Tunable cyclization strategy for the synthesis of zizaene-, allo- cedrane-, seco-kaurane-, and seco-atesane-type skeletons

Article abstract of DOI:10.1021/acs.orglett.7b02610

A versatile Lewis acid-mediated cyclization strategy has been developed for selectively establishing zizaene-, allo-cedrane-, seco-kaurane-, and secoatesane- type skeletons. The zizaene- and seco-atesane-type skeletons can be obtained in a cascade manner, which involves Diels-Alder reaction of cyclic enones with bissilyloxy dienes and carbocyclization of yne-enolates through Lewis acid dependent 5- or 6-exo-dig modes. This cyclization strategy was also employed for the core synthesis of tashironin.

Full text of DOI:10.1021/acs.orglett.7b02610

Letter
pubs.acs.org/OrgLett
Tunable Cyclization Strategy for the Synthesis of Zizaene-, allo-
Cedrane-, seco-Kaurane-, and seco-Atesane-Type Skeletons
Qianqian Yang, Wenjing Ma, Gaopeng Wang, Wenli Bao, Xiaoshu Dong, Xuefeng Liang, Lizhi Zhu,*
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
S
* Supporting Information
ABSTRACT: A versatile Lewis acid-mediated cyclization strategy has been
developed for selectively establishing zizaene-, allo-cedrane-, seco-kaurane-, and seco-
atesane-type skeletons. The zizaene- and seco-atesane-type skeletons can be obtained
in a cascade manner, which involves Diels−Alder reaction of cyclic enones with bis-
silyloxy dienes and carbocyclization of yne−enolates through Lewis acid dependent 5-
or 6-exo-dig modes. This cyclization strategy was also employed for the core synthesis
of tashironin.
ring, I will become a zizaene-2 or seco-kaurane-type3 skeleton,
icyclo[3.2.1]octanes (I) and bicyclo[2.2.2]octanes (II) are
respectively, and II will become an allo-cedrane-4 or seco-
Bcommon bridged ring systems found in natural products
atesane-type3 skeleton, respectively. These substructures are
common motifs in the core structures of a variety of bioactive
natural products. Our group has initiated a long-term project
for developing a tunable cascade cyclization strategy for these
bridged ring systems using dual-mode Lewis acids,5 which
could provide two different modes of activation for cyclization
via σ- and π-complexation.6 As shown in Figure 1b, we have
previously reported a dual-mode Lewis acid induced Diels−
Alder (DA)/carbocyclization cascade cyclization of enone III
with diene IV for establishing the seco-kaurane-type skeleton
V.6c,d However, this cascade cyclization strategy can only
provide the 5-exo-dig cyclization products V, and the DA
cycloaddition of diene IV with 5-membered enone VI (n = 1)
under Lewis acid conditions has been reported to be difficult.7
Instead of using Danishefsky’s base-mediated “sequential
Michael addition protocol”,7a we decided to employ more
electron-rich bis-silyloxy diene VII for cyclization with enone
VI to overcome the limitation of our previous strategy (Figure
1c). By tuning the reaction conditions, the DA intermediate
VIII could undergo either 5-exo-dig carbocyclization and lead to
zizaene- and seco-kaurane-type skeletons X or 6-exo-dig
carbocyclization and give allo-cedrane- and seco-atesane-type
skeletons IX. Moreover, the cyclization products bear a
hydroxyl at the ring junction, which could be useful for the
synthesis of natural products, such as steviol glucosides,8
gibberellic acid,9 tashironin,10 and platencin SL3.11
(Figure 1a).1 When they are fused with a 5- or 6-membered
Figure 1. (a) Skeletons containing bicyclo[3.2.1]octanes (I) and
bicyclo[2.2.2]octane (II). (b) Our previous work. (c) The goal of this
work.
Received: August 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To study the selectivity of the carbocyclization, bis-silyloxy
diene ( )-3 was prepared by DA cycloaddition between enone
1 and 2,3-bis(tert-butyldimethylsiloxy)-1,3-butadiene (2) using
Me2AlCl in CH2Cl2. However, ( )-3 underwent intramolecular
Mukaiyama aldol reaction at rt and gave ( )-4 as the major
side product. This side reaction was suppressed by quenching
the reaction at −20 °C. With ( )-3 in hand, the effects of
Lewis acids on the selectivity of the carbocyclization were
studied. As shown in Table 1, dual-mode Lewis acids,5 such as
type skeleton of ( )-5b was determined unambiguously by X-
ray crystallography.12
After studying the effects of dual-mode Lewis acids, a variety
of π-Lewis acids were investigated. Using AuCl13 in CH3CN
gave 82% yield of the cyclized products with slightly higher
selectivity for ( )-5a (Table 1, entry 8). Lowering the reaction
temperature to −40 °C led to a lower yield (59%) with a
similar product ratio (Table 1, entry 9). Switching the solvent
to CH2Cl2 gave only 46% yield of the cyclized products with a
higher selectivity for ( )-5a (3:1) (Table 1, entry 10). An
attempt at increasing the product ratio by lowering the reaction
temperature to −78 °C led to a much lower yield (28%) with a
similar level of selectivity (Table 1, entry 11). PPh3AuCl,13
a
Table 1. Effects of Lewis Acids on Cyclization of ( )-3
16
AuCl3,14 Cu(OTf)2,15 Pd(OAc)2, and PdCl2 did not provide
any cyclized product at 0 °C or rt (Table 1, entries 12−16).
17
PtCl2 in THF led to hydrolysis of ( )-3 and resulted in a
mixture of α-silyloxy ketones (Table 1, entry 17). Using PtCl2
in CH3CN also led to decomposition of the substrate at rt
(Table 1, entry 18) but surprisingly afforded ( )-5a in 10%
yield at 0 °C (Table 1, entry 19). This encouraging result
prompted us to study the effects of PtCl2 under different
conditions. Switching the solvent to CH2Cl2 afforded the
cyclized products in 65% yield with a ratio ( )-5a/( )-5b at
3.6:1 (Table 1, entry 20). After studying the effects of catalyst
loading and reaction temperature, the optimal results was
obtained by using 0.5 equiv of PtCl2 in CH2Cl2 at −78 °C,
which afforded 72% yield of the cyclized products in favor of
the seco-atesane-type skeleton of ( )-5a (7.8:1) (entry 23).
The results of this study indicated that π-Lewis acids generally
favored the 5-exo-dig cyclizations and afforded the seco-kaurane-
type skeleton preferentially.
Based on the results of the above study, ZnBr2 could be a
suitable dual-mode Lewis acid for the cascade cyclization
between enone 1 and diene 2. After a survey of different
reaction conditions, the cascade cyclization was optimized by
using 1 equiv of ZnBr2 in CH2Cl2 at rt, which afforded 93%
yield of ( )-5b in a single operation (Table 2, entry 1). With
the above optimal conditions in hand, a series of dienes and
enones with different steric hindrances were investigated.
Cascade cyclization of enone 1 with diene 6 led to only 35%
yield of the cyclized products (Table 2, entry 2) due to rapid
hydrolysis of diene 6. The selectivity for ( )-7b is low, and
equilibration of ( )-7a to ( )-7b became unfavorable after
hydrolysis of the TMS ethers of the cyclized products. The
more bulky diene 8 gave a reasonable good yield of the cyclized
product ( )-9b, but the equilibration of ( )-9a to ( )-9b is
slow (Table 2, entry 3). These results indicated that diene 2 has
the optimal size for balancing the stability and reactivity in the
cascade cyclization. Cascade cyclization of enone 1 with cyclic
diene 10 afforded 79% yield of ( )-11a (the structure was
determined by X-ray crystallography)12 as the only product
(Table 2, entry 4). However, diene 12 gave only the
Mukaiyama Michael side product 13 (Table 2, entry 5) due
to its steric hindrance. Cascade cyclization of ( )-enone 14
with diene 2 gave 79% yield of ( )-15b as a single
diastereomer (Table 2, entry 6), suggesting the possibility for
developing an diastereoslective version via substrate-control.
For synthesis of the zizaene- and allo-cedrane-type skeletons, 5-
membered enone 16 was employed for the cascade cyclization
with diene 2, which resulted in 71% of a 4:1 mixture of ( )-17a
(zizaene) and ( )-17b (allo-cedrane) (Table 2, entry 7).
Interestingly, the ratio of the cyclized products remains
unchanged upon heating with long reaction time probably
b
c
entry Lewis acid (equiv)/solvent temp (°C) yield (%) ( )-5a/5b
1
InCl3 (1)/CH2Cl2
InBr3 (1)/CH2Cl2
FeCl3 (1)/CH2Cl2
ZnCl2 (1)/CH2Cl2
ZnCl2 (1)/CH2Cl2
ZnBr2 (1)/CH2Cl2
ZnI2 (1)/CH2Cl2
rt
rt
rt
rt
2
3
4
43
46
98
50
82
59
46
28
1:9
d
5
rt
rt
( )-5b only
( )-5b only
1:2.8
d
6
e
7
rt
8
AuCl (1)/CH3CN
AuCl (1)/CH3CN
AuCl (1)/CH2Cl2
AuCl (1)/CH2Cl2
PPh3AuCl (0.2)/toluene
AuCl3 (0.2)/CH2Cl2
Cu(OTf)2 (1)/CH2Cl2
Pd(OAc)2 (1)/THF
PdCl2 (1)/CH3CN
PtCl2 (1)/THF
rt
1.3:1
9
−40
rt
1.4:1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3:1
−78
0 or rt
0 or rt
0 or rt
0 or rt
0 or rt
0 or rt
rt
3:1
PtCl2 (1)/CH3CN
PtCl2 (1)/CH3CN
PtCl2 (1)/CH2Cl2
PtCl2 (0.5)/CH2Cl2
PtCl2 (0.2)/CH2Cl2
PtCl2 (0.5)/CH2Cl2
0
10
65
62
60
72
( )-5a only
3.6:1
0
0
5.1:1
0
5:1
−78
7.8:1
b
a
The general procedures were followed (time = 30 min). Isolated
c
yield (%) after silica gel column chromatography. The product ratios
were determined by 1H NMR signals of the exocyclic alkenes.
d
e
Reaction time = 20 h. Reaction time = 40 h.
InCl3, InBr3, and FeCl3, led to decomposition of the substrates
(Table 1, entries 1−3). ZnCl2 gave 43% of the cyclized
products with a ( )-5a/( )-5b ratio of 1:9 (Table 1, entry 4).
Interestingly, only ( )-5b was obtained with an extended
reaction time (20 h) (Table 1, entry 5), indicating Pinaol-type
rearrangement of ( )-5a to ( )-5b occurred under the effect
of Lewis acid. Finally, the formation of ( )-5b was optimized
by using ZnBr2 in CH2Cl2 at rt for 20 h (Table 1, entry 6),
while ZnI2 gave only 50% of the cyclized products with a ratio
( )-5a/( )-5b at 1:2.8 (Table 1, entry 7). The seco-kaurane-
B
DOI: 10.1021/acs.orglett.7b02610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Substrate Scope of the Cascade Cyclization
a
b
c
The general procedures were followed. Isolated yield (%) after silica gel column chromatography. The product ratios were determined by the 1H
d
e
NMR signals of the exocyclic alkenes. The relative configurations of the OTBS group were not determined. The geometry of the alkene was not
determined.
due to the ring strain of the cyclized products. Introducing an
ethyl group to the alkyne terminus (enone 18) led to excellent
selectivity for the zizaene-type-skeleton ( )-19a as a single
isomer with moderate yields (Table 2, entry 8).
Scheme 1. Model Study toward the Synthesis of Tashironin
To demonstrate the utility of the cascade cyclization, a model
toward the synthesis of tashironin18 was studied. As shown in
Scheme 1, Morita−Baylis−Hillman reaction of cyclopentenone
with 3-(trimethylsilyl)propynal followed by silylation gave
( )-20, which underwent cascade cyclization with diene 2
using ZnBr2 and afforded good yields of cyclized product
( )-21 diastereoselectively. The structure of ( )-21 was
determined by X-ray crystallography of ( )-22,12 which was
obtained from by treating ( )-21 with TBAF at 0 °C. Addition
of excessive MeLi gave ( )-23 as a single diastereomer. The
relative configurations of the tertiary alcohols were not
determined since the stereogenic centers will be destroyed in
the subsequent step. Upon treatment of aq TsOH in refluxing
toluene,19 the carbocation (XI) generated in situ underwent
elimination and Pinol-type rearragement, which led to the allo-
cedrane-type skeleton of ( )-24.12 The model compound
( )-24 contains the core structure of tashironin, which
provides a foundation for developing a total synthesis for this
natural product and related compounds based on this cascade
cyclization strategy.
In summary, we have extensively studied the effects of Lewis
acids on the selectivity of the carbocyclization of the DA
intermediate ( )-3 and developed a tunable cyclization strategy
for establishing the zizaene-, allo-cedrane-, seco-kaurane-, and
seco-atesane-type skeletons. Upon treatment of ZnBr2/CH2Cl2
C
DOI: 10.1021/acs.orglett.7b02610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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(4) Mehta, G.; Maity, P. Tetrahedron Lett. 2011, 52, 1753−1756.
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at rt, the 6-membered enone 1 and diene 2 underwent cascade
cyclization and afforded the 6-exo-dig cyclized product (bearing
the seco-atesane-type skeleton) selectively in 93% yield. The 5-
exo-dig cyclized product (bearing the seco-kaurane-type
skeleton) can be obtained via carbocyclization of the DA
intermediate ( )-3 using PtCl2 at −78 °C (72%, 7.8:1). On the
other hand, the cascade cyclization between 5-membered enone
( )-20 and diene 2 using ZnBr2 favors the 5-exo-dig cyclization
product (bearing the zizaene-type skeleton), which was
converted to the allo-cedrane-type skeleton of ( )-24 (the
core of tashironin) with two steps in a model study.
Development of an asymmetric version using chiral Lewis
acids and a total synthesis of tashironin and related natural
products using this cascade cyclization strategy are ongoing in
our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02610.
Experimental procedures and characterization data for all
new compounds (PDF)
X-ray crystallographic data for compound ( )-5b (CIF)
X-ray crystallographic data for compound ( )-11a (CIF)
X-ray crystallographic data for compound ( )-17b (CIF)
X-ray crystallographic data for compound ( )-22 (CIF)
X-ray crystallographic data for compound ( )-24 (CIF)
(15) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc.
2003, 125, 10921−10925.
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L.; Malacria, M.; Marco-Contelles, J. J. Am. Chem. Soc. 2004, 126,
denas, D. J.; Echavarren, A. M.
3408−3409. (b) Martín-Matute, B.; Car
́
AUTHOR INFORMATION
Corresponding Authors
■
Angew. Chem., Int. Ed. 2001, 40, 4754−4757.
(18) (a) Cook, S. P.; Polara, A.; Danishefsky, S. J. J. Am. Chem. Soc.
2006, 128, 16440−16441. (b) Cook, S. P.; Danishefsky, S. J. Org. Lett.
2006, 8, 5693−5695. (c) Sharma, M. K.; Banwell, M. G.; Willis, A. C.;
Rae, A. D. Chem. - Asian J. 2012, 7, 676−679. (d) Austin, K. B.;
Elsworth, J. D.; Banwell, M. G.; Willis, A. C. Org. Biomol. Chem. 2010,
8, 751−754. (e) Mehta, G.; Maity, P. Tetrahedron Lett. 2011, 52,
5161−5165. (f) Polara, A.; Cook, S. P.; Danishefsky, S. J. Tetrahedron
Lett. 2008, 49, 5906−5908. (g) Ohtawa, M.; Krambis, M. J.; Cerne, R.;
Schkeryantz, J. M.; Witkin, J. M.; Shenvi, R. A. J. Am. Chem. Soc. 2017,
139, 9637−9644. (h) Mehta, G.; Maity, P. Tetrahedron Lett. 2007, 48,
8865−8868.
*E-mail: lzzhu86@pku.edu.cn.
*E-mail: lizc@pkusz.edu.cn.
ORCID
Chi-Sing Lee: 0000-0002-3564-8224
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(19) Cernijenko, A.; Risgaard, R.; Baran, P. S. J. Am. Chem. Soc. 2016,
138, 9425−9428.
We gratefully thank the NSFC (National Natural Science
Foundation of China, Nos. 21502002 and 21572006), Chinese
Postdoctoral Science Foundation (2015M580910), the SSTIC
(Shenzhen Science and Technology Innovation Committee,
JSGG20160301103446375, JCYJ20160330095659560, and
JCYJ20150626111042525), and Peking University Shenzhen
Graduate School for the financial support. Special acknowl-
edgement is made to Dr. Wesley Ting-kwok Chan (Hong Kong
Polytechnic University) for the X-ray crystallography of
compounds ( )-5b, ( )-11a, ( )-17b, ( )-22, and ( )-24.
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DOI: 10.1021/acs.orglett.7b02610
Org. Lett. XXXX, XXX, XXX−XXX