, 3 H),
4.32 (d, J = 10.0 Hz, 1 H), 4.59–4.70 (m, 4 H), 4.75–4.82 (m, 2 H),
6.48 (s, 1 H), 7.09 (t, J = 7.4 Hz, 1 H), 7.21 (t, J = 7.4 Hz, 1 H),
7.32 (t, J = 7.4 Hz, 1 H), 7.36–7.43 (m, 2 H), 7.56 (d, J = 8.0 Hz,
1 H), 7.59 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 19.2, 22.4, 25.4, 30.5, 37.4, 61.9, 64.9, 68.5, 98.8, 98.9, 108.4,
111.3, 119.9, 120.6, 122.1, 123.0, 123.6, 125.1, 126.4, 128.4, 128.6,
132.0, 133.5, 134.6, 139.8, 139.9, 144.5, 169.2 ppm. HRMS (ESI)
calcd. for C28H30N2O4Na [M + Na]+ 481.2103; found 481.2082.
N-[2-(1-Methoxy-1H-indol-2-yl)prop-2-en-1-yl]-N-{2-[3-(tetrahydro-
(4Z)-4-[1-(1-Methyl-1H-indol-2-yl)-2-(tetrahydro-2H-pyran-2-
yloxy)ethylidene]-3-methylidene-1-(prop-1-en-2-yl)-1,2,3,4-tetra-
2H-pyran-2-yloxy)prop-1-yn-1-yl]phenyl}acetamide (10b): IR (neat):
1
ν = 1670 cm–1. H NMR (500 MHz, CDCl ): δ = 1.48–1.65 (m, 4
˜
hydroquinoline (6a): M.p. 70–72 °C (hexane/EtOAc). IR (CHCl ): ν
˜
3
3
= 1651 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.43–1.80 (m, 6 H),
2.21 (s, 3 H), 3.30–3.36 (m, 1 H), 3.56 (s, 3 H), 3.57–3.63 (m, 1 H),
4.21 (d, J = 11.1 Hz, 1 H), 4.54 (s, 2 H), 4.64 (d, J = 11.1 Hz, 1
H), 4.82 (s, 1 H), 6.51 (s, 1 H), 7.10 (t, J = 7.4 Hz, 1 H), 7.19 (t, J
= 7.0 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1
H), 7.33 (t, J = 7.4 Hz, 1 H), 7.39 (t, J = 7.4 Hz, 1 H), 7.59 (d, J
= 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H) ppm, the signals of two
protons (N-CH2) do not appear. 13C NMR (125 MHz, CDCl3): δ
= 19.1, 22.3, 25.4, 30.3, 30.5, 47.3, 61.8, 69.5, 98.8, 101.4, 109.5,
113.6, 119.4, 120.4, 121.2, 124.9, 126.4, 126.8, 127.9, 128.8, 129.0,
132.9, 137.0, 139.0, 139.1, 140.0, 142.9, 169.3 ppm. HRMS (ESI):
calcd. for C28H30N2O3Na [M + Na]+ 465.2154; found 465.2139.
H), 1.67–1.88 (m, 2 H), 1.84 (s, 3 H), 3.52–3.60 (m, 1 H), 3.69 (s,
3 H), 3.80–3.90 (m, 1 H), 4.20–4.37 (m, 2 H), 4.38, 4.42 (2 d, J =
15.0 Hz, 1 H), 4.75, 4.79 (2 s, 1 H), 5.17 (s, 1 H), 5.38, 5.42 (2 d, J
= 15.0 Hz, 1 H), 5.91 (s, 1 H), 6.64, 6.65 (2 s, 1 H), 6.88 (dd, J =
3.5, 7.5 Hz, 1 H), 7.08 (t, J = 7.5 Hz, 1 H), 7.17 (t, J = 7.5 Hz, 1
H), 7.20–7.26 (m, 2 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.50 (d, J =
8.0 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 19.2, 22.8, 25.4, 30.4, 51.3, 54.5, 62.3, 81.6, 91.2, 97.0,
97.1, 99.9, 108.3, 117.8, 120.4, 121.5, 122.5, 123.1, 123.5, 128.1,
129.1, 129.6, 133.0, 133.1, 133.5, 133.6, 134.0, 143.2, 170.4 ppm.
HRMS (ESI): calcd. for C28H30N2O4Na [M + Na]+ 481.2103;
found 481.2103.
6π-Electrocyclization of 6a with Pentamethylcyclopentadienyl-
iridium(III) Dimer (1 equiv.): A solution of 6a (354 mg, 0.8 mmol)
in MeCN (3 mL) was added dropwise to a suspension of penta-
methylcyclopentadienyliridium(III) dimer (636 mg, 0.8 mmol) in
MeCN (20 mL) at room temperature, and the deep red mixture
was stirred for 4 h. Insoluble materials were removed by filtration
through a silica gel pad with suction. The filtrate was concentrated,
and the residue was separated by column chromatography on SiO2
(hexane/EtOAc, 5:1) to give 7a (246 mg, 70%) as a pale yellow oil.
N-[2-(1-Methyl-1H-indol-2-yl)prop-2-en-1-yl]-N-{2-[3-(tetrahydro-
2H-pyran-2-yloxy)prop-1-yn-1-yl]phenyl}acetamide (10a): IR
1
(CHCl ): ν = 1654 cm–1. H NMR (500 MHz, CDCl ): δ = 1.50–
˜
3
3
1.69 (m, 4 H), 1.72–1.89 (m, 2 H), 1.79 (s, 3 H), 3.52 (s, 3 H), 3.51–
3.60 (m, 1 H), 3.83–3.88 (m, 1 H), 4.20–4.33 (m, 2 H), 4.36 (d, J
= 14.9 Hz, 1 H), 4.78 (t, J = 3.4 Hz, 1 H), 5.16 (s, 1 H), 5.38 (dd,
J = 3.9, 14.9 Hz, 1 H), 5.39 (s, 1 H), 6.59 (s, 1 H), 6.70 (d, J =
8.0 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 7.17 (t, J = 7.5 Hz, 1 H),
7.21 (t, J = 7.5 Hz, 1 H), 7.20–7.29 (m, 2 H), 7.50 (d, J = 8.0 Hz,
1 H), 7.58 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 19.2, 22.5, 25.4, 30.3, 31.4, 52.2, 54.5, 62.3, 81.6, 91.1, 97.0,
102.1, 109.5, 118.8, 119.8, 120.9, 122.1, 122.5, 127.5, 127.5, 128.0,
129.1, 129.5, 133.5, 135.6, 135.8, 138.6, 138.8, 143.4, 170.8 ppm.
HRMS (ESI): calcd. for C28H30N2O3Na [M + Na]+ 465.2154;
found 465.2151.
1-{12-Methyl-13-[(tetrahydro-2H-pyran-2-yloxy)methyl]-6,12-di-
hydro-5H-indolo[3,2-j]phenanthridin-5-yl}ethanone (7a): IR (neat): ν
˜
= 1651 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.61–1.97 (m, 5 H),
2.20, 2.36 (2 s, 3 H), 3.61–3.64 (m, 2 H), 4.08–4.11 (m, 1 H), 4.27
(s, 3 H), 4.87 (s, 1 H), 4.54–6.00 (m, 4 H), 7.19–7.46 (m, 6 H), 7.50
(t, J = 7.4 Hz, 1 H), 8.04–8.06 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 21.0, 22.1, 25.5, 31.6, 32.7, 47.1, 64.7, 65.6, 100.7,
109.1, 109.2, 116.3, 118.1, 119.5, 120.2, 122.4, 123.4, 124.7, 125.9,
126.3, 128.8, 129.2, 131.0, 132.9, 140.0, 142.2, 142.9, 168.7 ppm.
HRMS (ESI): calcd. for C28H28N2O3Na [M + Na]+ 463.1998;
found 463.1979.
Palladium-Catalyzed Cross-Coupling Reaction of 4b with 5: nBuLi
(1.6 m in hexane, 8.25 mL, 13.2 mmol) was added to a solution of
N-methoxyindole (3b; 1.6 g, 11 mmol) in THF (100 mL) at –20 °C
under an argon atmosphere. After the mixture was stirred for
30 min, BEt3 (1 m in hexane, 13.2 mL, 13.2 mmol) was added. After
stirring for 30 min at –20 °C, the mixture was allowed to warm
gradually to room temperature and stirred for 1 h. Then, 5 (2.15 g,
5.5 mmol) and a catalytic amount of palladium complex (see
Table 1 for catalyst structures and quantities) were added. After
stirring at room temperature for 10 min, the mixture was heated at
60 °C (see Table 1 for reaction times). The mixture was then cooled
to 0 °C, and 10% aqueous NaOH solution (20 mL) and 30% aque-
ous H2O2 solution (10 mL) were added. After stirring for 20 min,
the mixture was diluted with EtOAc (500 mL), washed with brine,
and dried with MgSO4. The solvent was removed, and the residue
was separated by column chromatography on SiO2 (hexane/EtOAc,
15:1) to give 6b as pale yellow crystals and 10b as a pale yellow oil
(see Table 1 for yields of 6b and 10b).
6π-Electrocyclization of 6a or 6c with (CuOTf)2·toluene (1 equiv.):
A solution of 6a (354 mg, 0.8 mmol) or 6c (287 mg, 0.8 mmol) in
MeCN (3 mL) was added dropwise to a suspension of (CuOTf)2·
toluene (410 mg, 0.8 mmol) in MeCN (20 mL) at room tempera-
ture, and the deep red mixture was stirred for 1 h. Insoluble materi-
als were removed by filtration through a silica gel pad with suction.
The filtrate was concentrated in vacuo, and the residue was sepa-
rated by column chromatography on SiO2 (hexane/EtOAc, 2:1).
Triene 6a provided 7c (210 mg, 74%) as colorless crystals and 6c
(37 mg, 13%) as pale yellow crystals; 7c (233 mg, 82%) was ob-
tained from 6c.
6π-Electrocyclization of 6a or 6c with (CuOTf)2·toluene (0.1 equiv.):
A solution of 6a (354 mg, 0.8 mmol) or 6c (287 mg, 0.8 mmol) in
MeCN (3 mL) was added dropwise to a suspension of (CuOTf)2·
toluene (41 mg, 0.08 mmol) in MeCN (15 mL) under reflux, and
the deep red mixture was heated under reflux for 16 h. After cool-
ing, insoluble materials were removed by filtration through a silica
gel pad with suction. The filtrate was concentrated, and the residue
(4Z)-4-[1-(1-Methoxy-1H-indol-2-yl)-2-(tetrahydro-2H-pyran-2-
yloxy)ethylidene]-3-methylidene-1-(prop-1-en-2-yl)-1,2,3,4-tetra-
hydroquinoline (6b): M.p. 146–148 °C (hexane/EtOAc). IR (CHCl3):
1
ν = 1653 cm–1. H NMR (500 MHz, CDCl ): δ = 1.40–1.50 (m, 2
˜
3
H), 1.50–1.60 (m, 2 H), 1.60–1.68 (m, 1 H), 1.68–1.77 (m, 2 H),
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20657
/KAP1
Date: 25-07-12 16:02:51
Pages: 11
Total Synthesis of Calothrixins A and B
was separated by column chromatography on SiO2 (hexane/EtOAc,
2:1). Triene 6a provided 7c (184 mg, 65%) and 6c (29 mg, 10%); 7c
(201 mg, 71%) was obtained from 6c.
8.0 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1 H), 7.96 (s, 1 H), 8.05 (d, 1 H,
J = 7.5 Hz), 8.12–8.15 (m, 1 H), 8.27 (s, 1 H) ppm, the signals of
two protons (N-CH2) do not appear. 13C NMR (125 MHz,
CDCl3): δ = 22.2, 31.8, 46.2, 109.0, 116.2, 120.0, 120.6, 122.2,
122.5, 125.3, 125.5, 126.5, 127.0, 127.8, 128.2, 128.4, 129.3, 132.3,
132.9, 139.5, 142.6, 160.0, 169.1 ppm. HRMS (ESI): calcd. for
C23H18N2O3Na [M + Na]+ 393.1215; found 393.1181.
1-[13-(Hydroxymethyl)-12-methyl-6,12-dihydro-5H-indolo[3,2-j]-
phenanthridin-5-yl]ethanone (7c): M.p. 198–200 °C (hexane/EtOAc).
1
IR (CHCl ): ν = 3595, 1647 cm–1. H NMR (500 MHz, CDCl ): δ
˜
3
3
= 2.22 (s, 3 H), 2.20–2.22 (m, 1 H), 4.30 (s, 3 H), 4.60–5.90 (m, 4
H), 7.25 (t, J = 7.5 Hz, 1 H), 7.32–7.46 (m, 4 H), 7.50 (t, J = 1-(13-Hydroxy-12-methyl-6,12-dihydro-5H-indolo[3,2-j]phen-
7.5 Hz, 1 H), 8.02–8.07 (m, 2 H), 8.18 (br. s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 22.1, 32.4, 47.0, 59.7, 109.1, 118.0, 118.2,
119.6, 120.2, 122.3, 123.5, 124.8, 126.0, 126.4, 127.8, 129.2, 130.1,
130.7, 132.1, 140.0, 141.5, 142.9, 168.7 ppm. HRMS (ESI) calcd.
for C23H20N2O2Na [M + Na]+ 379.1422; found 379.1391.
anthridin-5-yl)ethanone (13): A mixture of 12 (50 mg, 0.14 mmol)
and NaOMe (8 mg, 0.14 mmol) in MeOH (10 mL) was stirred at
room temperature for 0.5 h under an argon atmosphere. The mix-
ture was diluted with CH2Cl2 (100 mL), washed with brine and
dried with MgSO4. The solvent was removed and the residue was
separated by column chromatography on SiO2 (hexane/EtOAc, 1:1)
to give 13 (43 mg, 90 %) as a colorless solid. M.p. 159–161 °C
1-[(4Z)-4-[2-Hydroxy-1-(1-methyl-1H-indol-2-yl)ethylidene]-3-
methylidene-3,4-dihydroquinolin-1(2H)-yl]ethanone (6c): M.p. 106–
(EtOAc/hexane). IR (CHCl ): ν = 3565, 1732 cm–1 1H NMR
.
˜
1
108 °C (hexane/EtOAc). IR (CHCl ): ν = 3620, 1653 cm–1. H
3
˜
3
([D6]acetone, 500 MHz): δ = 2.79 (s, 3 H), 4.25 (s, 3 H), 4.75 (br.
s, 2 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.28–7.36 (m, 2 H), 7.40–7.51 (m,
3 H), 7.71 (br. s, 1 H), 8.07 (d, J = 7.5 Hz, 1 H), 8.12 (br. s, 1 H),
8.42 (br. s, 1 H) ppm. 13C NMR (CD3OD, 125 MHz): δ = 20.6,
22.3, 31.1, 31.4, 46.6, 108.5, 110.0, 118.7, 118.8, 119.7, 122.5, 124.0,
124.7, 125.7, 126.2, 126.6, 128.1, 128.6, 130.2, 132.3, 138.5, 140.7,
142.4, 170.0 ppm. HRMS (ESI): calcd. for C22H18N2O2Na [M +
Na]+ 365.1266; found 365.1237.
NMR (500 MHz, CDCl3): δ = 2.22 (s, 3 H), 3.55 (s, 3 H), 3.58 (br.
s, 1 H), 4.55 (s, 1 H), 4.59 (s, 2 H), 4.84 (s, 1 H), 6.56 (s, 1 H), 7.13
(t, J = 7.5 Hz, 1 H), 7.23 (t, J = 7.4 Hz, 1 H), 7.24 (d, J = 7.5 Hz,
1 H), 7.32 (d, J = 7.6 Hz, 1 H), 7.34 (t, J = 7.4 Hz, 1 H), 7.40 (t,
J = 7.4 Hz, 1 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 1
H) ppm, the signals of two protons (N-CH2) do not appear. 13C
NMR (125 MHz, CDCl3): δ = 22.3, 30.3, 47.1, 64.0, 101.4, 109.8,
113.6, 119.9, 120.4, 121.8, 124.9, 126.4, 126.5, 127.8, 128.9, 129.0,
132.5, 136.5, 136.8, 137.5, 140.1, 143.1, 169.3 ppm. HRMS (ESI):
calcd. for C23H22N2O2Na [M + Na]+ 381.1579; found 381.1557.
Dakin Oxidation of 11a: Diphenyl diselenide (9 mg, 0.03 mmol)
was added to a mixture of 11a (100 mg, 0.28 mmol) and 30% aque-
ous H2O2 solution (0.5 mL) in CH2Cl2 (15 mL). The mixture was
stirred at room temperature for 24 h under an argon atmosphere.
10% aqueous NaOH solution (10 mL) was added, and the mixture
was stirred for 16 h under an oxygen atmosphere. The mixture was
diluted with CH2Cl2 (30 mL), washed with brine and dried with
MgSO4. The solvent was removed, and the residue was separated
by column chromatography on SiO2 (CH2Cl2/EtOAc, 30:1) to give
15a (44 mg, 50%) as an orange solid, and 16a (13 mg, 15%) as a
pale yellow oil.
Conversion of 6a to 6c: CSA (5 mg, 0.02 mmol) was added to a
solution of 6a (1 g, 2.26 mmol) in MeOH (100 mL) and CH2Cl2
(20 mL). The mixture was stirred for 24 h at room temperature un-
der an argon atmosphere. The mixture was filtered through a silica
gel pad with suction, and the filtrate was concentrated in vacuo.
The residue was separated by column chromatography on SiO2
(CH2Cl2/EtOAc, 3:1) to give 6c (728 mg, 90%).
5-Acetyl-12-methyl-6,12-dihydro-5H-indolo[3,2-j]phenanthridine-
13-carbaldehyde (11a): A mixture of PCC (363 mg, 1.68 mmol) and
Celite (1 g) in CH2Cl2 (20 mL) was stirred at room temperature for
10 min, and then a solution of 7c (200 mg, 0.56 mmol) in CH2Cl2
(5 mL) was added. The mixture was stirred at room temperature
for 3 h under an argon atmosphere. Insoluble materials were re-
moved by filtration with suction, the filtrate was concentrated, and
the residue was separated by column chromatography on SiO2
N-Methylcalothrixin B (15a): M.p. 268–271 °C (hexane/EtOAc). IR
(KBr): ν = 1656, 1639 cm–1. 1H NMR (500 MHz, [D6]DMSO): δ
˜
= 4.21 (s, 3 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1 H),
7.80 (d, J = 8.6 Hz, 1 H), 7.85 (t, J = 7.5 Hz, 1 H), 7.92 (t, J =
7.5 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 8.22 (d, J = 8.0 Hz, 1 H),
9.47 (d, J = 8.6 Hz, 1 H), 9.57 (s, 1 H) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 32.8, 112.8, 116.2, 122.8, 122.9, 123.1, 124.9,
125.3, 127.8, 127.9, 130.4, 130.7, 132.0, 134.0, 136.8, 140.6, 147.7,
152.0, 180.7, 182.1 ppm. HRMS (ESI): calcd. for C20H13N2O2 [M
+ H]+ 313.0977; found 313.09518.
(EtOAc/CH2Cl2, 1:3) to give 11a (158 mg, 80%) as a pale yellow
1
oil. IR (CHCl ): ν = 1658 cm–1. H NMR (500 MHz, CDCl ): δ =
˜
3
3
2.26 (s, 3 H), 4.04 (s, 3 H), 7.31 (t, J = 7.5 Hz, 1 H), 7.38–7.42 (m,
2 H), 7.45 (d, J = 7.5 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 7.52–
7.60 (m, 2 H), 8.07 (d, J = 7.5 Hz, 1 H), 8.23 (s, 1 H), 10.37 (s, 1
H) ppm, the signals of two protons (N-CH2) do not appear. 13C
NMR (125 MHz, CDCl3): δ = 22.1, 36.0, 45.8, 110.1, 118.6, 120.2,
120.6, 122.1, 122.3, 125.0, 126.1, 127.2, 128.9, 129.7, 132.4, 135.1,
139.9, 140.2, 143.9, 168.9, 192.1 ppm. HRMS (ESI): calcd. for
C23H18N2O2Na [M + Na]+ 377.1266; found 377.1217.
12-Methyl-12H-indolo[3,2-j]phenanthridine-13-carbaldehyde (16a):
IR (CHCl ): ν = 1732 cm–1. 1H NMR (500 MHz, CDCl ): δ = 4.23
˜
3
3
(s, 3 H), 7.46 (t, J = 6.9 Hz, 1 H), 7.59 (d, J = 8.6 Hz, 1 H), 7.68
(t, J = 8.0 Hz, 1 H), 7.75 (t, J = 8.1 Hz, 1 H), 7.87 (t, J = 8.1 Hz,
1 H), 8.27 (d, J = 8.0 Hz, 1 H), 8.36 (d, J = 8.0 Hz, 2 H), 8.91 (s,
1 H), 9.46 (s, 1 H), 10.66 (s, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 37.3, 110.6, 114.9, 120.8, 121.2, 121.8, 122.4, 123.1,
126.5, 127.1, 128.6, 129.5, 129.7, 129.8, 130.3, 131.1, 135.0, 144.4,
145.0, 153.5, 190.9 ppm. HRMS (ESI): calcd. for C21H15N2O [M
+ H]+ 311.1184; found 311.1180.
5-Acetyl-12-methyl-6,12-dihydro-5H-indolo[3,2-j]phenanthridin-13-
yl Formate (12): Diphenyl diselenide (9 mg, 0.03 mmol) was added
to a mixture of 11a (100 mg, 0.28 mmol) and 30% aqueous H2O2
solution (0.2 mL) in CH2Cl2 (15 mL). The mixture was stirred at
room temperature for 20 h under an argon atmosphere. The mix-
ture was diluted with CH2Cl2 (15 mL), washed with brine and dried
with MgSO4. The solvent was removed, and the residue was sepa-
rated by column chromatography on SiO2 (hexane/EtOAc, 2:1) to
Conversion of 16a into 15a: Diphenyl diselenide (28 mg, 0.09 mmol)
was added to a mixture of 16a (93 mg, 0.29 mmol) and 30% aque-
ous H2O2 solution (0.09 mL) in CH2Cl2 (10 mL). The mixture was
stirred for 48 h at room temperature under an argon atmosphere.
10% aqueous NaOH solution (10 mL) was added, and the mixture
give 12 (72 mg, 70%) as a pale orange oil. IR (CHCl ): ν = 1766,
˜
3
1651 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.18 (s, 3 H), 4.05 (s, was stirred for 16 h under atmospheric pressure of oxygen. The
3 H), 7.27 (t, J = 7.5 Hz, 1 H), 7.30–7.38 (m, 3 H), 7.39 (d, J = mixture was diluted with CH2Cl2, washed with brine, and dried
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20657
/KAP1
Date: 25-07-12 16:02:51
Pages: 11
M. Ishikura et al.
FULL PAPER
with MgSO4. The solvent was removed and the residue was sepa-
rated by column chromatography on SiO2 (CH2Cl2/EtOAc, 20:1)
to give 15a (54 mg, 60%).
(164 mg, 0.32 mmol) in MeCN (20 mL) and CH2Cl2 (20 mL), and
the deep red mixture was stirred at room temperature for 24 h.
Insoluble materials were removed by filtration through a silica gel
pad with suction. The filtrate was concentrated in vacuo, and the
residue was separated by column chromatography on SiO2 (hexane/
EtOAc, 2:1) to give 7d (470 mg, 79%) as a colorless solid.
N-Methylcalothrixin A (17): Oxone® (399 mg, 0.65 mmol) was
added portionwise to a mixture of 15a (40 mg, 0.13 mmol) and
K2CO3 (90 mg, 0.65 mmol) in acetone (8 mL) and water (8 mL) at
0 °C. The mixture was allowed to warm gradually to room tem-
perature and stirred for an additional 48 h. The mixture was diluted
with CH2Cl2 (50 mL), washed with brine and dried with MgSO4.
The solvent was removed, and 50% aqueous acetone was added to
the residue. The red-colored precipitate was collected by filtration
with suction and washed with a small portion of acetone to give
17 (26 mg, 63%) as a red solid. M.p. 280–286 °C decomposed (ace-
(5-Acetyl-12-methoxy-6,12-dihydro-5H-indolo[3,2-j]phenanthridin-
13-yl)methanol (7d): M.p. 168–169 °C (hexane/CH2Cl2). IR
1
(CHCl ): ν = 3574, 1647 cm–1. H NMR (500 MHz, CDCl ): δ =
˜
3
3
2.22, 2.35 (2 s, 3 H), 4.27 (s, 3 H), 4.93–5.39 (m, 4 H), 5.89 (br. s,
1 H), 7.38–7.42 (m, 2 H), 7.31 (t, J = 6.9 Hz, 1 H), 7.34 (d, J =
7.4 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 1 H),
7.92 (s, 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 7.4 Hz, 1 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 22.1, 46.7, 59.9, 64.6,
tone). IR (KBr): ν = 1660 cm–1. 1H NMR (500 MHz, [D ]DMSO):
˜
6
δ = 4.23 (S, 3 H), 7.43 (t, J = 8.6 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 1 110.1, 117.7, 120.8, 121.2, 121.3, 121.6, 122.0, 124.7, 126.4, 127.1,
H), 7.78 (d, J = 8.6 Hz, 1 H), 7.94 (t, J = 4.0 Hz, 2 H), 8.19 (d, J
= 8.0 Hz, 1 H), 8.60 (d, J = 9.7 Hz, 1 H), 8.86 (s, 1 H), 9.60 (d, J
128.1, 130.2, 130.4, 131.8, 132.0, 139.8, 139.9, 141.2, 168.9 ppm.
HRMS (ESI): calcd. for C23H20N2NaO3 [M + Na]+ 395.1372;
= 5.8 Hz, 1 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 32.9, found 395.1364.
112.8, 116.2, 119.7, 122.8, 123.0, 123.1, 125.5, 127.5, 127.7, 128.9,
5-Acetyl-12-methoxy-6,12-dihydro-5H-indolo[3,2-j]phenanthridine-
129.9, 131.8, 132.2, 132.4, 137.2, 140.3, 144.0, 178.2, 179.7 ppm.
HRMS (ESI): calcd. for C20H13N2O3 [M + H]+ 329.0926; found
329.0922.
13-carbaldehyde (11b): PCC (711 mg, 3.3 mmol) and Celite (2 g) in
CH2Cl2 (30 mL) were stirred for 10 min at room temperature, and
then a solution of 7d (410 mg, 1.1 mmol) in CH2Cl2 (10 mL) was
added. The mixture was stirred for 3 h at room temperature under
an argon atmosphere. Insoluble materials were removed by fil-
tration with suction. The filtrate was concentrated in vacuo, and
1-[(4Z)-4-[2-Hydroxy-1-(1-methoxy-1H-indol-2-yl)ethylidene]-3-
methylidene-3,4-dihydroquinolin-1(2H)-yl]ethanone (6d): CSA
(51 mg, 0.218 mmol) was added to a mixture of 6b (1 g, 2.18 mmol)
in MeOH (100 mL) and CH2Cl2 (20 mL). The mixture was stirred the residue was separated by column chromatography on SiO2 (hex-
for 24 h at room temperature under an argon atmosphere. The mix-
ture was filtered through a silica gel pad with suction, and the
filtrate was concentrated in vacuo. The residue was separated by
column chromatography on SiO2 (hexane/EtOAc, 2:1) to give 6d
ane/EtOAc, 2:1) to give 11b (326 mg, 80%) as a pale yellow oil. IR
(neat): ν = 1694, 1651 cm–1. 1H NMR (500 MHz, CDCl ): δ = 2.28,
˜
3
2.44 (2 s, 3 H), 4.08, 4.11, 4.16 (3 s, 3 H), 7.30 (t, J = 7.5 Hz, 1 H),
7.33 (t, J = 7.5 Hz, 1 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.42 (t, J =
7.5 Hz, 1 H), 7.45–7.55 (m, 3 H), 7.99, 8.03 (2 d, J = 8.0 Hz, 1 H),
(733 mg, 90 %) as a colorless solid. M.p. 152–155 °C (hexane/
1
CH Cl ). IR (CHCl ): ν = 3396, 1658 cm–1. H NMR (500 MHz, 8.09, 8.20 (2 s, 1 H), 10.46, 10.56, 10.75 (3 s, 1 H) ppm, the signals
˜
2
2
3
CDCl3): δ = 2.20, 2.35 (2 s, 3 H), 3.85 (s, 3 H), 4.67 (m, 5 H), 4.80
(s, 1 H), 6.46 (s, 1 H), 7.11 (t, J = 7.5 Hz, 1 H), 7.21–7.24 (m, 2
H), 7.33 (t, J = 7.5 Hz, 1 H), 7.38 (td, J = 1.2, 7.1 Hz, 1 H), 7.42
(d, J = 8.0 Hz, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.56 (d, J = 8.0 Hz,
of two protons (N-CH2) do not appear. 13C NMR (125 MHz,
CDCl3): δ = 21.2, 22.2, 22.8, 29.8, 45.9, 60.5, 63.5, 109.4, 111.6,
115.3, 118.8, 119.4, 120.6, 120.7, 121.4, 121.5, 121.6, 121.8, 123.6,
123.7, 124.0, 125.0, 125.1, 126.1, 126.2, 127.2, 127.6, 128.3, 128.6,
1 H) ppm, the signal of OH is not detected. 13C NMR (125 MHz, 128.8, 128.9, 129.0, 131.1, 131.3, 131.5, 131.9, 132.3, 133.9, 135.3,
CDCl3): δ = 22.5, 47.5, 63.1, 65.2, 98.7, 108.6, 111.5, 120.4, 120.8,
122.6, 123.7, 125.2, 125.9, 126.5, 128.5, 128.8, 132.4, 133.1, 133.3,
139.3, 139.8, 140.1, 140.7, 169.1, 171.3, 192.2, 193.1 ppm. HRMS
(ESI): calcd. for C23H18N2NaO3 [M + Na]+ 393.1215; found
138.0, 139.8, 144.4, 169.5 ppm. HRMS (ESI): calcd. for 393.1202.
C23H22N2NaO3 [M + Na]+ 397.1528; found 397.1538.
One-Pot Conversion of 6d to 11b: Compound 6d (500 mg,
6π-Electrocyclization of 6d with (CuOTf)2·Toluene (1 equiv.): A
solution of 6d (300 mg, 0.8 mmol) in MeCN (3 mL) was added
dropwise to a suspension of (CuOTf)2·toluene (410 mg, 0.8 mmol)
in MeCN (15 mL) at room temperature, and the deep red mixture
was stirred for 1 h. Insoluble materials were removed by filtration
through a silica gel pad with suction. The filtrate was concentrated
in vacuo, and the residue was separated by column chromatography
on SiO2 (hexane/EtOAc, 2:1) to give 7d (247 mg, 83%) as a color-
less solid.
1.33 mmol) was added to a mixture of PCC (860 mg, 4 mmol) and
(CuOTf)2·toluene (134 mg, 0.26 mmol) in CH2Cl2 (30 mL) and
MeCN (30 mL) at room temperature After stirring for 1 h, the mix-
ture was heated at 50 °C for 3 h. After cooling, the mixture was
concentrated, and the residue was separated by column chromatog-
raphy on SiO2 (CH2Cl2/EtOAc, 30:1) to give 11b (344 mg, 70%).
Dakin Oxidation of 11b: Diphenyl diselenide (28 mg, 0.09 mmol)
was added to a mixture of 11b (326 mg, 0.88 mmol), 30% aqueous
H2O2 solution (0.3 mL) and CH2Cl2 (30 mL). After the mixture
6π-Electrocyclization of 6d with (CuOTf)2·Toluene (0.1 equiv.): A was stirred at room temperature for 24 h under an argon atmo-
solution of 6d (600 mg, 1.6 mmol) in MeCN (5 mL) was added
dropwise to a refluxing suspension of (CuOTf)2·toluene (82 mg,
0.16 mmol) in MeCN (25 mL), and the deep red mixture was
heated under reflux for 16 h. After cooling, insoluble materials
were removed by filtration through a silica gel pad with suction.
The filtrate was concentrated in vacuo, and the residue was sepa-
rated by column chromatography on SiO2 (hexane/EtOAc, 2:1) to
give 7d (428 mg, 72%) as a colorless solid.
sphere, 10% aqueous NaOH solution (10 mL) was added, and the
mixture was stirred for 16 h under atmospheric pressure of oxygen.
The mixture was diluted with CH2Cl2 (50 mL), washed with brine,
and dried with MgSO4. The solvent was removed and the residue
was separated by column chromatography on SiO2 (CH2Cl2/
EtOAc, 30:1) to give 15b (153 mg, 53%) as a red powder, and 16b
(52 mg, 18%) as a colorless oil.
Conversion of 11b to 15b with Cu(OAc)2 and PCC: A mixture of
6π-Electrocyclization of 6d with (CuOTf)2·Toluene (0.2 equiv.): A Cu(OAc)2 (50 mg, 0.28 mmol) and PCC (240 mg, 1.1 mmol) in
solution of 6d (600 mg, 1.6 mmol) in MeCN (5 mL) and CH2Cl2
(5 mL) was added dropwise to a suspension of (CuOTf)2·toluene
CH2Cl2 (50 mL) was stirred at room temperature for 10 min, and
then 11b (100 mg, 0.27 mmol) was added. The mixture was heated
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20657
/KAP1
Date: 25-07-12 16:02:51
Pages: 11
Total Synthesis of Calothrixins A and B
under reflux for 10 h. After cooling, the mixture was separated by
column chromatography on SiO2 (CH2Cl2/EtOAc, 30:1) to give 15b
(55 mg, 60%).
Acknowledgments
This work was supported in part by the Ministry of Education,
Culture, Sports, Sciences and Technology of Japan through a
Grant-in-Aid for Scientific Research (No. 22590010 for M. I. and
No. 23590143 for N. H.).
12-Methoxy-7H-indolo[3,2-j]phenanthridine-7,13(12H)-dione (15b):
M.p. 268–271 °C decomposed (hexane/CH Cl ). IR (KBr): ν =
˜
2
2
1
1663, 1645 cm–1. H NMR (500 MHz, CDCl3): δ = 4.37 (s, 3 H),
7.45 (td, J = 1.2, 8.0 Hz, 1 H), 7.55 (td, J = 1.2, 8.1 Hz, 1 H), 7.62
(d, J = 8.6 Hz, 1 H), 7.87 (td, J = 1.2, 7.7 Hz, 1 H), 7.79 (td, J =
1.2, 7.4 Hz, 1 H), 8.21 (d, J = 8.0 Hz, 1 H), 8.42 (d, J = 8.0 Hz, 1
H), 9.62 (d, J = 8.6 Hz, 1 H), 9.80 (s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 66.6, 109.9, 113.3, 119.4, 123.1, 123.9,
124.6, 125.6, 127.7, 128.5, 130.3, 130.5, 131.6, 131.8, 133.2, 135.5,
148.1, 152.4, 179.6, 180.7 ppm. HRMS (ESI): calcd. for
C20H13N2O3 [M + H]+ 329.0926; found 329.0900.
[1] R. W. Rickards, J. M. Rothschild, A. C. Willis, N. M.
de Chazal, J. Kirk, K. Kirk, K. J. Saliba, G. D. Smith, Tetrahe-
dron 1999, 55, 13513–13520.
[2] P. H. Bernardo, C. L. L. Chai, G. A. Heath, P. J. Mahon, G. D.
Smith, P. Waring, B. A. Wilkes, J. Med. Chem. 2004, 47, 4958–
4963.
[3] Q. A. Khan, J. Lu, S. M. Hecht, J. Nat. Prod. 2009, 72, 438–
442.
[4] T. R. Kelly, Y. Zhao, M. Cavero, M. Torneiro, Org. Lett. 2000,
2, 3735–3737.
12-Methoxy-12H-indolo[3,2-j]phenanthridine-13-carbaldehyde (16b):
1
IR (CHCl ): ν = 1724, 1694 cm–1. H NMR (500 MHz, CDCl ): δ
˜
3
3
[5] a) For a review, see: T. Choshi, S. Hibino, Heterocycles 2009,
77, 85–97; b) M.-L. Bennasar, T. Roca, F. Ferrando, Org. Lett.
2006, 8, 561–564; c) P. H. Bernardo, C. L. L. Chai, J. Org.
Chem. 2003, 68, 8906–8909; d) P. H. Bernardo, C. L. L. Chai,
J. A. Elix, Tetrahedron Lett. 2002, 43, 2939–2940; e) D. Sis-
souma, L. Maingot, S. Collet, A. Guingant, J. Org. Chem.
2006, 71, 8434–8389; f) S. Tohyama, T. Choshi, K. Matsumoto,
A. Yamabuki, K. Ikegata, J. Nobuhiro, S. Hibino, Tetrahedron
Lett. 2005, 46, 5263–5264.
= 4.18 (s, 3 H), 7.42 (td, J = 1.2, 6.3 Hz, 1 H), 7.60–7.66 (m, 3 H),
7.78 (t, J = 8.0 Hz, 1 H), 8.21 (d, J = 7.5 Hz, 1 H), 8.23 (d, J =
8.1 Hz, 1 H), 8.28 (d, J = 8.0 Hz, 1 H), 8.75 (s, 1 H), 9.38 (s, 1 H),
11.29 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 63.6, 109.2,
116.5, 119.4, 121.2, 121.9, 122.1, 122.7, 123.4, 124.0, 126.5, 127.9,
128.6, 129.2, 130.3, 130.4, 137.3, 140.1, 145.7, 153.9, 194.4 ppm.
HRMS (ESI): calcd. for C21H14N2NaO2 [M + Na]+ 349.0953;
found 349.0950.
[6] a) A. Yamabuki, H. Fujinawa, T. Choshi, S. Tohyama, K. Mat-
sumoto, K. Ohnuma, J. Nobuhiro, S. Hibino, Tetrahedron Lett.
2006, 47, 5859–5861; b) S. Tohyama, T. Choshi, K. Matsumoto,
A. Yamabuki, Y. Hieda, J. Nobuhiro, S. Hibino, Heterocycles
2010, 82, 397–416.
[7] a) C. S. P. McErlean, J. Sperry, A. J. Blake, C. J. Moody, Tetra-
hedron 2007, 63, 10963–10970; b) J. Sperry, C. S. P. McErlean,
A. M. Z. Slawin, C. J. Moody, Tetrahedron Lett. 2007, 48, 231–
234.
Calothrixin B (2): Catalytic hydrogenation of 15b (200 mg,
0.6 mmol) was carried out in THF (300 mL) in the presence of 10%
Pd/C (200 mg) under atmospheric pressure of hydrogen for 20 h.
The catalyst was removed by filtration with suction, and the filtrate
was concentrated in vacuo. The residue was washed with diethyl
ether to give calothrixin B (2) (160 mg, 80%) as a red solid. M.p.
273–275 °C (acetone). IR (KBr): ν = 3393, 1655 cm–1. 1H NMR
˜
[8] a) N. Miyaura, A. Suzuki, J. Chem. Soc., Chem. Commun.
1979, 866–867; b) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95,
2457–2483; c) S. Kotha, K. Lahirik, D. Kashinath, Tetrahedron
2002, 58, 9633–9695.
[9] a) N. Miyaura, K. Yamada, H. Suginome, A. Suzuki, J. Am.
Chem. Soc. 1985, 107, 972–980; b) E. Negishi, T. Takahashi, S.
Baba, D. E. van Horn, N. Okukado, J. Am. Chem. Soc. 1987,
109, 2393–2401; c) S. Sharma, A. C. Oehlschlager, Tetrahedron
Lett. 1988, 29, 261–264.
(500 MHz, [D6]DMSO): δ = 7.37 (t, J = 7.7 Hz, 1 H), 7.45 (t, J =
7.6 Hz, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 7.85 (t, J = 7.7 Hz, 1 H),
7.92 (t, J = 8.4 Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 8.18 (d, J =
7.7 Hz, 1 H),9.55 (d, J = 8.4 Hz, 1 H), 9.62 (s, 1 H), 12.87 (br. s, 1
H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 114.5, 116.1,
122.8, 123.1, 123.9, 124.8, 125.5, 127.6, 127.7, 130.4, 130.8, 132.1,
133.2, 148.1, 151.8, 180.9, 181.4 ppm. HRMS (ESI): calcd. for
C19H11N2O2 [M + H]+ 299.0821; found 299.0823.
[10] a) G. A. Molander, C. S. Yun, M. Ribagorda, B. Biolatto, J.
Org. Chem. 2003, 68, 5534–5539; b) G. A. Molander, B. Can-
turk, L. E. Kennedy, J. Org. Chem. 2009, 74, 973–980.
[11] M. Ishikura, Heterocycles 2011, 83, 247–273.
Calothrixin A (1): Oxone® (307 mg, 0.5 mmol) was added in por-
tions to a mixture of 2 (30 mg, 0.1 mmol) and K2CO3 (69 mg,
0.5 mmol) in 50% aqueous acetone (10 mL) at 0 °C. Then, the mix-
ture was allowed to warm gradually to room temperature and
stirred for 48 h. The mixture was diluted with CH2Cl2 (50 mL),
washed with brine, and dried with MgSO4. The solvent was re-
moved, and 50% aqueous acetone (5 mL) was added to the residue.
The red precipitate was collected by filtration with suction and
washed with a small amount of acetone to give calothrixin A (1)
[12] T. Abe, T. Ikeda, R. Yanada, M. Ishikura, Org. Lett. 2011, 13,
3356–3359.
[13] a) S. Takahashi, Y. Kuroyama, K. Sonogashira, N. Hagihara,
Synthesis 1980, 627–631; b) S. Negishi, L. Anastasia, Chem.
Rev. 2003, 103, 1979–2017.
[14] a) F. Paul, J. Patt, J. F. Hartwig, Organometallics 1995, 14,
3030–3039; b) C. Amator, A. Jutand, J. Organomet. Chem.
1999, 576, 254–278; c) E. Galardon, S. Ramdeehul, J. M.
Brown, A. Cowley, K. K. Hii, A. Jutand, Angew. Chem. 2002,
114, 1838–1841; Angew. Chem. Int. Ed. 2002, 41, 1760–1763;
d) F. B. Landeros, J. F. Hartwig, J. Am. Chem. Soc. 2005, 127,
6944–6945; e) E. Negishi, F. Liu in Metal-catalyzed Cross-cou-
pling Reactions (Eds.: F. Diederich, J. F. Stang), Wiley–VCH,
Weinheim, Germany, 1997, pp. 1–47.
[15] a) G. Desimoni, G. Tacconi, A. Barco, G. P. Pollini in Natural
Products Synthesis through Pericyclic Reactions, American
Chemical Society, Washington, D. C., 1983; b) R. Hayashi,
M. C. Walton, R. P. Hsung, J. H. Schwab, X. Yu, Org. Lett.
2010, 12, 5768–5771; c) V. Sofiyev, G. Navarro, D. Trauner,
Org. Lett. 2008, 10, 149–152; d) S. B. J. Kan, E. A. Anderson,
(22 mg, 70%) as a red solid. M.p. 284–286 °C decomposed (ace-
1
tone). IR (KBr): ν = 3320, 1663 cm–1. H NMR (500 MHz, [D ]-
˜
6
DMSO): δ = 7.37 (t, J = 6.7 Hz, 1 H), 7.42 (t, J = 7.7 Hz, 1 H),
7.59 (d, J = 8.6 Hz, 1 H), 7.90–7.95 (m, 2 H), 8.11 (d, J = 7.7 Hz,
1 H), 8.58 (d, J = 10.1 Hz, 1 H), 8.87 (s, 1 H), 9.65 (d, J = 6.7 Hz,
1 H), 12.90 (br. s, 1 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ
= 114.6, 115.7, 119.7, 122.5, 122.6, 124.1, 125.0, 127.4, 127.6, 128.7,
130.5, 132.3, 132.5, 138.8, 139.3, 143.7, 178.3, 178.8 ppm. HRMS
(ESI): calcd. for C19H11N2O3 [M + H]+ 315.0770; found 315.0775.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H NMR and 13C NMR spectra.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20657
/KAP1
Date: 25-07-12 16:02:51
Pages: 11
M. Ishikura et al.
FULL PAPER
Org. Lett. 2008, 10, 2323–2326; e) C. Hulot, G. Blong, J. Suf-
fert, J. Am. Chem. Soc. 2008, 130, 5046–5047.
[16] M. Ishikura, A. Hino, T. Yaginuma, I. Agata, N. Katagiri, Tet-
rahedron 2000, 56, 193–207.
[17] a) L. M. Bishop, J. E. Barbarow, R. G. Bergman, D. Trauner,
Angew. Chem. 2008, 120, 8220–8223; Angew. Chem. Int. Ed.
2008, 47, 8100–8103; b) D. J. Tantillo, Angew. Chem. 2009, 121,
33–34; Angew. Chem. Int. Ed. 2009, 48, 31–32.
[18] a) J. D. Stewart, Curr. Org. Chem. 1998, 2, 195–216; b) C.
Bolm, O. Beckmann, T. K. K. Luong in Metal-Catalyzed
Baeyer–Villiger Reactions (Eds.: M. Beller, C. Bolm), Wiley–
VCH, Weinheim, 1998, pp. 213–218; c) L. Syper, J. Mlochow-
ski, Tetrahedron 1987, 43, 207–213; d) L. Syper, Synthesis 1989,
167–172.
a) V. J. Freer, P. Yates, Chem. Lett. 1984, 2031–2032; b) K.
Niknam, Asian J. Chem. 2005, 17, 2818–2820; c) G. Piancatelli,
A. Scettri, M. D’Auria, Synthesis 1982, 245–258; d) E. T. T.
Kumpulainen, A. M. P. Koskinen, Chem. Eur. J. 2009, 15,
10901–10911.
[19]
Received: May 16, 2012
Published Online: ᭿
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20657
/KAP1
Date: 25-07-12 16:02:51
Pages: 11
Total Synthesis of Calothrixins A and B
Domino Reactions
Palladium-catalyzed cross-coupling reac-
tion of indolylborate with vinyl bromide
proceeded smoothly, leading to triene. This
intermediate was successfully used for the
total synthesis of calothrixins A and B.
T. Abe, T. Ikeda, T. Choshi, S. Hibino,
N. Hatae, E. Toyata, R. Yanada,
M. Ishikura* ................................... 1–11
Total Synthesis of Calothrixins A and B by
Palladium-Catalyzed Tandem Cyclization/
Cross-Coupling Reaction of Indolylborate
Keywords: Cross-coupling
/ Total syn-
thesis / Palladium / Copper / Electrocyclic
reactions
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11