The first enantioselective approach to 13a-methyl-14- hydroxyphenanthroindolizidine alkaloids - Synthetic studies towards hypoestestatin 2

Article abstract of DOI:10.1002/ejoc.201201472

The first enantioselective approach to 13a-methyl-14- hydroxyphenanthroindolizidine alkaloids was achieved in six linear steps from phenanthryl alcohol and features a highly substrate-dependent Parham cycloacylation and Seebach's enantioselective alkylation as the key steps. The route is concise, protecting-group free, provides access to all stereoisomers, and works on a gram scale. In addition to the putative structure of hypoestestatin 2, the other three stereoisomers and two structurally related analogues were synthesized, none of which shows identical NMR spectra to those reported for natural hypoestestatin 2, which indicates that further structure revision is required. By using Seebach's stereoselective alkylation and Parham cyclization as key steps, the first strategy for the synthesis of 14-hydroxy-13a-methylphenanthroindolizidine alkaloids was developed. The route is practical (six steps in 30 % overall yield) and adaptable for all stereoisomers. In addition, we demonstrate for the first time that the structure of hypoestestatin 2 was misassigned.

Full text of DOI:10.1002/ejoc.201201472

FULL PAPER
DOI: 10.1002/ejoc.201201472
The First Enantioselective Approach to 13a-Methyl-14-
hydroxyphenanthroindolizidine Alkaloids – Synthetic Studies towards
Hypoestestatin 2
Bo Su,[a] Meng Deng,[a] and Qingmin Wang*[a]
Keywords: Natural products / Alkaloids / Total synthesis / Stereoselective alkylation / Cyclization
The first enantioselective approach to 13a-methyl-14-hy-
droxyphenanthroindolizidine alkaloids was achieved in six
linear steps from phenanthryl alcohol and features a highly
substrate-dependent Parham cycloacylation and Seebach’s
enantioselective alkylation as the key steps. The route is con-
mers, and works on a gram scale. In addition to the putative
structure of hypoestestatin 2, the other three stereoisomers
and two structurally related analogues were synthesized,
none of which shows identical NMR spectra to those reported
for natural hypoestestatin 2, which indicates that further
cise, protecting-group free, provides access to all stereoiso- structure revision is required.
Introduction
Phenanthroindolizidine alkaloids represent a group of
pentacyclic natural products isolated mainly from Cynan-
chum, Pergularia, Tylophora, and some genera of the Ascle-
piadaceas family. Owing to their low natural abundance and
potent biological activity, including antitumor, antiviral,
antibacterial, anti-inflammatory, and antifungal activities,
they have attracted great interest from synthetic and phar-
maceutical chemists.[1] More than 60 members of this class
have been isolated and characterized, among which 13a-H
members represented by antofine (1a) and 14-hydroxyanto-
fine (1b) have been widely investigated both in synthetic
strategies and in their biological activities (Figure 1). In
1984, two structurally unique 13a-methylphenanthro-
indolizidine alkaloids hypoestestatin 1 (2a) and hypoestes-
tatin 2 (2b) were reported by Pettit et al.[2] Meanwhile, they
reported that both hypoestestatins exhibited very impressive
cytotoxicity against murine P-388 cell line [ED50 (50% ef-
fective dose) values were as low as 10–5 μg/mL;]. Bhutani et
al. reported another two 13a-methylphenanthroindolizid-
ines, namely, 13a-methyltylohirsutine (3a) and 13a-meth-
yltylohirsutinidine (3b), in the same year.[3] Some other ana-
logues (3c and 4) and seco-analogues were also sub-
sequently isolated.[4]
Figure 1. Representative structures of phenanthroindolizidine
alkaloids.
Although a number of synthetic routes to phenanthro-
indolizidine alkaloids have been published in recent years,[5]
the synthesis of 13a-methyl members has rarely been re-
ported and, thus, their bioactivities are widely unexamined.
One of the major challenges is the installation (especially in
an enantioselective manner) of the angular methyl group.
In 2007, the first total synthesis of racemic 13a-methylphen-
anthroindolizidine was reported by Ishibashi et al., in which
cascade radical cyclization was used as the key step.[6] Re-
cently, we reported an enantioselective total synthesis of
13a-methyl phenanthroindolizidine, which uses Seebach’s
self-regeneration of stereochemistry (SRS) approach as the
key step, and reached the conclusion that the structure of
hypoestestatin 1 (2a) had been misassigned.[7] As a part of
[a] State Key Laboratory of Elemento-Organic Chemistry,
Research Institute of Elemento-Organic Chemistry, Nankai
University,
Tianjin 300071, People’s Republic of China
Fax: +86-22-23503952
E-mail: wangqm@nankai.edu.cn
wang98h@263.net
Homepage: http://skleoc.nankai.edu.cn/professors/wangqm/
index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201472.
Eur. J. Org. Chem. 2013, 1979–1985
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1979

B. Su, M. Deng, Q. Wang
FULL PAPER
our ongoing research into the synthesis and biological ily prepared by an intramolecular Friedel–Crafts reaction;
evaluation of phenanthroindolizidine alkaloids,[1d,5a,5e,8] we however, owing to the presence of the nitrogen atom, such
herein report the first enantioselective and general ap- an apparently easy transformation proved to be very inef-
proach to the widely unexplored 14-hydroxy-13a-meth- ficient.[11] Thus, the construction of ketone 5 was planned
ylphenanthroindolizidine alkaloids.
by a Parham-type cycloacylation and the methyl group in
ketone 5 was envisioned to be introduced enantioselectively
by Seebach’s SRS strategy from optical proline. The Par-
ham cycloacylation precursor 9 could be derived from read-
ily prepared phenanthryl alcohol 6 and commercially avail-
able l-proline 7 and methyl iodide.
Results and Discussion
Seebach’s concept of “self-regeneration of stereochemis-
try (SRS)”,[9] a strategy for the stereoselective alkylation of
amino acids was employed in our synthetic program, which
provided another opportunity to showcase its powerful ap-
plication in the total synthesis of natural products.[10] In
addition, a very substrate-dependent Parham-type cyclo-
acylation with an ester group as internal electrophile was
also performed highly efficiently in our synthesis.
Retrosynthetically, hypoestestatin 2 (2b) could be derived
from ketone 5 by stereoselective reduction, thus both 14-
hydroxy isomers could be obtained from the same interme-
diate (Scheme 1). It seems to be that ketone 5 could be read-
The synthesis of the key intermediate 9 commenced with
the known phenanthryl alcohol 6 (Scheme 2).[12] After
treatment of 6 with bromine in dichloromethane (DCM),
dibromide 8 was obtained in excellent yield.[13] The enantio-
pure proline derivative 12 was prepared from l-proline in
three steps by Seebach’s SRS strategy.[14] The modified ox-
azolidinone 10 was obtained through condensation of l-
proline and chloral hydrate as a white crystalline solid,
which makes its manipulation and storage very convenient.
After consequent stereoselective methylation and meth-
anolysis, enantiopure 12 could be obtained in 10 gram scale.
It is worth mentioning that the seemingly easy coupling of
compound 12 and dibromide 8 proved to be a weighty
problem, because compound 12 is very hygroscopic and the
dibromide 8 is sensitive to moisture. After extensive screen-
ing of bases [such as Et3N, iPr2NEt, diazabicycloundecene
(DBU), K2CO3, Na2CO3, AcONa, Na2SO3, LiOH, and ba-
sic Al2O3], solvents [dichloromethane, tetrahydrofuran
(THF), N,N-dimethylformamide (DMF) and mixtures of
them], and reaction temperature, the coupling reaction
proceeded smoothly under the optimal reaction con-
ditions [K2CO3 (5 equiv.), dichloromethane/DMF (1:1), re-
flux].
With the key intermediate 9 in hand, we were set for the
Parham-type cycloacylation (Scheme 3). Notably, although
a great many Parham cycloacylation reactions have been
documented, most of the internal electrophiles were ac-
ids,[15] amides,[16] Weinreb amides,[17] carboxamides, and
carbamates,[18] presumably as a consequence of the com-
Scheme 1. Retrosynthetic analysis of the proposed structure of hy-
poestestatin 2 (2b).
Scheme 2. Synthesis of the key intermediate 9.
1980
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1979–1985

13a-Methyl-14-hydroxyphenanthroindolizidine Alkaloids
Scheme 3. Completion of the synthesis of the proposed hypoestestatin 2.
plex-induced proximity effect (CIPE).[19] The use of an in- acid during the isolation process). With incremental
ternal ester group as the electrophile for a Parham cyclo- amounts of trifluoroacetic acid added to the synthetic sam-
acylation has rarely been reported and is less efficient,[20] ple of 2b, the signal of the angular methyl group shifted
mainly because of the instability of the intermediate gener- from δ = 1.09 to 1.88 ppm; however, the chemical shifts of
ated from acylation of the aryllithium and the possibility the aromatic protons also do not match the reported data.
of competitive deprotonation with metal–halogen exchange. By using a similar strategy, ent-2b {[α]2D0 = –60.4 (c = 0.55,
Fortunately, such a Parham cycloacylation in substrate 9 CH2Cl2)} and ent-2c {[α]2D0 = –82.0 (c = 0.56, CH2Cl2)}
worked very well even in gram scale after simple optimiza- were also synthesized from d-proline and phenanthryl
tion of the reaction conditions. The stereoselective re- alcohol 6 and its optical rotation had the same sign, which
duction of ketone 5 was examined with a variety of hydride indicated that the sign of the specific rotation was deter-
reagents. It was found that superhydride (LiEt3BH) as the mined by the absolute configuration of C-13a. Therefore,
reducing agent gave the best selectivity (2b/2c 8:2), LiAlH4 the absolute configuration of the proposed hypoestestatin 2
gave roughly the opposite selectivity, and NaBH4 and bulky might also be wrong if the original proposed skeleton of
hydride agents such as DIBAL-H and l-selectride gave no hypoestestatin 2 was correct.
reaction. As the diastereomers could be easily separated by
Based on the distributions of the methoxy groups of the
column chromatography, the selective reduction was not over 60 known phenanthroindolizidine alkaloids and Pet-
further optimized.
tit’s original elucidation,[2] we speculated that the 3,6,7-tri-
Unfortunately, the 1H NMR spectra (in CD3OD and methoxy arrangement is correct. By using alcohol 13 as
CDCl3) of the synthetic 2b {[α]2D0 = +65.5 (c = 0.58, starting material, another two analogues 17 and 18 were
CH2Cl2)} and 2c {[α]D20 = +82.1 (c = 0.56, CH2Cl2)} differ synthesized through the same strategy (Scheme 4). Notably,
significantly from that of natural hypoestestatin 2 {[α]D31
=
in addition to dibromide 14, about 30% tribromide was also
–80.0 (c = 0.53, CH2Cl2)}, and they have optical rotations produced and they were inseparable. Without separation,
1
opposite in sign.[2] In the H NMR spectrum (in CD3OD) the mixture was coupled with proline derivative ent-12 and
of a synthetic sample of 2b, the signal of the angular methyl then treated with 3 equiv. tBuLi; ketone 16 was obtained as
group appeared as singlet at δ = 1.09 ppm, whereas the cor- a single product in 43% yield from alcohol 13. Disappoint-
responding signal reported for hypoestestatin 2 appeared at ingly, although great synthetic effort was taken, the NMR
δ = 1.25 ppm. We speculated that the lower-field shift of the spectra of both 17 and 18 also did not match with those
1
isolated product is a result of the formation of the ammo- of hypoestestatin 2 (Table 1, NMR spectroscopic data of
nium salt (e.g., formed with trace amounts of hydrochloric isolated product and synthetic samples).
Scheme 4. Synthesis of 3,6,7-trimethoxy analogues.
Eur. J. Org. Chem. 2013, 1979–1985
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1981

B. Su, M. Deng, Q. Wang
FULL PAPER
Table 1. 1H NMR spectroscopic data (in CD3OD) of hypoestestatin
2 and synthetic structures.
1.88 (m, 1 H, 5-H), 1.82–1.68 (m, 1 H, 5-H) ppm. HRMS (ESI)
calcd. for C7H8Cl3NO2Na [M + Na]+ 265.9518, found 265.9518;
[α]2D5 = +33.4 (c = 2, C6H6; ref.[14] +34.2, c = 2, C6H6; ref.[21] +33,
c = 2, C6H6).
Hypo-
1H NMR: δ = 7.95 (2 H), 7.58 (1 H), 7.11 (1 H, d,
estestatin 2 J = 7.5 Hz), 7.09 (1 H, d, J = 7.5 Hz), 4.06 (3 H, s,
OMe), 4.01 (6 H, s, 2ϫ OMe), 1.25 (3 H, s, 13a-
Me) ppm. 13C NMR data was not given.
(3R,7aS)-7a-Methyl-3-(trichloromethyl)tetrahydropyrrolo[1,2-c]-
oxazol-1(3H)-one (11): To a solution of diisopropylamine (13.5 mL,
96 mmol) in THF (100 mL) was added nBuLi (42 mL, 2.4 m,
100.8 mmol) dropwise at –78 °C under an atmosphere of nitrogen.
Ten minutes later, the freshly prepared lithium diisopropylamide
(LDA) was transferred to a solution of oxazolidinone 10 (18 g,
80 mmol) in THF (300 mL) over 30 min at –78 °C, and the solution
slowly turned brown. After 90 min, MeI (5.9 mL, 115.2 mmol) was
added dropwise, and the reaction mixture was stirred at the same
temperature for one hour and then slowly warmed to room tem-
perature over 3 h. The reaction was quenched with aqueous satu-
rated ammonium chloride (100 mL). After separation, the aqueous
phase was extracted with ethyl acetate (3ϫ 50 mL), and the com-
bined extracts were evaporated under reduced pressure to give a
yellow oily liquid, which was dissolved in dichloromethane
(200 mL). The solution was washed with water (2ϫ 50 mL), dilute
hydrochloric acid (2ϫ 50 mL), and brine (2ϫ 50 mL), dried with
magnesium sulfate, filtered, and then evaporated in vacuo. The resi-
due was purified by flash column chromatography to give com-
pound 11 (14.3 g, 75%) as a colorless to light yellow solid, m.p.
58–59 °C (ref.[14] 55–57 °C). 1H NMR (400 MHz, CDCl3): δ = 4.99
2b
2c
17
18
1H NMR: δ = 8.10 (s, 1 H), 8.03 (s, 1 H), 8.00 (d,
J = 2.4 Hz, 1 H), 7.87 (d, J = 9.1 Hz, 1 H), 7.23
(dd, J = 9.0, 2.4 Hz, 1 H), 4.07 (s, 3 H), 4.03 (s, 3
H), 4.02 (s, 3 H), 1.09 (s, 3 H) ppm.
1H NMR: δ = 8.05 (s, 1 H), 7.95 (d, J = 2. 1 Hz,
1 H), 7.79 (s, 1 H), 7.40 (d, J = 9.0 Hz, 1 H), 7.02
(dd, J = 9.0, 2.1 Hz, 1 H), 4.86 (s, 1 H), 4.11 (s, 3
H), 4.07 (s, 3 H), 4.04 (s, 3 H), 0.82 (s, 3 H) ppm.
1H NMR: δ = 8.50 (d, J = 9.2 Hz, 1 H), 8.03 (s, 1
H), 7.97 (d, J = 2.3 Hz, 1 H), 7.26 (s, 1 H), 7.20
(dd, J = 9.2, 2.4 Hz, 1 H), 4.06 (s, 3 H), 4.01 (s, 6
H), 1.10 (s, 3 H) ppm.
1H NMR: δ = 8.10 (d, J = 9.2 Hz, 1 H), 7.73 (d,
J = 2.4 Hz, 1 H), 7.60 (s, 1 H), 7.08 (dd, J = 9.1,
2.4 Hz, 1 H), 6.06 (s, 1 H), 4.55 (s, 1 H), 3.87 (s, 3
H), 3.84 (s, 3 H), 3.59 (s, 3 H), 0.46 (s, 3 H) ppm.
Conclusions
In conclusion, the first enantioselective approach to 14-
hydroxy-13a-methylphenanthroindolizidine alkaloids was (s, 1 H, 7a-H), 3.44–3.34 (m, 1 H, 4-H), 3.28–3.15 (m, 1 H, 4-H),
2.27–2.18 (m, 1 H, 6-H), 2.03–1.92 (m, 1 H, 6-H), 1.92–1.73 (m, 2
H, 5-H), 1.53 (s, 3 H, Me) ppm.
achieved in six linear steps in 30% overall yield. The route
is protecting-group free, practical, and adaptable to all of
the stereoisomers, which is of importance for biological and
pharmaceutical studies. In addition, a detailed study of the
possible structure of hypoestestatin 2 was also conducted.
Methyl (S)-2-Methylpyrrolidine-2-carboxylate Hydrochloride (12):
To a solution of 11 (11.9 g, 50 mmol) in anhydrous methanol
(150 mL) at 0 °C under an atmosphere of nitrogen was added thio-
nyl chloride (8.7 mL, 120 mmol) dropwise. The reaction mixture
was stirred at the same temperature for 30 min, at room tempera-
ture for an additional 30 min, and then heated at reflux for 4 h.
The volatiles were removed under reduced pressure, and the residue
was suspended in anhydrous toluene (40 mL) and then concen-
trated to remove traces of thionyl chloride. Trituration with anhy-
drous diethyl ether yielded a brown solid. The yellow diethyl ether
was decanted, and the solid was washed with anhydrous diethyl
ether (3ϫ 30 mL). Trace amounts of diethyl ether were removed in
vacuo to give compound 12 (8.8 g, 98%) as a pale brown solid,
which was used without further purification, m.p. 142–144 °C
(ref.[22] 133–135 °C). 1H NMR (400 MHz, CDCl3): δ = 10.48 (br.
s, 1 H, NH2), 9.53 (br. s, 1 H, NH2), 3.86 (s, 3 H, OMe), 3.62 (br.
s, 2 H, 5-H), 2.54–2.31 (m, 1 H, 3-H), 2.22–1.98 (m, 3 H, 3-H, 4-
H), 1.86 (s, 3 H, Me) ppm. 13C NMR (100 MHz, CDCl3): δ =
171.1, 68.8, 53.7, 45.3, 35.9, 22.6, 21.3 ppm.
Experimental Section
General: Melting points were determined with an X-4 binocular
microscope melting-point apparatus (Beijing Tech Instruments Co,
Beijing, China). Chemical shifts (δ) are given in parts per million
(ppm) and were measured downfield from internal tetramethylsil-
ane. High-resolution mass spectra were obtained with an FT-ICR
MS spectrometer (Ionspec, 7.0 T). Optical rotations were measured
with an Autopol IV auto digital polarimeter (Rudolph Research
Analytical). All anhydrous solvents were dried and purified by
standard techniques before use. All reagents were purchased from
commercial suppliers without further purification. Reactions were
monitored by TLC on plates (GF254) supplied by Yantai Chemi-
cals (China) with UV light as visualizing agent. If not specially
mentioned, flash column chromatography was performed with sil-
ica gel (200–300 mesh) supplied by Tsingtao Haiyang Chemicals
(China).
10-Bromo-9-(bromomethyl)-2,3,6-trimethoxyphenanthrene (8): To a
suspension of compound 6 (7.4 g, 24.8 mmol) in dichloromethane
(500 mL) was added bromine [1.42 mL, 27.3 mmol, in dichloro-
methane (50 mL)] dropwise at room temperature. Three hours later,
the reaction mixture was evaporated at reduced pressure, and the
residue was purified by column chromatography [petroleum ether
(PE)/DCM, 1:3] to give compound 8 (9.3 g, 85%) as a pale solid,
m.p. 184–186 °C (ref.[13c] 180–186 °C). 1H NMR (400 MHz,
CDCl3): δ = 8.07 (d, J = 9.1 Hz, 1 H, Ar-H), 7.80 (d, J = 2.4 Hz,
1 H, Ar-H), 7.78 (s, 2 H, Ar-H), 7.27 (dd, J = 9.1, 2.3 Hz, 1 H,
Ar-H), 5.33 (s, 2 H, 9-H), 4.10 (s, 3 H, OMe), 4.08 (s, 3 H, OMe),
4.01 (s, 3 H, OMe) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.4,
150.1, 150.1, 130.9, 129.4, 126.5, 125.8, 125.6, 124.1, 123.0, 116.0,
109.6, 104.9, 103.2, 56.1, 56.0, 55.6, 45.0 ppm.
(3R,7aS)-3-(Trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-
one (10):[14] To a suspension of l-proline 7 (11.5 g, 100 mmol) in
chloroform (500 mL) was added 2,2,2-trichloroethane-1,1-diol
(chloral hydrate, 26.5 g, 120 mmol). A 25-mL Dean–Stark trap
topped with a reflux condenser was attached to the reaction vessel,
and the reaction mixture was heated at reflux until l-proline was
no longer visibly suspended. The reaction mixture was evaporated
under reduced pressure, and the resulting brown crystalline solid
was recrystallized from ethanol to give 10 (18.6 g, 83%) as colorless
to light brown crystals, m.p. 110–111 °C (ref.[14] 107–109 °C). 1H
NMR (400 MHz, CDCl3): δ = 5.17 (s, 1 H, 7a-H) 4.12 (dd, J =
8.8, 4.6 Hz, 1 H, 3-H), 3.48–3.38 (m, 1 H, 4-H), 3.18–3.08 (m, 1 Methyl (S)-[(10-Bromo-2,3,6-trimethoxyphenanthren-9-yl)methyl]-2-
H, 4-H), 2.29–2.17 (m, 1 H, 6-H), 2.16–2.08 (m, 1 H, 6-H), 2.00– methylpyrrolidine-2-carboxylate (9): To a suspension of 8 (5.3 g,
1982
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1979–1985

13a-Methyl-14-hydroxyphenanthroindolizidine Alkaloids
12 mmol) and potassium carbonate (8.3 g, 60 mmol) in a mixture
of dichloromethane and dimethylformamide (1:1, 200 mL) was
added 12 (2.58 g, 14.4 mmol). The reaction mixture was heated at
reflux for 10 h. The mixture was cooled to room temperature, the
volatiles were evaporated at reduced pressure, and the residue was
dissolved in dichloromethane (200 mL) and then washed with water
(3ϫ 100 mL) and brine (100 mL). The organic phase was dried
with magnesium sulfate, filtered, and then evaporated in vacuo. Af-
ter concentration, the crude product was purified by column
chromatography (PE/DCM, 2:1, PE/DCM, 1:3) to give compound
9 (4.87 g, 81 %) as a white solid, m.p. 150–152 °C. 1H NMR
H, 11-H), 2.99–2.90 (m, 1 H, 11-H), 2.17–1.90 (m, 4 H, 12-H, 13-
H), 1.09 (s, 3 H, Me) ppm. 13C NMR (100 MHz, CD3OD): δ =
159.8, 150.1, 149.8, 132.3, 129.2, 128.9, 128.0, 126.2, 125.9, 124.7,
116.8, 109.0, 105.3, 105.2, 75.2, 64.7, 56.5, 56.3, 56.0, 51.9, 48.8,
39.5, 21.5, 12.3 ppm. HRMS (MALDI) calcd. for C24H28NO4 [M
+ H]+ 394.2018, found 394.2015; [α]2D0 = +65.5 (c = 0.58, CH2Cl2).
Compound 2c was obtained as a light yellow solid, m.p. 130–
133 °C. 1H NMR (400 MHz, CD3OD): δ = 8.05 (s, 1 H, Ar-H),
7.95 (d, J = 2. 1 Hz, 1 H, Ar-H), 7.79 (s, 1 H, Ar-H), 7.40 (d, J =
9.0 Hz, 1 H, Ar-H), 7.02 (dd, J = 9.0, 2.1 Hz, 1 H, Ar-H), 4.86 (s,
1 H, 14-H), 4.11 (s, 3 H, OMe), 4.07 (s, 3 H, OMe), 4.04 (s, 3 H,
(400 MHz, CDCl3): δ = 8.49 (d, J = 9.2 Hz, 1 H, Ar-H), 7.89 (s, 1 OMe), 3.83 (d, J = 16.0 Hz, 1 H, 9-H), 3.60 (d, J = 16.0 Hz, 1 H,
H, Ar-H), 7.87 (s, 1 H, Ar-H), 7.83 (s, 1 H, Ar-H), 7.21 (d, J = 9-H), 3.22–3.14 (m, 1 H, 11-H), 2.69 (dd, J = 17.2, 8.8 Hz, 1 H,
9.2 Hz, 1 H, Ar-H), 4.50 (t, J = 14.0 Hz, 2 H, benzyl-CH2), 4.12 11-H), 2.61 (dd, J = 17.2, 8.8 Hz, 1 H, 13-H), 2.07–1.95 (m, 2 H,
(s, 3 H, OMe), 4.09 (s, 3 H, OMe), 4.02 (s, 3 H, OMe), 3.84 (s, 3
H, OMe), 3.01–2.92 (m, 1 H, 5-H), 2.72–2.66 (m, 1 H, 5-H), 2.34–
12-H, 13-H), 1.73–1.64 (m, 1 H, 12-H), 0.82 (s, 3 H, Me) ppm. 13
NMR (100 MHz, CD3OD): δ = 159.8, 151.0, 150.1, 132.3, 128.6,
C
2.22 (m, 1 H, 3-H), 1.82–1.53 (m, 3 H, 3-H, 4-H), 1.61 (s, 3 H, Me) 127.9, 127.6, 125.9, 125.6, 124.2, 116.7, 106.7, 105.4, 105.2, 70.4,
ppm. 13C NMR (100 MHz, CDCl3): δ = 175.9, 158.1, 149.8, 149.4,
131.4, 130.7, 128.2, 126.2, 126.1, 125.1, 122.6, 115.1, 109.9, 104.2,
103.3, 67.6, 56.1, 56.0, 55.5, 51.5, 50.6, 49.8, 38.0, 21.5, 21.0 ppm.
HRMS (ESI) calcd. for C25H29BrNO5 [M + H]+ 502.1229, found
502.1223; [α]2D0 = +42.7 (c = 1.03, CHCl3).
64.1, 56.6, 56.4, 55.9, 51.9, 48.9, 32.8, 21.1, 13.8 ppm. HRMS
(MALDI) calcd. for C24H28NO4 [M + H]+ 394.2018, found
394.2019; [α]2D0 = +82.1 (c = 0.56, CH2Cl2).
Methyl (R)-1-[(10-Bromo-2,3,6-trimethoxyphenanthren-9-yl)meth-
yl]-2-methylpyrrolidine-2-carboxylate (ent-9): By using a similar
synthetic procedure as that for 9, ent-9 (80%) was obtained as a
(S)-2,3,6-Trimethoxy-13a-methyl-11,12,13,13a-tetrahydrodibenzo-
[f,h]pyrrolo[1,2-b]isoquinolin-14(9H)-one (5): To a solution of 9
(1.83 g, 3.6 mmol) in anhydrous THF (150 mL) was added tBuLi
(5.0 mL, 1.6 m, 7.9 mmol) dropwise at –78 °C under an atmosphere
of nitrogen. The reaction mixture was stirred at the same tempera-
ture for 1.5 h and then quenched with aqueous ammonium chloride
(50 mL). After separation, the aqueous phase was extracted with
ethyl acetate (3ϫ 100 mL). The organic extracts were evaporated
under reduced pressure, and the residue was dissolved in dichloro-
methane (100 mL). The solution was then washed with water (3ϫ
100 mL) and brine (100 mL), dried with magnesium sulfate, and
filtered. After concentration, the crude product was purified by col-
umn chromatography [PE/ethyl acetate(EA), 1:1, DCM/methanol,
30:1] to give compound 5 (0.99 g, 70%) as a yellow solid, m.p. 150–
152 °C. 1H NMR (400 MHz, CDCl3): δ = 9.10 (s, 1 H, Ar-H), 7.99
(d, J = 9.2 Hz, 1 H, Ar-H), 7.87 (d, J = 2.4 Hz, 1 H, Ar-H), 7.87
(s, 1 H, Ar-H), 7.25 (dd, J = 9.2, 2.4 Hz, 1 H, Ar-H), 4.71 (s, 2 H,
9-H), 4.11 (s, 3 H, OMe), 4.10 (s, 3 H, OMe), 4.05 (s, 3 H, OMe),
3.23–3.16 (m, 1 H, 11-H), 3.09–3.01 (m, 1 H, 11-H), 2.72–2.65 (m,
1 H, 13-H), 1.95–1.76 (m, 3 H, 12-H, 13-H), 1.41 (s, 3 H, Me) ppm.
13C NMR (100 MHz, CDCl3): δ = 202.7, 160.4, 150.3, 148.7, 137.9,
134.4, 126.8, 124.6, 124.5, 122.4, 120.7, 115.8, 108.1, 104.6, 103.1,
68.2, 55.9, 55.9, 55.6, 51.8, 45.6, 35.2, 20.7, 19.5 ppm. HRMS (ESI)
1
pale white solid, m.p. 137–142 °C. H NMR (400 MHz, CDCl3): δ
= 8.47 (d, J = 9.2 Hz, 1 H, Ar-H), 7.87 (s, 1 H, Ar-H), 7.84 (s, 1
H, Ar-H), 7.81 (d, J = 2.5 Hz, 1 H, Ar-H), 7.20 (dd, J = 9.2, 2.5 Hz,
1 H, Ar-H), 4.49 (d, J = 12.4 Hz, 1 H, benzyl-CH2), 4.46 (d, J =
12.4 Hz, 1 H, benzyl-CH2), 4.11 (s, 3 H, OMe), 4.08 (s, 3 H, OMe),
4.01 (s, 3 H, OMe), 3.84 (s, 3 H, COOMe), 3.01–2.90 (m, 1 H, 5-
H), 2.72–2.66 (m, 1 H, 5-H), 2.34–2.22 (m, 1 H, 3-H), 1.82–1.53
(m, 3 H, 3-H, 4-H), 1.62 (s, 3 H, Me) ppm. 13C NMR (100 MHz,
CDCl3): δ = 175.9, 158.0, 149.8, 149.3, 131.3, 130.7, 128.2, 126.2,
126.0, 125.1, 122.5, 115.1, 109.9, 104.2, 103.2, 67.5, 56.1, 56.0, 55.5,
51.5, 50.6, 49.8, 38.0, 21.5, 21.0 ppm. HRMS (ESI) calcd. for
C25H29BrNO5 [M + H]+ 502.1229, found 502.1224; [α]2D0 = –37.5 (c
= 0.64, CHCl3).
(9aS)-3,6,7-Trimethoxy-9a-methyl-9a,10,11,12,12a,13-hexahydro-
9H-cyclopenta[b]triphenylen-9-one (ent-5): By using a similar syn-
thetic procedure as that for 5, ent-5 (65%) was obtained as a light
yellow solid, m.p. 147–150 °C. 1H NMR (400 MHz, CDCl3): δ =
9.10 (s, 1 H, Ar-H), 8.0 (d, J = 9.2 Hz, 1 H, Ar-H), 7.88 (d, J =
2.4 Hz, 1 H, Ar-H), 7.87 (s, 1 H, Ar-H), 7.25 (dd, J = 9.2, 2.4 Hz,
1 H, Ar-H), 4.71 (s, 2 H, 9-H), 4.11 (s, 3 H, OMe), 4.10 (s, 3 H,
OMe), 4.05 (s, 3 H, OMe), 3.23–3.16 (m, 1 H, 11-H), 3.09–3.01 (m,
1 H, 11-H), 2.72–2.65 (m, 1 H, 13-H), 1.95–1.76 (m, 3 H, 12-H,
13-H), 1.41 (s, 3 H, Me) ppm. 13C NMR (100 MHz, CDCl3): δ =
202.7, 160.4, 150.3, 148.6, 138.0, 134.3, 126.8, 124.6, 124.5, 122.4,
120.7, 115.8, 108.1, 104.6, 103.1, 68.1, 55.9, 55.9, 55.6, 51.8, 45.6,
35.2, 20.7, 19.5 ppm. HRMS (ESI) calcd. for C24H26NO4
[M + H]+ 392.1862, found 392.1863; [α]2D0 = –103.8 (c = 0.48,
CHCl3).
calcd. for C24H26NO4 [M + H]+ 392.1862, found 392.1863; [α]2D0
+42.1 (c = 0.56, CHCl3).
=
Proposed Structure of Hypoestestatin 2 (2b): To a solution of 5
(1.02 g, 2.6 mmol) in THF (100 mL) was slowly added lithium tri-
ethylboronhydride (13 mL, 1 m, 13 mmol) at 0 °C under an atmo-
sphere of nitrogen. Two hours later, the reaction mixture was
quenched with aqueous saturated ammonium chloride (20 mL).
After separation, the aqueous phase was extracted with ethyl acet-
ate (3ϫ 60 mL), and the organic extracts were evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy (DCM/MeOH, 30:1, DCM/MeOH, 10:1) to give 2b (0.76 g)
and 2c (0.19 g) in a combined yield of 93%. Compound 2b was
obtained as a light yellow solid, m.p. 120–124 °C. 1H NMR
(400 MHz, CD3OD): δ = 8.10 (s, 1 H, Ar-H), 8.03 (s, 1 H, Ar-H),
8.00 (d, J = 2.4 Hz, 1 H, Ar-H), 7.87 (d, J = 9.1 Hz, 1 H, Ar-H),
ent-2b and ent-2c were obtained (combined yield: 96%) by using a
similar synthetic procedure as that for 2b and 2c. ent-2b: M.p. 132–
137 °C. 1H NMR (400 MHz, CD3OD): δ = 8.09 (s, 1 H, Ar-H),
8.03 (s, 1 H, Ar-H), 8.00 (d, J = 2.4 Hz, 1 H, Ar-H), 7.87 (d, J =
9.0 Hz, 1 H, Ar-H), 7.23 (dd, J = 9.0, 2.4 Hz, 1 H, Ar-H), 5.21 (s,
1 H, 14-H), 4.30 (d, J = 16.0 Hz, 1 H, 9-H), 4.10 (d, J = 16.0 Hz,
1 H, 9-H), 4.07 (s, 3 H, OMe), 4.02 (s, 6 H, 2ϫ OMe), 3.19–3.09
(m, 1 H, 11-H), 2.99–2.90 (m, 1 H, 11-H), 2.17–1.90 (m, 4 H, 12-
7.23 (dd, J = 9.0, 2.4 Hz, 1 H, Ar-H), 5.21 (s, 1 H, 14-H), 4.29 (d, H, 13-H), 1.09 (s, 3 H, Me) ppm. 13C NMR (100 MHz, CD3OD):
J = 16.0 Hz, 1 H, 9-H), 4.10 (d, J = 16.0 Hz, 1 H, 9-H), 4.07 (s, 3 δ = 159.8, 150.1, 149.8, 132.4, 129.1, 128.8, 128.0, 126.2, 125.9,
H, OMe), 4.03 (s, 3 H, OMe), 4.02 (s, 3 H, OMe), 3.19–3.09 (m, 1 124.7, 116.9, 109.0, 105.2, 105.2, 75.2, 64.7, 56.5, 56.3, 56.0, 51.9,
Eur. J. Org. Chem. 2013, 1979–1985
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1983

B. Su, M. Deng, Q. Wang
FULL PAPER
48.8, 39.5, 21.5, 12.2 ppm. HRMS (MALDI) calcd. for C24H28NO4 2c, 8–11 and 16–18, DEPT 135 spectroscopic data for 2c, ent-2b,
[M + H]+ 394.2018, found 394.2014; [α]2D0 = –60.36 (c = 0.55,
CH2Cl2). ent-2c: M.p. 127–131 °C. H NMR (400 MHz, CD3OD):
ent-2c, 17 and 18, and NOE data for 2c.
1
δ = 8.05 (s, 1 H, Ar-H), 7.95 (d, J = 2.1 Hz, 1 H, Ar-H), 7.80 (s, 1
H, Ar-H), 7.39 (d, J = 9.0 Hz, 1 H, Ar-H), 7.02 (dd, J = 9.0, 2.1 Hz,
1 H, Ar-H), 4.86 (s, 1 H, 14-H), 4.12 (s, 3 H, OMe), 4.08 (s, 3 H,
OMe), 4.05 (s, 3 H, OMe), 3.80 (d, J = 16.0 Hz, 1 H, 9-H), 3.59
(d, J = 16.0 Hz, 1 H, 9-H), 3.22–3.14 (m, 1 H, 11-H), 2.69 (dd, J
= 17.2, 8.8 Hz, 1 H, 11-H), 2.62 (dd, J = 17.2, 8.8 Hz, 1 H, 13-H),
2.08–1.96 (m, 2 H, 12-H, 13-H), 1.73–1.65 (m, 1 H, 12-H), 0.82 (s,
3 H, Me) ppm. 13C NMR (100 MHz, CD3OD): δ = 159.7, 151.0,
150.1, 132.2, 128.6, 127.8, 127.5, 125.8, 125.5, 124.2, 116.6, 106.6,
105.3, 105.1, 70.4, 64.1, 56.6, 56.4, 55.9, 51.9, 48.8, 32.8, 21.0, 13.7
ppm. HRMS (MALDI) calcd. for C24H28NO4 [M + H]+ 394.2018,
found 394.2018; [α]2D0 = –82.0 (c = 0.56, CH2Cl2).
Acknowledgments
The authors are grateful to the National Key Project for Basic Re-
search (granz number 2010CB126106), the National Natural Sci-
ence Foundation of China (NSFC) (grant numbers 21132003,
21121002), the Tianjin Natural Science Foundation (grant
11JCZDJC20500), and the National Key Technology Research and
Development Program (grant 2011BAE06B05) for generous finan-
cial support for our programs. The authors thank China Agricul-
tural University for supplying some of the chemical reagents and
the National Key Technology Research and Development Program
(grant 2012BAK25B03-3).
(S)-3,6,7-Trimethoxy-13a-methyl-11,12,13,13a-tetrahydrodibenzo-
[f,h]pyrrolo[1,2-b]isoquinolin-14(9H)-one (16): Compound 15 was
prepared by a similar procedure as that for compound 9 from the
known compound 13.[13c] A solution of 15 (1.02 g, 2 mmol) was
treated with excess tBuLi (3 equiv.), and ketone 16 was obtained as
a single isolated product in good yield (43% based on 13) after
column chromatographic purification. Yellow solid; m.p. 141–
147 °C. 1H NMR (400 MHz, CDCl3): δ = 9.35 (d, J = 9.4 Hz, 1
H, Ar-H), 7.93 (s, 1 H, Ar-H), 7.90 (d, J = 2.3 Hz, 1 H, Ar-H),
7.32 (s, 1 H, Ar-H), 7.29 (s, 1 H, Ar-H), 4.69 (d, J = 17.8 Hz, 1 H,
9-H), 4.61 (d, J = 17.8 Hz, 1 H, 9-H), 4.16 (s, 3 H, OMe), 4.10 (s,
3 H, OMe), 4.04 (s, 3 H, OMe), 3.25–3.18 (m, 1 H, 11-H), 3.10–
3.02 (m, 1 H, 11-H), 2.76–2.64 (m, 1 H, 13-H), 2.01–1.77 (m, 3 H,
12-H, 13-H), 1.42 (s, 3 H, Me) ppm. 13C NMR (100 MHz, CDCl3):
δ = 202.1, 157.9, 151.2, 149.7, 136.1, 131.2, 129.4, 127.7, 123.8,
122.8, 122.5, 115.6, 104.7, 104.6, 103.9, 68.0, 56.1, 56.0, 55.5, 52.0,
45.8, 35.2, 20.8, 19.4 ppm. HRMS (ESI) calcd. for C24H26NO4 [M
+ H]+ 392.1862, found 392.1862; [α]2D7 = –100.3 (c = 0.76, CHCl3).
[1] For recent selected examples, see: a) W. Gao, A. P. C. Chen,
C. H. Leung, E. A. Gullen, A. Fürstner, Q. Shi, L. Wei, K. H.
Lee, Y. C. Cheng, Bioorg. Med. Chem. Lett. 2008, 18, 704–709;
b) L. Wei, Q. Shi, K. F. Bastow, A. Brossi, S. L. Morris-
Natschke, K. Nakagawa-Goto, T. S. Wu, S. L. Pan, C. M.
Teng, K. H. Lee, J. Med. Chem. 2007, 50, 3674–3680; c) W.
Gao, S. Bussom, S. P. Grill, E. A. Gullen, Y. C. Hu, X. Huang,
S. Zhong, C. Kaczmarek, J. Gutierrez, S. Francis, D. C. Baker,
S. Yu, Y. C. Cheng, Bioorg. Med. Chem. Lett. 2007, 17, 4338–
4342; d) K. Wang, B. Su, Z. Wang, M. Wu, Z. Li, Y. Hu, Z.
Fan, N. Mi, Q. Wang, J. Agric. Food Chem. 2010, 58, 2703–
2709; e) S. R. Chemler, Curr. Bioact. Compd. 2009, 5, 2–19; f)
H. Y. Min, H. J. Chung, E. H. Kim, S. Kim, E. J. Park, S. K.
Lee, Biochem. Pharmacol. 2010, 80, 1356–1364; g) C. W. Yang,
Z. Y. Lee, I. J. Kang, D. L. Barnard, J. T. Jan, D. Lin, C. W.
Huang, T. K. Yeh, Y. S. Chao, S. J. Lee, Antiviral Res. 2010, 88,
160–168; h) T. Ikeda, T. Yaegashi, T. Matsuzaki, S. Hashimoto,
S. Sawada, Bioorg. Med. Chem. Lett. 2011, 21, 342–345; i) A.
Boto, J. Miguelez, R. Marin, M. Diaz, Bioorg. Med. Chem.
Lett. 2012, 22, 3402–3407.
Compounds 17 and 18 were obtained (combined yield: 92%) by
using a similar procedure as that for compounds 2b and 2c.
[2] G. R. Pettit, A. Goswami, G. M. Cragg, J. M. Schmit, J. C.
Zou, J. Nat. Prod. 1984, 47, 913–919.
Compound 17: Light yellow solid; m.p. 113–117 °C. 1H NMR
(400 MHz, CD3OD): δ = 8.50 (d, J = 9.2 Hz, 1 H, Ar-H), 8.03 (s,
1 H, Ar-H), 7.97 (d, J = 2.3 Hz, 1 H, Ar-H), 7.26 (s, 1 H, Ar-H),
7.20 (dd, J = 9.2, 2.4 Hz, 1 H, Ar-H), 5.24 (s, 1 H, 14-H), 4.24 (d,
J = 16.0 Hz, 1 H, 9-H), 4.09 (d, J = 16.0 Hz, 1 H, 9-H), 4.06 (s, 3
H, OMe), 4.01 (s, 6 H, 2ϫ OMe), 3.18–3.07 (m, 1 H, 11-H), 3.02–
2.92 (m, 1 H, 11-H), 2.14–1.91 (m, 4 H, 12-H, 13-H), 1.10 (s, 3 H,
Me) ppm. 13C NMR (100 MHz, CD3OD): δ = 159.2, 151.1, 150.5,
132.9, 130.7, 129.3, 127.5, 126.3, 126.3, 125.7, 116.0, 105.5, 105.1,
105.0, 74.8, 64.7, 56.6, 56.4, 55.9, 52.0, 48.8, 39.5, 21.6, 12.6 ppm.
HRMS (MALDI) calcd. for C24H28NO4 [M + H]+ 394.2018, found
394.2018; [α]2D7 = –102.7 (c = 0.67, CH3Cl).
Compound 18: Yellow solid; m.p. 123–126 °C. 1H NMR (400 MHz,
CD3OD): δ = 8.10 (d, J = 9.2 Hz, 1 H, Ar-H), 7.73 (d, J = 2.4 Hz,
1 H, Ar-H), 7.60 (s, 1 H, Ar-H), 7.08 (dd, J = 9.1, 2.4 Hz, 1 H,
Ar-H), 6.06 (s, 1 H, Ar-H), 4.55 (s, 1 H, 14-H), 3.87 (s, 3 H, OMe),
3.84 (s, 3 H, OMe), 3.59 (s, 3 H, OMe), 3.01 (d, J = 16.0 Hz, 1 H,
9-H), 2.92–2.79 (m, 1 H, 11-H), 2.83 (d, J = 16.0 Hz, 1 H, 9-H),
2.40 (dd, J = 16.8, 9.4 Hz, 1 H, 11-H), 2.29 (dd, J = 16.8, 9.4 Hz,
1 H, 13-H), 1.87–1.66 (m, 2 H, 12-H, 13-H), 1.45–1.34 (m, 1 H,
12-H), 0.46 (s, 3 H, Me) ppm. 13C NMR (100 MHz, CD3OD): δ =
159.4, 150.3, 150.2, 132.4, 128.2, 127.5, 127.0, 126.8, 125.5, 125.2,
116.5, 105.1, 104.5, 104.1, 70.4, 64.0, 56.3, 56.0, 55.9, 51.9, 48.6,
32.6, 20.8, 13.4 ppm. HRMS (MALDI) calcd. for C24H28NO4 [M
+ H]+ 394.2018, found 394.2036; [α]2D7 = –100.3 (c = 0.76, CH3Cl).
[3] K. K. Bhutani, M. Ali, C. K. Atal, Phytochemistry 1984, 23,
1765–1769.
[4] a) M. Ali, K. K. Bhutani, Phytochemistry 1987, 26, 2089–2092;
b) M. Ali, K. K. Bhutani, Phytochemistry 1989, 28, 3513–3517.
[5] For the most recent examples, see: a) M. B. Cui, Q. M. Wang,
Eur. J. Org. Chem. 2009, 5445–5451; b) L. M. Rossiter, M. L.
Slater, R. E. Giessert, S. A. Sakwa, R. J. Herr, J. Org. Chem.
2009, 74, 9554–9557; c) X. Yang, Q. Shi, K. F. Bastow, K. H.
Lee, Org. Lett. 2010, 12, 1416–1419; d) A. Stoye, T. Opatz, Org.
Lett. 2010, 12, 2140–2141; e) M. B. Cui, H. G. Song, A. Z.
Feng, Z. W. Wang, Q. M. Wang, J. Org. Chem. 2010, 75, 7018–
7021; f) G. I. Georg, M. J. Niphakis, J. Org. Chem. 2010, 75,
6019–6022; g) J. P. Wolfe, D. N. Mai, J. Am. Chem. Soc. 2010,
132, 12157–12159; h) T. H. Lambert, L. M. Ambrosini, T. A.
Gernak, Tetrahedron 2010, 66, 4882–4887; i) D. Dumoulin, S.
Lebrum, A. Couture, E. Deniau, P. Grandclaudon, Eur. J. Org.
Chem. 2010, 1493–1590; j) S. F. Hsu, C. W. Ko, Y. T. Wu, Adv.
Synth. Catal. 2011, 353, 1756–1762; k) G. I. Georg, M. J. Ni-
phakis, Org. Lett. 2011, 13, 196–199.
[6] K. Takeuchi, A. Ishita, J. Matsuo, H. Ishibashi, Tetrahedron
2007, 63, 11101–11107.
[7] B. Su, C. L. Cai, Q. M. Wang, J. Org. Chem. 2012, 77, 7981–
7987.
[8] a) T. Y. An, R. Q. Huang, Z. Yang, D. K. Zhang, G. R. Li,
Y. C . Ya o, J. G a o, Phytochemistry 2001, 58, 1267–1269; b) Z.
Jin, S. P. Li, Q. M. Wang, R. Q. Huang, Chin. Chem. Lett.
2004, 15, 1164–1166; c) K. L. Wang, M. Y. Lv, Q. M. Wang,
R. Q. Huang, Tetrahedron 2008, 64, 7504–7510; d) K. L. Wang,
M. Y. Lv, A. Yu, X. Q. Zhu, Q. M. Wang, J. Org. Chem. 2009,
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectroscopic data for 2b, 2c, ent-2b, ent-
1984
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1979–1985

13a-Methyl-14-hydroxyphenanthroindolizidine Alkaloids
74, 935–938; e) Z. W. Wang, Q. M. Wang, Tetrahedron Lett. [16]
2010, 51, 1377–1379.
a) M. Poirier, F. Chen, C. Bernard, Y. S. Wong, G. G. Wu, Org.
Lett. 2001, 3, 3795–3798; b) A. Ardeo, E. Lete, N. Sotomayor,
Tetrahedron Lett. 2000, 41, 5211–5214; c) M. Villacampa, E.
Cuesta, C. Avendano, Tetrahedron 1995, 51, 1259–1264; d) G. J.
Quallich, D. E. Fox, R. C. Friedman, C. W. Murtiashaw, J. Org.
Chem. 1992, 57, 761–764; e) Z. Wang, Z. Li, K. Wang, Q.
Wang, Eur. J. Org. Chem. 2010, 292–299.
[9] a) D. Seebach, M. Boes, R. Naef, W. B. Schweizer, J. Am.
Chem. Soc. 1983, 105, 5390–5398; b) D. Seebach, A. R. Sting,
M. Hoffmann, Angew. Chem. 1996, 108, 2881–2921; Angew.
Chem. Int. Ed. Engl. 1996, 35, 2708–2748.
[10] a) C. C. Hughes, D. Trauner, Angew. Chem. 2002, 114, 4738–
4741; Angew. Chem. Int. Ed. 2002, 41, 4556–4559; b) G. D. Art-
man, A. W. Gruubs, R. M. Williams, J. Am. Chem. Soc. 2007,
129, 6336–6342; c) H. Bittermann, F. Bockler, J. Einsiedel, P.
Gmeiner, Chem. Eur. J. 2006, 12, 6315–6322; d) F. Frebault,
N. S. Simpkins, A. Fenwick, J. Am. Chem. Soc. 2009, 131,
4214–4215; e) M. Lumini, F. M. Cordero, F. Pisaneschi, A.
Brandi, Eur. J. Org. Chem. 2008, 2817–2824; f) A. Vartak, V. G.
Yong, R. L. Johnson, Org. Lett. 2005, 7, 35–38; g) R. M. Wil-
liams, T. Glinka, E. Kwast, J. Am. Chem. Soc. 1988, 110, 5927–
5929; h) N. Isono, M. Mori, J. Org. Chem. 1995, 60, 115–119.
[11] a) T. R. Govindachari, B. R. Pai, S. Prabhakar, T. S. Savitri,
Tetrahedron 1965, 21, 2573; b) T. R. Marchini, B. Belleau, Can.
J. Chem. 1958, 36, 581.
[12] C. R. Su, A. G. Damu, P. C. Chiang, K. F. Bastow, S. L. Mor-
risNatschke, K. H. Lee, T. S. Wu, Bioorg. Med. Chem. 2008,
16, 6233–6241.
[13] a) R. Olivera, R. SanMartin, E. Domínguez, X. Solans, M. K.
Urtiaga, M. I. Arriortua, J. Org. Chem. 2000, 65, 6398–6411;
b) A. Stoye, T. Opatz, Org. Lett. 2010, 12, 2140–2141; c) Z.
Wang, Z. Li, K. Wang, Q. Wang, Eur. J. Org. Chem. 2010, 292–
299.
[17]
[18]
a) J. Ruiz, N. Sotomayor, E. Lete, Org. Lett. 2003, 5, 1115–
1117; b) I. S. Aidlhen, J. R. Ahuja, Tetrahedron Lett. 1992, 33,
5431–5432; c) Y. Lear, T. Durst, Can. J. Chem. 1997, 75, 817–
824.
a) C. K. Bradsher, D. C. Reames, J. Org. Chem. 1978, 48, 3800–
3802; b) C. Paleo, C. Lamas, L. Castedo, D. Dominguez, J.
Org. Chem. 1992, 57, 2029–2033; c) M. P. Gore, S. J. Gould,
D. D. Weller, J. Org. Chem. 1991, 56, 2289–2291; d) K. Orito,
M. Miyazawa, R. Kanbayashi, T. Tatsuzawa, M. Tokuda, H.
Suginome, J. Org. Chem. 2000, 65, 7495–7500; e) D. L. Comins,
P. M. Thakker, M. F. Baevsky, Tetrahedron 1997, 53, 16327–
16340.
This concept has been invoked to explain the enhancement of
metalation in hydrogen–metal, metal–metal (P. Beak, A. I. Me-
yers, Acc. Chem. Res. 1986, 19, 356–363), or halogen–metal
exchanges (P. Beak, T. Musick, C. Liu, T. Cooper, D. J. Gal-
lagher, J. Org. Chem. 1993, 58, 7330–7335).
[19]
[20] a) S. J. Gould, C. R. Melville, M. C. Cone, J. Chen, J. R. Car-
ney, J. Org. Chem. 1997, 62, 320–324; b) F. Heike, B. Christoph,
W. Birgittam, V. B. Karin, H. Ullrich, R. Kristijan, L. Juergen,
Eur. J. Org. Chem. 2004, 16, 3484–3496.
[21] P. Wang, J. P. Germanas, Synlett 1999, 1, 33–36.
[22] L. B. Jose, G. N. Guillermo, T. Kevin, M. J. P. Vega, I. Lourdes,
G. L. M. Teresa, G. M. Rosario, M. M. Mercedes, J. Org.
Chem. 2009, 74, 8203–8211.
[14] P. W. R. Harris, M. A. Brimble, V. J. Muir, M. Y. H. Lai, N. S.
Trotter, D. J. Callis, Tetrahedron 2005, 61, 10018–10035.
[15] a) D. Tilly, S. S. Samanta, A. De, A. Castanet, J. Mortier, Org.
Lett. 2005, 7, 827–830; b) K. P. Bogeso, J. Med. Chem. 1983,
26, 935–947; c) R. J. Boatman, B. J. Whitlock, H. W. Whitlock,
J. Am. Chem. Soc. 1977, 99, 4822–4824; d) W. E. Parham, L. D.
Jones, Y. Sayed, J. Org. Chem. 1975, 40, 2394–2399.
Received: November 3, 2012
Published Online: February 11, 2013
Eur. J. Org. Chem. 2013, 1979–1985
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1985