Development of a Br?nsted acid-promoted arene-ynamide cyclization toward the total syntheses of marinoquinolines A and C and aplidiopsamine A

Article abstract of DOI:10.1021/jo502467m

(Chemical Equation Presented) A Br?nsted acid-promoted arene-ynamide cyclization has been developed to construct the 3H-pyrrolo[2,3-c]quinolines. This reaction consists of the generation of a highly reactive keteniminium intermediate from arene-ynamide activated by a Br?nsted acid and electrophilic aromatic substitution reaction to give arene-fused quinolines in high yields. This methodology enabled facile access to marinoquinolines A and C and aplidiopsamine A.

Full text of DOI:10.1021/jo502467m

Article
pubs.acs.org/joc
Development of a Brønsted Acid-Promoted Arene−Ynamide
Cyclization toward the Total Syntheses of Marinoquinolines A and C
and Aplidiopsamine A
Yousuke Yamaoka,* Takahiro Yoshida, Makiko Shinozaki, Ken-ichi Yamada, and Kiyosei Takasu*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
S
* Supporting Information
ABSTRACT: A Brønsted acid-promoted arene−ynamide cyclization has been developed to construct the 3H-pyrrolo[2,3-
c]quinolines. This reaction consists of the generation of a highly reactive keteniminium intermediate from arene−ynamide
activated by a Brønsted acid and electrophilic aromatic substitution reaction to give arene-fused quinolines in high yields. This
methodology enabled facile access to marinoquinolines A and C and aplidiopsamine A.
wide range of nucleophiles have been shown to react at the α
position of ynamides, which is activated as keteniminium ions
by the action of a Brønsted acid.7 We recently reported a
domino reaction of ynamides with aldimines or ketimines in the
presence of a catalytic amount of triflic imide to afford α,β-
unsaturated amidines or dihydroquinolines in good yields.8 In
this paper, we report a Brønsted acid-promoted cyclization of
arene−ynamides to afford the arene-fused quinoline derivatives
and the total syntheses of marinoquinolines A and C and
aplidiopsamine A as an application of this methodology.
The retrosynthetic analysis of 3H-pyrrolo[2,3-c]quinolines is
shown in Scheme 1. We anticipated that the tricyclic
heterocycle could be synthesized by electrophilic aromatic
substitution reaction with the keteniminium intermediate of
arene−ynamide,7,9 which could be easily prepared by the
INTRODUCTION
■
Heterocycles are an important and attractive class of
compounds for medicinal and material chemistries. Of these,
the quinoline skeleton is an important nucleus that is frequently
found as a component in pharmaceutical agents and biologically
active natural products.1 Recently, the 3H-pyrrolo[2,3-c]-
quinoline ring system was found in marine natural products.
Marinoquinolines A−F were isolated from the marine bacteria
and found to possess weak antibacterial and antifungal activities
and moderate cytotoxicity against growing mammalian cell
lines.2 Furthermore, as the structurally related binuclear
alkaloid, aplidiopsamine A was isolated from the temperate
Australian ascidian, Aplidiopsis confluata, and exhibited sig-
nificant growth inhibition of chloroquine-resistant strains of the
malaria parasite, Plasmodium falciparum (Figure 1).3 Although
the efficient synthesis of these natural products was reported,
there is no report of the synthesis of these analogues that have
other fused aromatic rings, instead of a pyrrole ring.4,5 Recently,
ynamides have received much attention as fascinating building
blocks for the synthesis of nitrogen-containing compounds.6 A
Scheme 1. Retrosynthetic Analysis of 3H-Pyrrolo[2,3-
c]quinoline Ring Construction
Figure 1. Natural products possessing a 3H-pyrrolo[2,3-c]quinoline
ring system.
Received: October 28, 2014
© XXXX American Chemical Society
A
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coupling reactions of N-(tert-butoxycarbonyl)-2-bromoaniline
with the corresponding boronic acid and bromoacetylene.
Scheme 2. Proposed Mechanism for Arene−Ynamide
Cyclization Reaction
RESULTS AND DISCUSSION
We examined the cyclization reaction of arene−ynamide 4a
under several conditions (Table 1). Initially, we investigated
■
a
Table 1. Optimization of Reaction Conditions
b
entry
acid
Tf2NH
time
solvent
yield (%)
1
2
5 min
12 h
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
hexane
85
TFA
26
3
p-TsOH
CSA
12 h
59
4
12 h
58
5
HBF4
5 min
5 min
12 h
72
6
TfOH
86 (6a)
11
7
AgOTf
Cu(OTf)2
AuCl(PPh3)
TfOH
8
12 h
26
9
12 h
0
When the reaction was quenched by NaBH4 in methanol, the
1,2-dihydroquinoline 7 was obtained in a moderate yield.
Under the optimized reaction conditions (1.2 equiv of TfOH
in CH2Cl2 at rt), the arene−ynamide cyclization reaction of
various ynamides 4 was achieved, and the results are
summarized in Scheme 3. The reaction with substrates 4b−d
bearing other heteroaromatic groups, such as 3-furyl, 3-thenyl,
and 3-indolyl, afforded the desired products 6b−d in high
yields. Substrate 4e, with a simple phenyl ring, afforded
phenanthridine 6e in a moderate yield. Substrates bearing
electron-donating (4f) or electron-withdrawing (4g) groups at
the para position on the phenyl ring are well-tolerated, giving
products 6f and 6g in high yields, respectively. Finally, the
substituents on a terminal position of ynamide were
investigated. Not only a silyl group but also a hydrogen atom
(4h) and phenyl (4i) and ester (4j) groups are applicable under
this reaction to give the desired cyclized products 6h−j in good
yields. As a consequence, we accomplished the total syntheses
of marinoquinolines A (6h) and C (6i). Overall, our
methodology represents the divergent synthesis of analogues
of 3H-pyrrolo[2,3-c]quinolines.
Finally, the total synthesis of aplidiopsamine A was pursued.
First, halogenation of the N-Boc-protected derivative of
marinoquinoline A (6h) was investigated. However, all
attempts of radical or ionic bromination of the quinolinyl-
methyl moiety failed.11 Thus, we examined the synthesis of 2-
(halomethyl)quinolines 8 or 9 from ynamides 4k,l (Table 2).
The acid treatment of halogenated ynamides 4k and 4l afforded
complex mixtures containing a small amount of the desired
products (entries 1 and 2). Gratifyingly, the acid treatment of
ynamide 4a and desilylation with tetra-n-butylammonium
fluoride (TBAF), followed by bromination with N-bromosucci-
nimide (NBS) at −78 °C in one pot, gave the desired bromide
8 in 43% yield (entry 3). After several modifications, we found
that an addition of TBAF was not required when 4a was treated
with the acid for 60 min at −78 °C prior to the addition of NBS
to give the desired product in 64% yield (entry 4). We
presumed that the bromodesilylation reaction promoted by
NBS would occur after the acid treatment of ynamide 4a: the
cyclic bromonium ion V was generated from the vinylsilane
10
11
5 min
5 min
12 h
76
TfOH
73
c
12
Tf2NH
CH2Cl2
18
a
Unless otherwise noted, reactions were performed with 4a (0.2
b
mmol) and acid (0.24 mmol) in solvent (0.1 M) at rt. Isolated yields.
c
Using 20 mol % of Tf2NH.
several Brønsted acids for a cyclization reaction with 4a in
dichloromethane at room temperature. Gratifyingly, the use of
1.2 equiv of triflic imide (Tf2NH) as a strong acid gave the
desired tricyclic quinoline derivative 5a in 85% yield in 5 min
(entry 1). It is noteworthy that the acidity of acids is very
important in this cyclization reaction. The yields were lower,
and some starting material was recovered, as the acidity of acids
was weaker (entries 2−5). Interestingly, the cyclization reaction
with triflic acid (TfOH) was accompanied by removal of the
tert-butoxycarbonyl group on the pyrrole moiety to afford the
product 6a in 86% yield (entry 6). Moreover, we investigated
the reaction with π-acidic transition metal salts, such as Au, Ag,
and Cu salts, for the cyclization reaction; however, the reaction
did not proceed well, and the recovery of starting material 4a
was mainly observed (entries 7−9). The reaction in other
solvents, such as toluene and hexane, gave moderate yields
(entries 10 and 11). The reaction was carried out with a
catalytic amount of triflic imide (20 mol %) to provide low
yield (entry 12).
Based on these results, a plausible mechanism is shown in
Scheme 2. First, the reaction of ynamide 4a would be initiated
by an addition of triflic imide to generate the highly reactive
keteniminium intermediate I. Electrophilic aromatic substitu-
tion reaction would occur to yield the intermediate III along
with a regeneration of a Brønsted acid. Probably, intermediate
III would react further with a Brønsted acid to afford
quinolinium IV, which was then hydrolyzed during an aqueous
workup to give the desired product 5a.10 The formation of IV
as an initial product is supported by the following results: (1)
The reaction could not be promoted by a catalytic amount of
an acid (Table 1, entry 12). (2) The reaction with the N-
methoxycarbonyl analogue of 4a also gave 5a in 65% yield. (3)
B
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a
Scheme 3. Substrate Scope
Scheme 4. Plausible Mechanism for the Synthesis of
Bromide 8 from Ynamide 4a
Scheme 5. Total Synthesis of Aplidiopsamine A
protected adenine13 with Cs2CO3 in CH3CN, followed by the
acidic deprotection of all three tert-butoxycarbonyl groups in
10, afforded aplidiopsamine A in a high yield. Overall, the total
synthesis of aplidiopsamine A was accomplished in 46% yield
over five steps from tert-butyl (2-bromophenyl)carbamate.
CONCLUSION
■
We have developed a Brønsted acid-promoted arene−ynamide
cyclization to provide arene-fused quinolines in high yields. The
arene−ynamide could be easily prepared from commercially
available N-(tert-butoxycarbonyl)-2-bromoaniline in two steps.
The key reaction of arene−ynamide relied on the generation of
the highly reactive keteniminium intermediate by the activation
with a strong Brønsted acid and electrophilic aromatic
substitution reaction. Furthermore, the total syntheses of
marinoquinolines A and C as well as aplidiopsamine A clearly
demonstrated a utility of this methodology. Further applica-
tions and biological evaluation of their analogues are ongoing in
our laboratory.
a
Reactions were performed with 4 (0.2 mmol) and TfOH (0.24
mmol) in CH2Cl2 (0.1 M) at rt. Isolated yields.
a
Table 2. Preparation of 2-(Halomethyl)quinoline
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out in flame-dried
glassware under argon atmosphere and stirred via magnetic stir plates.
All reactions were monitored by analytical thin-layer chromatography.
Visualization was accomplished by UV light (254 nm), phosphomo-
lybdic acid, or anisaldehyde. Flash column chromatography was
performed using silica gel 60 (mesh 230−400). All reactions were
carried out with anhydrous solvents unless otherwise noted. All
reagents and starting materials, unless otherwise noted, were
purchased from commercial vendors. Quadrupole, double-focusing
magnetic sector, and TOF mass spectrometers were used for EI-,
FAB-, and ESI-MS, respectively. Infrared spectra were recorded as thin
b
entry
R
conditions
TfOH, CH2Cl2
yield (%)
1
2
3
4
5
Br (4k)
trace
trace
43
Cl (4l)
TfOH, CH2Cl2
TIPS (4a)
TIPS (4a)
TIPS (4a)
TfOH, CH2Cl2; TBAF; NBS
TfOH, CH2Cl2; NBS
64
TfOH, CH2Cl2; Br2
32
a
b
Reactions were performed with 4 (0.2 mmol). Isolated yields.
intermediate III, followed by the ring opening of the cyclic
brominium ion to give the intermediate VI. Then, the basic
species, such as succinimide and triflate anion, attached to the
silicon atom to give vinyl bromide VII, which after workup
afforded the desired product 8 (Scheme 4).12 The use of
bromine in place of NBS resulted in no improvement (entry 5).
The total synthesis of aplidiopsamine A was accomplished as
shown in Scheme 5. The reaction of bromide 8 and di-Boc-
1
films on sodium chloride plates. NMR spectra (500 MHz for H, 125
MHz for 13C) were measured in CDCl3 unless otherwise mentioned.
Chemical shift values (δ) are reported in parts per million
(tetramethylsilane was used as an internal standard). The H NMR
spectra are reported as follows δ (multiplicity, coupling constant J,
number of protons). Multiplicities are indicated by s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), and br (broad). The
13C chemical shifts are reported relative to CDCl3 (77.0 ppm),
1
C
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DMSO-d6 (39.5 ppm), and acetone-d6 (206.7 and 30.4 ppm).
Bromoacetylenes 3 were prepared according to previous procedures.14
General Procedure for N-(tert-Butoxycarbonyl) o-Bromoani-
lines (1a−c).15 To a solution of sodium hydride (1.1 equiv) in THF
(0.2 M) was added o-bromoaniline derivative (10 mmol). The mixture
was refluxed for 1 h and then cooled to room temperature. Di-tert-
butyl dicarbonate (1.2 equiv) was added, and the slurry was stirred for
30 min. To the mixture was added a second portion of sodium hydride
(1.1 equiv), and the reaction was brought back to reflux overnight. The
reaction was cooled to room temperature and carefully quenched with
water. This mixture was extracted with ether, and the organic layers
were dried over Mg2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography (hexanes/
AcOEt) to afford N-protected o-bromoaniline.
NMR (CDCl3) δ 8.05 (d, J = 7.7 Hz, 1H), 7.59−7.57 (m, 1H), 7.56
(dd, J = 1.6, 1.6 Hz, 1H), 7.31 (ddd, J = 8.2, 8.2, 1.5 Hz, 1H), 7.27−
7.23 (m, 1H), 7.07 (ddd, J = 7.5, 7.5, 1.2 Hz, 1H), 6.62 (br s, 1H),
6.56 (dd, J = 1.7, 0.9 Hz, 1H), 1.50 (s, 9H); 13C NMR (CDCl3) δ
152.9, 143.8, 140.1, 135.7, 129.7, 129.0, 128.4, 123.2, 122.5, 120.1,
111.1, 80.5, 28.3; IR (KBr) νmax 3422, 3348, 2978, 2920, 1728, 1589,
1516, 1501, 1447, 1366 cm−1; MS (FAB) m/z 259 (M+), 203 (M − t-
Bu + H), 186 (M − t-BuO), 159 (M − Boc); HRMS-ESI (m/z) calcd
for C15H18NO3 [M + H]+ 260.1281, found 260.1280. Anal. Calcd for
C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.26; H, 6.73; N,
5.26.
tert-Butyl (2-(Thiophen-3-yl)phenyl)carbamate. The product
was obtained following the general procedure (3.0 mmol scale) as a
pale brown oil (586 mg, 71%) after purification by column
chromatography: Rf = 0.30 (5% AcOEt/hexanes); 1H NMR
(CDCl3) δ 8.09 (d, J = 8.0 Hz, 1H), 7.48 (dd, J = 4.9, 2.9 Hz, 1H),
7.35−7.30 (m, 2H), 7,28−7.24 (m, 1H), 7.17 (dd, J = 4.9, 1.5 Hz,
1H), 7.10−7.05 (m, 1H), 6.63 (br s, 1H), 1.49 (s, 9H); 13C NMR
(CDCl3) δ 152.8, 138.6, 135.5, 130.0, 128.4, 128.3, 126.7, 126.2, 123.4,
123.0, 119.8, 80.5, 28.3; IR (KBr) νmax 3422, 3102, 3003, 2978, 2930,
1732, 1585, 1533, 1514, 1447, 1393, 1368, 1302 cm−1; MS (FAB) m/z
275 (M+), 220 (M − t-Bu + 2H), 219 (M − t-Bu + H). Anal. Calcd for
C15H17NO2S: C, 65.43; H, 6.22; N, 5.09. Found: C, 65.24; H, 6.20; N,
5.08.
Spectral data of tert-butyl (2-bromophenyl)carbamate (1a) and tert-
butyl (2-bromo-5-fluorophenyl)carbamate (1b) are identical to those
reported in ref 15.
tert-Butyl (2-Bromo-5-methylphenyl)carbamate (1c). 1c was
obtained following the general procedure as a yellow oil (2.81 g, 98%)
after purification by column chromatography: Rf = 0.21 (5% AcOEt/
1
hexanes); H NMR (CDCl3) δ 7.99 (br s, 1H), 7.36 (d, J = 8.3 Hz,
1H), 6.96 (br s, 1H), 6.72 (dd, J = 8.0, 2.0 Hz, 1H), 2.31 (s, 3H), 1.53
(s, 9H); 13C NMR (CDCl3) δ 152.4, 138.5, 135.8, 131.8, 124.7, 120.5,
109.0, 81.0, 28.3, 21.3; IR (neat) 3412, 3019, 2641, 1726, 1584, 1520,
1445, 1217 cm−1; MS m/z 287 (M+), 230 (M − t-Bu), 186 (M −
Boc); HRMS (m/z) calcd for C12H16BrNNaO2 [M + Na]+ 308.0262,
found 308.0262.
tert-Butyl 3-(2-((tert-Butoxycarbonyl)amino)phenyl)-1H-in-
dole-1-carboxylate. The product was obtained following the general
procedure (0.5 mmol scale) as white solids (191 mg, 94%) after
purification by column chromatography: mp 123−126 °C (hexanes/
(1-(tert-Butoxycarbonyl)-1H-pyrrol-3-yl)boronic Acid (2a).
To a THF (200 mL) solution of 3-bromo-N-(tert-butoxycarbonyl)-
pyrrole16 (5.0 g, 20.3 mmol) was added dropwise n-butyllithium in
hexane (1.6 M hexane solution, 15.2 mL, 24.4 mmol) at −78 °C. After
being stirred for 20 min, a THF (10 mL) solution of trimethylborate
(6.8 mL, 60.9 mmol) was added to the reaction mixture. After being
stirred for 5 min, 50% aq MeOH (20 mL) was added to the reaction
mixture. The reaction mixture was diluted with Et2O (300 mL), and
the organic layer was washed with water (200 mL) and brine (100
mL), dried over MgSO4, and concentrated under reduced pressure. To
the crude product was added hexane to give a pale brown solid.
Filtration gave the titled compound (1.97g, 47%): 1H NMR (acetone-
d6) δ 7.65 (m, 1H), 7.20 (dd, J = 3.2, 2.0 Hz, 1H), 6.51 (dd, J = 3.2,
1.4 Hz, 1H), 1.58 (s, 9H); 13C NMR (acetone-d6) δ 149.5, 128.6,
121.0, 117.3, 84.3, 28.0 (one carbon overlapped).
General Procedure for N-Boc-Protected o-Aryl Anilines. A
mixture of N-Boc-protected o-bromoaniline 1 (1 equiv), the
corresponding boronic acid (1.6 equiv), tetrakis(triphenylphosphine)-
palladium (5 mol %), and potassium carbonate (2.5 equiv) in toluene/
EtOH (4/1) (0.1 M) was stirred at 80 °C under an argon atmosphere
for 2−4 h. The reaction mixture was diluted with AcOEt, washed with
water and brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by column chromatography
(hexanes/AcOEt) to afford the desired product.
1
EtOAc); Rf = 0.30 (5% AcOEt/hexanes); H NMR (CDCl3) δ 8.23
(br d, J = 7.5 Hz, 1H), 8.13 (br d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.43−
7.35 (m, 3H), 7.32 (dd, J = 7.6, 1.6 Hz, 1H), 7.28−7.23 (m, 1H), 7.12
(ddd, J = 7.5, 7.5, 1.3 Hz, 1H), 6.54 (s, br, 1H), 1.70 (s, 9H), 1.44 (s,
9H); 13C NMR (CDCl3) δ 152.9, 149.6, 136.6, 135.5, 130.8, 129.4,
128.7, 125.0, 124.5, 123.1, 122.9, 122.4, 120.2, 120.0, 117.9, 115.4,
84.1, 80.4, 28.3, 28.2; IR (KBr) νmax 3421, 3009, 2980, 2931, 1732,
1578, 1516, 1477, 1450, 1373, 1308 cm−1; MS (FAB) m/z 408 (M+),
352 (M − t-Bu + H), 308 (M − Boc + 2H). Anal. Calcd for
C24H28N2O4: C, 70.57; H, 6.91; N, 6.86. Found: C, 70.78; H, 7.00; N,
6.82.
tert-Butyl [1,1′-Biphenyl]-2-ylcarbamate.17 The product was
obtained following the general procedure (4.0 mmol scale) as yellow
solids (916 mg, 85%) after purification by column chromatography: Rf
= 0.29 (5% AcOEt/hexanes); 1H NMR (CDCl3) δ 8.11 (d, J = 7.8 Hz,
1H), 7.49 (dd, J = 7.5, 7.5 Hz, 2H), 7.45−7.31 (m, 4H), 7.20 (dd, J =
7.5, 1.4 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.57−6.45 (br s, 1H), 1.46
(s, 9H).
tert-Butyl 3-(2-((tert-Butoxycarbonyl)amino)-4-methylphen-
yl)-1H-pyrrole-1-carboxylate. The product was obtained following
the general procedure (3.0 mmol scale) as an amorphous solid (805
mg, 72%) after purification by column chromatography: Rf = 0.35 (5%
1
AcOEt/hexanes); H NMR (CDCl3) δ 7.91 (br s, 1H), 7.35 (br s,
1H), 7.30 (br s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 8.3 Hz,
1H), 6.75 (br s, 1H), 6.33 (dd, J = 3.2, 1.7 Hz, 1H), 2.37 (s, 3H), 1.62
(s, 9H), 1.51 (s, 9H); 13C NMR (CDCl3) δ 153.0, 148.6, 138.1, 135.4,
129.5, 124.0, 123.8, 121.5, 121.0, 120.2, 117.9, 112.7, 84.1, 80.3, 28.3,
28.0, 21.5; IR (neat) 3418, 2980, 1728, 1522, 1387, 1344 cm−1; MS
(FAB) m/z 372 (M+), 316 (M − t-Bu), 260 (M − 2t-Bu), 173 (M −
2Boc); HRMS-ESI (m/z) calcd for C21H28KN2O4 411.1686, found
411.1692.
tert-Butyl 3-(2-((tert-Butoxycarbonyl)amino)phenyl)-1H-pyr-
role-1-carboxylate. The product was obtained following the general
procedure (1.8 mmol scale) as pale yellow solids (606 mg, 94%) after
purification by column chromatography: mp 94−98 °C (hexanes/
1
EtOAc); Rf = 0.32 (10% AcOEt/hexanes); H NMR (CDCl3) δ 8.05
(d, J = 8.0 Hz, 1H), 7.39−7.31 (m, 2H), 7.31−7.23 (m, 2H), 7.05
(ddd, J = 7.5, 7.5, 1.3 Hz, 1H), 6.77 (br s, 1H), 6.36 (dd, J = 3.2 Hz,
1.7 Hz, 1H), 1.62 (s, 9H), 1.50 (s, 9H); 13C NMR (CDCl3) δ 152.9,
148.5, 135.6, 129.6, 128.0, 124.5, 124.0, 123.0, 121.0, 119.8, 118.1,
112.6, 84.1, 80.3, 28.3, 28.0; IR (KBr) νmax 3414, 2326, 1744, 1721,
1585, 1512, 1485, 1447, 1381, 1346 cm−1; MS (FAB) m/z 358 (M+),
303 (M − t-Bu + 2H), 246 (M − 2t-Bu + 2H); HRMS-ESI (m/z)
calcd for C20H27N2O4 [M + H]+ 359.1965, found 359.1954. Anal.
Calcd for C20H26N2O4: C, 67.02; H, 7.31; N, 7.82. Found: C, 66.84;
H, 7.39; N, 7.78.
tert-Butyl 3-(2-((tert-Butoxycarbonyl)amino)-4-fluorophen-
yl)-1H-pyrrole-1-carboxylate. The product was obtained following
the general procedure (3.0 mmol scale) as an amorphous solid (915
mg, 81%) after purification by column chromatography: Rf = 0.33 (5%
1
AcOEt/hexanes); H NMR (CDCl3) δ 7.94 (d, J = 11.7 Hz, 1H),
7.39−7.35 (m, 1H), 7.31−7.27 (m, 1H), 7.17 (dd, J = 8.5, 6.4 Hz,
1H), 6.86 (br s, 1H), 6.72 (ddd, J = 8.2, 8.2, 2.7 Hz, 1H), 6.31 (dd, J =
3.2, 1.7 Hz, 1H), 1.63 (s, 9H), 1.50 (s, 9H); 13C NMR (CDCl3) δ
162.4 (d, J = 225 Hz), 152.4, 148.5, 137.2 (d, J = 10.8 Hz), 130.7 (d, J
= 9.6 Hz), 123.1, 121.2, 119.6 (d, J = 2.4 Hz), 118.1, 112.5, 109.3 (d, J
= 21.6 Hz), 106.3 (d, J = 27.6 Hz), 84.3, 80.8, 28.2, 27.9; IR (neat)
tert-Butyl (2-(Furan-3-yl)phenyl)carbamate. The product was
obtained following the general procedure (1.8 mmol scale) as yellow
solids (444 mg, 95%) after purification by column chromatography:
1
mp 62−64 °C (hexanes/EtOAc); Rf = 0.32 (5% AcOEt/hexanes); H
D
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3414, 2980, 1732, 1522, 1489, 1473, 1458, 1385, 1369 cm−1; MS
(FAB) m/z 376 (M+), 320 (M − t-Bu), 264 (M − 2t-Bu + H);
HRMS-ESI (m/z) calcd for C20H25FN2NaO4 399.1696, found
399.1703.
(CDCl3, 50 °C) δ 153.3, 149.6, 138.2, 135.7, 131.34, 131.25, 129.6,
128.2, 128.1, 128.0, 124.4, 124.0, 122.8, 120.1, 118.8, 115.2, 97.8, 83.6,
82.6, 67.4, 28.3, 27.8, 18.6, 11.4; IR (KBr) νmax 2978, 2941, 2891,
2864, 2176, 1732, 1454, 1373, 1308 cm−1; MS (FAB) m/z 589 ([M +
H]+), 532 (M − t-Bu + H), 489 (M − Boc + 2H), 433 (M − t-Bu −
Boc + 3H), 389 (M − 2Boc + 3H), 345, 301, 259, 231; HRMS-ESI
(m/z) calcd for C35H49N2O4Si 589.3456, found 589.3454. Anal. Calcd
for C35H48N2O4Si: C, 71.39; H, 8.22; N, 4.76. Found: C, 71.21; H,
8.38; N, 4.76.
General Procedure for Ynamides 4a−l.18d To a solution of N-
Boc-protected o-aryl aniline (1.0 equiv), the corresponding bromoa-
cetylene (1.5 equiv), copper iodide (0.30 equiv), and 1,10-
phenanthroline (0.36 equiv) in toluene (0.1 M) was added a 0.5 M
toluene solution of potassium bis(trimethylsilyl)amide (KHMDS, 1.5
equiv) at 90 °C over 1 h under an argon atmosphere. After being
stirred at 90 °C for 2 h, the reaction mixture was diluted with AcOEt,
washed with water and brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by column
chromatography (hexanes/AcOEt) to afford the desired product.
tert-Butyl 3-(2-((tert-Butoxycarbonyl)((triisopropylsilyl)-
ethynyl)amino)phenyl)-1H-pyrrole-1-carboxylate (4a). The
product was obtained following the general procedure (2.5 mmol
scale, tert-butyl 3-(2-((tert-butoxycarbonyl)amino)phenyl)-1H-pyrrole-
1-carboxylate and (bromoethynyl)triisopropylsilane as starting materi-
als) as a yellow oil (1.27 g, 94%) after purification by column
chromatography: Rf = 0.33 (10% AcOEt/hexanes); 1H NMR (CDCl3)
δ 7.50 (dd, J = 7.6, 1.3 Hz, 1H) 7.44−7.40 (m, 1H), 7.38 (d, J = 7.7
Hz, 1H), 7.36−7.31 (m, 1H), 7.31−7.26 (m, 2H), 6.51−6.47 (m, 1H),
1.60 (s, 9H), 1.39 (br s, 9H), 1.01(s, 21H); 13C NMR (CDCl3) δ
153.2, 148.8, 137.0, 132.7, 129.4, 128.4, 128.2, 127.6, 124.6, 120.4,
117.9, 112.2, 98.1, 83.6, 82.6, 67.3, 28.0, 27.9, 18.6, 11.5; MS (ESI) m/
z 539 ([M + H]+), 483 (M − t-Bu + 2H), 439 (M − Boc + 2H), 383,
295; IR (KBr) νmax 2941, 2891, 2864, 2176, 1748, 1732, 1501, 1477,
1458, 1393, 1369, 1346, 1327 cm−1; HRMS-ESI (m/z) calcd for
C31H47N2O4Si 539.3300, found 539.3293.
tert-Butyl [1,1′-Biphenyl]-2-yl((triisopropylsilyl)ethynyl)-
carbamate (4e). The product was obtained following the general
procedure (1.5 mmol scale, tert-butyl [1,1′-biphenyl]-2-ylcarbamate
and (bromoethynyl)triisopropylsilane as starting materials) as a brown
oil (303 mg, 45%) after purification by column chromatography: Rf =
1
0.23 (2.5% AcOEt/hexanes); H NMR (CDCl3, 55 °C) δ 7.50−7.40
(m, 3H), 7.40−7.34 (m, 5H), 7.32−7.27 (m, 1H), 1.22 (s, 9H), 1.07−
1.01 (m, 21H); 13C NMR (CDCl3, 55 °C) δ 152.9, 140.1, 139.1,
137.5, 130.7, 128.8, 128.5, 128.32, 128.25, 127.9, 127.3, 98.7, 82.5,
67.6, 27.7, 18.7, 11.5; IR (KBr) νmax 2957, 2941, 2891, 2864, 2178,
1734, 1481, 1458, 1437, 1383, 1369, 1304 cm−1; MS (ESI) m/z 449
(M+), 406 (M − i-Pr), 349 (M − Boc + H), 324, 306 (M − i-Pr − Boc
+ H), 264, 220. Anal. Calcd for C28H39NO2Si: C, 74.78; H, 8.74; N,
3.11. Found: C, 74.54; H, 8.81; N, 3.10.
tert-Butyl 3-(2-((tert-Butoxycarbonyl)((triisopropylsilyl)-
ethynyl)amino)-4-methylphenyl)-1H-pyrrole-1-carboxylate
(4f). The product was obtained following the general procedure (1.0
mmol scale, tert-butyl 3-(2-((tert-butoxycarbonyl)amino)-4-methyl-
phenyl)-1H-pyrrole-1-carboxylate and (bromoethynyl)triisopropyl-
silane as starting materials) as a yellow oil (415 mg, 75%) after
purification by column chromatography: Rf = 0.33 (5% AcOEt/
1
hexanes); H NMR (CDCl3) δ 7.40−7.34 (m, 2H), 7.29−7.23 (m,
tert-Butyl (2-(Furan-3-yl)phenyl)((triisopropylsilyl)ethynyl)-
carbamate (4b). The product was obtained following the general
procedure (2.3 mmol scale, tert-butyl (2-(furan-3-yl)phenyl)carbamate
and (bromoethynyl)triisopropylsilane as starting materials) as white
solids (850 mg, 84%) after purification by column chromatography:
1H), 7.20 (br s, 1H), 7.14 (br d, J = 8.0 Hz, 1H), 6.46 (dd, J = 2.7, 1.6
Hz, 1H), 2.36 (s, 3H), 1.60 (s, 9H), 1.41 (br s, 9H), 1.00 (s, 21H); 13C
NMR (CDCl3, 50 °C) δ 153.3, 148.8, 137.6, 136.6, 129.6, 129.24,
129.17, 128.7, 124.6, 120.3, 117.6, 112.3, 98.2, 83.5, 82.5, 67.1, 28.0,
27.9, 20.8, 18.6, 11.5; IR (neat) 2940, 2893, 2862, 2171, 1736, 1508,
1458, 1389, 1346 cm−1; MS (FAB) m/z 553 (M + H+), 496 (M − t-
Bu), 441 (M − 2t-Bu), 353 (M − 2Boc), 309 (M − 2Boc − i-Pr);
HRMS-ESI (m/z) calcd for C32H48N2NaO4Si 575.3281, found
575.3298.
1
mp 56−59 °C (hexanes/EtOAc); Rf = 0.32 (5% AcOEt/hexanes); H
NMR (CDCl3, 50 °C) δ 7.71 (d, J = 0.96 Hz, 1H), 7.48−7.43 (m,
2H), 7.40 (m, 1H), 7.37−7.27 (m, 2H), 6.70−6.65 (m, 1H), 1.35 (s,
9H), 1.03 (s, 21H); 13C NMR (CDCl3, 50 °C) δ 153.0, 143.0, 140.3,
137.2, 130.9, 129.3, 128.6, 128.3, 128.0, 123.0, 110.3, 98.1, 82.8, 67.6,
27.8, 18.6, 11.5; IR (KBr) νmax 2943, 2924, 2893, 2866, 2176, 1736,
1462, 1393, 1369 cm−1; MS m/z 440 ([M + H]+), 384 (M − t-Bu +
2H), 340 (M − Boc + 2H), 296 (M − Boc + 2H − i-Pr), 254; HRMS-
ESI (m/z) calcd for C26H38NO3Si 440.2615, found 440.2614.
tert-Butyl 3-(2-((tert-Butoxycarbonyl)((triisopropylsilyl)-
ethynyl)amino)-4-fluorophenyl)-1H-pyrrole-1-carboxylate
(4g). The product was obtained following the general procedure (1.0
mmol scale, tert-butyl 3-(2-((tert-butoxycarbonyl)amino)-4-fluoro-
phenyl)-1H-pyrrole-1-carboxylate and (bromoethynyl)triisopropyl-
silane as starting materials) as a yellow oil (362 mg, 65%) after
purification by column chromatography: Rf = 0.31 (5% AcOEt/
tert-Butyl (2-(Thiophen-3-yl)phenyl)((triisopropylsilyl)-
ethynyl)carbamate (4c). The product was obtained following the
general procedure (1.8 mmol scale, tert-butyl (2-(thiophen-3-yl)-
phenyl)carbamate and (bromoethynyl)triisopropylsilane as starting
materials) as a yellow oil (714 mg, 87%) after purification by column
1
hexanes); H NMR (CDCl3, 50 °C) δ 7.43 (dd, J = 8.7, 6.2 Hz, 1H),
7.37 (dd, J = 1.7, 1.7 Hz, 1H), 7.25 (dd, J = 3.6, 1.3 Hz, 1H), 7.12 (dd,
J = 8.9, 2.6 Hz, 1H), 7.04 (ddd, J = 8.3, 8.3, 2.6 Hz, 1H), 6.43 (dd, J =
3.2, 1.7 Hz, 1H), 1.60 (s, 9H), 1.37 (br s, 9H), 1.01 (m, 21H); 13C
NMR (CDCl3, 50 °C) δ 161.5 (d, J = 248 Hz), 152.8, 148.7, 137.9 (d,
J = 10.8 Hz), 130.6 (d, J = 8.4 Hz), 129.0 (d, J = 4.8 Hz), 123.8, 120.5,
117.7, 115.6 (d, J = 20.4 Hz), 105.4 (d, J = 24.0 Hz), 112.1, 97.4, 83.7,
83.0, 67.9, 28.0, 27.8, 18.6, 11.4; IR (neat) 2959, 2866, 2360, 2175,
1744, 1508, 1458, 1389, 1346 cm−1; MS (FAB) m/z 557 (M + H+),
550 (M − t-Bu), 444 (M − 2t-Bu), 357 (M − 2Boc), 314 (M − 2Boc
− i-Pr); HRMS-ESI (m/z) calcd for C31H45FN2NaO4Si 579.3030,
found 579.3035.
1
chromatography: Rf = 0.36 (5% AcOEt/hexanes); H NMR (CDCl3,
50 °C) δ 7.48−7.45 (m, 1H), 7.45−7.43 (m, 1H), 7.43−7.40 (m, 1H),
7.36−7.32 (m, 3H), 7.31−7.28 (m, 1H), 1.27(br s, 9H), 1.04 (s, 21H);
13C NMR (CDCl3, 50 °C) δ 152.8, 139.1, 137.3, 134.6, 130.1, 128.4,
128.2, 128.0, 125.3, 122.7, 98.5, 82.5, 67.6, 27.7, 18.6, 11.5 (one carbon
is overlapped); IR (KBr) νmax 3102, 2943, 2893, 2866, 2176, 1736,
1462, 1393, 1369 cm−1; MS (FAB) m/z 456 ([M + H]+), 400 (M − t-
Bu + 2H), 356 (M − Boc + 2H), 312; HRMS-ESI (m/z) calcd for
C26H38NO2SSi 456.2387, found 456.2393. Anal. Calcd for
C26H37NO2SSi: C, 68.52; H, 8.18; N, 3.07. Found: C, 68.35; H,
8.31; N, 3.08.
tert-Butyl 3-(2-((tert-Butoxycarbonyl)((triisopropylsilyl)-
ethynyl)amino)phenyl)-1H-indole-1-carboxylate (4d). The
product was obtained following the general procedure (1.5 mmol
scale, tert-butyl 3-(2-((tert-butoxycarbonyl)amino)phenyl)-1H-indole-
1-carboxylate and (bromoethynyl)triisopropylsilane as starting materi-
als) as a yellow oil (627 mg, 71%) after purification by column
chromatography: Rf = 0.44 (10% AcOEt/hexanes); 1H NMR (CDCl3)
δ 8.19 (d, J = 7.5 Hz, 1H), 7.65 (s, 1H), 7.59−7.49 (m, 3H), 7.45−
7.37 (m, 2H), 7.32 (dd, J = 7.6, 7.6 Hz, 1H), 7.20 (dd, J = 7.3, 7.3 Hz,
1H), 1.67 (s, 9H), 1.27 (br s, 9H), 0.99−0.78 (m, 21H); 13C NMR
tert-Butyl 3-(2-((tert-Butoxycarbonyl)(ethynyl)amino)-
phenyl)-1H-pyrrole-1-carboxylate (4h). To a solution of 4a
(1.49 g, 2.8 mmol) in THF (28 mL) was added tetra-n-
butylammonium fluoride (3.3 mL, 1 M in THF) at room temperature
under an argon atmosphere. After being stirred for 30 min, the
reaction mixture was diluted with Et2O (30 mL), washed with water
and brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by column chromatography
(hexanes/AcOEt 50:1 to 20:1) to afford the desired product (890
1
mg, 84%) as a yellow oil: Rf = 0.28 (10% AcOEt/hexanes); H NMR
(CDCl3, 55 °C) δ 7.50−7.46 (m, 2H), 7.38−7.35 (m, 1H), 7.33 (ddd,
E
DOI: 10.1021/jo502467m
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
J = 7.5, 7.5, 1.4 Hz, 1H), 7.30−7.26 (m, 2H), 6.49 (dd, J = 3.3, 1.9 Hz,
1H), 2.79 (s, 1H), 1.61 (s, 9H), 1.30 (br s, 9H); 13C NMR (CDCl3) δ
153.0, 148.6, 136.2, 132.7, 129.3, 128.7, 128.0, 127.7, 124.3, 120.4,
117.8, 112.0, 83.8, 82.9, 57.6, 27.9, 27.5; IR (KBr) νmax 3310, 2980,
2934, 2918, 2145, 1734, 1749, 1458, 1449, 1393, 1369, 1346, 1314
cm−1; MS (FAB) m/z 383 (M + H)+, 326 (M − t-Bu + H). Anal.
Calcd for C22H26N2O4: C, 69.09; H, 6.85; N, 7.32. Found: C, 69.13;
H, 7.03; N, 7.30.
atmosphere. After being stirred at the same temperature for 30 min, to
the mixture was added N-chlorosuccinimide (122 mg, 0.91 mmol).
The mixture was warmed to the ambient temperature and stirred for
30 min. The reaction mixture was quenched by saturated aq NH4Cl (5
mL), diluted with Et2O (15 mL), washed with water (5 mL) and brine
(5 mL), dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by column chromatography (hexanes/AcOEt
= 20:1) to afford the desired product (249 mg, 85%) as an amorphous
1
solid: Rf = 0.22 (10% AcOEt/hexanes); H NMR (CDCl3) δ 7.52−
tert-Butyl 3-(2-((tert-Butoxycarbonyl)(phenylethynyl)-
amino)phenyl)-1H-pyrrole-1-carboxylate (4i). The product was
obtained following the general procedure (1.0 mmol scale, tert-butyl 3-
(2-((tert-butoxycarbonyl)amino)phenyl)-1H-pyrrole-1-carboxylate
and (bromoethynyl)benzene as starting materials) as a brown oil (330
mg, 72%) after purification by column chromatography: Rf = 0.21 (5%
7.48 (m, 1H), 7.47−7.44 (m, 1H), 7.38−7.34 (m, 2H), 7.32−7.28
(2H, m), 6.47 (dd, J = 3.4, 1.7 Hz, 1H), 1.62 (s, 9H), 1.37 (br s, 9H);
13C NMR (CDCl3, 50 °C) δ 153.0, 148.6, 136.2, 132.8, 129.3, 128.7,
128.0, 127.7, 124.2, 120.4, 117.8, 111.9, 83.8, 83.0, 77.2, 27.9, 27.5; IR
(KBr) νmax 2978, 2931, 2900, 1732, 1500, 1454 cm−1; MS (FAB) m/z
416 (M+), 361 (M − Boc), 305 (M − 2Boc); HRMS-ESI (m/z) calcd
for C22H26ClN2O4 417.1576, found 417.1588.
1
AcOEt/hexanes); H NMR (CDCl3, 50 °C) δ 7.53−7.48 (m, 2H),
7.43 (dd, J = 7.7, 1.4 Hz, 1H), 7.37−7.27 (m, 5H), 7.27−7.18 (m,
3H), 6.53 (dd, J = 3.4, 1.7 Hz, 1H), 1.58 (s, 9H), 1.34 (br s, 9H); 13C
NMR (CDCl3, 50 °C) δ 152.9, 148.7, 137.0, 133.0, 131.1, 129.4,
128.6, 128.3, 128.1, 127.7, 127.2, 124.5, 123.7, 120.5, 118.1, 112.2,
84.6, 83.8, 82.7, 69.7, 28.0, 27.7; IR (KBr) νmax 2980, 2931, 2918,
2253, 1734, 1499, 1477, 1449, 1389, 1369, 1346 cm−1; MS (FAB) m/z
459 (M + H)+, 403 (M − t-Bu + 2H), 402 (M − t-Bu + H), 347 (M −
2t-Bu + 3H), 346 (M − 2t-Bu + 2H), 301, 259 (M − 2Boc + 3H);
HRMS-ESI (m/z) calcd for C28H31N2O4 459.2278, found 459.2272.
tert-Butyl 3-(2-((tert-Butoxycarbonyl)(3-ethoxy-3-oxoprop-
1-yn-1-yl)amino)phenyl)-1H-pyrrole-1-carboxylate (4j). To a
solution of ynamide (4h) (716 mg, 1.87 mmol) in THF (9.0 mL)
was added 1.0 M THF solution of LiHMDS (2.1 mL, 2.06 mmol) at
−78 °C under an argon atmosphere. After being stirred at the same
temperature for 30 min, to the mixture was added ethyl chloroformate
(215 μL, 2.25 mmol) and stirred for 30 min at −78 °C. The reaction
mixture was quenched by saturated aq NH4Cl (3.0 mL) and diluted
with Et2O (15 mL), washed with water (15 mL) and brine (10 mL),
dried over MgSO4, and concentrated under reduced pressure. The
residue was purified by column chromatography (hexanes/AcOEt =
10:1) to afford the desired product (748 mg, 88%) as amorphous: Rf =
0.15 (10% AcOEt/hexanes); 1H NMR (CDCl3, 35 °C) δ 7.48 (dd, J =
7.7, 1.4 Hz, 1H), 7.40 (dd, J = 1.9, 1.9 Hz, 1H), 7.39−7.26 (m, 4H),
6.42 (dd, J = 3.2, 1.7 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.61 (s, 9H),
1.34 (br s, 9H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 48 °C) δ
154.5, 151.9, 148.6, 135.3, 133.0, 129.7, 129.2, 128.0, 127.9, 124.0,
120.6, 118.0, 112.1, 84.3, 83.9, 83.5, 65.5, 61.3, 27.9, 27.5, 14.1; IR
(KBr) νmax 2982, 2229, 1744, 1701, 1501, 1477, 1458, 1388, 1346
cm−1; MS (FAB) m/z 455 (M + H+), 255 (M − 2Boc), 209 (M −
2Boc − EtO); HRMS-ESI (m/z) calcd for C25H30N2NaO6 477.1996,
found 477.1991.
General Procedure for the Cyclization Reaction with
Ynamide 4a−j. To a solution of ynamide (0.20 mmol) in
dichloromethane (2.0 mL) was added TfOH (0.24 mmol) at room
temperature under an argon atmosphere. After being stirred at the
ambient temperature for 5 min, the reaction was quenched by
triethylamine, and the mixture was diluted with CHCl3 (5 mL),
washed with water (2 × 5 mL) and brine (3 mL), dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified by
column chromatography (hexanes/AcOEt) to afford the desired
product.
4-((Triisopropylsilyl)methyl)-3H-pyrrolo[2,3-c]quinoline (6a).
The product 6a (58.3 mg, 86%) was obtained following the general
procedure using 4a with TfOH as a yellow amorphous solid: Rf = 0.26
(20% AcOEt/hexanes); 1H NMR (CDCl3) δ 8.82 (br s, 1H), 8.12 (d,
J = 8.0 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.54−7.50 (m, 1H), 7.49−
7.44 (m, 1H), 7.35 (d, J = 3.2 Hz, 1H), 7.03 (d, J = 2.9 Hz, 1H), 2.66
(s, 2H), 1.22−1.08 (m, 3H), 0.99 (d, J = 7.5 Hz, 18H); 13C NMR
(CDCl3) δ 149.1, 142.9, 128.6, 128.5, 127.5, 125.7, 124.8, 124.5, 122.7,
122.4, 102.2, 18.6, 18.4, 11.7; IR (KBr) νmax 2943, 2862, 1581, 1562,
1528, 1458, 1389, 1362, 1339, 1315 cm−1; MS (FAB) m/z 339 (M +
H+), 295 (M − i-Pr); HRMS-ESI (m/z) calcd for C21H31N2Si
339.2251, found 339.2268.
tert-Butyl 4-((Triisopropylsilyl)methyl)-3H-pyrrolo[2,3-c]-
quinoline-3-carboxylate (5a). The product 5a (74.6 mg, 85%)
was obtained following the general procedure using 4a with Tf2NH as
1
a yellow oil: Rf = 0.28 (10% AcOEt/hexanes); H NMR (CDCl3) δ
8.10−8.04 (m, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 3.7 Hz, 1H),
7.59 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.50−7.43 (m, 1H), 7.03 (d, J =
3.5 Hz, 1H), 3.21 (s, 2H), 1.67 (s, 9H), 1.12−1.00 (m, 3H), 0.93 (d, J
= 7.2 Hz, 18H); 13C NMR (CDCl3) δ 151.9, 149.0, 143.9, 133.6,
130.0, 128.4, 128.1, 127.1, 124.7, 122.8, 121.0, 104.7, 84.6, 28.0, 21.6,
18.7, 11.6; IR (KBr) νmax 2928, 2862, 1744, 1501, 1458, 1354 cm−1;
MS (FAB) m/z 439 (M + H+), 395 (M − i-Pr); HRMS-ESI (m/z)
calcd for C26H39N2O2Si 439.2775, found 439.2783.
tert-Butyl 3-(2-((Bromoethynyl)(tert-butoxycarbonyl)-
amino)phenyl)-1H-pyrrole-1-carboxylate (4k). To a solution of
ynamide (4h) (99.3 mg, 0.26 mmol) in THF (1.5 mL) was added 1.0
M THF solution of LiHMDS (0.34 mL, 0.34 mmol) at −78 °C under
an argon atmosphere. After being stirred at the same temperature for
30 min, to the mixture was added N-bromosuccinimide (60 mg, 0.34
mmol). The mixture was warmed to the ambient temperature and
stirred for 30 min. The reaction mixture was quenched by saturated aq
NH4Cl (2 mL) and diluted with Et2O (10 mL), washed with water (2
mL) and brine (2 mL), dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (hexanes/AcOEt = 20:1) to afford the desired product (102 mg,
4-((Triisopropylsilyl)methyl)furo[2,3-c]quinoline (6b). The
product 6b (62.5 mg, 92%) was obtained following the general
procedure using 4b as a colorless solids: mp 48−50 °C (hexanes); Rf =
1
0.30 (5% AcOEt/hexanes); H NMR (CDCl3) δ 8.06 (d, J = 8.0 Hz,
1H), 8.02 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.61 (dd, J =
7.6, 7.6 Hz, 1H), 7.50 (dd, J = 7.5, 7.5 Hz, 1H), 7.21 (d, J = 2.0 Hz,
1H), 2.86 (s, 2H), 1.19−1.10 (m, 3H), 1.02 (d, J = 7.2 Hz, 18H); 13C
NMR (CDCl3) δ 150.0, 148.1, 145.9, 144.3, 128.9, 128.1, 127.0, 125.0,
123.2, 122.1, 105.6, 18.5, 17.7, 11.5; IR (neat) νmax 2940, 2889, 2866,
1593, 1520, 1462, 1358 cm−1; MS (EI) m/z 339 (M+), 296 (M − i-
Pr), 254, 210; HRMS-ESI (m/z) calcd for C21H30NOSi 340.2091 [M
+ H]+, found 340.2090. Anal. Calcd for C21H29NOSi: C, 74.28; H,
8.61; N, 4.13. Found: C, 74.19; H, 8.84; N, 4.06.
1
85%) as an amorphous solid: Rf = 0.22 (10% AcOEt/hexanes); H
NMR (CDCl3) δ 7.36−7.31 (m, 2H), 7.24−7.19 (m, 2H), 7.18−7.13
(m, 2H), 6.33 (dd, J = 3.2, 1.7 Hz, 1H), 1.47 (s, 9H), 1.22 (br s, 9H);
13C NMR (CDCl3, 50 °C) δ 152.9, 148.7, 136.2, 132.9, 129.4, 128.8,
128.1, 127.7, 124.3, 120.5, 118.0, 112.1, 83.9, 83.1, 73.9, 28.0, 27.6; IR
(KBr) νmax 2978, 2931, 2900, 1732, 1501, 1477 cm−1; MS (FAB) m/z
461 (M + H+), 348 (M − 2Boc); HRMS-ESI (m/z) calcd for
C22H26BrN2O4 461.1070, found 461.1043.
tert-Butyl 3-(2-((tert-Butoxycarbonyl)(chloroethynyl)amino)-
phenyl)-1H-pyrrole-1-carboxylate (4l). To a solution of ynamide
(4h) (268 mg, 0.7 mmol) in THF (7.0 mL) was added 1.0 M THF
solution of LiHMDS (0.91 mL, 0.91 mmol) at −78 °C under an argon
4-((Triisopropylsilyl)methyl)thieno[2,3-c]quinoline (6c). The
product 6c (62.6 mg, 88%) was obtained following the general
procedure using 4c as a pale yellow oil: Rf = 0.38 (5% AcOEt/
1
hexanes); H NMR (CDCl3) δ 8.20 (ddd, J = 8.2, 0.6, 0.6 Hz, 1H),
8.06 (ddd, J = 8.3, 0.6, 0.6 Hz, 1H), 7.96 (dd, J = 5.4, 0.9 Hz, 1H), 7.76
(dd, J = 5.5, 1.2 Hz, 1H), 7.64 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.53
(ddd, J = 7.5, 7.5, 1.2 Hz, 1H), 2.79 (s, 2H), 1.33−1.16 (m, 3H), 1.03
F
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(d, J = 7.5 Hz, 18H); 13C NMR (CDCl3) δ 156.9, 145.1, 141.2, 133.7,
129.8, 128.9, 127.7, 125.1, 123.1, 122.7, 122.2, 22.5, 18.6, 11.7; IR
(KBr) νmax 3061, 2941, 2889, 2864, 1614, 1555, 1495, 1464, 1412,
1381, 1346, 1321 cm−1; MS (FAB) m/z 356 (M + H), 312 (M − i-
Pr); HRMS-ESI (m/z) calcd for C21H30NSSi 356.1863, found
356.1854. Anal. Calcd for C21H29NSSi: C, 70.93; H, 8.22; N, 3.94.
Found: C, 70.86; H, 8.44; N, 3.93.
Ethyl 2-(3H-Pyrrolo[2,3-c]quinolin-4-yl)acetate (6j). The
product 6j (40.2 mg, 79%) was obtained following the general
procedure using 4j as an amorphous solid: Rf = 0.23 (30% AcOEt/
1
hexanes); H NMR (CDCl3) δ 9.85 (br s, 1H), 8.22−8.17 (m, 1H),
8.16−8.12 (m, 1H), 7.62−7.53 (m, 2H), 7.46 (dd, J = 2.7 Hz, 1H),
7.09−7.06 (m, 1H), 4.28 (s, 2H), 4.19 (q, J = 7.2 Hz, 2H), 1.25 (t, J =
7.2 Hz, 3H); 13C NMR (CDCl3) δ 171.1, 142.5, 141.1, 129.2, 129.1,
128.4, 126.5, 126.1, 126.0, 123.4, 122.9, 101.6, 61.8, 43.7, 14.0; IR
(neat) 3329, 2981, 2931, 1732, 1635, 1589, 1527, 1462, 1442, 1365
cm−1; MS (FAB) m/z 255 (M + H+); HRMS-ESI (m/z) calcd for
C15H15N2O2 255.1128, found 255.1124.
6-((Triisopropylsilyl)methyl)-7H-indolo[2,3-c]quinoline (6d).
The product 6d (59.8 mg, 77%) was obtained following the general
procedure using 4d as a yellow amorphous solid: Rf = 0.16 (10%
1
AcOEt/hexanes); H NMR (CDCl3) δ 8.66 (d, J = 7.5 Hz, 1H), 8.56
Di-tert-butyl 4-((Triisopropylsilyl)methyl)-3H-pyrrolo[2,3-c]-
quinoline-3,5(4H)-dicarboxylate (7). To a solution of ynamide 4a
(107.8 mg, 0.20 mmol) in dichloromethane (2.0 mL) was added
Tf2NH (0.24 mL of 1.0 M CH2Cl2 solution, 0.24 mmol) at room
temperature under an argon atmosphere. After being stirred at the
ambient temperature for 15 min, a solution of NaBH4 (37.8 mg, 1.0
mmol) in MeOH (1.0 mL) was added to the reaction mixture. After
30 min, the mixture was washed with water (5 mL) and brine (3 mL),
dried over Mg2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography (hexanes/AcOEt =
50:1) to afford the desired product 7 (37.9 mg, 35%) as an amorphous
solid: Rf = 0.30 (10% AcOEt/hexanes); 1H NMR (CDCl3) δ 7.52 (br
s, 1H), 7.43−7.37 (m, 1H), 7.20−7.13 (m, 2H), 7.10 (d, J = 3.4 Hz,
1H), 6.60 (br d, J = 9.5 Hz, 1H), 6.42 (d, J = 3.4 Hz, 1H), 1.60 (s,
9H), 1.46 (s, 9H), 1.17−1.08 (m, 3H), 1.07 (d, J = 6.9 Hz, 9H), 1.02
(d, J = 6.9 Hz, 9H), 0.93−0.86 (m, 2H); 13C NMR (CDCl3) δ 153.6,
148.2, 135.6, 132.8, 128.0, 126.0, 124.9, 124.7, 122.1, 120.4, 118.1,
105.8, 83.7, 81.0, 48.7, 28.2, 28.0, 19.0, 18.8, 11.4; IR (KBr) νmax 2939,
2866, 1744, 1697, 1505, 1454 cm−1; MS (FAB) m/z 541 (M + H+),
485 (M − 2t-Bu), 429 (M − 2t-Bu); HRMS-ESI (m/z) calcd for
C31H49N2O4Si 541.3456, found 541.3475.
Total Synthesis of Aplidiopsamine A. tert-Butyl 4-(bromo-
methyl)-3H-pyrrolo[2,3-c]quinoline-3-carboxylate (8). To a
solution of ynamide 4a (107.8 mg, 0.20 mmol) in dichloromethane
(2.0 mL) was added TfOH (19.5 μL, 0.22 mmol) at −78 °C under an
argon atmosphere. After being stirred at the same temperature for 60
min, N-bromosuccinimide (42.8 mg, 0.24 mmol) was added to the
reaction mixture. After 1 h, the reaction mixture was diluted with
AcOEt (10 mL), washed with saturated aq NaHCO3 (10 mL) and
brine (10 mL), dried over Mg2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography
(hexanes/AcOEt) to afford the desired product 8 (46.2 mg, 64%
yield) as colorless solids: mp 127−129 °C (hexanes/AcOEt); Rf = 0.19
(10% AcOEt/hexanes); 1H NMR (CDCl3) δ 8.18−8.11 (m, 2H), 7.79
(d, J = 3.4 Hz, 1H), 7.68 (ddd, J = 8.5, 7.0, 1.4 Hz, 1H), 7.61 (ddd, J =
8.1, 7.0, 1.3 Hz, 1H), 7.11 (d, J = 3.4 Hz, 1H), 5.43 (s, 2H), 1.72 (s,
9H); 13C NMR (CDCl3) δ 148.7, 145.5, 134.7, 130.3, 129.3, 127.8,
127.0, 126.0, 122.9, 122.6, 104.5, 85.3, 37.1, 28.0 (one carbon
overlapped); IR (KBr) νmax 2980, 2932, 1748, 1576, 1518, 1501, 1476,
1458, 1414, 1396, 1360, 1312 cm−1; MS (EI) m/z 362 [(M + 2)+],
360 (M+), 306 [(M + 2) − t-Bu + H], 304 (M − t-Bu + H), 262 [(M
+ 2) − Boc + H], 260 (M − Boc + H); HRMS-ESI (m/z) calcd for
C17H18N2O2Br 361.0546, found 361.0529.
(d, J = 8.6 Hz, 1H), 8.43 (br s, 1H), 8.17−8.10 (m, 1H), 7.71−7.52
(m, 4H), 7.47−7.37 (m, 1H), 2.79 (s, 2H), 1.32−1.19 (m, 3H), 1.05
(d, J = 7.5 Hz, 18H); 13C NMR (CDCl3) δ 149.4, 143.1, 138.5, 131.7,
129.3, 126.4, 125.50, 125.45, 123.5, 123.3, 123.2, 122.9, 120.8, 120.5,
112.0, 18.7, 18.4, 11.7; IR (KBr) νmax 2940, 2862, 1620, 1566, 1524,
1497, 1462, 1389, 1362, 1335 cm−1; MS (EI) m/z 388 (M+), 345 (M
− i-Pr). Anal. Calcd for C25H32N2Si: C, 77.27; H, 8.30; N, 7.21.
Found: C, 77.04; H, 8.37; N, 7.13.
6-((Triisopropylsilyl)methyl)phenanthridine (6e). The product
6e (36.4 mg, 52%) was obtained following the general procedure using
4e as a yellow oil: Rf = 0.23 (2.5% AcOEt/hexanes); 1H NMR
(CDCl3, 50 °C) δ 8.61 (d, J = 8.3 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H),
8.29 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.79 (dd, J = 7.6 Hz,
1H), 7.70−7.61 (m, 2H), 7.54 (dd, J = 7.6 Hz, 1H), 2.98 (s, 2H),
1.29−1.18 (m, 3H), 1.03 (d, J = 7.5 Hz, 18H); 13C NMR (CDCl3) δ
162.4, 143.9, 132.7, 130.0, 129.1, 128.4, 126.83, 126.76, 126.0, 125.5,
122.9, 122.4, 121.8, 19.6, 18.7, 11.8; IR (neat) 2959, 2865, 1734, 1582,
1522, 1458, 1350, 1317 cm−1; MS (FAB) m/z 350 (M + H+), 306 (M
− i-Pr), 220 (M − 3i-Pr); HRMS-ESI (m/z) calcd for C23H32NSi
350.2299, found 350.2292.
7-Methyl-4-((triisopropylsilyl)methyl)-3H-pyrrolo[2,3-c]-
quinoline (6f). The product 6f (55.7 mg, 79%) was obtained
following the general procedure using 4f as an amorphous solid: Rf =
1
0.20 (12% AcOEt/hexanes); H NMR (CDCl3) δ 8.55 (br s, 1H),
8.02 (d, J = 7.5 Hz, 1H), 7.81 (s, 1H), 7.34 (d, J = 2.9 Hz, 1H), 7.31
(d, J = 8.0 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 2.66 (s, 2H), 2.54 (s,
3H), 1.23−1.14 (m, 3H), 1.01 (d, J = 7.5 Hz, 18H); 13C NMR
(CDCl3, 50 °C) δ 148.8, 135.4, 133.5, 128.4, 128.1, 127.7, 126.5,
124.7, 122.5, 120.2, 102.0, 21.6, 18.7, 18.3, 11.8; IR (neat) 3012, 2943,
2866, 1581, 1523, 1462, 1361, 1315 cm−1; MS (FAB) m/z 353 (M +
H+), 309 (M − i-Pr), 223 (M − 3i-Pr); HRMS-ESI (m/z) calcd for
C22H33N2Si 353.2408, found 353.2401.
7-Fluoro-4-((triisopropylsilyl)methyl)-3H-pyrrolo[2,3-c]-
quinoline (6g). The product 6g (64.2 mg, 90%) was obtained
following the general procedure using 4g as colorless solids: mp 85−
1
87 °C (hexanes/AcOEt); Rf = 0.20 (12% AcOEt/hexanes); H NMR
(CDCl3) δ 8.71 (br s, 1H), 8.07 (dd, J = 8.7, 6.2 Hz, 1H), 7.66 (dd, J =
10.9, 2.6 Hz, 1H), 7.37 (d, J = 2.9 Hz, 1H), 7.24 (ddd, J = 8.5, 8.5, 2.4
Hz, 1H), 6.99 (d, J = 2.9 Hz, 1H), 2.65 (s, 2H), 1.23−1.12 (m, 3H),
1.00 (d, J = 7.5 Hz, 18H); 13C NMR (CDCl3, 50 °C) δ 161.2 (J =
243.5 Hz), 150.3, 143.9 (J = 12.0 Hz), 128.3, 127.7, 125.1, 124.2 (J =
9.6 Hz), 119.2, 113.9 (J = 24.0 Hz), 112.8 (J = 20.4 Hz), 102.1, 18.6,
18.4, 11.8; IR (neat) 2943, 2866, 2360, 1627, 1581, 1531, 1462, 1438,
1381, 1358 cm−1; MS (FAB) m/z 357 (M + H+), 313 (M − i-Pr), 227
(M − 3i-Pr); HRMS-ESI (m/z) calcd for C21H30FN2Si 357.2157,
found 357.2166.
N-Boc-Protected Aplidiopsamine A (10). To a solution of N,N-
di(tert-butoxycarbonyl)adenine (67.1 mg, 0.2 mmol) in acetonitrile
(2.0 mL) was added Cs2CO3 (71.7 mg, 0.22 mmol) under an argon
atmosphere. After being stirred at the same temperature for 30 min,
compound 8 (86.7 mg, 0.22 mmol) was added and stirred for 2 h. The
reaction mixture was diluted with AcOEt (5.0 mL), washed with water
(2.0 mL) and brine (2.0 mL), dried over Na2SO4, and concentrated at
reduced pressure. The residue was purified by column chromatog-
raphy (hexanes/AcOEt = 2:1) to afford the desired product 10 (111.4
4-Methyl-3H-pyrrolo[2,3-c]quinoline (Marinoquinoline A)
(6h).4c The product 6h (26.6 mg, 73%) was obtained following the
1
general procedure using 4h as white solids: Rf = 0.10 (AcOEt); H
NMR (acetone-d6) δ 11.2 (br s, 1H), 8.24−8.18 (m, 1H), 8.02−7.96
(m, 1H), 7.57 (d, J = 2.9 Hz, 1H), 7.53−7.45 (m, 2H), 7.11 (d, J = 3.2
Hz, 1H), 2.82 (s, 3H).
1
mg, 91%) as a yellow oil: Rf = 0.19 (33% AcOEt/hexanes); H NMR
4-Benzyl-3H-pyrrolo[2,3-c]quinoline (Marinoquinoline C)
(6i).4c The product 6i (38.2 mg, 74%) was obtained following the
general procedure using 4i as white solids: Rf = 0.34 (50% AcOEt/
hexanes); H NMR (acetone-d6) δ 11.1 (br s, 1H), 8.28−8.17 (m,
1H), 8.10−7.99 (m, 1H), 7.57−7.47 (m, 3H), 7.41 (d, J = 7.7 Hz,
1H), 7.22 (t, J = 7.6 Hz, 2H), 7.17−7.08 (m, 2H), 4.55 (s, 2H).
(CDCl3) δ 8.77 (s, 1H), 8.35 (s, 1H), 8.14−8.04 (m, 1H), 7.86−7.78
(m, 1H), 7.78−7.70 (m, 1H), 7.59−7.48 (m, 2H), 7.16−7.06 (m, 1H),
6.29 (s, 2H), 1.70 (s, 9H), 1.45 (s, 18H); 13C NMR (CDCl3) δ 154.0,
151.6, 150.2, 149.8, 149.1, 147.1, 142.8, 142.2, 134.4, 130.0, 129.3,
128.6, 127.5, 126.7, 126.0, 122.7, 122.0, 105.2, 85.5, 83.3, 49.1, 28.0,
27.7; IR (KBr) νmax 2980, 2916, 2849, 1786, 1751, 1603, 1578, 1449,
1
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1382, 1369, 1356, 1341, 1306 cm−1; MS (FAB) m/z 616 ([M + H]+),
516 (M − Boc + 2H), 442, 386, 342; HRMS-ESI (m/z) calcd for
C32H38N7O6 616.2878, found 616.2870.
(7) (a) Mulder, J. A.; Hsung, R. P.; Frederick, M. O.; Tracey, M. R.;
Zificsak, C. A. Org. Lett. 2002, 4, 1383. (b) Mulder, J. A.; Kurtz, K. C.
M.; Hsung, R. P.; Coverdale, H.; Frederick, M. O.; Shen, L.; Zificsak,
C. A. Org. Lett. 2003, 5, 1547. (c) Frederick, M. O.; Hsung, R. P.;
Lambeth, R. H.; Mulder, J. A.; Tracey, M. R. Org. Lett. 2003, 5, 2663.
(d) Compain, G.; Jouvin, K.; Martin-Mingot, A.; Evano, G.; Marrot, J.;
Thibaudeau, S. Chem. Commun. 2012, 48, 5196. (e) Zhang, Y.
Tetrahedron Lett. 2005, 46, 6483. (f) Zhang, Y.; Hsung, R. P.; Zhang,
X.; Huang, J.; Slafer, B. W.; Davis, A. Org. Lett. 2005, 7, 1047.
(g) Zhang, Y. Tetrahedron 2006, 62, 3917. (h) Kong, Y.; Jiang, K.;
Cao, J.; Fu, L.; Yu, L.; Lai, G.; Cui, Y.; Hu, Z.; Wang, G. Org. Lett.
2013, 15, 422. (i) Peng, B.; Huang, X.; Xie, L.-G.; Maulide, N. Angew.
Chem., Int. Ed. 2014, 53, 8718. (j) Theunissen, C.; Metayer, B.; Henry,
́
N.; Compain, G.; Marrot, J.; Martin-Mingot, A.; Thibaudeau, S.;
Evano, G. J. Am. Chem. Soc. 2014, 136, 12528.
(8) (a) Shindoh, N.; Takemoto, Y.; Takasu, K. Chem.Eur. J. 2009,
15, 7026. (b) Shindoh, N.; Takemoto, Y.; Takasu, K. Heterocycles
2011, 82, 1133. (c) Shindoh, N.; Kitaura, K.; Takemoto, Y.; Takasu, K.
J. Am. Chem. Soc. 2011, 133, 8470. (d) Kuroda, Y.; Shindoh, N.;
Takemoto, Y.; Takasu, K. Synthesis 2013, 45, 2328.
Aplidiopsamine A.3 To a solution of 10 (49.5 mg, 0.080 mmol)
in CH2Cl2 (2.0 mL) was added trifluoroacetic acid (1.7 mL) at room
temperature under an argon atmosphere. After being stirred at the
same temperature for 7 h, the solvent was removed under reduced
pressure and CHCl3 (10 mL) was added to the residue. The mixture
was alkalized by saturated aq NaHCO3 and extracted with CHCl3 (10
mL). The combined organic layer was washed with brine (5 mL),
dried over Na2SO4, and concentrated at reduced pressure. The residue
was purified by column chromatography (CHCl3/MeOH = 20:1) to
afford aplidiopsamine A (22.8 mg, 90%) as a white powder: Rf = 0.22
1
(5% MeOH/CHCl3); H NMR (DMSO-d6) δ 12.37 (br s, 1H), 8.33
(s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.08 (s, 1H), 7.79−7.73 (m, 2H),
7.55−7.43 (m, 2H), 7.26 (br s, 2H), 7.20 (m, 1H), 5.94 (s, 2H); 13C
NMR (DMSO-d6) δ 156.0, 152.4, 149.8, 143.3, 142.2, 141.5, 129.0,
128.2, 127.9, 126.7, 125.64, 125.61, 123.2, 118.5, 101.3, 44.5.
ASSOCIATED CONTENT
■
(9) Cheng, Y.; Zhan, Y.-H.; Guan, H.-X.; Yang, H.; Meth-Cohn, O.
Synthesis 2002, 2426.
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all new compounds.
(10) A 6π electrocyclization reaction from the keteniminium
intermediate I is not excluded as an alternative pathway.
(11) The use of BPO/NBS, AIBN/NBS, s-BuLi/Br2, and LDA/Br2
gave complex mixtures.
(12) (a) Tamao, K.; Akita, M.; Maeda, K.; Kumada, M. J. Org. Chem.
1987, 52, 1100. (b) Nagao, M.; Asano, K.; Umeda, K.; Katayama, H.;
Ozawa, F. J. Org. Chem. 2005, 70, 10511. (c) Pawluc, P.; Hreczycho,
́
G.; Szudkowska, J.; Kubicki, M.; Marciniec, B. Org. Lett. 2009, 11,
3390.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: kay-t@pharm.kyoto-u.ac.jp. Fax: +81 75 753 4604.
Tel: +81 75 753 4553.
■
*E-mail: yyamaoka@pharm.kyoto-u.ac.jp.
Notes
The authors declare no competing financial interest.
(13) Dey, S.; Garner, P. J. Org. Chem. 2000, 65, 7697.
(14) Chen, X. Y.; Wang, L.; Frings, M.; Bolm, C. Org. Lett. 2014, 16,
3796.
́
(15) Colobert, F.; Valdivia, V.; Choppin, S.; Leroux, F. R.; Fernandez,
́
I.; Alvarez, E.; Khiar, N. Org. Lett. 2009, 11, 5130.
ACKNOWLEDGMENTS
■
(16) Leroy, J.; Porhiel, E.; Bondon, A. Tetrahedron 2002, 58, 6713.
(17) Brasche, G.; Buchwald, S. L.; Munday, R. H.; Tsang, W. C. P.;
Zheng, N. J. Org. Chem. 2008, 73, 7603.
(18) Representative papers of synthesis of ynamides from
bromoalkynes: (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.;
Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am.
Chem. Soc. 2003, 125, 2368. (b) Dunetz, J. R.; Danheiser, R. L. Org.
Lett. 2003, 5, 4011. (c) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz,
K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151. (d) Riddell, N.;
Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 3681.
This work was supported by a Grant-in-Aid for Young
Scientists (B), and “Platform for Drug Design, Discovery and
Development” from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
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H
DOI: 10.1021/jo502467m
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