Total synthesis of PDE-I and -II by copper-mediated double aryl amination This paper is dedicated to Professor Teruaki Mukaiyama in celebration of the 40th anniversary of the Mukaiyama aldol reaction

Article abstract of DOI:10.1016/j.tet.2013.10.057

A concise total synthesis of PDE-I and -II featuring copper-mediated double aryl amination with the combination of CuI, CsOAc, and Cs₂CO ₃ is described. The highly substituted pyrroloindole skeleton was constructed by a one-pot five-step sequence including double aryl amination, β-elimination, deprotection of a Cbz group, and unexpected formation of an indole via removal of an Ns group followed by rearomatization. The undesired elimination of the protecting group (Ns group) was hampered by using the Boc group as a protecting group in the second-generation synthesis, which excluded the reduction of the indole required in the first-generation synthesis.

Full text of DOI:10.1016/j.tet.2013.10.057

Tetrahedron 69 (2013) 10946e10954
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of PDE-I and -II by copper-mediated double aryl
amination
*
Kentaro Okano, Nakako Mitsuhashi, Hidetoshi Tokuyama
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise total synthesis of PDE-I and -II featuring copper-mediated double aryl amination with the
combination of CuI, CsOAc, and Cs2CO3 is described. The highly substituted pyrroloindole skeleton
Received 20 September 2013
Received in revised form 17 October 2013
Accepted 20 October 2013
Available online 24 October 2013
was constructed by a one-pot five-step sequence including double aryl amination,
b-elimination,
deprotection of a Cbz group, and unexpected formation of an indole via removal of an Ns group followed
by rearomatization. The undesired elimination of the protecting group (Ns group) was hampered by
using the Boc group as a protecting group in the second-generation synthesis, which excluded the
reduction of the indole required in the first-generation synthesis.
This paper is dedicated to Professor Teruaki
Mukaiyama in celebration of the 40th an-
niversary of the Mukaiyama aldol reaction
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amination
Cascade reaction
Copper
One-pot reaction
PDE
1. Introduction
toward the synthesis of this class of compounds, an efficient syn-
thetic route is still needed for medicinal and biochemistry.
PDE-I (1) and PDE-II (2), isolated from Streptomyces MD769-C6
by Umezawa and co-workers in 1978, are inhibitors of cyclic
adenosine-30,50-monophosphate phosphodiesterase (Fig. 1).1 The
structures of PDEs were initially identified on the basis of NMR
spectroscopy and later confirmed by X-ray crystallography2 and
total synthesis.3 Since potent sequence-selective DNA alkylating
agents, such as CC-10654 and yatakemycin,5 consist of PDEs as
a partial structure, construction of the highly functionalized
1,2-dihydro-3H-pyrrolo[3,2-e]indole has attracted considerable
attention from the synthetic community.6 Cava and Rawal reported
formal synthesis of PDEs based on a photocyclization of a sym-
metrical bispyrrole derivative to construct the pyrroloindole.7
Boger and Coleman achieved total synthesis of PDEs by de-
velopment of an intramolecular DielseAlder reaction of alkyne and
1,2-diazines.8 Martin also accomplished formal synthesis of PDEs
using a hetero Cope rearrangement of in situ generated O-vinyl-N-
phenylhydroxamic derivative.9 In spite of the significant effort
Recently we developed a method for synthesis of PDE analogs as
an application of a mild copper-mediated aryl amination reaction10
using a combination of CuI and CsOAc,11 which led to the synthesis
of duocarmycins12 and yatakemycin.5d,5d In 2010 we also reported
a total synthesis of PDE-II (2) utilizing the copper-mediated double
aryl amination to construct a tricyclic pyrroloindole in one-pot.13 In
this paper, we describe the full details of the first-generation syn-
thesis of PDE-I and -II based on a one-pot construction of a pyrro-
loindole skeleton and the second-generation improved synthesis
established after careful investigation on the effect of the protecting
group on nitrogen in the copper-mediated aryl amination reaction.
2. Results and discussion
To develop a synthetic route to PDE-I (1) and -II (2) having
a carbamoyl or an acetyl group on the nitrogen atom, we envisaged
unprotected dihydropyrroloindole 3 as a key synthetic intermediate
(Scheme 1). We planned to construct two aryl-nitrogen bonds of 3
via the copper-mediated one-pot double amination of 4 that would
be generated from its synthetic equivalent 5 via
amine functionality. We chose a 2-nitrobenzenesulfonyl (Ns) am-
ide14 as a superior leaving group for the
-elimination due to the
b-elimination of the
* Corresponding author. E-mail address: tokuyama@mail.pharm.tohoku.ac.jp
(H. Tokuyama).
b
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.057

K. Okano et al. / Tetrahedron 69 (2013) 10946e10954
10947
Scheme 2. Preparation of the substrate for the key double amination.
tricyclic compound 13,16 indole 14, and pyrroloindole 15. These
results indicated that the reaction was initiated by amination of the
Cbz carbamate to provide tricyclic compound 13, which would
undergo
b-elimination to give 16 (Scheme 3). Then, the second
amination or removal of the Cbz group furnished 12 or 14, re-
spectively. Finally, conversion to 17 and subsequent removal of the
Ns group followed by aromatization resulted in a formal oxidation
providing pyrroloindole 15. Next, screening of an additional base
was carried out to promote the b-elimination of 13 and the second
amination of 14. To this end, even in the presence of various bases,
compounds 13 and 14 still remained. On the other hand, the yields
of pyrroloindole 15 were substantially improved (entries 2e4).
With these results, we turned our attention to improvement of the
yield of pyrroloindole 15 since this compound is also a synthetic
intermediate of PDEs.6c We then examined the amounts of CuI and
K3PO4/Cs2CO3 and found that the use of 1.5 equiv of CuI and
3.0 equiv of Cs2CO3 was effective in improving the yield of 15 to 57%
(entries 5 and 6).
Fig. 1. Natural products having dihydropyrroloindole skeleton.
With the tricyclic pyrroloindole 15 in hand, we then embarked
on the total synthesis of PDE-II (2) (Scheme 4). Selective reduction
of the electron-rich indole of pyrroloindole 15 was carried out
according to the reported procedure6a to generate dihy-
dropyrroloindole 18, which was acetylated in one-pot to provide
compound 19 in 98% yield. We then attempted a regioselective
removal of the methyl group adjacent to acetyl group according to
the Coe’s report.17 Thus, the reaction was carried out using BCl3 and
TBAI to provide the desired product 20, but the reaction was irre-
producible (Table 2, entry 1). Since separation of TBAI was difficult,
we then increased the amount of trichloroboron; however, the
demethylation was not complete with concomitant generation of
PDE-II (2) (entry 2). Interestingly, additional optimization indicated
that high dilution conditions promoted consumption of the starting
material 19. When the reaction was conducted under 0.01 M con-
centration of 19, the desired product 20 was obtained in 60% yield
with recovery of 19 in 16% (entry 3). Furthermore, we found that
1 mM concentration of 19 was the best reaction conditions and
isolated the corresponding demethylated compound 20 in 73%
(entry 4). Finally, saponification of the methyl ester was carried out
according to Boger’s conditions using Na2S2O4 as a mild reductant18
to afford PDE-II (2), whose physical properties were identical in all
aspects to those reported for the natural product.1
Scheme 1. Retrosynthetic analysis of PDE-I and -II.
strong electron-withdrawing nature of the Ns group. Tetrahy-
droisoquinoline 5 would be prepared by Mannich-type addition of
a glycine unit to hemiaminal 6.
The synthesis commenced with dibromination and benzylic
oxidation of commercially available tetrahydroisoquinoline 7 to
provide hemiaminal 8 in five steps according to our synthesis of
yatakemycin5b,5d (Scheme 2). Treatment of the hemiaminal 8 with
trimethyl orthoformate and PPTS smoothly gave 9, which was
subjected to Mannich reaction with ketene silyl acetal 10 derived
from glycine in the presence of BF3$OEt2 to furnish 11 as a mixture
of diastereomers.15 Treatment with TBAF was necessary for com-
plete removal of a TMS group on nitrogen.
The Mannich adduct 11 was subjected to the standard amination
conditions with a combination of CuI and CsOAc to test the one-pot
double amination (Table 1, entry 1). Gratifyingly, the desired
dihydropyrroloindole 12 was isolated in 12% yield associated with
End game sequence for the total synthesis of PDE-II (2) was also
applicable to the synthesis of PDE-I (1) and we have established di-
vergent total synthesis of PDE-I (1) and -II (2) from compound 15 as
a common intermediate (Scheme 5). Treatment of the unprotected
indoline 18 with trimethylsilyl isocyanate provided urea 21 in one-
pot. A carbamoyl group-directed regioselective demethylation was

10948
K. Okano et al. / Tetrahedron 69 (2013) 10946e10954
Table 1
Effect of bases on the double amination cascade
Entry
CuI (equiv)
Additive
13 (%)a
14 (%)a
12 (%)a
15 (%)a
1
2
3
1.0
1.0
1.0
1.0
1.5
1.5
None
14
9
5
6
13
d
22
15
13
26
d
d
12
5
9
3
d
11
41
50
38
18
57
KOt-Bu
K3PO4
Cs2CO3
K3PO4
Cs2CO3
4
5b
6
d
a
Isolated yield.
Reaction time: 5 h.
b
Scheme 4. Total synthesis of PDE-II (2).
Table 2
Regioselective demethylation using trichloroboron
Entry BCl3 (equiv) Additive (4 equiv) Concentration of 19 (M) 20 (%)a
1b
2b
3
3.0
10
8.0
8.0
TBAI
0.05
0.05
0.01
0.001
50e97
dc
None
None
None
60d
4
73
a
Isolated yield.
b
c
Reaction temperature: ꢀ78 to 0 ꢁC.
Crude material contained 19:20:PDE-II (2)¼1:0.7:0.06 by 1H NMR.
Starting material 19 was recovered (16%).
d
Although the first-generation approach allowed us to synthesize
PDE-I (1) and -II (2), there was a considerable drawback with regard
to the unnecessary reduction of the indole, which was caused by
the unexpected removal of the Ns group. We decided to improve
the highly efficient one-pot double amination strategy to realize
redox-economical synthesis of PDE-I and -II. The outline of the
formation of pyrroloindole 15 in Scheme 3 indicated that the un-
desired deprotection of the Ns group occurred after removal of the
Cbz group on the indole nitrogen. Thus, we switched the Cbz group
to the Boc group, which is more robust under basic conditions.
Gratifyingly, BF3$OEt2-mediated addition of the Boc-protected
ketene silyl acetal 23 also provided the corresponding adduct 24
Scheme 3. Outline of the one-pot formation of pyrroloindole.
also carried out under the high dilution conditions (21: 1 mM) to
provide PDE-I methyl ester (22). Subsequent hydrolysis of the ester
gave PDE-I (1), whose physical properties were identical in all as-
pects to those reported for the natural product.1

K. Okano et al. / Tetrahedron 69 (2013) 10946e10954
10949
Table 3
Effect of amount of CsOAc in the double amination cascade
Entry
CsOAc (equiv)
26 (%)a
15 (%)a
1
2
3.0
2.0
36
33
13
Scheme 5. Total synthesis of PDE-I (1).
db
a
Isolated yield.
Not observed.
in quantitative yield (Scheme 6). Subjection of 24 to the established
amination conditions (Table 1, entry 6) gave the desired dihy-
dropyrroloindole 25 as we expected, with concomitant generation
of pyrroloindole 15.
b
Scheme 7. Synthesis of dihydropyrroloindole 27.
Scheme 6. Effect of the Boc group in the amination reaction.
Due to the difficulty in separation of compounds 25 and 15, we
examined the effect of stoichiometric amount of CsOAc by evalu-
ating yields after deprotection of the nosyl group (Table 3). The
amination reaction with 3 equiv of CsOAc followed by removal of
nosyl group provided dihydropyrroloindole 26 (36%) and pyrro-
loindole 15 (13%) (entry 1). In the case of 2 equiv of CsOAc, gener-
ation of 15 was not observed, but the yield of 26 was slightly
decreased to 33% (entry 2).
Finally, we successfully developed an efficient synthetic route
from Mannich adduct 24 to dihydropyrroloindole 27 (Scheme 7).
After the double amination, subsequent one-pot switching of the
Ns group to the acetyl group via 26 was executed to provide
compound 27 in 46% yield from 24.
We then attempted an acid-mediated deprotection of the Boc
and methyl groups (Scheme 8). Thus, treatment of compound
27 with trichloroboron resulted in generation of unidentified
byproducts. On the other hand, thermal deprotection of the Boc
group19 provided unprotected indole 19 that is the intermediate in
the first-generation synthesis. Compared to the first-generation
Scheme 8. Second-generation synthesis of PDE-II (2).

10950
K. Okano et al. / Tetrahedron 69 (2013) 10946e10954
synthesis (9 to 19, 34%, three steps), the second synthesis excluded
the extra reduction step and provided compound 19 in better
overall yield (9 to 19, 43%, four steps), thus establishing a redox-
economical second-generation synthesis.
hemiaminal 9. Trituration with hexaneseethyl acetate¼1:1 and the
resulting solid was filtered to afford analytically pure 9 (905.7 mg,
1.60 mmol, 83%, 85% combined yield) as a colorless powder. Rf¼0.30
(hexaneseethyl acetate¼1:1). 1H NMR (400 MHz, CDCl3):
d
8.10e8.04 (m, 1H), 7.73e7.61 (m, 3H), 6.00 (s, 1H), 3.99 (dd, 1H,
3. Conclusion
J¼14.6, 7.0 Hz), 3.90 (s, 3H), 3.87 (s, 3H), 3.69 (ddd, 1H, J¼14.6, 13.6,
4.4 Hz), 3.50 (s, 3H), 2.79 (dd, 1H, J¼17.6, 4.4 Hz), 2.46 (ddd, 1H,
In summary, we have achieved a highly efficient total synthesis
of PDE-I (1) and -II (2) utilizing a one-pot copper-mediated intra-
molecular double amination. The methodology enabled us to con-
struct the tricyclic pyrroloindole skeleton in one-pot. We then
successfully improved our highly efficient double amination strat-
egy to apply for the redox-economical divergent synthesis of PDE-I
and -II, in which we found that the Boc group on the indole nitrogen
was essential for the suppression of removal of the Ns group, thus
eliminating the unnecessary reduction.
J¼17.6, 13.6, 7.0 Hz). 13C NMR (100 MHz, CDCl3):
d 151.3, 150.0, 147.7,
134.0, 133.6, 131.9, 131.1, 130.72, 130.65, 124.6, 119.6, 119.3, 84.6,
60.9, 60.7, 56.2, 37.7, 28.8. IR (neat, cmꢀ1): 2939, 1541, 1458, 1404,
1396,1339,1313,1302,1173,1080,1026, 968, 760. HRMS-EI calcd for
C
18H18Br2N2O7S (Mþ) 563.9201; found 563.9209.
4.3. Benzyl 2-methoxy-2-(trimethylsilyloxy)vinyl(trimethyl-
silyl)carbamate (10)13
A 300-mL three-necked round-bottomed flask equipped with
a magnetic stirring bar and fitted with two dropping funnels was
charged with glycine (10.0 g, 133 mmol) and 2 M aqueous sodium
hydroxide (67.5 mL). The flask was then cooled to 0 ꢁC. To the
vigorously stirred solution were added CbzCl (22.8 mL,
160 mmol, 1.2 equiv) and 4 M sodium hydroxide (33.8 mL) si-
multaneously over a period of 10 min via each dropping funnel.
The reaction mixture was stirred for an additional 40 min at 0 ꢁC,
after which time TLC (H2OeAcOEten-BuOHeMeOH¼1:1:1:1)
indicated complete consumption of glycine. The aqueous solution
was washed three times with diethyl ether and acidified with
6 M hydrochloric acid to pH 1. The resulting mixture was cooled
at 0 ꢁC to give a precipitate, which was collected by filtration,
washed with small portions of cold water, and dried under re-
duced pressure to afford analytically pure N-Cbz-glycine (26.4 g,
126 mmol, 95%) as colorless crystals. Rf¼0.66 (H2OeAcOEten-
4. Experimental section
4.1. General remarks
All reactions were performed in oven-dried glassware, sealed
with a rubber septum under a slight positive pressure of argon
unless otherwise noted. Anhydrous THF and dichloromethane were
purchased from Kanto Chemical Co., Inc. Diisopropylamine and
TMSCl were distilled from CaH2. Unless otherwise mentioned,
materials were obtained from commercial suppliers and were used
without further purification. Chromatography was carried out us-
ing Kanto silica gel 60 (230e400 mesh). Gel permeation chroma-
tography was carried out using a Japan Analytical Industry Co., Ltd
LC-9201. Preparative TLC was performed with precoated silica gel
60 F254 plates (Merck). IR spectra were measured on a JASCO IR
Report-100 spectrometer or a Shimazu FTIR-8300 spectrometer.
NMR spectra were measured on a Varian Gemini 2000, a JEOL AL
400, a JEOL ECP 500, or a JEOL ECA 600 spectrometer. For 1H NMR
spectra, chemical shifts are expressed in parts per million down-
BuOHeMeOH¼1:1:1:1). 1H NMR (400 MHz, DMSO-d6):
d 12.58
(br s, 1H), 7.62e7.48 (br s, 1H), 7.44e7.25 (m, 5H), 5.05 (s, 2H),
3.70 (d, 2H, J¼5.6 Hz). 13C NMR (100 MHz, DMSO-d6):
d 171.7,
156.6, 137.1, 128.4, 127.9, 127.8, 65.6, 42.2. IR (neat, cmꢀ1): 3335,
1695, 1541, 1408, 1290, 1252, 1055. HRMS-EI calcd for C10H11NO4
(Mþ), 209.0688; found 209.0682.
field from internal tetramethylsilane (
7.26), CHD2OD ( 3.30), DMSO-d5 (
For 13C NMR spectra, chemical shifts are expressed in ppm down-
field from relative internal CDCl3 ( 77.0), CD3OD ( 49.0), DMSO-d6
39.7), or acetone-d6 ( 29.8 and 206.5). Coupling constants are in
d
0) or relative internal CHCl3
(d
d
d
2.49), or acetone-d5 ( 2.04).
d
A 300-mL three-necked round-bottomed flask equipped with
a magnetic stirring bar and fitted with a dropping funnel was
charged with N-Cbz-glycine (2.50 g, 12.0 mmol) and methanol
(60 mL). The flask was cooled to 0 ꢁC, and thionyl chloride (1.20 mL,
16.5 mmol, 1.4 equiv) was added to the vigorously stirred solution
over a period of 10 min. The mixture was stirred for additional 2 h,
after which time TLC (ethyl acetate) indicated complete con-
sumption of the starting N-Cbz-glycine. The reaction mixture was
concentrated under reduced pressure to give a crude material,
which was purified by silica gel column chromatography (ethyl
acetate) to afford N-Cbz-glycine methyl ester (2.66 g, 11.9 mmol,
99%) as a colorless oil. Rf¼0.55 (ethyl acetate). 1H NMR (400 MHz,
d
d
(d
d
hertz. Mass spectra were recorded on a JEOL JMS-DX-303 (EI),
a JMS-700 (FAB), or a BRUKER micrOTOF-II spectrometer (ESI).
Elemental analyses were performed by a Yanaco CHN CORDER
MT-6 spectrometer.
4.2. 5,8-Dibromo-2-(2-nitrophenylsulfonyl)-1,2,3,4-
tetrahydro-6,7-dimethoxy-1-methoxyisoquinoline (9)13
A 300-mL round-bottomed flask equipped with a magnetic
stirring bar was charged with 85b (1.00 g, 1.92 mmol), PPTS
(528.3 mg, 2.10 mmol), dry THF (4.1 mL), trimethyl orthoformate
(1.0 mL), and MeOH (12.3 mL). The resulting mixture was stirred
vigorously at room temperature for 21.5 h, after which time TLC
(hexaneseethyl acetate¼1:1) indicated complete consumption of
the starting material. The reaction mixture was concentrated under
reduced pressure. The residue was treated with saturated aqueous
ammonium chloride followed by saturated aqueous sodium bi-
carbonate. The mixture was filtered, and the solid was washed with
CDCl3): d 7.32e7.18 (m, 5H), 5.58 (br s, 1H), 5.02 (s, 2H), 3.84 (d, 2H,
J¼5.6 Hz), 3.62 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 170.4, 156.2,
136.1,128.2,127.9,127.8, 66.7, 51.9, 42.3. IR (neat, cmꢀ1): 3337, 2953,
1701, 1508, 1443, 1364, 1207, 1051, 1004. HRMS-EI calcd for
C
11H13NO4 (Mþ) 223.0845; found 223.0833.
A flame-dried 200-mL three-necked round-bottomed flask
equipped with a magnetic stirring bar and fitted with dropping
funnel was charged with freshly distilled diisopropylamine (2.8 mL,
20 mmol, 2.0 equiv) and dry THF (22.4 mL). The resulting solution
was cooled to 0 ꢁC. To the reaction mixture was added n-BuLi
(1.51 M in n-hexane, 13.3 mL, 20 mmol, 2.0 equiv) dropwise over
the period of 5 min at 0 ꢁC. The reaction mixture was stirred at 0 ꢁC
for 20 min then cooled to ꢀ78 ꢁC. To the reaction mixture was
added dry THF (6.3 mL) solution of N-Cbz-glycine methyl ester
(2.25 g, 10.1 mmol) and trimethylsilyl chloride (5.1 mL, 40 mmol,
4.0 equiv) slowly over the period of 15 min via a dropping funnel.
ethyl acetate and water to afford product 9 (20.7 mg, 36.6 mmol,
1.9%) as a colorless powder. The filtrate was separated, and the
aqueous layer was extracted twice with ethyl acetate. The com-
bined organic extracts were washed with 1:1 mixture of saturated
aqueous ammonium chloride and saturated aqueous sodium bi-
carbonate, brine, dried over anhydrous sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give crude

K. Okano et al. / Tetrahedron 69 (2013) 10946e10954
10951
After stirred for 20 min at ꢀ78 ꢁC, the reaction mixture was then
warmed to room temperature and stirred for another 2 h. The re-
action mixture was concentrated under reduced pressure. The
residue was diluted with dry hexanes (50 mL) and passed through
CeliteÒ, and the filter cake was washed with hexanes (50 mL). The
filtrate was concentrated under reduced pressure to afford the
crude ketene silyl acetal 10 (3.99 g) as a pale yellow oil, which was
used to the next reaction without further purification.
reduced pressure. The residue was purified by silica gel column
chromatography and preparative TLC to afford pyrroloindole 15
(64.0 mg, 233
m
mol, 57%) as a white solid. Rf¼0.48 (hex-
aneseethyl acetate¼1:1). 1H NMR (500 MHz, acetone-d6):
d 10.59
(br s, 1H), 10.36 (br s, 1H), 7.35 (d, 1H, J¼1.5 Hz), 7.25 (dd, 1H,
J¼2.4, 2.0 Hz), 6.71 (dd, 1H, J¼2.4, 1.6 Hz), 4.03 (s, 3H), 3.98
(s, 3H), 3.85 (s, 3H). 13C NMR (125 MHz, acetone-d6):
d 162.5,
138.8, 134.7, 129.3, 126.4, 126.1, 123.5, 118.4, 117.9, 108.3, 101.9,
62.0, 61.3, 51.6. IR (neat, cmꢀ1): 3335, 2939, 1693, 1518, 1443,
1379, 1288, 1265, 1202, 1169, 1148, 1053, 760. HRMS-EI calcd for
4.4. Methyl 2-(benzyloxycarbonylamino)-2-(5,8-dibromo-6,7-
dimethoxy-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroiso-
quinolin-1-yl)ethanoate (11)13
C
14H14N2O4 (Mþ) 274.0954; found 274.0942.
4.6. Methyl 6-benzyloxycarbonyl-4,5-dimethoxy-3-(2-
nitrophenylsulfonyl)-1,2-dihydro-pyrrolo[3,2-e]indole-7-
carboxylate (12)13
An oven-dried 200-mL round-bottomed flask equipped with
a magnetic stirring bar was charged with hemiaminal 9 (1.14 g,
201 mmol), ketene silyl acetal 10 (3.99 g, theoretically 5.0 equiv),
and dry dichloromethane (20.0 mL). The resulting mixture was
Rf¼0.33 (hexaneseethyl acetate¼1:1). 1H NMR (500 MHz,
cooled to 0 ꢁC. To the reaction mixture was added BF3$OEt2 (745
mL,
CDCl3): d 8.14e8.10 (m, 1H), 7.71e7.60 (m, 3H), 7.50e7.42 (m, 2H),
6.04 mmol, 3.0 equiv) slowly at 0 ꢁC over the period of 12 min. The
reaction mixture was stirred at 0 ꢁC for 2 h, after which time TLC
(dichloromethaneemethanol¼50:1) indicated complete con-
sumption of the starting hemiaminal 9 (Rf¼0.72). Tetrabuty-
lammonium fluoride (1.0 M in THF, 20 mL, 20 mmol, 10 equiv) was
added dropwise to the solution over the period of 3 min. After
stirred for 15 min at 0 ꢁC, the reaction mixture was warmed to
room temperature and stirred for another 1 h, after which time
TLC (dichloromethaneemethanol¼50:1) indicated complete re-
moval of the TMS group on nitrogen (Rf¼0.42). The reaction was
quenched with saturated aqueous ammonium chloride. The mix-
ture was concentrated under reduced pressure to remove organic
solvents. The residue was extracted three times with ethyl acetate.
The combined organic extracts were washed with aqueous
ammonium chloride and brine, dried over anhydrous sodium sul-
fate, and filtered. The filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography followed by GPC to provide 11 (952 mg, 1.23 mmol, 62%)
as a white amorphous as a mixture of diastereomers. Rf¼0.56
(dichloromethaneemethanol¼50:1). 1H NMR (400 MHz, CDCl3):
7.41e7.30 (m, 3H), 7.06 (s, 1H), 5.43 (s, 2H), 4.43 (t, 2H, J¼7.5 Hz),
3.83 (s, 3H), 3.70 (s, 3H), 3.38 (s, 3H), 3.14 (t, 2H, J¼7.5 Hz). 13C NMR
(125 MHz, CDCl3):
d 160.8, 152.6, 147.5, 142.9, 138.2, 134.9, 134.2,
133.0, 131.8, 131.4, 130.6, 130.3, 128.9, 128.74, 128.71, 128.5, 124.0,
123.3, 119.9, 109.9, 71.0, 61.1, 59.8, 54.2, 52.2, 28.9. IR (neat, cmꢀ1):
1771, 1717, 1541, 1491, 1369, 1350, 1252, 1163, 754. HRMS-FAB calcd
for C28H25N3O10S (Mþ) 595.1261; found 595.1265.
4.7. 1-Benzyloxycarbonyl-6-bromo-7,8-dimethoxy-3-(2-
nitrophenylsulfonyl)-2-methoxycarbonyl-1,2,2a,3,4,5-
hexahydro-1,3-diazaacenaphthylene (13)13
Rf¼0.42 (hexaneseethyl acetate¼1:1). 1H NMR (500 MHz,
CDCl3):
d 8.05e8.01 (m, 1H), 7.75e7.68 (m, 2H), 7.63e7.59 (m, 1H),
7.43e7.32 (m, 5H), 5.30e5.17 (m, 3H), 4.83e4.80 (m, 1H), 4.24e4.18
(m, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.60 (s, 3H), 3.11e3.04 (m, 1H),
2.93e2.88 (m, 1H), 2.44e2.31 (m, 1H). 13C NMR (100 MHz, CDCl3):
d
170.5, 153.0, 152.3, 148.3, 141.8, 135.1, 134.3, 131.9, 131.8, 131.6,
131.4, 130.1, 128.7, 128.5, 124.2, 122.3, 112.8, 71.8, 68.7, 60.9, 60.7,
59.0, 52.5, 45.7, 28.2 (one signal of an aromatic carbon is missing
due to overlapping). IR (neat, cmꢀ1): 1695, 1539, 1435, 1416, 1337,
d
8.00e7.90 (m, 1H), 7.69e7.46 (m, 3H), 7.40e7.15 (m, 5H),
5.78e5.54 (m, 2H), 5.08e4.85 (m, 3H), 4.15e3.54 (m, 11H),
3.10e2.80 (m, 2H). 13C NMR (100 MHz, CDCl3):
169.3, 155.7, 151.0,
1259, 1207, 1161, 1080, 756. HRMS-FAB calcd for C28H26BrN3O10
S
d
(Mþ) 675.0522; found 675.0529.
149.4, 148.0, 136.0, 133.8, 132.2, 131.7, 131.5, 130.9, 126.4, 128.5,
128.2, 127.8, 124.2, 119.6, 118.7, 96.1, 67.2, 60.8, 58.1, 57.2, 53.0, 40.6,
27.3 (observed peaks). IR (neat, cmꢀ1): 1730, 1717, 1541, 1506, 1458,
1373, 1217, 1169, 1028, 772. Elemental analysis; calcd (%) for
4.8. Methyl 5-bromo-6,7-dimethoxy-4-(2-(2-nitrophenyl-sul-
fonamido)ethyl)-1H-indole-2-carboxylate (14)13
C
28H27Br2N3O10S: C 44.40, H 3.59, N 5.55; found: C 44.62, H 3.66, N
Rf¼0.31 (hexaneseethyl acetate¼1:1). 1H NMR (500 MHz,
5.47.
CDCl3): d 9.01 (br s, 1H), 8.12e8.07 (m, 1H), 7.87e7.76 (m, 1H),
7.70e7.65 (m, 2H), 7.13 (d, 1H, J¼2.5 Hz), 5.44 (t, 1H, J¼6.3 Hz), 4.03
4.5. Methyl 3,6-dihydro-4,5-dimethoxy-benzo[1,2-b:4,3-b0]di-
(s, 3H), 3.96 (s, 3H), 3.88 (s, 3H), 3.50e3.42 (m, 2H), 3.26 (t, 2H,
pyrrole-2-carboxylate (15)13
J¼7.3 Hz). 13C NMR (125 MHz, CDCl3):
d 161.8, 147.7, 145.9, 138.0,
133.7, 133.4, 132.7, 130.9,130.2,127.7, 126.1, 125.5, 125.3, 114.0,107.3,
61.2, 61.0, 52.2, 42.9, 33.5. IR (neat, cmꢀ1): 1747, 1545, 1468, 1435,
1362, 1296, 1271, 1169, 1016, 968, 754. HRMS-FAB calcd for
A 20-mL flame-dried round-bottomed flask was equipped
with a magnetic stirring bar was charged with 11 (312.6 mg,
413
m
mol) and copper iodide (118.0 mg, 620
m
mol, 1.5 equiv).
C
20H20BrN3O8S (Mþ) 541.0154; found 541.0154.
Cesium acetate (393.9 mg, 2.05 mmol, 5.0 equiv) and cesium
carbonate (408.1 mg, 1.25 mmol, 3.0 equiv) were weighed and
added to the flask in a glove box. The flask was then evacuated
then backfilled with argon three times. To the mixture was added
dry DMSO (4.1 mL). The resulting pale yellow solution was stirred
at 90 ꢁC for 3 h and was cooled to room temperature. The re-
action mixture was treated with 5% aqueous sodium chloride in
10% aqueous ammonium hydroxide. The aqueous layer was
extracted three times with ethyl acetate. The combined organic
extracts were washed with 5% aqueous sodium chloride in 10%
aqueous ammonium hydroxide, brine, dried over anhydrous so-
dium sulfate, and filtered. The filtrate was concentrated under
4.9. Methyl 6-acetyl-3,6,7,8-tetrahydro-4,5-dimethoxy-benzo
[1,2-b:4,3-b0]dipyrrole-2-carboxylate (19)13
A 50-mL round-bottomed flask equipped with a magnetic stir-
ring bar was charged with pyrroloindole 15 (206.3 mg, 752 mmol)
and acetic acid (2.1 mL, 0.36 M). NaBH3CN (ca. 1 g, excess) was
added to the flask, and the resulting reaction mixture was stirred at
room temperature for 1 h, after which time TLC (hexaneseethyl
acetate¼1:1) indicated complete consumption of the starting pyr-
roloindole 15 (Rf¼0.48). The resulting mixture was cooled to 0 ꢁC.
To the reaction mixture was added pyridine (2.1 mL, 0.36 M) and

10952
K. Okano et al. / Tetrahedron 69 (2013) 10946e10954
acetic anhydride (284.4
m
L, 3.01 mmol, 4.0 equiv). The resulting
with water and washed with dichloromethane. The aqueous layer
was acidified by 1 M hydrochloric acid (541 L, 10.7 equiv) to give
PDE-II as a white precipitate. The precipitate was washed twice with
20 mM hydrochloric acid (2 mL). Benzene (2 mL) was added to the
precipitate and the resulting mixture was completely dried under
reduced pressure to afford analytically pure PDE-II (2) (6.8 mg,
solution was stirred at room temperature for 1.5 h, after which time
TLC (hexaneseethyl acetate¼1:1) indicated complete consumption
of the dihydropyrroloindole. The reaction mixture was diluted with
ethyl acetate and basified with saturated aqueous sodium bi-
carbonate (20 mL) and 1 M NaOH (1 mL). After separation of or-
ganic layer, the aqueous layer was extracted twice with ethyl
acetate. The combined organic extracts were washed with satu-
rated aqueous sodium bicarbonate, 1 M HCl and brine, dried over
anhydrous sodium sulfate, and filtered. The filtrate was concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (dichloromethaneemethanol¼50:1)
to provide crude 19, which was purified by GPC to afford pure 19
m
23 mmol, 46%) as a white solid. The physical properties of the syn-
thetic PDE-II (2) were identical in all aspects to those reported for the
natural product.6 Rf¼0.11 (dichloromethaneemethanol¼10:1). 1H
NMR (400 MHz, DMSO-d6): d 12.18 (s, 1H), 11.40 (br s, 1H), 6.94 (br s,
1H), 4.22 (t, 2H, J¼8.2 Hz), 3.78 (s, 3H), 3.20 (t, 2H, J¼8.2 Hz), 2.29 (s,
3H). 13C NMR (150 MHz, DMSO-d6):
d 169.3, 162.4, 138.1, 132.6, 131.3,
128.8, 126.5, 120.7, 117.2, 106.9, 60.0, 50.8, 26.4, 23.6. IR (KBr, cmꢀ1):
3288, 2922, 2853, 1672, 1574, 1466, 1259, 1097, 1026, 799. HRMS-EI
calcd for C14H14N2O5 (Mþ) 209.0903; found 209.0890.
(235.3 mg, 739
m
mol, 98%) as a yellow amorphous. Rf¼0.40
(dichloromethaneemethanol¼20:1). 1H NMR (400 MHz, CDCl3):
d
9.04 (br s, 1H), 7.07 (d, 1H, J¼2.0 Hz), 4.34 (t, 2H, J¼7.6 Hz), 4.05 (s,
3H), 3.95 (s, 3H), 3.84 (s, 3H), 3.10 (t, 2H, J¼7.6 Hz), 2.27 (s, 3H). 13
C
4.12. Methyl 6-(aminocarbonyl)-3,6,7,8-tetrahydro-4,5-
NMR (100 MHz, CDCl3):
d
171.7,161.9,141.3,137.7,131.2,129.8,128.2,
dimethoxy-benzo[1,2-b:4,3-b0]dipyrrole-2-carboxylate (21)
123.1, 121.1,107.0, 61.3, 60.5, 52.04, 51.99, 28.3, 22.9. IR (neat, cmꢀ1):
3306, 3001, 2947, 2839, 1715, 1634, 1537, 1504, 1030, 995, 756.
HRMS-EI calcd for C16H18N2O5 (Mþ) 318.1216; found 318.1219.
A 50-mL round-bottomed flask equipped with a magnetic stir-
ring bar was charged with pyrroloindole 15 (309 mg, 1.13 mmol)
and acetic acid (3.0 mL). NaBH3CN (835 mg, 13.5 mmol, 12 equiv)
was added to the flask, and the resulting reaction mixture was
stirred at room temperature for 1 h, after which time TLC (hex-
aneseethyl acetate¼1:1) indicated complete consumption of the
starting pyrroloindole 15 (Rf¼0.48). To the reaction mixture was
added dry dichloromethane (15 mL), trimethylsilyl isocyanate
4.10. Methyl 6-acetyl-3,6,7,8-tetrahydro-5-hydroxy-4-
methoxy-benzo[1,2-b:4,3-b0]dipyrrole-2-carboxylate (20, PDE-
II methyl ester)13
A
2-L oven-dried three-necked round-bottomed flask was
equipped with a magnetic stirring bar was charged with dry
dichloromethane (670 mL, 1.03 mM) and dry dichloromethane
(30 mL) solution of 19 (219.3 mg, 689 mmol). The resulting mixture
(152 mL, 1.13 mmol, 1.0 equiv), and DMAP (41.5 mg, 340 mmol,
0.30 equiv). The resulting solution was stirred at room temperature
for 5 h, after which time TLC (hexaneseethyl acetate¼1:1) in-
dicated complete consumption of dihydropyrroloindole 18. The
reaction was quenched with saturated aqueous sodium bicarbonate
(20 mL). After separation of organic layer, the aqueous layer was
extracted twice with ethyl acetate. The combined organic extracts
were washed with brine, dried over anhydrous sodium sulfate, and
filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(hexaneseethyl acetate¼1:3) to afford the desired urea 21
was cooled to 0 ꢁC. To the solution was added BCl3 (1.0 M in
dichloromethane, 5.51 mL, 5.51 mmol, 8.0 equiv) dropwise at 0 ꢁC
over the period of 8 min. After stirred for 1 h at 0 ꢁC, the reaction
mixture was warmed to room temperature and stirred for additional
19 h, after which time TLC (dichloromethaneemethanol¼20:1) in-
dicated complete consumption of the starting material. The reaction
mixture was treated with saturated aqueous sodium bicarbonate
(50 mL). The organic solvents were removed under reduced pres-
sure. The residue was extracted with ethyl acetate three times. The
combined organic extracts were washed with brine, dried over
anhydrous sodium sulfate, and filtered. The filtrate was concen-
trated under reduced pressure. The residue was purified by re-
crystallization (dichloromethane) to give pure 20 (131.3 mg,
(266 mg, 833
m
mol, 74%) as
a
pale yellow solid. Rf¼0.28
(dichloromethaneemethanol¼20:1). 1H NMR (400 MHz, CDCl3):
d
9.00 (br s, 1H), 7.05 (d, 1H, J¼2.0 Hz), 5.80 (br s, 2H), 4.41 (t, 2H,
J¼7.8 Hz), 4.06 (s, 3H), 3.95 (s, 3H), 3.89 (s, 3H), 3.11 (t, 2H, J¼7.8 Hz).
13C NMR (100 MHz, CDCl3):
d 161.9, 158.3, 139.3, 137.7, 131.2, 129.1,
431
by preparative TLC (dichloromethaneemethanol¼50:1) to afford
20 (21.6 mg, 71.0 mol, 10%) as
white solid. Rf¼0.46
(dichloromethaneemethanol¼20:1). Mp: 248.9e252.1
ꢁC
(dichloromethane). 1H NMR (600 MHz, CDCl3):
12.03 (s, 1H), 8.85
mmol, 63%) as light brown crystals. The residue was purified
128.6, 123.2, 122.0, 107.0, 61.7, 61.2, 52.1, 51.1, 27.7. IR (neat, cmꢀ1):
3423, 3339, 1691, 1651, 1582, 1402, 1300, 1215, 1150, 1099, 745.
HRMS-EI calcd for C15H17N3O5 (Mþ) 319.1168; found 319.1163.
m
a
d
4.13. Methyl 6-(aminocarbonyl)-3,6,7,8-tetrahydro-5-
hydroxy-4-methoxy-benzo[1,2-b:4,3-b0]dipyrrole-2-
carboxylate (22, PDE-I methyl ester)
(br s, 1H), 7.02 (d, 1H, J¼2.4 Hz), 4.18 (t, 2H, J¼7.8 Hz), 4.02 (s, 3H),
3.93 (s, 3H), 3.28 (t, 2H, J¼7.8 Hz), 2.34 (s, 3H). 13C NMR (150 MHz,
CDCl3):
d 168.8, 161.9, 139.1, 133.0, 131.3, 127.7, 127.0, 120.4, 117.3,
107.4, 60.6, 51.9, 51.3, 27.0, 23.9. IR (neat, cmꢀ1): 3323, 1688, 1452,
A 500-mL oven-dried three-necked round-bottomed flask was
equipped with a magnetic stirring bar was charged with 21
(54.4 mg, 170 mmol) and dry dichloromethane (170 mL, 1.00 mM).
1437, 1298, 1261, 1097. HRMS-EI calcd for
304.1059; found 304.1053.
C
15H16N2O5 (Mþ)
The resulting mixture was cooled to 0 ꢁC. To the solution was added
BCl3 (1.0 M in dichloromethane, 1.70 mL, 1.70 mmol, 10 equiv)
dropwise at 0 ꢁC over a period of 30 s. After stirred for 3 h at 0 ꢁC,
the reaction mixture was warmed to room temperature and stirred
for another 19 h. The reaction mixture was treated with saturated
aqueous sodium bicarbonate (17 mL). The organic solvents were
removed under reduced pressure. The residue was extracted with
ethyl acetate. The combined organic extracts were washed with
brine, dried over anhydrous sodium sulfate, and filtered. The filtrate
was concentrated under reduced pressure. The residue was purified
by MPLC (acetone, flow rate: 2.5 mL/min, ULTRA PACK: DIOL-A) to
4.11. 6-Acetyl-3,6,7,8-tetrahydro-5-hydroxy-4-methoxy-benzo
[1,2-b:4,3-b0]dipyrrole-2-carboxylic acid (2, PDE-II)13
A 10-mL test tube equipped with a magnetic stirring bar was
charged with PDE-II methyl ester (20) (15.4 mg, 50.6
THF (617 L). To the solution were added Na2S2O4 (26.2 mg,
152 mol, 3.0 equiv) and 1 M LiOH (506 L, 10 equiv), and the
mmol) and dry
m
m
m
resulting mixture was stirred at room temperature for 5.5 h, after
which time TLC (dichloromethaneemethanol¼10:1) indicated
complete consumption of the starting material. The organic solvents
were removed under reduced pressure, and the residue was diluted
afford pure 22 (39.4 mg, 129 mmol, 76%) as light brown crystals and

K. Okano et al. / Tetrahedron 69 (2013) 10946e10954
10953
starting material (15.3 mg). The starting material was subjected to
4.16. Methyl 2-(tert-butyloxycarbonylamino)-2-(5,8-
the above conditions to afford phenol 22 (9.1 mg, 30
m
mol, 18%, 93%
dibromo-6,7-dimethoxy-2-(2-nitrophenylsulfonyl)-1,2,3,4-
tetrahydroisoquinolin-1-yl)ethanoate (24)
as
a
combined yield). Rf¼0.67 (acetone). Mp: 213 ꢁC (de-
composition). 1H NMR (400 MHz, acetone-d6):
d 12.75 (s, 1H), 10.36
(br s,1H), 6.97 (d,1H, J¼2.0 Hz), 6.22 (br s, 2H), 4.17 (t, 2H, J¼8.8 Hz),
An oven-dried 50-mL round-bottomed flask equipped with
a magnetic stirring bar was charged with hemiaminal 9 (521 mg,
3.88 (s, 3H), 3.83 (s, 3H), 3.30 (t, 2H, J¼8.8 Hz). 13C NMR (150 MHz,
acetone-d6):
d
162.3, 158.5, 139.8, 133.8, 131.7, 128.8, 127.7, 119.2,
920
and dry dichloromethane (9.2 mL). The resulting mixture was
cooled to 0 ꢁC. To the reaction mixture was added BF3$OEt2 (340
L,
mmol), ketene silyl acetal 23 (943 mg, theoretically 3.0 equiv),
118.1, 107.6, 60.3, 51.7, 50.3, 27.5. IR (KBr, cmꢀ1): 3427, 3339, 3219,
1684, 1638, 1472, 1439, 1333, 1298, 1261, 1225, 1198, 1096, 772, 748.
HRMS-EI calcd for C14H15N3O5 (Mþ) 305.1012; found 305.1026.
m
2.76 mmol, 3.0 equiv) slowly at 0 ꢁC over a period of 2 min. The
reaction mixture was stirred at 0 ꢁC for 2 h, after which time TLC
(hexaneseethyl acetate¼3:1) indicated complete consumption of
the starting hemiaminal 9. The reaction was quenched with satu-
rated aqueous ammonium chloride. The mixture was concentrated
under reduced pressure to remove organic solvents. The residue
was extracted with ethyl acetate. The combined organic extracts
were washed with saturated aqueous ammonium chloride and
brine, dried over anhydrous sodium sulfate, and filtered. The filtrate
was concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexaneseethyl acetate¼1:1)
4.14. 6-Aminocarbonyl-3,6,7,8-tetrahydro-5-hydroxy-4-
methoxy-benzo[1,2-b:4,3-b0]dipyrrole-2-carboxylic acid
(1, PDE-I)
A 20-mL round-bottomed flask equipped with a magnetic stir-
ring bar was charged with PDE-I methyl ester (22) (36.8 mg,
121
mmol), Na2S2O4 (63.0 mg, 362 mmol, 3.0 equiv) and THF
(1.5 mL). To the reaction mixture was added 1 M aqueous lithium
hydroxide (1.21 mL, 10 equiv). The reaction mixture was stirred at
room temperature for 9 h, after which time TLC (ethyl acetate)
indicated complete consumption of the starting material. THF was
removed under reduced pressure, and the residue was diluted with
water and then the aqueous layer was washed with dichloro-
methane. The aqueous layer was acidified by 1 M aqueous hydro-
chloric acid (1.29 mL, 10.7 equiv) to give PDE-I as a white
precipitate. The precipitate was washed twice with 20 mM aqueous
hydrochloric acid (3 mL). Benzene (2 mL) was added to the pre-
cipitate and the resulting mixture was completely dried under re-
duced pressure to afford crude PDE-I (1). Trituration with ethyl
acetate and the resulting solid to afford PDE-I (1) (30.5 mg,
to afford the desired Mannich adduct 24 (663 mg, 917 mmol, quant)
as a colorless amorphous as a mixture of diastereomers. Rf¼0.46
(hexaneseethyl acetate¼1:1). 1H NMR (500 MHz, CDCl3):
d
8.00e7.85 (m, 1H), 7.66e7.46 (m, 3H), 5.75e5.52 (m, 1H),
5.45e5.27 (m, 1H), 4.98e4.75 (m, 1H), 3.85 (s, 9H), 3.75e3.72 (m,
2H), 3.06e2.85 (m, 2H), 1.36e1.20 (m, 9H). 13C NMR (125 MHz,
CDCl3):
d 169.5, 154.6, 150.8, 149.3, 147.9, 133.8, 132.1, 131.6, 131.5,
131.4, 130.8, 129.2, 124.1, 124.0, 119.4, 118.7, 80.1, 80.0, 60.8, 60.72,
60.67, 58.2, 58.1, 56.5, 55.4, 52.8, 52.6, 52.1, 40.5, 39.3, 28.2, 28.0,
27.5, 27.0 (observed peaks). IR (neat, cmꢀ1): 3381, 2982, 1744, 1715,
1547, 1504, 1462, 1406, 1367, 1348, 1302, 1165, 1028, 970, 912, 853,
105
mmol, 46%) as a white solid. The physical properties of the
733. HRMS-ESI calcd for
745.9819; found 745.9837.
C
25H2979Br81BrN3O10SNa (MþNaþ)
synthetic PDE-I (1) were identical with those reported for the
natural product.1,6d,8b Rf¼0.12 (ethyl acetate). Mp: 236 ꢁC (de-
composition). [lit. 235 ꢁC (decomposition)]; 1H NMR (500 MHz,
4.17. 3-tert-Butyl 2-methyl-7,8-dihydro-4,5-dimethyl-6-[(2-
nitrophenyl)sulfonyl]-benzo[1,2-b:4,3-b’]dipyrrole-2,3(6H)-di-
carboxylate (25)
DMSO-d6):
d
12.81 (s, 1H), 11.22 (s, 1H), 6.87 (d, 1H, J¼2.0 Hz), 6.84
(br s, 2H), 3.99 (t, 2H, J¼9.0 Hz), 3.76 (s, 3H), 3.18 (t, 2H, J¼9.0 Hz)
(two proton signals were missing owing to broadening). 13C NMR
(125 MHz, DMSO-d6):
d
162.5, 157.5, 137.8, 132.5, 130.2, 128.1, 127.2,
A
flame-dried 10-mL two-necked round-bottomed flask
equipped with a magnetic stirring bar was charged with 24
(146.6 mg, 203 mol), copper iodide (58.6 mg, 308 mol,
1.5 equiv). Cesium acetate (195.6 mg, 1.02 mmol, 5.0 equiv) and
cesium carbonate (197.9 mg, 607 mol, 3.0 equiv) were weighed
118.1, 117.0, 106.5, 59.9, 49.3, 26.4. IR (KBr, cmꢀ1): 3495, 3458, 3352,
3219, 1663, 1641, 1578, 1489, 1439, 1329, 1290, 1258, 1161, 1132,
1090, 955, 883, 768, 746. HRMS-FAB calcd for C13H13N3O5 (Mþ)
291.0855; found 291.0856.
m
m
m
and added to the flask in a glove box. The flask was then evacuated
then backfilled with argon. To the mixture was added dry DMSO
(2.0 mL). The resulting solution was stirred at 90 ꢁC for 3 h. The
reaction mixture was cooled to room temperature. Then treated
with 5% aqueous sodium chloride in 10% aqueous ammonium
hydroxide, and the mixture was extracted with ethyl acetate. The
combined organic extracts were washed with 5% aqueous sodium
chloride in 10% aqueous ammonium hydroxide, brine, dried over
anhydrous sodium sulfate, and filtered. The filtrate was concen-
trated under reduced pressure to afford crude dihy-
dropyrroloindole 25 (106 mg) as a brown oil, which was purified
by column chromatography (hexaneseethyl acetate¼2:1 to 1:3,
4.15. tert-Butyl 2-methoxy-2-(trimethylsilyloxy)vinyl(-
trimethylsilyl)carbamate (23)
A
flame-dried 50-mL two-necked round-bottomed flask
equipped with a magnetic stirring bar was charged with diisopro-
pylamine (774 L, 5.52 mmol, 2.0 equiv) and dry THF (6.1 mL). The
m
resulting mixture was cooled to 0 ꢁC. To the reaction mixture was
added n-BuLi (1.47 M in n-hexane, 3.75 mL, 5.52 mmol, 2.0 equiv)
dropwise at 0 ꢁC over a period of 1 min. The reaction mixture was
stirred at 0 ꢁC for 20 min then cooled to ꢀ78 ꢁC. To the reaction
mixture was added dry THF (1.7 mL) solution of N-Boc-glycine
methyl ester (522 mg, 2.76 mmol) and trimethylsilyl chloride
(1.4 mL, 11 mmol, 4.0 equiv) slowly over a period of 3 min via
cannula. After being stirred for 25 min at ꢀ78 ꢁC, the reaction
mixture was then warmed to room temperature and stirred for
another 1 h. After removal of stirring bar, the reaction mixture
was concentrated under reduced pressure. The residue was diluted
with hexanes and passed through CeliteÒ, and the filter cake
was washed with hexanes. The filtrate was concentrated under
reduced pressure to afford a crude ketene silyl acetal 23 (943 mg) as
a yellow oil, which was used to the next reaction without further
purification.
gradient) to provide dihydropyrroloindole 25 (38.4 mg, 68.3 mmol,
34%) and pyrroloindole 15 (11.0 mg, 40.1 mmol, 20%). Physical data
for 25; Rf¼0.47 (hexaneseethyl acetate¼1:1). 1H NMR (500 MHz,
acetone-d6): d8.07e8.01 (m, 1H), 7.90e7.77 (m, 3H), 7.10 (s, 1H),
4.36 (t, 2H, J¼7.5 Hz), 3.85 (s, 3H), 3.80 (s, 3H), 3.46 (s, 3H), 3.11
(t, 2H, J¼7.5 Hz), 1.59 (s, 9H). 13C NMR (125 MHz, acetone-d6):
d
161.4, 151.0, 148.7, 144.0, 139.1, 134.9, 134.7, 132.7, 132.4, 131.2,
130.9, 129.3, 125.1, 124.8, 120.5, 109.9, 85.8, 61.4, 60.2, 54.8, 52.4,
30.5, 27.5. IR (neat, cmꢀ1): 1771, 1717, 1541, 1489, 1350, 1254, 1229,
1146, 1030, 849, 754. HRMS-FAB calcd for C25H27N3O10S (Mþ)
561.1417; found 561.1422.

10954
K. Okano et al. / Tetrahedron 69 (2013) 10946e10954
4.18. Methyl 1-(tert-butyloxycarbonyl)-3,6,7,8-tetrahydro-4,5-
dimethoxy-benzo[1,2-b:4,3-b0]dipyrrole-2-carboxylate (26)
complete consumption of the starting Boc carbamate 27. Purifica-
tion was performed by silica gel column chromatography (ethyl
acetate) to provide unprotected indole 19 (7.2 mg, 23 mmol, 93%),
Crude dihydropyrroloindole 25, which was obtained by the
whose spectral data were identical with those reported in the first-
amination using 24 (102.2 mg, 141
424 mol, 3.0 equiv), Cs2CO3 (138.0 mg, 424
treated with cesium carbonate (230.0 mg, 705
dry MeCN (284 L). To the resulting mixture was added PhSH
(14.0 L, 141 mol, 1.0 equiv) and the mixture was stirred at room
temperature for h, after which time TLC (hexaneseethyl
m
mol), CsOAc (81.3 mg,
mol, 3.0 equiv), was
mol, 5.0 equiv), and
generation synthesis of PDE-II.13
m
m
m
Acknowledgements
m
m
m
This work was financially supported by the Cabinet Office,
Government of Japan through its ‘Funding Program for Next Gen-
eration World-Leading Researchers’ (LS008), the Ministry of Edu-
cation, Culture, Sports, Science, and Technology, Japan, the
KAKENHI, a Grant-in-Aid for Scientific Research (B) (20390003),
Tohoku University Global COE program ‘International Center of
Research and Education for Molecular Complex Chemistry’, Kato
Memorial Bioscience Foundation, Astellas Foundation for Research
on Metabolic Disorders, and Banyu Life Science Foundation
International.
4
acetate¼1:1) indicated complete consumption of the starting nosyl
amide 25. The mixture was diluted with EtOAc and filtered through
Celite plug and the filtrate was concentrated under reduced pres-
sure. The crude material was purified by preparative TLC (hex-
aneseethyl acetate¼1:1, developed twice) to provide unprotected
dihydropyrroloindole 26 (19.0 mg, 50.4
mmol, 36% over two steps)
as a colorless amorphous and pyrroloindole 15 (5.0 mg, 18.2
mmol,
13% over two steps). Physical data for 26; Rf¼0.26 (hexaneseethyl
acetate¼1:1). 1H NMR (400 MHz, CDCl3):
d 6.99 (s, 1H), 3.93 (s, 3H),
3.90 (s, 3H), 3.89 (s, 3H), 3.66 (t, 2H, J¼8.5 Hz), 3.16 (t, 2H, J¼8.5 Hz),
References and notes
1.66 (s, 9H). 13C NMR (150 MHz, CDCl3):
d 161.2, 151.1, 141.3, 139.2,
1. Enomoto, Y.; Furutani, Y.; Naganawa, H.; Hamada, M.; Takeuchi, T.; Umezawa, H.
Agric. Biol. Chem. 1978, 42, 1331.
2. Nakamura, H.; Enomoto, Y.; Takeuchi, T.; Umezawa, H.; Iitaka, Y. Agric. Biol.
138.0, 127.6, 127.0, 120.7, 115.2, 108.9, 84.7, 61.1, 60.2, 51.8, 48.3, 29.3,
27.4. IR (neat, cmꢀ1): 3368, 2939, 1765, 1715, 1493, 1258, 1238, 1148,
1030, 845, 731. HRMS-FAB calcd for C19H24N2O6 (Mþ) 376.1634;
found 376.1625.
Chem. 1978, 42, 1337.
3. (a) Komoto, N.; Enomoto, Y.; Miyagaki, M.; Tanaka, Y.; Nitanai, K.; Umezawa, H.
Agric. Biol. Chem. 1979, 43, 555; (b) Komoto, N.; Enomoto, Y.; Tanaka, Y.; Nitanai,
K.; Umezawa, H. Agric. Biol. Chem. 1979, 43, 559.
4.19. Methyl 6-acetyl-1-(tert-butyloxycarbonyl)-3,6,7,8-
tetrahydro-4,5-dimethoxy-benzo[1,2-b:4,3-b0]dipyrrole-2-
carboxylate (27)
4. (a) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A. Chem. Rev. 1997, 97,
787; (b) Parrish, J. P.; Trzupek, J. D.; Hughes, T. V.; Hwang, I.; Boger, D. L. Bioorg.
Med. Chem. 2004, 12, 5845.
5. (a) Tichenor, M. S.; Kastrinsky, D. B.; Boger, D. L. J. Am. Chem. Soc. 2004, 126,
8396; (b) Okano, K.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2006, 128,
7136; (c) Tichenor, M. S.; Trzupek, J. D.; Kastrinsky, D. B.; Shiga, F.; Hwang, I.;
Boger, D. L. J. Am. Chem. Soc. 2006, 128, 15683; (d) Okano, K.; Tokuyama, H.;
Fukuyama, T. Chem.dAsian J. 2008, 3, 296; (e) Tichenor, M. S.; Boger, D. L. Nat.
Prod. Rep. 2008, 25, 220.
6. (a) Bolton, R. E.; Moody, C. J.; Rees, C. W.; Tojo, G. J. Chem. Soc., Chem. Commun.
1985, 1775; (b) Carter, P.; Fitzjohn, S.; Magnus, P. J. Chem. Soc., Chem. Commun.
1986, 1162; (c) Bolton, R. E.; Moody, C. J.; Rees, C. W.; Tojo, G. Tetrahedron Lett.
1987, 28, 3163; (d) Bolton, R. E.; Moody, C. J.; Rees, C. W.; Tojo, G. J. Chem. Soc.,
Perkin Trans. 1 1987, 931; (e) Carter, P.; Fitzjohn, S.; Halazy, S.; Magnus, P. J. Am.
Chem. Soc. 1987, 109, 2711.
7. Rawal, V. H.; Cava, M. P. J. Am. Chem. Soc. 1986, 108, 2110.
8. (a) Boger, D. L.; Coleman, R. S. Tetrahedron Lett. 1987, 28, 1027; (b) Boger, D. L.;
Coleman, R. S. J. Am. Chem. Soc. 1987, 109, 2717.
A
flame-dried 20-mL two-necked round-bottomed flask
equipped with a magnetic stirring bar was charged with the crude
25 (74.5 mg), cesium carbonate (231.0 mg, 710 mol, 5.0 equiv), and
dry MeCN (284 L). To the resulting mixture was added PhSH
(14.6 L, 142 mol, 1.0 equiv) and the mixture was stirred at room
temperature for h, after which time TLC (hexaneseethyl
acetate¼1:1) indicated complete consumption of the starting nosyl
amide 25. To the mixture were added Ac2O (67.1 L, 710 mol,
5.0 equiv) and pyridine (568 L). The mixture was stirred at room
temperature for h, after which time TLC (hexaneseethyl
m
m
m
m
4
m
m
m
1
9. Martin, P. Helv. Chim. Acta 1989, 72, 1554.
acetate¼1:1) indicated complete consumption of the unprotected
dihydropyrroloindole 26. The mixture was filtered through Celite
plug and the filtrate was concentrated under reduced pressure. The
resulting mixture was partitioned between ethyl acetate and sat-
urated aqueous ammonium chloride. The aqueous layer was
extracted twice with ethyl acetate. The combined organic extracts
were dried over sodium sulfate and filtered. The organic solvents
were removed under reduced pressure to give a crude material,
which was purified by silica gel column chromatography (hex-
aneseethyl acetate¼1:1) to provide dihydropyrroloindole 27
10. (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120, 12459; (b)
Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583; (c) Kwong, F. Y.; Klapars, A.; Buchwald, S.
L. Org. Lett. 2002, 4, 581; (d) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793;
(e) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400; (f) Buchwald,
S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348, 23; (g) Ma,
D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
11. (a) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002, 231; (b)
Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5, 4987; (c) Kubo, T.;
Katoh, C.; Yamada, K.; Okano, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2008,
64, 11230; (d) Okano, K.; Fukuyama, T.; Tokuyama, H. J. Synth. Org. Chem. Jpn.
2010, 68, 1036; (e) Komori, T.; Satoh, N.; Yokoshima, S.; Fukuyama, T. Synlett
2011, 1859.
12. Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2003,
(27.3 mg, 65.2 mmol, 46% over two steps) as a colorless amorphous.
125, 6630.
Rf¼0.19 (hexaneseethyl acetate¼1:1). 1H NMR (600 MHz, CDCl3):
13. Okano, K.; Mitsuhashi, N.; Tokuyama, H. Chem. Commun. 2010, 2641.
14. (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373; (b)
Kan, T.; Fukuyama, T. J. Synth. Org. Chem. Jpn. 2001, 59, 779; (c) Kan, T.; Fu-
kuyama, T. Chem. Commun. 2004, 353.
15. (a) Mannich reaction of 8 with 10 did not proceed at all; (b) Corey, E. J.; Gross,
A. W. Tetrahedron Lett. 1984, 25, 495 Preparation of ketene silyl acetal 10 was
carried out according to the Corey’s internal quench method.
16. Compound 13 was isolated as a mixture of diastereomers. The relative ste-
reochemistry was not determined due to the presence of the carbamate
rotamers.
d
7.07 (s, 1H), 4.33 (t, 2H, J¼7.8 Hz), 3.96 (s, 3H), 3.91 (s, 3H), 3.84 (s,
3H), 3.08 (t, 2H, J¼7.8 Hz), 2.26 (s, 3H), 1.67 (s, 9H). 13C NMR
(150 MHz, CDCl3):
d 172.3, 160.8, 150.5, 142.6, 138.7, 131.9, 129.7,
128.6, 123.3, 120.2, 109.1, 85.3, 61.3, 60.4, 52.1, 51.9, 28.1, 27.4, 22.9.
IR (neat, cmꢀ1): 2982, 2942, 1767, 1720, 1659, 1410, 1372, 1336, 1257,
1220, 1152, 1028, 733. HRMS-FAB calcd for C21H26N2O7 (Mþ)
418.1740; found 418.1725.
17. Brooks, P. R.; Wirtz, M. C.; Vetelino, M. G.; Rescek, D. M.; Woodworth, G. F.;
Morgan, B. P.; Coe, J. W. J. Org. Chem. 1999, 64, 9719.
18. (a) Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1988, 110, 1321; (b) Boger, D. L.;
Coleman, R. S. J. Am. Chem. Soc. 1988, 110, 4796; (c) MacMillan, K. S.; Nguyen, T.;
Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2009, 131, 1187.
4.20. Methyl 6-acetyl-3,6,7,8-tetrahydro-4,5-dimethoxy-
benzo[1,2-b:4,3-b0]dipyrrole-2-carboxylate (19)
19. (a) Rawal, V. H.; Cava, M. P. Tetrahedron Lett. 1985, 26, 6141; (b) Baran, P. S.;
Guerrero, C. A.; Ambhaikar, N. B.; Hafensteiner, B. D. Angew. Chem., Int. Ed. 2005,
44, 606; (c) Baran, P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem., Int. Ed. 2005,
44, 3714.
A 10-mL test tube was charged with 27 (10.2 mg, 24.4 mmol),
evacuated, and backfilled with argon. The test tube was heated at
180 ꢁC for 30 min, after which time TLC (ethyl acetate) indicated