Synthetic study of perophoramidine: Construction of pentacyclic core structure via SmI2-mediated reductive cyclization

Article abstract of DOI:10.1016/j.tet.2013.04.039

An intramolecular SmI₂-mediated reductive cyclization of carbodiimides and unsaturated lactams was applied to functionalized substrates bearing tetrasubstituted olefins. The reaction afforded arylated spiro-2-iminoindolines in high yield. Although the stereochemistry of the product was different from the desired one, the optimized palladium-catalyzed aryl amidination realized the isomerization and C-N bond formation in a single step and resulted in efficient construction of pentacyclic core of perophoramidine synthetically equivalent to the Rainier's intermediate.

Full text of DOI:10.1016/j.tet.2013.04.039

Tetrahedron 69 (2013) 4517e4523
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic study of perophoramidine: construction of pentacyclic
core structure via SmI2-mediated reductive cyclization
*
Takayuki Ishida, Yoshiji Takemoto
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 March 2013
Received in revised form 8 April 2013
Accepted 11 April 2013
Available online 13 April 2013
An intramolecular SmI2-mediated reductive cyclization of carbodiimides and unsaturated lactams was
applied to functionalized substrates bearing tetrasubstituted olefins. The reaction afforded arylated
spiro-2-iminoindolines in high yield. Although the stereochemistry of the product was different from the
desired one, the optimized palladium-catalyzed aryl amidination realized the isomerization and CeN
bond formation in a single step and resulted in efficient construction of pentacyclic core of perophor-
amidine synthetically equivalent to the Rainier’s intermediate.
Keywords:
Natural product
Alkaloid
Ó 2013 Elsevier Ltd. All rights reserved.
Samarium diiodide
Palladium catalysis
Amidine
1. Introduction
of the syntheses for the construction of 2-iminoindoline moiety,
we planned a distinct synthetic strategy based on the assembly of
Natural products isolated from ascidians, as represented by
a kind of ecteinascidins,1 possess unique structures and biological,
especially antitumor, activities that intrigue synthetic chemists as
well as pharmaceutical scientists. Perophoramidine (1, Fig. 1),
whose isolation, structural determination, and biological activities
were reported in 2002,2 is one of this class of natural products.
Ireland and co-workers isolated this alkaloid from an extract of
Philippine ascidian perophora namei. They revealed its highly
complex polycyclic structure using spectrometry, including 2D
INADEQUATE, and discovered that this natural product induces
apoptosis via PARP cleavage and exhibits cytotoxicity toward the
3,3-disubstituted 2-iminoindolines at the initial stage.
Fig. 1. Perophoramidine and the related compound.
HCT116 colon carcinoma cell line, with an IC50 of 60 mM. Its struc-
ture was validated by the total synthesis of (ꢀ)-perophoramidine
reported by Funk in 2004, and its absolute configuration was con-
firmed by the total synthesis of (þ)-perophoramidine by Qin in
2010.3 These syntheses were achieved by taking advantage of
DielseAlder reactions of indoles and ortho-quinone methide im-
ines, the biosynthetic pathway proposed independently by Stoltz
and by Funk in 2003.4 To date, much effort has been devoted to its
synthetic studies,5 represented by a synthesis of (ꢀ)-dehaloper-
ophoramidine 2 by Rainier in 2006.5b Since Funk, Qin, and Rainier
utilized indoles and their oxidized intermediates at the late stages
Indole or indoline derivatives that are nitrogenated at a 2-
position, including 2-aminoindolines and 2-iminoindolines, are
universal and fundamental structures often found in natural
products as well as in pharmaceutical ingredients that exhibit im-
portant biological activities.6 Recently we reported a reductive cy-
clization, mediated by samarium diiodide (SmI2) that transforms
carbodiimides 3 bearing unsaturated carbonyl moieties into 2-
iminoindolines 4 with all-carbon quaternary centers at a 3-
position (Scheme 1).7 Later we successfully applied this reaction
to a more highly functionalized substrate and converted the re-
sultant product into a pentacyclic amidine by palladium-catalyzed
aryl amidination. Herein we describe the construction of the pen-
tacyclic core of perophoramidine in detail.
* Corresponding author. Tel.: þ81 75 753 4528; fax: þ81 75 753 4569; e-mail
address: takemoto@pharm.kyoto-u.ac.jp (Y. Takemoto).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.039

4518
T. Ishida, Y. Takemoto / Tetrahedron 69 (2013) 4517e4523
SmI2-mediated reductive cyclization of carbodiimide 7 bearing an
electron-deficient tetrasubstituted olefin. Carbodiimide of substrate
7 was expected to be obtained from the corresponding aniline, and
the tetrasubstituted olefin would be synthesized via the
a-bromi-
nation and coupling reaction of b-aryl-a,b-unsaturated lactam 8.
3. Results and discussion
Scheme 1. SmI2-mediated reductive cyclization.
Synthesis of carbodiimides 7, based on the synthetic plan de-
scribed above, is presented in Scheme 3. Commercially available
ethyl N-benzylaminopropionate 9 was acylated with ethyl malonyl
chloride to give amide 10 in 93% yield. The following Dieckmann
condensation of the product afforded lactam 11, which was hy-
2. Synthetic plan
Our synthetic plan in this study is illustrated in Scheme 2. We
expected that the formation of the A ring of 2 could be achieved from
pentacyclic compound 5 by the established procedure.5b The D ring
of compound 5 was planned to be constructed via transition-metal-
catalyzed intramolecular CeN bond formation between an amidine
nitrogen and a haloarene moiety in spiro-2-iminoindoline 6. The
synthesis of spiro-2-iminoindoline 6 would be achieved by the
drolyzed and subsequently decarboxylated to b-ketolactam 12 by
heating in refluxing aqueous acetonitrile in 88% yield from 9.
Treatment of 12 with N-phenyl trifluoromethanesulfonimide
(Tf2NPh)8 provided vinyl triflate 13 in 97% yield. The Suzuki cou-
pling reaction of triflate 13 and boronic acid 149 gave Boc-protected
aniline 15 in 88% yield, and successive treatment of the coupling
product with bromine and with DBU resulted in a-bromination to
produce lactam 16 in 84% yield, the N-Boc group of which was re-
moved in the course of the sequence. Since direct cross coupling of
lactam 16 and 2-chlorophenyl boronic acid 18 was unsuccessful due
to the intramolecular CeN bond formation between the aniline and
a-position of the lactam in 16, the aniline 16 was converted into
corresponding tritylated aniline 17 in 79% yield. Then the protected
aniline 17 was subjected to the Suzuki coupling with the boronic
acid 18 and the crude material including the product 19 was treated
with trifluoroacetic acid to provide aniline 20 in 50% yield from 17.
Treatment of the product 20 with para-methoxyphenyl (PMP)10
and para-methoxybenzyl (PMB) isocyanates afforded N-PMP urea
21a in 87% yield and N-PMB urea 21b in 71% yield, respectively.
Urea 21a and 21b were transformed into carbodiimides 7a and 7b,
respectively, by dehydration using triphenylphosphine and carbon
tetrabromide.11 These substrates were rather stable at ambient
temperature, while carbodiimides 22 without a-substituents of a,b-
unsaturated lactams were consumed via 6p electrocyclic reaction,
providing 2-aminoquinolines,12 such as 23 in a gradual manner
Scheme 2. Synthetic plan in this study.
under the same condition (Scheme 4).
Scheme 3. Synthesis of carbodiimides 7.

T. Ishida, Y. Takemoto / Tetrahedron 69 (2013) 4517e4523
4519
Scheme 4. Thermal 6p electrocyclic reaction.
Fig. 3. Protonation of samarium enolate 24.
After we had obtained carbodiimides bearing tetrasubstituted
olefins, we applied SmI2-mediated reductive cyclization to these
substrates. When N-PMP carbodiimide 7a was treated with SmI2
(2.8 equiv) in the presence of tert-butyl alcohol (10 equiv) at am-
bient temperature, the desired cyclization proceeded and spiro-2-
iminoindoline 6a was obtained in 86% yield (Scheme 5). While
the product 6a was observed as a mixture of two isomers at a ratio
of 4:1 in CDCl3 on the 1H NMR spectrum, we reasoned they were
amidine-tautomers of a single diastereomer, based on the obser-
vation that the ratio was decreased to 2:1 by changing the solvent
to pyridine-d5. A single crystal of iminoindoline 6a was obtained via
crystallization from Et2O, and X-ray crystallographic analysis of 6a
revealed two aryl groups on a 2-piperidinone ring with a cis con-
figuration (Fig. 2).13
Table 1
Reductive cyclization of carbodiimide 7b
Entry
Additives
Temperature
Results
1
2
3
None
None
HMPA (10%vol)
rt
60 ꢁC
rt
No reaction
No reaction
90%
reaction, and the desired cyclization proceeded at ambient tem-
perature to afford iminoindoline 6b in 90% yield (entry 3).
Toward the construction of a pentacyclic core of perophor-
amidine, we planned intramolecular palladium-catalyzed aryl
amidination15 of the spiro-2-iminoindoline 6a and 6b. Since direct
aryl amidination of diastereomers 6a and 6b was expected to result
in a rather strained pentacyclic species, the ideal cyclization in this
Scheme 5. Reductive cyclization of carbodiimide 7a.
case would involve stereochemical inversion of the a-position of
the lactam in advance of the desired amidination. To examine the
isomerization conditions, spiro-2-iminoindoline 6a was treated
with 3 equiv of sodium tert-butoxide in DMA. No reaction occurred
at ambient temperature, however, 31% conversion of 6a to the
stereoisomer 6c was observed after heating to 60 ꢁC for 2 h by 1H
NMR analysis (Scheme 6). Surprisingly, when the reaction mixture
was heated to 120 ꢁC for 24 h, another product was obtained
that proved to be the desired pentacyclic compound 5a (Table 2,
entry 1).16 On examination of the effects of palladium catalysts and
phosphine ligands, we first added 10 mol % of palladium acetate
and 20 mol % of alkylphosphine ligands (entries 2e6). All of the
conditions tested contributed to the improvement of product
yields, but their degrees of enhancement were different. While the
condition using cataCXiumÒ A17 resulted in a slight increase in yield
(entry 2), tri-tert-butylphosphine,18 CyclehexylJohnPhos,19 Dave-
Phos,20 and tricyclohexylphosphine (Cy3P)21 showed greatly im-
proved yields (entries 3e6). The reaction rate enhancement by Cy3P
was especially notable, and the reaction was completed in 17 h to
afford product 5a in 78% yield (entry 6). Decreased amounts of
palladium catalyst and ligand increased the yield to 86% (entry 7).
The stereochemistry of pentacycle 5a was determined by NOESY,
which showed the proton at a-position of lactam has correlation to
two different protons on the aromatic rings (Fig. 4). Unfortunately,
Fig. 2. X-ray structure of 6a.
This result can be explained by stereoselective protonation of
samarium enolate 24 from a side of the ring that is less sterically
hindered (Fig. 3). We also attempted reductive cyclization of N-PMB
carbodiimide 7b (Table 1). Interestingly, the usual reaction condi-
tions resulted in complete recovery of the starting material (entry
1), even when the reaction mixture was heated to 60 ꢁC (entry 2).
The addition of HMPA as a co-solvent, generally utilized to increase
14
Scheme 6. Isomerization of iminoindoline 6a.
the reduction potential of SmI2, had a dramatic effect on the

4520
T. Ishida, Y. Takemoto / Tetrahedron 69 (2013) 4517e4523
Table 2
chromatography was performed with Kanto Silica gel 60 (spherical,
Intramolecular aryl amidination of iminoindoline 6a
63e210 mm), Kanto Silica gel 60 N (spherical, neutral, 40e100 mm)
or Fuji Silysia BW silica gel. Proton nuclear magnetic resonance (1H
NMR) spectra were recorded on a JEOL JNM-ECA500 KP at 500 MHz.
Chemical shifts are reported relative to Me4Si (d 0.00). Multiplicity
is indicated by one or more of the following: s (singlet); d (doublet);
dd (double doublet); dt (double triplet); t (triplet); q (quartet);
m (multiplet); br (broad). Carbon nuclear magnetic resonance (13C
NMR) spectra were recorded on a JEOL JNM-ECA500 KP at 125 MHz.
Chemical shifts are reported relative to CDCl3 (d 77.0). Infrared
spectra were recorded on FT/IR-4100 (JASCO). Low resolution mass
spectra (LRMS) and high resolution mass spectra (HRMS) were
recorded on SHIMADZU PARVUM 2 mass spectrometer.
Entry
Pd(OAc)2
Ligand (mol %)
Time
Yield
1
2
3
4
5
6
7
None
None
24 h
24 h
24 h
24 h
24 h
17 h
17 h
27%
31%
63%
66%
70%
78%
86%
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
5 mol %
cataCXiumÒ A (20)
tBu3P$HBF4 (20)
CyclohexylJohnPhos (20)
Davephos (20)
Cy3P$HBF4 (20)
Cy3P$HBF4 (10)
5.2. Ethyl 3-[Benzyl(3-ethoxy-3-oxopropyl)amino]-3-
oxopropanoate (10)
To a stirred solution of ethyl 3-(N-benzylamino)propionate 9
(414 mg, 2.00 mmol) and ethyldiisopropylamine (342
2.00 mmol) in 4 mL of CH2Cl2 at 0 ꢁC, was added ethyl malonyl
chloride (303 L, 2.40 mmol). The reaction mixture was warmed to
mL,
these optimized conditions did not work at all in the case of
N-PMB-protected iminoindoline 6b, resulting in the recovery of the
starting material. The difference in reactivity was probably derived
from the electronic property of amidines bearing different sub-
stituents. However the precise mechanism that encumbers the
desired reaction remained unclear. The pentacyclic compound 5a
thus obtained was comparable to Rainier’s pentacycle,5b which led
to dehaloperophoramidine via further transformations.
m
ambient temperature and stirred for 10 min. H2O was added at 0 ꢁC
and the separated aqueous layer was extracted with CHCl3. The
combined organic layers were washed with a saturated aqueous
NaHCO3 solution and with brine, dried over Na2SO4, and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (AcOEt) to give the titled compound
(598 mg, 93%) as a viscous colorless oil. 1H NMR (CDCl3,
d);
7.32e7.27 (m, 5H), 4.65 (s, 2H), 4.61* (s, 2H), 4.25e4.08 (m, 4H),
3.65 (t, 2H, J¼6.9 Hz), 3.56* (t, 2H, J¼6.9 Hz), 3.44 (s, 2H), 2.65 (t, 2H,
J¼6.9 Hz), 2.54* (t, 2H, J¼6.9 Hz), 1.31e1.22 (m, 6H); 13C NMR
(CDCl3, d) 171.9, 170.9*, 167.6*, 167.4, 166.7, 166.5*, 136.7*, 136.2,
129.0, 128.6*, 127.81, 127.77*, 127.4*, 126.3, 61.5*, 61.4, 61.0*, 60.5,
52.7, 47.9*, 43.1*, 43.0, 41.4, 41.1*, 33.1*, 32.5, 14.09*, 14.06, 14.0; IR
(ATR) 1736, 1654 cmꢂ1; Anal. Calcd for C17H23NO5: C, 63.54; H, 7.21;
N, 4.36. Found: C, 63.68; H, 7.29; N, 4.39. HRMS (MHþ) calcd for
C17H24NO5: 322.1654. Found: 322.1654 (major:minor¼57:43,
*peaks of minor conformer).
Fig. 4. NOESY correlation of pentacycle 5a.
5.3. Ethyl 1-benzyl-4-hydroxy-2-oxo-1,2,5,6-
tetrahydropyridine-3-carboxylate (11)
4. Conclusion
To a stirred solution of NaH (60% wt, 708 mg, 17.7 mmol) in
80 mL of EtOH at 0 ꢁC, was added a solution of amide 10 (5.18 g,
16.1 mmol) in 20 mL of EtOH dropwise over 10 min. The reaction
mixture was warmed to ambient temperature and stirred for 12 h.
A 2 M aqueous HCl solution was added and the resultant solution
was evaporated. The residue was dissolved in H2O and extracted
with CHCl3 three times (pH of the aqueous layer<2). The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure. The crude was purified by silica gel column
chromatography (hexane/AcOEt¼6/4 to 4/6) to give the titled
In summary, an intramolecular SmI2-mediated reductive cycli-
zation between carbodiimide moieties and unsaturated amides
was successfully developed and applied to functionalized sub-
strates bearing tetrasubstituted olefins. The reaction afforded ary-
lated spiro-2-iminoindolines in high yield, and the structure of the
product was determined by X-ray crystallography. Although the
stereochemistry of the product was different from the desired one,
the optimized palladium-catalyzed aryl amidination realized the
isomerization of a-stereochemistry of the lactam and CeN bond
formation in a single step, resulting in the efficient construction of
a pentacyclic core of perophoramidine synthetically equivalent to
Rainier’s pentacyclic amidine.5b
compound (4.03 g, 91%) as a viscous oil. 1H NMR (CDCl3,
d);
7.34e7.27 (m, 5H), 4.64 (s, 2H), 4.41 (q, 2H, J¼7.2 Hz), 3.32 (t, 2H,
J¼6.9 Hz), 2.54 (t, 2H, J¼6.9 Hz), 1.42 (t, 2H, J¼7.2 Hz); 13C NMR
(CDCl3, d) 182.9, 172.0, 162.4, 137.7, 128.6, 128.0, 127.4, 98.2, 61.8,
5. Experimental section
5.1. General methods
49.4, 41.5, 29.6, 14.2; IR (CHCl3) 1729, 1658 cmꢂ1; HRMS (MHþ)
calcd for C15H18NO4: 276.1236. Found: 276.1244.
5.4. 1-Benzylpiperidine-2,4-dione (12)
Unless otherwise noted, all reactions were performed under
nitrogen or argon atmosphere. Tetrahydrofuran was distilled from
metal sodium and benzophenone. Samarium diiodide (0.1 M in
THF) was prepared from metal samarium and diiodoethane.22
Analytical thin-layer chromatography was performed with Merck
Silica gel 60 and Merck 25 DC-Alufolein. Flash silica gel column
A solution of lactam 11 (3.78 g, 13.7 mmol) and 0.1 mL of H2O in
100 mL of MeCN was heated to reflux for 3.5 h. The reaction mix-
ture was evaporated and purified by silica gel column chromatog-
raphy (CHCl3/MeOH¼98/2 to 95/5) to give the titled compound
(2.73 g, 98%) as colorless solids. Mp 59e60 ꢁC; 1H NMR (CDCl3,
d);

T. Ishida, Y. Takemoto / Tetrahedron 69 (2013) 4517e4523
4521
7.34e7.26 (m, 5H), 4.69 (s, 2H), 3.49 (t, 2H, J¼6.3 Hz), 3.43 (s, 2H),
118.4, 116.2, 51.3, 44.4, 31.4; IR (ATR) 3420, 3342, 1635 cmꢂ1; HRMS
(MHþ) calcd for C18H1879BrN2O : 357.0603. Found: 357.0601.
2.54 (t, 2H, J¼6.3 Hz). 13C NMR (CDCl3,
d) 203.4, 166.3, 136.2, 128.8,
128.0, 127.9, 50.0, 48.9, 42.3, 38.6; IR (ATR) 1715, 1651 cmꢂ1; MS
(FABþ) m/z¼204 (MHþ); Anal. Calcd for C12H13NO2: C, 70.92; H,
6.45; N, 6.89. Found: C, 70.78; H, 6.48; N, 6.85.
5.8. 1-Benzyl-3-bromo-4-[2-(tritylamino)phenyl]-5,6-
dihydropyridin-2(1H)-one (17)
5.5. 1-Benzyl-6-oxo-1,2,3,6-tetrahydropyridin-4-yl tri-
To a solution of a-bromolactam 16 (4.64 g, 13.0 mmol) and
fluoromethanesulfonate (13)
triethylamine (18.1 mL, 130 mmol) in 100 mL of CH2Cl2, was added
triphenylmethyl chloride (21.7 g, 78.0 mmol) in two portions at
To a solution of ketolactam 12 (6.09 g, 30.0 mmol) and Et3N
(8.35 mL, 60.0 mmol) in 100 mL of CH2Cl2 at 0 ꢁC, was added
N-phenyl trifluoromethanesulfonimide (12.9 g, 36.0 mmol). After
60 min, the reaction mixture was warmed to ambient temperature
and stirred for 2 h. A 0.1 M aqueous HCl was added to the mixture at
0
ꢁC. The reaction mixture was warmed to ambient temperature
and stirred for 5 h. Then a saturated aqueous NaHCO3 solution was
added and the separated organic layer was washed with water and
a saturated aqueous NaHCO3 solution, dried over Na2SO4, and
concentrated under reduced pressure. The crude was purified by
silica gel column chromatography (hexane/AcOEt¼9/1 to 7/3) to
give the titled compound (6.16 g, 79%) as colorless solids. Mp
0
ꢁC and a separated aqueous layer was extracted with CHCl3. The
combined organic layers were successively washed with a 0.1 M
aqueous HCl solution, brine, a saturated aqueous NaHCO3 solution,
and brine. The resultant solution was dried over Na2SO4 and con-
centrated under reduced pressure. This crude material was purified
by silica gel column chromatography (hexane/AcOEt¼9/1 to 8/2) to
give the titled compound (9.81 g, 97%) as a colorless oil. 1H NMR
201e203 ꢁC; 1H NMR (CDCl3,
d); 7.35e7.19 (m, 20H), 6.89 (dd, 1H,
J¼7.4, 1.7 Hz), 6.77 (m, 1H), 6.63 (m, 1H), 6.14 (d, 1H, J¼8.0 Hz), 4.91
(s, 1H), 4.73 (d, 1H, J¼14.3 Hz), 4.67 (d, 1H, J¼14.3 Hz), 3.46e3.33
(m, 2H), 2.68e2.67 (m, 2H). 13C NMR (CDCl3,
d) 160.3, 149.2, 140.9,
136.8, 128.8, 128.7, 128.2, 128.1, 128.0, 127.9, 127.7, 127.1, 127.0, 126.4,
(CDCl3,
d
); 7.35e7.28 (m, 5H), 6.06 (s, 1H), 4.62 (s, 2H), 3.44 (t, 2H,
119.9, 117.2, 116.0, 71.0, 51.2, 44.5, 31.5; IR (ATR) 3431, 1651 cmꢂ1
;
J¼7.2 Hz), 2.69 (t, 2H, J¼7.2 Hz). 13C NMR (CDCl3,
d) 162.7, 157.5,
HRMS (MHþ) calcd for C37H3281BrN2O : 601.1678. Found: 601.1677.
136.3,128.7,127.9,127.7,118.3 (q, J¼320.7 Hz),114.2, 49.3, 43.3, 27.1;
IR (ATR) 1680, 1366, 1219 cmꢂ1; MS (FABþ) m/z¼336 (MHþ); Anal.
Calcd for C13H12F3NO4S: C, 46.57; H, 3.61; N, 4.18. Found: C, 46.52;
H, 3.61; N, 4.28.
5.9. 4-(2-Aminophenyl)-1-benzyl-3-(2-chlorophenyl)-5,6-
dihydropyridin-2(1H)-one (20)
A solution of N-trityl aniline 18 (300 mg, 0.500 mmol),
5.6. tert-Butyl [2-(1-Benzyl-6-oxo-1,2,3,6-tetrahydropyridin-
2-chlorophenyl boronic acid (235 mg, 1.50 mmol), and PdCl2(PPh3)2
4-yl)phenyl]carbamate (15)
(17.5 mg, 25.0 mmol) in 10 mL of dioxane and 10 mL of a 2.0 M
aqueous Na2CO3 solution was heated to reflux for 60 min. The re-
action mixture was gradually cooled to ambient temperature. The
separated aqueous layer was extracted with AcOEt. The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure. This material was dissolved in 9.5 mL of CH2Cl2
and the resultant solution was cooled to 0 ꢁC. To the solution was
added 0.5 mL of TFA. After 5 min, a saturated aqueous NaHCO3
solution was added and the separated aqueous layer was extracted
with CHCl3. The combined organic layers were dried over Na2SO4
and concentrated under reduced pressure. The crude was purified
by silica gel column chromatography (hexane/AcOEt¼8/2 to 5/5) to
give the titled compound (96.6 mg, two steps 50%) as a yellow
A solution of vinyl triflate 13 (19.2 g, 57.3 mmol), boronic acid
149 (16.3 g, 68.8 mmol), and PdCl2(PPh3)2 (2.01 g, 2.87 mmol) in
150 mL of THF and 150 mL of a 2.0 M aqueous Na2CO3 solution was
heated to reflux for 60 min. The reaction mixture was gradually
cooled to ambient temperature. The separated aqueous layer was
extracted with AcOEt. The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure. The crude was purified by silica gel column chromatog-
raphy (hexane/AcOEt¼8/2 to 4/6) to give the titled compound
(19.0 g, 88%) as colorless solids. Mp 171e172 ꢁC; 1H NMR (CDCl3,
d);
7.84 (d, 1H, J¼8.6 Hz), 7.34e7.32 (m, 6H), 7.14e7.08 (m, 2H), 6.49 (s,
1H), 6.09 (s, 1H), 4.69 (s, 2H), 3.47 (t, 2H, J¼7.0 Hz), 2.63 (t, 2H,
amorphous. 1H NMR (CDCl3,
d); 7.38e7.35 (m, 4H), 7.30e7.28 (m,
J¼7.0 Hz), 1.49 (s, 9H). 13C NMR (CDCl3,
d
) 164.3, 152.9, 149.4, 137.2,
2H), 7.11e7.04 (m, 3H), 6.94e6.90 (m, 2H), 6.56 (br, 2H), 4.83 (d, 1H,
J¼14.9 Hz), 4.66 (d, 1H, J¼14.9 Hz), 3.68e3.59 (m, 3H), 3.41e3.39
134.3,130.8, 129.3,128.7,128.2, 127.6, 127.5,124.0,123.8, 122.0, 80.9,
49.7, 44.8, 29.1, 28.3; IR (ATR) 3160, 1709, 1656 cmꢂ1; HRMS (MHþ)
calcd for C23H27N2O3: 379.2022. Found: 379.2020.
(m, 1H), 2.88 (br, 1H), 2.55 (br, 1H). 13C NMR (CDCl3,
d) 163.6, 147.3,
142.2, 137.2, 134.8, 132.6, 130.6, 128.5, 128.43, 128.39, 128.34, 128.1,
127.9, 127.4, 127.2, 125.9, 124.4, 117.5, 115.5, 50.0, 44.4, 29.7; IR (ATR)
3450, 2247, 1649 cmꢂ1; HRMS (MHþ) calcd for C24H2235ClN2O :
389.1421. Found: 389.1421.
5.7. 4-(2-Aminophenyl)-1-benzyl-3-bromo-5,6-dihydropyri-
din-2(1H)-one (16)
To a solution of N-Boc aniline 15 (567 mg,1.50 mmol) in 10 mL of
5.10. 1-{2-[1-Benzyl-5-(2-chlorophenyl)-6-oxo-1,2,3,6-
tetrahydropyridin-4-yl]phenyl}-3-(4-methoxyphenyl)urea
(21a)
CCl4, was added bromine (84.6
After 10 min, the reaction mixture was directly evaporated and this
residue was dissolved in 10 mL of dioxane. DBU (447 L, 3.00 mmol)
m
L, 1.65 mmol) dropwise at 0 ꢁC.
m
was added at 0 ꢁC in a dropwise manner. After 20 min, a saturated
aqueous NH4Cl solution was added and the separated aqueous layer
was extracted with CHCl3. The combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. The crude
was purified by silica gel column chromatography (hexane/
AcOEt¼8/2 to 6/4) to give the titled compound (450 mg, 84%) as
To a solution of diaryllactam 20 (335 mg, 861
CH2Cl2, were added 4-methoxyphenyl isocyanate (123
947 mol) and DMAP (10.0 mg, 81.9 mol) at ambient temperature.
m
mol) in 5 mL of
mL,
m
m
The reaction mixture was stirred for 2 h. Et2O 10 mL was added to
the reaction mixture and colorless precipitate was observed. The
precipitate was filtered, washed with CH2Cl2, and dried in vacuo to
give the titled compound (405 mg, 87%) as colorless solids. Mp
brown solids. Mp 66e68 ꢁC; 1H NMR (CDCl3,
d); 7.37e7.28 (m, 5H),
7.16 (m, 1H), 6.95 (dd, 1H, J¼7.5, 1.5 Hz), 6.80 (m, 1H), 6.75 (d, 1H,
225e227 ꢁC; 1H NMR (DMSO-d6,
d); 8.91 (s, 1H), 7.88 (s, 1H), 7.73 (d,
J¼8.0 Hz), 4.76 (d, 1H, J¼14.3 Hz), 4.67 (d, 1H, J¼14.3 Hz), 3.66 (br s,
1H, J¼8.3 Hz), 7.35e7.29 (m, 9H), 7.15e7.13 (m, 1H), 7.11e7.07 (m,
3H), 6.89e6.83 (m, 2H), 6.76 (d, 1H, J¼3.4 Hz), 4.95 (d, 1H,
J¼14.6 Hz), 4.41 (d, 1H, J¼14.6 Hz), 3.72 (s, 3H), 3.55e3.54 (m, 2H),
2H), 3.47 (t, 2H, J¼6.9 Hz), 2.70e2.59 (m, 2H). 13C NMR (CDCl3,
d)
160.4, 149.0, 141.7, 136.8, 129.6, 128.7, 128.2, 127.7, 127.3, 125.9, 118.7,

4522
T. Ishida, Y. Takemoto / Tetrahedron 69 (2013) 4517e4523
3.00e2.91 (m, 1H), 2.49e2.37 (m, 2H). 13C NMR (DMSO-d6,
d) 163.0,
1H). 13C NMR (CDCl3,
d) 163.9, 159.1, 147.8, 138.7, 137.5, 136.9, 135.8,
154.5, 152.5, 147.3, 146.2, 137.5, 136.2, 135.4, 133.5, 132.6, 131.4,
130.9, 128.9, 128.5, 128.4, 128.0, 127.7, 127.3, 127.2, 126.5, 122.4,
121.7, 120.0, 114.1, 55.2, 49.5, 44.7, 29.0; IR (ATR) 3338, 1702,
1641 cmꢂ1; HRMS (MHþ) calcd for C32H2935ClN3O3: 538.1897.
Found: 538.1896.
135.6, 134.1, 133.9, 131.9, 131.7, 129.8, 128.60, 128.57, 128.5, 128.4,
128.3, 128.2, 127.3, 126.0, 124.3, 124.0, 114.1, 55.2, 50.2, 49.9, 44.4,
29.9; IR (ATR) 2125, 1653 cmꢂ1
;
HRMS (MHþ) calcd for
C33H2935ClN3O2: 534.1948. Found: 534.1951.
5.14. (3RS,30RS,Z)-10-Benzyl-30-(2-chlorophenyl)-2-(4-methoxy-
5.11. 1-{2-[1-Benzyl-5-(2-chlorophenyl)-6-oxo-1,2,3,6-
tetrahydropyridin-4-yl]phenyl}-3-(4-methoxybenzyl)urea
(21b)
phenylimino)spiro[indoline-3,40-piperidin]-20-one (6a)
t
A solution of carbodiimide 7a (354 mg, 681
(651
m
mol) and BuOH
m
L, 6.81 mmol) in 12 mL of THF was degassed by freeze pump
To a solution of diaryllactam 20 (93.0 mg, 239
CH2Cl2, were added 4-methoxybenzyl isocyanate (40.5
263 mol) and DMAP (9.6 mg, 78.6 mol) at ambient temperature.
mmol) in 1 mL of
thaw cycles chilled with liquid nitrogen. To the stirred solution at
ambient temperature, was added a solution of samarium diiodide
(0.1 M in THF, 19 mL) in a dropwise manner over 4.5 h. Then
a saturated aqueous NH4Cl solution was added to the reaction
mixture and the organic solvent was removed by evaporation. The
resultant mixture was extracted with AcOEt twice and the com-
bined organic layers were washed with a saturated aqueous NH4Cl
solution and dried over Na2SO4. The crude solution was concen-
trated under reduced pressure and dried in vacuo. The crude was
subjected to silica gel column chromatography (hexane/AcOEt¼8/2
to 6/4) to give the titled compound (307 mg, 86%) as colorless
mL,
m
m
The reaction mixture was heated to 40 ꢁC and stirred for 24 h. After
gradual cooling to ambient temperature, the reaction mixture was
directly subjected to silica gel column chromatography (hexane/
AcOEt¼9/1 to 5/5) to give the titled compound (94.2 mg, 71%) as
colorless solids. Mp 192e193 ꢁC; 1H NMR (CDCl3,
d); 7.79e7.65 (br,
1H), 7.31e7.06 (m, 12H), 6.82e6.78 (br, 3H), 6.65e6.55 (br, 2H),
6.35e6.16 (br, 1H), 5.58e4.62 (m, 1H), 4.24e4.19 (br, 2H), 4.01e3.98
(br, 1H), 3.76 (s, 3H), 3.62e3.59 (br, 1H), 3.24e2.91 (br, 2H),
2.38e2.27 (br, 1H). 13C NMR (CDCl3,
d) 164.8, 158.5, 155.8, 148.4,
solids. Mp 208e209 ꢁC; 1H NMR (CDCl3,
d) 7.50e7.32 (m, 6H),
135.9,135.7,135.1,133.5,133.0,132.0,131.9,129.1,128.9,128.8,128.7,
128.6, 128.2, 128.1, 127.9, 127.4, 126.2, 122.5, 113.8, 113.7, 55.2, 51.0,
45.4, 43.0, 29.0 (The peaks on 1H and 13C spectra were highly
broadened.); IR (ATR) 3366, 1640 cmꢂ1; HRMS (MHþ) calcd for
C33H3135ClN3O3: 552.2054. Found: 552.2059.
7.19e7.13 (m, 3H), 6.94e6.92 (m, 1H), 6.87e6.68 (m, 5H), 6.59e6.53
(m, 3H), 5.03 (s, 1H), 4.97* (d, 1H, J¼13.7 Hz), 4.87 (d, 1H, J¼14.3 Hz),
4.83* (s, 1H), 4.76 (d, 1H, J¼14.3 Hz), 4.66* (d, 1H, J¼13.7 Hz),
3.88e3.82 (m, 1H), 3.79 (s, 3H), 3.77* (s, 3H), 3.64e3.62 (m, 1H),
2.58e2.52 (m, 1H), 2.22 (ddd, 1H, J¼13.7, 5.7, 5.7 Hz), 2.01e1.98* (m,
1H). 13C NMR (CDCl3,
d) 169.9*, 169.1, 168.2*, 161.4, 156.1*, 155.7,
5.12. 1-Benzyl-3-(2-chlorophenyl)-4-[2-(4-methoxyphenylimi-
nomethyleneamino)phenyl]-5,6-dihydropyridin-2(1H)-one (7a)
142.6, 142.2, 136.7, 136.4, 134.6, 134.4*, 133.9*, 132.4*, 132.3*, 130.3*,
130.0, 129.4, 129.3*, 129.2, 129.0*, 128.9*, 128.8, 128.7*, 128.6, 128.5,
128.3, 128.0*, 127.5, 126.1*, 125.9, 124.5, 123.0*, 122.1, 121.6*, 120.9,
118.1*, 114.7, 114.0*, 108.7, 56.8*, 55.4, 51.7, 51.3, 51.0*, 50.8, 49.5*,
43.9*, 43.2, 31.5*, 31.3; IR (ATR) 3246, 1667 cmꢂ1; HRMS (MHþ)
calcd for C32H2935ClN3O2: 522.1948. Found: 522.1946 (*peaks of
minor isomer).
To a stirred solution of urea 21a (404 mg, 0.751 mmol), PPh3
(295 mg, 1.13 mmol), and Et3N (230
CH2Cl2, was added CBr4 (299 mg, 901
m
m
L, 1.65 mmol) in 10 mL of
mol) at 0 ꢁC. The reaction
mixture was stirred for 60 min and warmed to ambient tem-
perature. Then additional PPh3 (300 mg, 1.14 mmol) was added in
three portions and the reaction mixture was stirred for additional
5 h and directly evaporated. The resultant residue was purified by
silica gel column chromatography (hexane/AcOEt¼8/2 to 7/3) to
give the titled compound (379 mg, 97%) as a colorless oil. 1H NMR
5.15. (3RS,30RS,Z)-10-Benzyl-30-(2-chlorophenyl)-2-(4-
methoxybenzylimino)spiro[indoline-3,40-piperidin]-20-one
(6b)
(CDCl3, d); 7.40e7.38 (m, 2H), 7.36e7.33 (m, 2H), 7.30e7.27 (m,
t
2H), 7.13e7.00 (m, 7H), 6.94e6.84 (m, 4H), 4.83 (d, 1H, J¼14.9 Hz),
A solution of carbodiimide 7b (98.3 mg, 184
(176
mmol) and BuOH
4.66 (d, 1H, J¼14.9 Hz), 3.79 (s, 3H), 3.68e3.66 (m, 1H), 3.48e3.43
m
L, 1.84 mmol) in 1.8 mL of THF was degassed by freeze pump
(m, 1H), 3.07 (br, 1H), 2.60 (br, 1H). 13C NMR (CDCl3,
d
) 163.9,
thaw cycles chilled with liquid nitrogen. To the stirred solution at
ambient temperature, was added a solution of samarium diiodide
(0.9 M in THF/HMPA¼9/1, 8.18 mL) over 2 min. The reaction mix-
ture was stirred for 5 min. Then a saturated aqueous NH4Cl solution
was added to the reaction mixture and the organic solvent was
removed by evaporation. The resultant mixture was extracted with
AcOEt twice and the combined organic layers were washed with
a saturated aqueous LiCl solution twice and dried over Na2SO4. The
crude solution was concentrated under reduced pressure and dried
in vacuo. The crude was subjected to silica gel column chroma-
tography (hexane/AcOEt¼8/2 to 4/6) to give the titled compound
157.5, 147.4, 137.5, 135.9, 135.6, 134.3, 134.2, 134.1, 132.4, 131.8,
130.3, 128.9, 128.8, 128.56, 128.55, 128.53, 128.2, 127.3, 126.1,
125.12, 125.05, 124.8, 114.8, 55.5, 50.3, 44.5, 30.2; IR (ATR) 2129,
1654 cmꢂ1; HRMS (MHþ) calcd for C37H2735ClN3O2: 520.1792.
Found: 520.1800.
5.13. 1-Benzyl-3-(2-chlorophenyl)-4-[2-(4-methoxybenzyl)
iminomethyleneaminophenyl]-5,6-dihydropyridin-2(1H)-
one (7b)
To a stirred solution of urea 21b (167 mg, 0.303 mmol), PPh3
(88.6 mg, 90%) as colorless amorphous. 1H NMR (CDCl3,
d)
(119 mg, 454
was added CBr4 (121 mg, 364
m
mol), and Et3N (127
m
L, 909
m
mol) in 6 mL of CH2Cl2,
7.44e7.43 (m, 2H), 7.39e7.37 (m, 3H), 7.27e7.27 (m, 1H), 7.24e7.22
(m, 1H), 7.17e7.15 (m, 3H), 7.09e7.05 (m, 1H), 6.85e6.82 (m, 5H),
6.44 (d, 1H, J¼8.0 Hz), 4.93e4.89 (m, 2H), 4.64e4.62 (m, 2H),
4.54e4.50 (m, 1H), 4.35e4.32 (m, 1H), 3.81 (s, 3H), 3.77e3.74 (m,
m
mol) at 0 ꢁC. The reaction mixture
was stirred for 60 min and warmed to ambient temperature. The
reaction mixture was stirred for 10 h and directly evaporated. The
resultant residue was purified by silica gel column chromatography
(hexane/AcOEt¼8/2 to 6/4) to give the titled compound (98.3 mg,
1H), 3.59 (m, 1H), 2.36 (m, 1H), 1.94 (m, 1H). 13C NMR (CDCl3,
d)
173.1, 168.1, 159.0, 155.9, 136.2, 134.5, 134.2, 130.1, 129.6, 129.5,
129.4, 129.3, 129.0, 128.8, 128.7, 128.6, 127.9, 126.2, 123.0, 121.2,
117.3, 113.9, 55.6, 55.2, 50.8, 49.5, 46.4, 43.7, 31.9; IR (ATR) 3433,
1642 cmꢂ1; HRMS (MHþ) calcd for C33H3135ClN3O2: 536.2105.
Found: 536.2100.
61%) as a colorless oil. 1H NMR (CDCl3,
d); 7.40e7.33 (m, 4H),
7.28e7.23 (m, 4H), 7.05e6.99 (m, 2H), 6.91e6.80 (m, 7H), 4.81 (d,
1H, J¼14.6 Hz), 4.65 (d, 1H, J¼14.6 Hz), 4.45 (s, 2H), 3.75 (s, 3H),
3.60e3.58 (m, 1H), 3.40e3.35 (m, 1H), 2.96 (s, 1H), 2.43e2.41 (m,

T. Ishida, Y. Takemoto / Tetrahedron 69 (2013) 4517e4523
4523
2. Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.; Ireland, C. M. J. Org.
Chem. 2002, 67, 7124.
3. (a) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068; (b) Wu, H.; Xue, F.;
5.16. (4aRS,14bRS)-2-Benzyl-10-(4-methoxyphenyl)-3,4,10,
14b-tetrahydrobenzo[c]indolo[3,2-j][2,6]naphthyridin-1(2H)-
one (5a)
Xiao, X.; Qin, Y. J. Am. Chem. Soc. 2010, 132, 14052.
4. (a) May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203; (b)
Crawley, S. L.; Funk, R. L. Org. Lett. 2003, 5, 3169.
A solution of iminoindoline 6a (52.2 mg, 100
(28.8 mg, 300 mol), Pd(OAc)2 (2.1 mg, 5.09 mol), and tricyclo-
hexylphosphonium tetrafluoroborate (3.7 mg, 10.0 mol) in 2 mL of
m
mol), NaOtBu
5. (a) Artman, G. D., III; Weinreb, S. M. Org. Lett. 2003, 5, 1523; (b) Sabahi, A.;
Novikov, A.; Rainier, J. D. Angew. Chem., Int. Ed. 2006, 45, 4317; (c) Yang, J.;
Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187; (d) Seo, J. H.;
Artman, G. D., III; Weinreb, S. M. J. Org. Chem. 2006, 71, 8891; (e) Evans, M. A.;
Sacher, J. R.; Weinreb, S. M. Tetrahedron 2009, 65, 6712; (f) Trost, B. M.; Zhang, Y.
Chem.dEur. J. 2011, 17, 2916; (g) Wu, H.; Xiao, X.; Qin, Y. Synlett 2011, 907; (h)
Du, Y.; Wu, H.; Song, H.; Qin, Y.; Zhang, D. Chin. J. Chem. 2012, 30, 1970; (i)
Schammel, A. W.; Chiou, G.; Garg, N. K. Org. Lett. 2012, 14, 4556.
6. (a) Barraja, P.; Diana, P.; Lauria, A.; Almerico, A. M.; Dattolo, G.; Cirrincione, G.
m
m
m
DMA was heated at 120 ꢁC for 17 h. Then the reaction mixture was
cooled to ambient temperature and a saturated aqueous NH4Cl
solution was added to it. The mixture was extracted with CHCl3
three times and the combined organic layers were washed with
water, dried over Na2SO4, and concentrated under reduced pres-
sure. The crude was purified by silica gel column chromatography
(CHCl3/AcOEt¼10/0 to 9/1) to give the titled compound (41.6 mg,
€
Helv. Chim. Acta 2001, 84, 2212; (b) Wang, K.; Herdtweck, E.; Domling, A. ACS
Comb. Sci. 2011, 13, 140; (c) Shinada, M.; Narumi, F.; Osada, Y.; Matsumoto, K.;
Yoshida, T.; Higuchi, K.; Kawasaki, T.; Tanaka, H.; Satoh, M. Bioorg. Med. Chem.
ꢀ
2012, 20, 4901; (d) Carle, J. S.; Christophersen, C. J. Org. Chem. 1981, 46, 3440
86%) as colorless solids. Mp 249e250 ꢁC; 1H NMR (CDCl3,
d); 7.69 (d,
and references therein.
1H, J¼8.0 Hz), 7.39e7.34 (m, 7H), 7.19e7.08 (m, 6H), 6.85e6.81 (m,
2H), 6.57 (d, 1H, J¼8.0 Hz), 4.93 (d, 1H, J¼14.3 Hz), 4.74 (d, 1H,
J¼14.3 Hz), 4.03 (s, 1H), 3.87 (s, 3H), 3.51 (ddd, 1H, J¼12.5, 7.0,
6.0 Hz), 3.30 (dd, 1H, J¼12.6, 7.0 Hz), 2.56 (ddd, 1H, J¼12.5, 7.0,
7. Ishida, T.; Tsukano, C.; Takemoto, Y. Chem. Lett. 2012, 41, 44.
8. Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 46, 4607.
9. Sharp, M. J.; Snieckus, V. Tetrahedron Lett. 1985, 26, 5997.
10. Whiting, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 3157.
€
11. Appel, R.; Kleinstuck, R.; Ziehn, K. D. Chem. Ber. 1971, 104, 1335.
6.0 Hz), 1.42 (dd, 1H, J¼12.6, 6.0 Hz). 13C NMR (CDCl3,
d) 171.8, 167.1,
12. (a) Saito, T.; Ohmori, H.; Furuno, E.; Motoki, S. J. Chem. Soc., Chem. Commun.
ꢀ
1992, 22; (b) Molina, P.; Alajarín, M.; Vidal, A.; Sanchez-Andrada, P. J. Org. Chem.
159.4, 155.0, 140.6, 136.4, 136.1, 131.7, 128.9, 128.8, 128.7, 128.3,
127.9, 127.8, 123.3, 122.3, 122.0, 120.0, 118.8, 117.0, 115.7, 115.5, 55.5,
50.4, 49.2, 45.6, 43.7, 24.8; IR (ATR) 1644, 1548 cmꢂ1; MS (MHþ)
calcd for C32H28N3O2: 486.2182. Found: 486.2182.
1992, 57, 929.
13. Crystallographic data reported in this manuscript have been deposited with
Cambridge Crystallographic Data Centre as supplementary publication No.
CCDC-927186. Copies of the data can be obtained free of charge via http://
www.ccdc. cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge, CB2 1EZ, UK.; fax: þ44 1223
336033; or deposit@ccdc.cam.ac.uk).
14. Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987, 1485.
15. (a) Brain, C.; Brunton, T. Tetrahedron Lett. 2002, 43, 1893; (b) McGowan, M. A.;
McAvoy, C. Z.; Buchwald, S. L. Org. Lett. 2012, 14, 3800.
16. It is interesting that amidination of aryl chloride proceeded without addition
of transition metal catalysts. Since detailed analysis, such as ICP-MS and ICP-
AES has not been carried out, the possibility cannot be ruled out that trace
amounts of catalysts included in the system promoted the reaction. We
would emphasize that uncatalyzed reaction was inefficient and low-yielding,
although some mechanisms independent of transition metal catalysts also
can be proposed.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific
Research (B) (Y.T.), ‘Platform for Drug Design, Discovery and De-
velopment’ from the Ministry of Education, Culture, Sports, Science
and Technology of Japan, and JSPS Research Fellowship for Young
Scientists (T.I.).
References and notes
17. Zepf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000, 39, 4153.
18. Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10.
19. Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358.
20. Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413.
21. (a) Huser, M.; Youinou, M.-T.; Osborn, J. A. Angew. Chem., Int. Ed. Engl. 1989, 28,
1386; (b) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4807.
22. Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693.
1. (a) Wright, A. E.; Forleo, D. A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.;
McConnell, O. J. J. Org. Chem. 1990, 55, 4508; (b) Rinehart, K. L.; Holt, T. G.;
Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem.
1990, 55, 4512; (c) For review: Menna, M. L.; Fattorusso, E.; Imperatore, C.
Molecules 2011, 16, 8694.