A highly convergent cascade cyclization to cis-hydrindanes with all-carbon quaternary centers and its application in the synthesis of the aglycon of dendronobiloside A

Article abstract of DOI:10.1021/ol102781p

An efficient and versatile ZnBr₂-catalyzed Diels-Alder/ carbocyclization cascade reaction has been developed for construction of highly functionalized cis-hydrindanes (70-96% yields with high diastereoselectivity), and it has been successfully utilized in the synthesis of the aglycon of dendronobiloside A.

Full text of DOI:10.1021/ol102781p

ORGANIC
LETTERS
2011
Vol. 13, No. 4
588–591
A Highly Convergent Cascade Cyclization
to cis-Hydrindanes with All-Carbon
Quaternary Centers and Its Application in
the Synthesis of the Aglycon of
Dendronobiloside A
Yejian Han, Lizhi Zhu, Yuan Gao, and Chi-Sing Lee*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen University Town, Xili,
Shenzhen 518055, China
lizc@szpku.edu.cn
Received November 16, 2010
ABSTRACT
An efficient and versatile ZnBr2-catalyzed Diels-Alder/carbocyclization cascade reaction has been developed for construction of highly
functionalized cis-hydrindanes (70-96% yields with high diastereoselectivity), and it has been successfully utilized in the synthesis of the
aglycon of dendronobiloside A.
The cis-hydrindane skeleton with an all-carbon quater-
nary center at the ring junction is a common motif in many
biologically active natural products (Figure 1).1 Developing
efficient and stereoselective methods for this type of ske-
leton with the appropriate functionalities already in place
would provide a quick synthetic entry to cis-hydrindane-
containing natural products. One of our major research
interests is to develop convergent and versatile cascade
cyclization reactions for the construction of various types
of fused ring systems.2 We herein reported a highly con-
vergent Diels-Alder/carbocyclization cascade reaction
for the construction of the cis-hydrindanes and its applica-
tion in the synthesis of the aglycon of dendronobiloside A.
As shown in Scheme 1, our strategy involved a Lewis acid
catalyzed Diels-Alder (DA) cycloaddition of a silyl enol
ether diene with an electron-deficient dienophile. The silyl
enol ether moiety of the resulting DA adduct is expected
to undergo an intramolecular carbocyclization with the
(3) For reviews, see: (a) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41,
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G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698. (c) Hayashi, Y. Cycloaddit.
React. Org. Synth. 2002, 5–55. Selected references for Lewis acid catalyzed DA
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Int. Ed. 1999, 38, 2398–2400. (e) Ge, M.; Stoltz, B. M.; Corey, E. J. Org. Lett.
2000, 2, 1927–1929. (f) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125,
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2004, 6, 4387–4390. (h) Teo, Y.-C.; Loh, T.-P. Org. Lett. 2005, 7, 2539–2541. (i)
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Zhou, X.; Lee, C.-S. Eur. J. Org. Chem. 2010, 1124–1133.
(1) (a) Dendrobine: Wang, H.; Zhao, T. J. Nat. Prod. 1985, 48, 796–
801. (b) Dendronobiloside A: Zhao, W.; Ye, Q.; Tan, X.; Jiang, H.; Li, X.;
Chen, K.; Kinghorn, A. D. J. Nat. Prod. 2001, 64, 1196–1200.
(c) Aplykurodinone-1: Gavagnin, M.; Carbone, M.; Nappo, M.; Mollo, E.;
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r
10.1021/ol102781p
Published on Web 01/10/2011
2011 American Chemical Society

the catalyst8 and then an asymmetric version with a Pd
catalyst in 2007.9 Since some of the transition metal salts
have been shown to be able to function as both σ- and
π-electrophilic Lewis acids,10 we have decided to employ a
transition metal salt as the bifunctional catalyst in our
cascade cyclization reactions.
Table 1. Optimization of the DA/Carbocyclization Cascade
Reactiona
Figure 1. Examples of cis-hydrindane-containing natural prod-
ucts.
terminal alkyne and afford the cis-hydrindane cycloaddi-
tion products in a one-pot manner (Scheme 1). This cascade
cyclization required a bifunctional Lewis acid catalyst
which can form both σ- and π-complexes with the sub-
strates and intermediates.
entry
Mnþ
solvent time yieldsb endo/exoc
1d
2
AuClPPh3/AgBF4 CH2Cl2
1 h
5 h
-
-
PtCl2
toluene
toluene
DCE
-
-
3
PdCl2(PPh3)2
AgBF4
InCl3
24 h
24 h
24 h
24 h
24 h
72 h
-
-
4e
5f
6
42
40
50
trace
trace
-
6:1
3:1
4:1
-
DCE
ZnI2
DCE
7
ZnI2
toluene
THF
Scheme 1. DA/Carbocyclization Cascade Cyclization Ap-
proach to cis-Hydrindanes
8
ZnI2
-
9
ZnI2
dioxane 72 h
CH3CN 36 h
CH3CN 36 h
CH3CN 36 h
CH3CN 24 h
-
10
11
12
13
ZnI2
92
68
90
96
4.8:1
5.3:1
7.4:1
12:1
Zn(OTf)2
ZnCl2
ZnBr2
a The general procedures: To a stirred solution of ZnBr2 (25 mg, 0.10
mmol) in anhydrous acetonitrile (2.0 mL) was added freshly distilled
acrolein (0.20 mL, 3.0 mmol) at 0 °C. After 15 min of stirring at 0 °C, the
reaction mixture was treated with a solution of silyl enol ether 1 (2 mL of
a 0.25 M solution in CH3CN, 0.50 mmol) slowly over 15 min. The
resulting mixture was stirred at 0 °C for 5.5 h and then stirred at 60 °C for
12 h. b Isolated yields (%) after silica gel column chromatography. c The
endo/exo ratios were determined by the isolated yields or by comparison
of the signal at δendo 5.13 ppm and δexo 4.72 ppm in 1H NMR. d Similar
results were obtained in CH2Cl2 with 10% water. e Other Ag(I) salts
including AgOTf, AgBF6, and AgClO4 gave similar results. f In(OTf)3
led to rapid hydrolysis of 1.
DA cycloaddtion catalyzed by Lewis acids that can form
strong σ-complexes with the dienophiles has been studied
extensively.3 In contrary, reports on catalytic carbocycli-
zation via nucleophilic addition of silyl enol ethers to
unactivated alkynes are still limited.4 This type of reaction
was first reported by Drouin and Conia in 1985 using a
stoichiometric amount of HgCl2 which can form strong
π-complexes with the unactivated alkynes.5 The first catalytic
carbocyclization of ω-acetylenic silyl enol ethers was re-
To this end, the cascade cyclization reaction between
silyl enol ether 111 and acrolein was first studied with the
transition metal salts that had been used as a catalyst for
carbocyclization. As shown in Table 1, AuClPPh3/AgBF4
in either dry or wet dichloromethane8 resulted in the
complete hydrolysis of 1 (entry 1). Switching to PtCl2 in
toluene7 led to a similar result (entry 2). PdCl2(PPh3)2 in
toluene9 gave the DA intermediate as the major product
along with a minor unidentifiable side product (entry 3).
ported by Iwasawa’s group in 1998 using W(CO)5 THF as
3
the catalyst, which required 3-5 days with 10-30 mol %
of the catalyst.6 In 2005, the same group reported a photo-
irradiated tandem carbomelation reaction using [ReCl(CO)5]
as the catalyst.7 And a year later, Toste’s group reported
mild and efficient conditions using AuClPPh3/AgBF4 as
ꢀ ꢁ
2366–2447.
ꢀ
(4) Denes, F.; Perez-Luna, A.; Chemla, F. Chem. Rev. 2010, 110,
(8) (a) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.;
LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991–5994.
Other references using Au(I) as the catalyst:(b) Lee, K.; Lee, P. H. Adv. Synth.
(5) Drouin, J.; Boaventura, M. A.; Conia, J.-M. J. Am. Chem. Soc.
1985, 107, 1726–1729.
(6) (a) Maeyama, K.; Iwasawa, N. J. Am. Chem. Soc. 1998, 120,
ꢀ
ꢀ
Catal. 2007, 349, 2092–2096. (c) Barabe, F.; Betournay, G.; Bellavance, G.;
Barriault, L. Org. Lett. 2009, 11, 4236–4238.
(9) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2764–
2765.
(10) (a) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817–7831. (b) Itoh,
Y.; Tsuji, H.; Yamagata, K.-i.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura,
E. J. Am. Chem. Soc. 2008, 130, 17161–17167.
1928–1929. Other references using W(CO)5 THF as the catalyst:(b)
3
Iwasawa, N.; Maeyama, K.; Kusama, H. Org. Lett. 2001, 3, 3871–3873.
(c) Kusama, H.; Yamabe, H.; Iwasawa, N. Org. Lett. 2002, 4, 2569–2571. (d)
Iwasawa, N.; Miura, T.; Kiyota, K.; Kusama, H.; Lee, K.; Lee, P. H. Org.
Lett. 2002, 4, 4463–4466.
(7) Kusama, H.; Yamabe, H.; Onizawa, Y.; Hoshino, T.; Iwasawa,
N. Angew. Chem., Int. Ed. 2005, 44, 468–470.
(11) The procedures for preparation of 1 are available in the Support-
ing Information.
Org. Lett., Vol. 13, No. 4, 2011
589

Table 2. Scope of the DA/Carbocyclization Cascade Reactiona
a The general procedures were followed. b The relative configurations of the cyclized products were determined by 2D NMR experiments. c Isolated
yields (%) after silica gel column chromatography. d The endo/exo ratios were determined by the isolated yields or by comparison of the signals at δendo
4.95-5.16 ppm and δexo 4.70-4.73 ppm in 1H NMR. e The catalyst loading can be reduced to 5 mol % in a 10 mmol scale with comparable yields and
selectivity. f 0.1 mL of NEt3 was added after the cyclization reaction. g The endo product was defined with respect to the cynao group. h 5 mol % of triflic
acid was added after the cyclization reaction.
After surveying some of the late transition metal salts that
are known to be potential bifunctional catalysts, we found
that the cascade cyclization proceeded smoothly with
AgBF4, InCl3 or ZnI2 in 1,2-dichloroethane (DCE) and
gave the expected bicyclic product (2) in modest yields
along with the side products that resulted from hydrolysis
of 1 and the DA intermediate (entry 4-7). The bicyclic
products were separable by silica gel flesh column chro-
matography and were fully characterized by 1H, 13C NMR
and HRMS. The major product was found to be the endo
product by 2D NMR experiments. These encouraging
results promoted us to further optimize the reaction con-
ditions with ZnI2. When toluene, THF, or 1,4-dioxane was
used as the solvent, the hydrolysis of 1 and the DA
intermediate became a serious problem and led to only a
trace amount of the expected products (entry 7-9). Sur-
prisingly, 1 was found to be very stable in CH3CN. The
cascade cyclization proceeded smoothly under the reaction
conditions and gave 92% of the cyclized products with
endo/exo equaling 4.8:1 (entry 10). Various Zn(II) salts
provided modest to excellent yields of the bicyclic products
with modest to very good endo selectivity (entry 11-13).
The optimal conditions included using 0.2 equiv of ZnBr2
in CH3CN, which afforded 96% yields of the cyclized
products with the endo/exo ratio equaling 12:1 (entry 13).
With the optimized conditions in hand, the scope of this
cascade cyclization reaction was studied and the results are
summarized in Table 2. In the presence of Et3N, the cas-
cade cyclization gave only the exo product in 89% yield
(entry 2). The exo product could be formed via epimeriza-
tion of the aldehyde moiety. This condition could be a very
useful complementary tool for obtaining the correspond-
ing exo product efficiently. Cascade cyclizations of 1 with
a variety of dienophiles were investigated, and they all gave
the expected cyclized products (3-6) in very good yields (85-
93%) with modest to excellent endo selectivity (entry 3-6).
590
Org. Lett., Vol. 13, No. 4, 2011

Among the dienophiles being tested, N-phenylmaleimide
provided the best endo selectivity (entry 4). Cyclization of
silyl enol ether 7 with acrolein led to a mixture of double
bond isomers, which can be completely converted to the
R,β-unsaturated ketone by addition of a catalytic amount
of triflic acid, which also induced the epimerization of the
aldehyde moiety and gave the exo product (8) in 70%
yields (entry 7). Replacing the methyl group of 1 with an n-
propyl groupalsoaffordeda very good yield ofthe cyclized
products (10) with modest endo selectivity (entry 8).
dition completely suppressed the over-reduction problem
and epimerization at C1 and gave 11 in 97% yields. After
TIPS protection of the resulting alcohol, the ketone moiety
was oxidized to the R,β-unsaturated ketone via Saegusa
oxidation.12 Cuprate addition to enone 13 successfully
installed the isopropyl group with the desired stereochem-
istry at C2. After removal of the TIPS ether, hydroboroa-
tion/oxidation of the exocyclic alkene of 14 gave triol 15
with the desired stereochemistry at C6. Interestingly, hy-
droboroation of 12 (a model with TIPS on the hydroxy
group) gave the same stereochemical results as that of 15.
This result suggested that the diastereoselectivity of this
reaction could be induced by coordination of the borane to
the ketone moiety prior to hydroboroation of the alkene.
After selective protection of the two primary alcohols of
triol 15, the remaining secondary alcohol was first mesy-
lated (85%) and was intended to be displaced by super
hydride. However, only a trace amont of the elimination
product (17) resulted along with some unidentifiable side
products. Thus 17 was obtained directly from dehydration
of 16 using Burgess reagent.13 Finally, TBS deprotection
and hydrogenation of the alkene finished the synthesis of
the aglycon of dendronobiloside A (18). The spectral data
of 18 were found to be consistent with those reported in the
literature.1b
Scheme 2. Synthesis of the Aglycon of Dendronobiloside A
In conclusion, we have successfully developed a new
class of highly convergent cascade cyclization reactions for
the construction of highly functionalized cis-hydrindanes
with an all-carbon quaternary center(s) and have demon-
strated its utility in the synthesis of the aglycon of dendro-
nobiloside A. With 0.2 equiv of an environmentally
friendly and less expensive bifunctional catalyst, ZnBr2, in
CH3CN, 1 reacted with a variety of dienophiles and gave
the bicyclic products in very good yields with high selec-
tivity. We are currently investigating the utility of this
cyclization strategy for the construction of other bicyclic
fused ring systems and exploring their utility in natural
product synthesis.
To demonstrate the utility of this cascade cyclization
reaction, 2a was employed as the building block for the
synthesis of the aglycon of dendronobiloside A, which is a
sequiterpene glycoside isolated from the stems of Dendro-
bium nobile (a plant used in traditional Chinese medicine)
with immunomodulatory activity.1b As shown in Scheme 2,
attemptsofselective reduction of the aldehyde moietyof2a
with NaBH4 alone led to the over-reduction product and
epimerization at C1. These problems were solved by the
addition of a stoichiometric amount of 2,4-pentanedione
before the addition of NaBH4. This additive would act as a
proton source aswellas a scavenger for excess hydrides. To
the best of our knowledge, this is the first example of
utilizing 2,4-pentanedione in a selective reduction. This con-
Acknowledgment. The financial support for this project
from the National Natural Science Foundation of China
(Grant No. 20672003) andthePeking UniversityShenzhen
Graduate School is gratefully acknowledged. A special
acknowledgment is made to the Hong Kong Polytechnic
University, which is funded by the University Grants
Committee of Hong Kong Special Equipment Grant, for
the 500 and 600 MHz NMR spectrometers.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Am. Chem.
Soc. 1970, 92, 5224–5226. (b) Burgess, E. M.; Penton, H. R., Jr.; Taylor,
E. A. J. Org. Chem. 1973, 38, 26–31.
(12) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–
1013.
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