Tuned C-H functionalization to construct aza-podophyllotoxin/aza- conidendrin derivatives by means of domino cyclization

Article abstract of DOI:10.1002/asia.200900307

An efficient domino cyclization method for the construction of aza-podophyllotoxin/aza-conidendrin derivatives has been established. Reactions of different dienes with aryl halides in the presence of a palladium catalytic system produced different kinds of podophyllotoxin derivatives through a highly regioselective C-H functionalization. Treatment of dienes with aryl halides that have electron-withdrawing substituents on the phenyl ring created aza-podophyllotoxin derivatives by means of the functionalization of the C-H bonds ortho to the C-Halide bonds of the incoming aryl halides. The reaction of dienes with 1-iodobenzene or aryl halides that incorporate electron-donating groups produced azaconidendrin derivatives by means of the functionalization of both sp³ C-H and sp² C-H bonds. The regioselective C-H functionalization for the formation of different pseudo-podophyllotoxin/- conidendrin derivatives is proven by analyses of the ¹H NMR spectra of the products and selective X-ray analyses of the structures of the products. Thus the palladium-catalyzed domino cyclization of 1,6-dienes for the preparation of aza-podophyllotoxin/aza-conidendrin derivatives can be controlled by selectively controlling the C-H functionalization.

Full text of DOI:10.1002/asia.200900307

DOI: 10.1002/asia.200900307
À
Tuned C H Functionalization to Construct Aza-Podophyllotoxin/Aza-
Conidendrin Derivatives by Means of Domino Cyclization
Yimin Hu,*[a] Yuan Qu,[a] Fenghua Wu,[a] Jinghan Gui,[a] Yun Wei,[a] Qiong Hu,[a] and
Shaowu Wang*[a, b]
2
À
Abstract: An efficient domino cycliza-
tion method for the construction of
aza-podophyllotoxin/aza-conidendrin
derivatives has been established. Reac-
tions of different dienes with aryl hal-
ides in the presence of a palladium cat-
alytic system produced different kinds
of podophyllotoxin derivatives through
means of the functionalization of the
and sp C H bonds. The regioselective
À
À
À
C H bonds ortho to the C halide
bonds of the incoming aryl halides. The
reaction of dienes with 1-iodobenzene
or aryl halides that incorporate elec-
tron-donating groups produced aza-
C H functionalization for the forma-
tion of different pseudo-podophyllotox-
in/-conidendrin derivatives is proven by
1
analyses of the H NMR spectra of the
products and selective X-ray analyses
of the structures of the products. Thus,
the palladium-catalyzed domino cycli-
zation of 1,6-dienes for the preparation
aza-podophyllotoxin/aza-coniden-
drin derivatives can be controlled by
conidendrin derivatives by means of
3
À
the functionalization of both sp C H
À
a highly regioselective C H functional-
ization. Treatment of dienes with aryl
halides that have electron-withdrawing
substituents on the phenyl ring created
aza-podophyllotoxin derivatives by
of
Keywords: C-H activation · cycliza-
tion · dienes · domino reactions ·
palladium
À
selectively controlling the C H func-
tionalization.
Introduction
The synthetic methodology for natural products or their an-
alogues has attracted much attention for their medicinal ap-
plications. Podophyllotoxin (Scheme 1) is one of the natural
products isolated from Podophyllum peltatum and Podo-
phyllum emodi,[1] as it has long been known to possess anti-
tumor properties in clinical use in the treatment of warts
and small-cell lung carcinoma.[2] Various synthetic strategies
have been developed for the preparation of podophyllotoxin
and its analogues.[3] The groups of Linker and Bach devel-
Scheme 1. Selected natural products containing skeletons of aryl tetrahy-
dronaphthalene lactones.
oped the strategies independently by synthesizing (À)-epi-
podophyllotoxin[4a] and (À)-podophyllotoxin[4b] through
enantioselective total synthesis. The total synthesis of (À)-
epipodophyllotoxin has also been accomplished in 12 steps
starting from the commercially available piperonal, with the
final product isolated in 30% overall yield. Sherburn and
co-workers constructed the core structure of podophyllotox-
in in nine steps with a high regio- and stereoselectivity using
a silicon-tethered radical reaction.[4c] In addition, Davies
[a] Prof. Dr. Y. Hu, Y. Qu, F. Wu, J. Gui, Y. Wei, Q. Hu,
Prof. Dr. S. Wang
Laboratory of Functional Molecular Solids, Ministry of Education
Anhui Key Laboratory of Molecular-Based Materials
School of Chemistry and Materials Science
Anhui Normal University, Wuhu, Anhui 241000 (P.R. China)
Fax : (+86)553-388-3517
E-mail: yiminhu@mail.ahnu.edu.cn
swwang@mail.ahnu.edu.cn
À
et al. described an efficient C H activation of primary ben-
[b] Prof. Dr. S. Wang
zylic positions by means of rhodium carbenoid in the syn-
State Key Laboratory of Organometallic Chemistry Department
Chinese Academy of Sciences, Shanghai 200032 (P.R. China)
thesis of (À)-a-conidendrin.[5]
As an analogue of podophyllotoxin, aza-epiisopicropodo-
phyllin has been synthesized by Poli and Giambastiani by
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900165.
Chem. Asian J. 2010, 5, 309 – 314
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
309

FULL PAPERS
Table 1. The palladium-catalyzed reaction for construction of the tetracyclic heterocycles.[a]
employing two synthetic strat-
egies.[6] In recent years, the
tandem reaction has been de-
veloped for the synthesis of het-
erocycles, which are valuable
building blocks for the con-
struction of pharmaceuticals.[7]
These condensed ring com-
pounds can be constructed by
means of the palladium-cata-
lyzed cycloaddition of dienes,[8]
Diels–Alder reaction,[9] intra-
molecular Heck reaction,[10] and
À
Entry
[Pd] ([mol%])
Base ([equiv])
Solvent
t [h]
T [8C]
Yield [%][b]
aa
j
1
2
3
4
5
6
7
8
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
G
DMF
DMF
DMF
DMF
DMF
dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
15
24
24
18
24
24
30
24
24
30
24
36
48
24
120
130
140
145
150
140
140
140
140
140
140
140
150
140
5
34
82
60
45
58
24
61
56
33
69
5
–
–
G
G
10
31
53
24
5
19
16
8
C H
functionalization.[11,12]
À
Meanwhile, C C bond-forming
events in established methodol-
ogies involve Friedel–Crafts,
Michael, and enzyme-assisted
reactions.[13,14] Through this ap-
proach, enynes can be trans-
formed into cyclic skeletons in
a one-pot fashion with an im-
pressive regio- and stereoselec-
tivity.[15,16] Carretero, Ruck, and
9
[Pd
R
10
11
12
13
14
E
12
–
2% polymer–Pd (0)
1% chitosan–Pd (0)
4
30
15
–
[a] All reactions were carried out under argon using a (1.0 equiv), 1-bromonaphthalene (1.2 equiv), PdACHTUNGTRENNUNG(OAc)2
(2 mol%), PPh3, base, and solvent (10 mL) at the temperature indicated. [b] Yield of isolated product.
their co-workers reported
a
À
novel tandem Heck/C H functionalization reaction to gen-
(1 equiv) were treated with different aryl halides (1.2 equiv)
in the presence of a palladium(II) catalyst (2 mol%) and
Ph3P (4 mol%) with (nBu)3N (1.2 equiv) as an additive in
DMF at 1408C.
erate spiro-oxindoles.[17,18]
Owing to the many steps required and only moderate
yields and stereoselectivities achieved in the synthesis of po-
À
dophyllotoxin/conidendrin derivatives, the tandem C C
À
bond formation and different C H bond functionalization
À
Tuned C H Functionalization
involving a tandem cyclization process to construct aza-po-
dophyllotoxin/aza-conidendrin derivatives is extremely rare.
As part of our ongoing studies in this field,[19] we report
herein an efficient domino cyclization method for the prepa-
ration of different aza-podophyllotoxin/aza-conidendrin by
carbopalladation and subsequent regioselectively functional-
To examine the scope of this domino reaction, the reactions
of a range of substituted aryl halides with a were examined
(Table 2). The outputs of the domino reactions of a with
aryl halides were strongly influenced by the electronic prop-
À
erties of the aryl halides. Functionalization of different C H
À
ization of the unactivated C H bond.
bonds with the formation of different cyclic compounds
could be achieved by varying the electronic properties of
the aryl halides. When substrate a reacted with aryl halides
with substituents such as COOC2H5, COOMe, CHO,
COMe, SO2Me, and CN under the selected reaction condi-
tions, the cyclic products aa–ai were obtained through the
functionalization of the C H bonds ortho to the C halide
groups of the incoming aryl halides (Table 2, entries 1–9). It
is interesting to note that another type of cyclic products,
aj–al, was isolated during treatment of a with aryl halides
such as p-chlorophenylbromide, p-methylphenylbromide,
and 1-iodobenzene, respectively. This clearly indicates that
the formation of aj–al is through the functionalization of
Results and Discussion
The reaction conditions using N-allyl-N-p-tolylcinnamamide
(a) and 1-bromonaphthalene as a typical reaction in the
presence of a palladium catalytic system were surveyed
(Table 1). In a test experiment, reaction of a with 1-bromo-
naphthalene in N,N-dimethylformamide (DMF) in the pres-
À
À
ence of a catalytic amount of Pd
ACHTUNGTRENNUNG
9-p-tolyl-7,7a,9,10,10a,11-hexahydronaphthoAHCTUNGTRENNUNG
one (aa) in 34% yield at 1308C for 24 h. Altering the exper-
imental conditions indicated that the output of the domino
reaction producing product aa was greatly affected by the
reaction temperature (Table 1, entries 1–5), the additive
bases (Table 1, entries 3, 6, 7), the catalytic system (Table 1,
entries 6, 9–11), and the solvents (Table 1, entries 3, 6).
Thus, the following standard reaction conditions were select-
ed for carrying out the following studies: 1,6-dienes
3
2
À
À
both sp C H and sp C H bonds (Table 2, entries 10–12),
although the output of the reaction of a with p-methylphe-
À
nylbromide is low. The structures of the different C H func-
tionalization products could be determined by analysis of
their corresponding H NMR spectra. For example, the pro-
1
À
À
tons (Ha, Hb) of the N CH group of product ai resonate
at d=3.94 and 3.63 ppm, whereas the corresponding protons
310
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 309 – 314

Aza-Podophyllotoxin/Aza-Conidendrin Derivatives
Table 2. Palladium-catalyzed domino reaction of aryl halides with a.[a]
ration of the more functional-
ized aza-podophyllotoxin/aza-
conidendrin derivatives, we
studied the reactions of differ-
ent 1,6-dienes (b–e) with aryl
halides. The results are shown
in Table 3. The results indicate
that different aza-podophyllo-
toxin could be constructed in
ꢁone potꢂ with good yields by
running the reaction of the cor-
responding dienes with aryl hal-
ides (Table 3, entries 1, 2, and
5–11). However, the reaction of
dienes c either with a-naphtha-
lenylbromide or with 1-iodo-
benzene produced the corre-
sponding tricyclic compounds
ca (30%) or cb (25%) in rela-
tively low yields (Table 3, en-
tries 3 and 4), thus indicating
electronic effects on the outputs
Entry
Rn (n=1,2)
RnC6H4X
Product
Yield [%][b]
1
2
3
4
–
a-naphthalenyl–Br
p-CH3CH2OOCC6H4Br
p-CH3OOCC6H4Br
p-OHCC6H4Br
p-NCC6H4Br
aa
ab
ac
ad
ae
af
ag
ah
ai
82
79
70
41
45
65
78
55
62
58
5[c]
54
COOC2H5
COOMe
CHO
CN
5
6
7
8
COMe
SO2Me
CN
p-CH3OCC6H4Br
p-CH3O2SC6H4Br
m-NCC6H4Br
9
Cl
m-ClC6H4Br
10
11
12
Cl
Me
H
p-ClC6H4Br
p-CH3C6H4Br
C6H5I
aj
ak
al
[a] General conditions: a (1.0 equiv), RnC6H4X (X=Br, I; 1.1 equiv), Pd
ACTHNUTRGEN(UNG OAc)2 (2 mol%), PPh3 (4 mol%),
(nBu)3N (1.2 equiv), DMF (10 mL), 1408C. [b] Yield of isolated product after flash column chromatography.
[c] Other products of this reaction.
(Ha’, Hb’) of product aj resonate at d=3.86 and 3.38 ppm.
À
À
At the same time, the protons (Hc) of the Ar CH group
of product ai give signals at d=4.27 ppm, whereas the corre-
À
À
sponding protons (Hc’) of the Ar CH group of product aj
À
À
appear at d=3.23 ppm. The proton (Hd) of the O=C CH
group in ai exhibits a chemical shift at d=3.10 ppm, whereas
À
À
the corresponding proton (Hd’) of the O=C CH group in
aj resonates at d=3.71 ppm. These differences may result
from the different electronic properties of the corresponding
protons. The structures of ae and al were further determined
by X-ray crystallography (Figures 1 and 2), and are in agree-
Figure 1. Molecular structure of compound ae.
1
ment with the H NMR spectroscopic results. The above re-
À
sults clearly indicate that the C H bond functionalization
can be controlled by selecting treatment of different aryl
halides with 1,6-dienes.
Domino Reaction of Different 1,6-Dienes with Aryl Halides
À
To search for the effect of dienes on C H functionalization,
and to search for the generality of the method for the prepa-
Figure 2. Molecular structure of compound al.
Chem. Asian J. 2010, 5, 309 – 314
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
311

Y. Hu, S. Wang et al.
FULL PAPERS
Table 3. Domino reaction for the construction of the multicyclic heterocycles.[a]
All the resulting tri- and tet-
racyclic compounds were con-
firmed by one- (1H, 13C) and
two-dimensional (COSY) NMR
spectra, and elemental or
HRMS analyses. The represen-
tative compounds of ae and al
were additionally characterized
by X-ray crystallographic analy-
ses (Figures 1 and 2). Further
details can be found in the Sup-
porting Information (see also
the Experimental Section).[20]
Although racemic products
were obtained in all cases, it is
interesting to note that trans-
oriented 5,6-ring systems were
obtained in all of the reactions
of dienes with aryl halides. The
X-ray crystal structures proved
the stereochemistry.
Entry
Dienes
R1C6H4X
t [h]
Product
Yield [%][b]
1
2
3
4
5
6
7
8
b
b
c
p-CH3CH2OOCC6H4Br
a-naphthalenyl–Br
a-naphthalenyl–Br
C6H5I
a-naphthalenyl–Br
p-CH3OCC6H4Br
C6H5Br
20
20
20
20
20
20
18
18
18
18
18
ba
bb
ca
cb
da
db
ea
eb
ec
ed
ee
79
80
30
25
75
60
82
84
35
59
75
c
d
d
e
e
e
e
e
C6H5I
9
10
11
p-CH3OC6H4Br
p-HOCC6H4Br
p-CH3CH2OOCC6H4Br
[a] General conditions: b–e (1.0 equiv), R1C6H4X (X=Br, I; 1.1 equiv), Pd
ACTHNUTRGEN(UNG OAc)2 (2 mol%), PPh3 (4 mol%),
(nBu)3N (1.2 equiv), DMF (10 mL), 1408C. [b] Yield of isolated product after flash column chromatography.
of the reaction. It was found that the tricyclic compounds
À
were formed by means of functionalization of the C H
Mechanism
À
bond ortho to the C halide groups of the incoming aryl hal-
ides in most cases. However, the formation of products cb
and eb was clearly through the functionalization of both the
Two proposed catalytic cycle pathways for the formation of
the multicyclic compounds are shown in Scheme 2. The se-
lective insertion of aryl–palladium(II) halide into the allyl
moiety of a produced intermediate 1, which then reacted
with the carbon–carbon double bond through a carbopalla-
dation reaction to afford 2 or 4. s-Bond metathesis[20] onto
sp3- and sp2-hybridized C H bonds as shown by the
À
1H NMR spectra of the products. Comparison of products
cb and ea, which were formed from the reaction of diene c
or e with 1-iodobenzene, respectively, indicated that the
electronic properties of the diene substrate also influenced
À
the different C H bonds in 3 or 5 via intermediates 2 or 4,
À
the regioselectivity of the functionalization of the C H
which are in equilibrium depending on the electronic prop-
erties of the aryl halides, generated the final products ad or
ak, respectively. The reaction of dienes with aryl halides that
À
bond, and produced different C H bond functionalization
products. Again, the electronic effect of the aryl halides that
influence the regioselectivity of
À
the functionalization of the C
H bond was found by analyzing
the 1H NMR spectra of prod-
À
ucts ea to ed, and the C H
bond functionalization for the
formation of product eb was
clearly different to that of the
formation of products ea, ec,
and ed. As shown in Table 3,
we can also conclude that dif-
ferent diene substrates have a
great deal of influence on the
domino reaction. The outputs
of the reaction of substrates c
and d with aryl halides were
much lower than those of the
reactions of b and e with aryl
halides, which is probably as a
result of the existence of strong
electron-withdrawing
groups
such as p-toluenesulfonyl (Ts).
Scheme 2. Proposed mechanistic pathways for the formation of different multicyclic compounds (PG=protect-
ing group).
312
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 309 – 314

Aza-Podophyllotoxin/Aza-Conidendrin Derivatives
Synthesis
have an electron-withdrawing substituent produced products
of type ad, whereas the reaction of dienes with 1-iodoben-
zene or the aryl halides with electron-donating properties
gave products of type ak. When the less-hindered olefin was
used, the Heck reaction as the first step to form the substi-
tuted phenyl functionalized 1,6-dienes was proposed. Thus,
A typical procedure for the palladium-catalyzed domino reaction of the
linear 1,6-dienes with aryl halides: substrate a (1.38 g, 5 mmol), 1-iodo-
benzene (1.22 g, 6 mmol), PdACHTNUTRGNE(UNG OAc)2 (18.2 mg, 0.05 mmol), and PPh3
(25.6 mg, 0.1 mmol) were added to the degassed solution of (nBu)3N
(1.56 mL, 7.5 mmol) in DMF (10 mL). After the mixture was stirred for
half an hour at room temperature, it was then heated at 1408C for 24 h,
and then quenched with water and extracted with AcOEt (3ꢄ5 mL). The
combined organic layers were washed with hydrochloric acid (5%) and
sodium carbonate (5%), and saturated with sodium chloride solution.
After separation, the organic layer was dried with MgSO4 and then con-
centrated. The residue was purified by flash column chromatography (6:1
petroleum ether/AcOEt) to give the corresponding product.
[21]
À
the C H bond functionalization
selecting differently substituted aromatic halides.
could be controlled by
Conclusion
X-ray Crystallographic Analysis
In summary, we have developed an efficient method with
good yields for the synthesis of aza-podophyllotoxin/aza-
conidendrin derivatives related to natural products through
a domino cyclization of 1,6-dienes with aryl halides in the
CCDC-679144 (ab), -679145 (al), -679146 (ae), and -679148 (bb) contain
the supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre at www.ccdc.cam.ac.uk/data_request/cif
presence of
a PdACHTUNGTRENNUNG(OAc)2/PPh3/NAHCTUNGTREG(NNUN nBu)3 catalytic system
under mild conditions. The catalytic system has the advant-
age of a tolerance towards a wide range of dienes and aryl
halides. However, the electronic properties of the substitu-
ents on the aryl halides have a great influence on the regio-
Acknowledgements
À
selectivity of the C H functionalization, thus producing dif-
This research was partly supported by the National Science Foundation
of China (20872002, 20832001) and the Education Department of Anhui
Province (TD200707). The authors are grateful to Prof. J. Hu and Dr. H.
Zhang for their assistance in running NMR spectroscopy and X-ray dif-
fraction analyses.
À
ferent tricyclic compounds. The C H functionalization oc-
À
curred on the phenyl ring (ortho to the C X groups) of in-
coming aryl halides that incorporate electron-withdrawing
groups when they were treated with the corresponding
dienes, and the functionalization of both the sp3- and sp2-hy-
À
bridized C H bonds happened when they were treated with
[1] a) H. F. Stꢅhelin, A. V. Wartburg, Cancer Res. 1991, 51, 5–15;
b) F. E. Koehn, G. T. Carter, Nat. Rev. Drug Discovery 2005, 4, 206–
220; c) M. S. Butler, Nat. Prod. Rep. 2005, 22, 162–195.
[2] a) R. L. Margolis, L. Wilson, Cell 1978, 13, 1–8; b) R. L. Margolis,
L. Wilson, Cell 1979, 18, 673–679.
1-iodobenzene or aryl halides with electron-donating groups
on the phenyl ring. Further study of the tandem reaction for
the synthesis of more complex products and their biological
activity tests are now in progress in our laboratory.
[3] R. S. Ward, Nat. Prod. Rep. 1999, 16, 75–96, and references therein.
[4] a) U. Engelhardt, A. Sarkar, T. Linker, Angew. Chem. 2003, 115,
2591–2593; Angew. Chem. Int. Ed. 2003, 42, 2487–2489; b) D. Sta-
dler, T. Bach, Angew. Chem. 2008, 120, 7668–7670; Angew. Chem.
Int. Ed. 2008, 47, 7557–7559; c) A. J. Reynolds, A. J. Scott, C. I.
Turner, M. S. Sherburn, J. Am. Chem. Soc. 2003, 125, 12108–12109.
[5] H. M. L. Davies, Q. Jin, Tetrahedron: Asymmetry 2003, 14, 941–949.
[6] G. Poli, G. Giambastiani, J. Org. Chem. 2002, 67, 9456–9459.
[7] For reviews on this topic, see: a) L. F. Tietze, G. Brasche, K. Ger-
icke, Domino Reactions in Organic Synthesis, Wiley-VCH, Wein-
heim, 2006; b) L. F. Tietze, Chem. Rev. 1996, 96, 115–136; c) N.
Hall, Science 1994, 266, 32–34; d) A. de Meijere, Acc. Chem. Res.
2005, 38, 413–422; e) R. M. Borzilleri, S. M. Weinreb, M. Parvez, J.
Am. Chem. Soc. 1996, 118, 2309–2391; f) R. M. Borzilleri, S. M.
Weinreb, M. Parvez, J. Am. Chem. Soc. 1995, 117, 10905–10913;
g) A. G. M. Barrett, M. L. Boys, T. L. Boehm, J. Org. Chem. 1996,
61, 685–699.
[8] a) M. Gulias, J. Duran, F. Lopez, L. Castedo, J. Mascarenas, J. Am.
Chem. Soc. 2007, 129, 11026–11027; b) I. C. Lennon, A. V. Bhatia,
Org. Process Res. Dev. 2008, 12, 467; c) R. Shintani, M. Murakami,
T. Hayashi, J. Am. Chem. Soc. 2007, 129, 12356–12357; d) B. M.
Trost, J. P. Stambuli, S. M. Silverman, U. Schworer, J. Am. Chem.
Soc. 2006, 128, 13328–13329.
[9] a) G. D. Artman, III, A. W. Grubbs, R. M. Williams, J. Am. Chem.
Soc. 2007, 129, 6336–6342; b) J. J. Fleming, M. D. McReynolds, J.
Du Bois, J. Am. Chem. Soc. 2007, 129, 9964–9975; c) M. A. Kien-
zler, S. Suseno, D. Trauner, J. Am. Chem. Soc. 2008, 130, 8604–8605.
[10] a) L. Firmansjah, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 11340–
11341; b) J. S. Nakhla, J. W. Kampf, J. P. Wolfe, J. Am. Chem. Soc.
2006, 128, 2893–2901; c) H. Lebel, C. Ladjel, L. Brethous, J. Am.
Chem. Soc. 2007, 129, 13321–13326.
Experimental Section
General
All the catalytic reactions were performed under an argon atmosphere
using an oven-dried Schlenk flask. The chemicals were purchased from
Alfa Aesar and Acros Chemicals. All solvents and materials were pre-
dried, redistilled, or recrystallized before use. 1H NMR (300 MHz) and
13C NMR (75 MHz) spectra were recorded using a Bruker Avance 300
spectrometer with CDCl3 as the solvent. Chemical shifts are reported in
1
ppm by assigning TMS resonance in the H NMR spectra as d=0.00 ppm
and CDCl3 resonance in the 13C spectra as d=77.0 ppm. All coupling
constants (J values) were reported in Hz. Column chromatography was
performed on silica gel (300–400 mesh). Melting points were determined
using a Gallenkamp melting-point apparatus and are uncorrected. The
FTIR spectra were recorded with KBr pellets in the 4000–400 cmÀ1
ranges using a Nicolet 5DX spectrometer. Mass spectra were performed
using a Micromass GCT-MS. Two-dimensional NMR and HRMS spec-
troscopy were performed at the State-Authorized Analytical Center at
the University of Science and Technology of China. X-ray crystallograph-
ic diffraction data of ab, ae, al, and bb were collected at room tempera-
ture using a Bruker SMART Apex CCD diffractometer with MoKa radia-
tion (l=0.71073 ꢃ) with a graphite monochromator using the w-scan
mode. Data reductions and absorption corrections were performed with
SAINT and SADABS software, respectively.[22] The structure was solved
by direct methods and refined on F2 by full-matrix least squares using
SHELXTL.[23] All non-hydrogen atoms were treated anisotropically. The
positions of hydrogen atoms were generated geometrically.
Chem. Asian J. 2010, 5, 309 – 314
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
313

Y. Hu, S. Wang et al.
FULL PAPERS
[11] For reviews on this topic, see: a) H. M. L. Davies, J. R. Manning,
Nature 2008, 451, 417–424; b) S. F. Kirsch, J. T. Binder, B. Crone, A.
Duschek, T. T. Haug, C. Liꢆbert, H. Menz, Angew. Chem. 2007, 119,
2360–2363; Angew. Chem. Int. Ed. 2007, 46, 2310–2313; c) R. G.
Bergman, Nature 2007, 446, 391–393; d) D. Alberico, M. E. Scott,
M. Lautens, Chem. Rev. 2007, 107, 174–238; e) L. C. Campeau, M.
Parisien, M. Leblanc, K. Fagnou, J. Am. Chem. Soc. 2004, 126,
9186–9187; f) C. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem. Res.
2001, 34, 633–639; g) N. Guimond, K. Fagnou, J. Am. Chem. Soc.
2009, 131, 12050–12051; h) T. Watanabe, T. Bando, Y. Xu, R. Ta-
shiro, H. Sugiyama, J. Am. Chem. Soc. 2005, 127, 44–45.
[12] a) F. Diederich, P. J. Stang, Metal-Catalyzed Cross-Coupling Reac-
tions, Wiley-VCH, Weinheim, 1998; b) T. L. Ho, Tandem Organic
Reactions, Wiley, New York, 1992; c) K. C. Nicolaou, E. J. Sorensen,
Classics in Total Synthesis, Wiley-VCH, Weinheim, 1996; d) K. C.
Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118,
7292–7344; Angew. Chem. Int. Ed. 2006, 45, 7134–7186; e) D.
Enders, M. R. M. Hꢇttl, C. Grondal, G. Raabe, Nature 2006, 441,
861–863; f) K. C. Nicolaou, T. Montagnon, S. A. Snyder, Chem.
Commun. 2003, 551–564; g) B. M. Trost, Angew. Chem. 1995, 107,
285–307; Angew. Chem. Int. Ed. Engl. 1995, 34, 259–281; h) B. M.
Trost, Acc. Chem. Res. 2002, 35, 695–705.
[13] a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174–
238; b) J. P. Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651–2710;
c) A. de Meijere, P. von Zezschwitz, S. Brase, Acc. Chem. Res. 2005,
38, 413–422; d) R. Yanada, S. Obika, T. Inokuma, K. Yanada, M.
Yamashita, S. Ohta, Y. Takemoto, J. Org. Chem. 2005, 70, 6972–
6975.
[14] a) Q. Huang, A. Fazio, G. Dai, M. A. Campo, R. C. Larock, J. Am.
Chem. Soc. 2004, 126, 7460–7461; b) M. A. Campo, Q. Huang, T.
Yao, Q. Tian, R. C. Larock, J. Am. Chem. Soc. 2003, 125, 11506–
11507; c) H. Y. Thu, W. Y. Yu, C. M. Che, J. Am. Chem. Soc. 2006,
128, 9048–9049; d) R. Giri, N. Maugel, J. J. Li, D. H. Wang, S. P.
Breazzano, L. B. Saunders, J. Q. Yu, J. Am. Chem. Soc. 2007, 129,
3510–3511; e) J. Zhao, D. Yue, M. A. Campo, R. C. Larock, J. Am.
Chem. Soc. 2007, 129, 5288–5290; f) J. Zhao, M. Campo, R. C.
Larock, Angew. Chem. 2005, 117, 1907–1909; Angew. Chem. Int.
Ed. 2005, 44, 1873–1875.
[16] a) I. V. Magedov, M. Manpadi, S. Van Slambrouck, W. F. A. Steelant,
E. Rozhkova, N. M. Przhevalꢂskii, S. Rogelj, A. Kornienko, J. Med.
Chem. 2007, 50, 5183–5192; b) D. B. Berkowitz, S. Choi, J. H.
Maeng, J. Org. Chem. 2000, 65, 847–860.
[17] a) R. T. Ruck, M. A. Huffman, M. M. Kim, M. Shevlin, W. V.
Kandur, I. W. Davies, Angew. Chem. 2008, 120, 4789–4792; Angew.
Chem. Int. Ed. 2008, 47, 4711–4714; b) J. Adrio, J. C. Carretero, J.
Am. Chem. Soc. 2007, 129, 778–779; c) J. Esquivias, R. G. Arrayas,
J. C. Carretero, J. Am. Chem. Soc. 2007, 129, 1480–1481; d) S. Cab-
rera, R. G. Arrayas, I. Alonso, J. C. Carretero, J. Am. Chem. Soc.
2005, 127, 17938–17947; e) A. Loꢂpez-Peꢂrez, J. Adrio, J. C. Carre-
tero, J. Am. Chem. Soc. 2008, 130, 10084–10085; f) P. Mauleꢈn, I.
Alonso, J. C. Carretero, Angew. Chem. 2001, 113, 1331–1333;
Angew. Chem. Int. Ed. 2001, 40, 1291–1293; g) P. Mauleꢈn, A. A.
Nunez, I. Alonso, J. C. Carretero, Chem. Eur. J. 2003, 9, 1511–1520.
[18] a) M. A. Tarselli, M. R. Gagne, J. Am. Chem. Soc. 2007, 129, 2196;
b) C. Liu, R. A. Widenhoefer, J. Am. Chem. Soc. 2004, 126, 10250–
10251; c) J. Suffert, B. Salem, P. Klotz, J. Am. Chem. Soc. 2001, 123,
12107–12108; d) T. Sugihara, C. Coperet, Z. Owczarczyk, L. S. Har-
ring, E. Negishi, J. Am. Chem. Soc. 1994, 116, 7923–7924; e) A. B.
Dounay, P. G. Humphreys, L. E. Overman, A. D. Wrobleski, J. Am.
Chem. Soc. 2008, 130, 5368–5377; f) B. M. Trost, W. Tang, F. D.
Toste, J. Am. Chem. Soc. 2005, 127, 14785–14803.
[19] a) Y. M. Hu, C. L. Yu, D. Ren, Q. Hu, L. D. Zhang, D. Cheng,
Angew. Chem. 2009, 121, 5556–5559; Angew. Chem. Int. Ed. 2009,
48, 5448–5451; b) Y. M. Hu, Y. Ouyang, Y. Qu, Q. Hu, H. Yao,
Chem. Commun. 2009, 4575–4577; c) Y. M. Hu, F. F. Song, F. H.
Wu, D. Cheng, S. W. Wang, Chem. Eur. J. 2008, 14, 3110–3117.
[20] a) D. Garcꢉa-Cuadrado, P. D. Mendoza, A. A. C. Braga, F. Maseras,
A. M. Echavarren, J. Am. Chem. Soc. 2007, 129, 6880–6886; b) D.
Garcia-Cuadrado, A. A. C. Braga, F. Maseras, A. M. Echavarren, J.
Am. Chem. Soc. 2006, 128, 1066–1067.
[21] O. Baudoin, A. Herrbach, F. Guꢆritte, Angew. Chem. 2003, 115,
5914–5918; Angew. Chem. Int. Ed. 2003, 42, 5736–5740.
[22] SAINT and SADABS software Reference Manual, Bruker AXS
Inc., Madison, Wisconsin (USA), 2003.
[23] a) G. M. Sheldrick, SHELXL97, Program for Crystal Structure Re-
finement, University of Gçttingen (Germany), 1997; b) G. M. Shel-
drick, SHELXS97, Program for Crystal Structure Refinement, Uni-
versity of Gçttingen (Germany), 1997; c) G. M. Sheldrick, Acta
Crystallogr. Sect. A 1990, 46, 467–473.
[15] Total syntheses of (À)-podophyllotoxin: a) R. C. Andrews, S. J.
Teague, A. I. Meyers, J. Am. Chem. Soc. 1988, 110, 7854–7858;
b) R. Van Speybroeck, H. Guo, J. Van der Eycken, M. Vandewalle,
Tetrahedron 1991, 47, 4675–4682; c) J. L. Charlton, K. Koh, J. Org.
Chem. 1992, 57, 1514–1516; d) E. J. Bush, D. W. Jones, J. Chem.
Soc. Perkin Trans. 1 1996, 151–155; e) S. B. Hadimani, R. P. Tan-
pure, S. V. Bhat, Tetrahedron Lett. 1996, 37, 4791–4794.
Received: July 24, 2009
Published online: December 29, 2009
314
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 309 – 314