Copper(I)-catalyzed hydroalkoxylation/hydrogen-bonding-induced asymmetric hetero-diels-alder cycloaddition cascade: An approach to aromatic spiroketals

Article abstract of DOI:10.1002/asia.201101056

One thing leads to another: Bis(benzannelated) 5,6-spiroketal skeletons can be constructed by an efficient cascade process involving an unprecedented Cu^I-catalyzed intramolecular alkyne hydroalkoxylation and an asymmetric hetero-Diels-Alder cyc

Full text of DOI:10.1002/asia.201101056

DOI: 10.1002/asia.201101056
Copper(I)-Catalyzed Hydroalkoxylation/Hydrogen-Bonding-Induced
Asymmetric Hetero-Diels–Alder Cycloaddition Cascade: An Approach to
Aromatic Spiroketals
Xin Li,[a] Jijun Xue,*[a] Chusheng Huang,[b] and Ying Li[a]
Aromatic spiroketals are important subunits found in var-
ious biologically active natural products,[1] such as rubromy-
cin (1),[2] paecilospirone (2),[3] papulacandin (3),[4] and ber-
kelic acid (4; Scheme 1).[5] The unique aromatic spiroketal
ring system has been proven to be essential for the biologi-
like aromatic spiroketal libraries for further biological and
pharmacological investigation.
For decades, domino reactions have received much atten-
tion for their high efficiency, low waste and easy manipula-
tion.[11] Although they are widely applied to the synthesis of
complex molecules, these appealing synthetic strategies have
rarely been used in the synthesis of aromatic spiroketals. To
date, only one successful synthesis has been achieved.[8p] As
part of our continuing efforts directed towards the synthesis
of aromatic spiroketals using a hetero-Diels–Alder protoco-
l,[8a,b] we report herein a domino process for the diastereose-
lective synthesis of a series of multifunctionalized spiroketal
derivatives. As shown in Scheme 2, a metal-catalyzed cycli-
zation of phenols 7 provides the exocyclic enol ethers 9,
Scheme 1. Examples of biologically active aromatic spiroketals.
cal activity of several of these compounds and is regarded as
the privileged pharmacophore.[6] Despite the progress ach-
ieved in recent years,[7,8] preparation of diversely functional-
ized aromatic spiroketals remains a challenge. In contrast,
the construction of their aliphatic counterparts has been ex-
tensively explored.[9] Notably, some simplified aliphatic spi-
roketals derived from their parent natural products retain
biological activity.[10] Therefore, there is still a demand for
the development of a convenient, efficient, and stereoselec-
tive methodology that can readily provide natural-product-
Scheme 2. Domino process for the construction of aromatic spiroketals.
which subsequently undergo an asymmetric hetero-Diels–
Alder cycloaddition with o-quinone methides 10 (o-QMs,
generated in situ by heating their precursor o-methyleneace-
toxyphenols 8[12]) to furnish the aromatic spiroketal skele-
ton. The entire process is designed to be carried out in a
one-pot manner, and excellent diastereoselectivities are ach-
ieved due to an intermolecular hydrogen-bonding of the two
reacting species (9 and 10). Both building blocks (7 and 8)
can readily be prepared in only two steps from the corre-
sponding commercially available salicylaldehydes.[13]
[a] X. Li, Dr. J. Xue, Prof. Y. Li
State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University
Lanzhou 730000 (P. R. of China)
Fax : (+86)0931-8912582
E-mail: Xuejj@lzu.edu.cn
[b] Prof. C. Huang
Chemistry and Life Science College
Guangxi Teachers Education University
Nanning 530001 (P. R. of China)
Our investigation began with the search for an appropri-
ate catalyst. Although numerous intramolecular alkyne hy-
droalkoxylations have been reported, there are only three
papers on the cyclization of 2-(1-hydroxyprop-2-ynyl)phenol
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201101056.
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903

COMMUNICATION
Table 2. Optimization of the reaction conditions.[a]
derivatives. In these studies, the reaction was catalyzed by
gold, palladium, or silver.[14] This situation prompted us to
develop a new catalyst system. Initial experiments were per-
formed using phenols 7a and 8a as model substrates, which
were treated with 5 mol% CuI and 10 mol% Cs2CO3 in dry
benzene in a sealed tube at 1108C for 26 h. Gratifyingly, the
desired spiroketal product 11a could be isolated in 42%
yield (Table 1, entry 1). Remarkably, the addition of PPh3
(5 mol%) improved the yield to 52%, which probably indi-
Entry
Solvent
T [8C]
t [h]
Product
Yield [%][b]
1
2
3
4
5
6
7
8
THF
110
110
110
110
110
100
90
100
100
100
26
26
26
26
26
26
26
26
22
31
11a
11a
11a
9a, 12a
9a, 12b
11a
11a
11a
29
31
64
dioxane
CHCl3
MeOH
EtOH
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
85, 92[c]
82, 99[c]
79
Table 1. Screening of catalysts.[a]
52
74[d]
77
9
10
11a
11a
70
[a] Reaction conditions: 7a (0.1 mmol), 8a (0.12 mmol), CuI (5 mol%),
PPh3 (5 mol%), solvent (0.5 mL) in a sealed tube, reacted at the temper-
ature indicated. [b] Yields were calculated after column chromatography.
[c] Based on 7a and 8a, respectively. [d] CuI (2.5 mol%), PPh3
(2.5 mol%) were used.
Entry Catalyst [mol%]
8a/7a [mol/mol] Yield [%][b]
1
CuI/Cs2CO3 (5/10)
1
1
1
1
1
1
1
1
1
1
1
1
42
52
36
48
38
41
52
45
38
26
51
0
2
3
4
5
CuI/PPh3/Cs2CO3 (5/5/10)
CuCl/PPh3/Cs2CO3 (5/5/10)
CuBr/PPh3/Cs2CO3 (5/5/10)
CuCl2/PPh3/Cs2CO3 (5/5/10)
6
CuN
yields (Table 2, entries 4 and 5). Scheme 3 accounts for the
formation of 12.[15] The collective results (Table 1, entry 12
and Table 2, entries 4 and 5) provide evidence for the mech-
anism of the domino process: compounds 8 are easily con-
7
8
9
10
11
12
13
CuI/PPh3/K3PO4 (5/5/10)
CuI/PPh3/LiOH·H2O (5/5/10)
CuI/PPh3/piperidine (5/5/10)
CuI/PPh3/TMG[c] (5/5/10)
CuI/PPh3 (5/5)
none
CuI/PPh3 (5/5)
1.2
59
[a] Reaction conditions: 7a (0.1 mmol), 8a, catalysts, dry benzene
(0.5 mL) in a sealed tube, 1108C for 26 h. [b] Yields were calculated after
column chromatography. [c] TMG=1,1,3,3-tetramethylguanidine.
Scheme 3. The formation of 12.
cates CuI activation by PPh3 (Table 1, entry 2). We then ex-
amined the efficiency of other copper salts under the same
experimental conditions. Compared to CuI, other copper
salts were less active and afforded lower yields (Table 1, en-
tries 3–6). The effect of added base was also examined
(Table 1, entries 7–11). Surprisingly, a good yield of spiroke-
tal can be maintained in the absence of added base (Table 1,
entry 11), which is quite different from the results of other
research groups.[14] On the other hand, after heating the re-
action mixture for 26 h without a catalyst, 8a was decom-
posed and 7a was recovered (entry 12), indicating that 7a
was neither converted to 9a (R1 =H) nor did it undergo
hetero-Diels–Alder cycloaddition with the o-QMs in the ab-
sence of the catalyst. Further research showed that the yield
of spiroketal can be promoted simply by increasing the
amount of 8a to 1.2 equivalents (entry 13).
An efficient method was identified for construction of ar-
omatic spiroketals in a one-pot manner. To improve yields,
further optimization studies were made. First, the influence
of solvents was examined. The results show that the same
reaction can also be performed in THF, 1,4-dioxane
(Table 2, entries 1 and 2), or CHCl3, which afforded the
highest yield (Table 2, entry 3). When alcohols were used as
the solvents, however, undesired 1,4-addition products 12
and the enol ether 9a (R1 =H) were obtained in excellent
verted to o-QMs 10 at high temperature and 9 are formed
very quickly from 7 in the presence of the catalyst. As enol
ethers 9 are good dienophiles and o-QMs 10 are very reac-
tive diene species, once 9 and 10 are formed, they immedi-
ately react with each other to produce the spiroketals 11. In
addition, o-QMs 10 react more readily with nucleophiles
(such as alcohols) to form 1,4-addition products than they
do with dienophiles. Next, the effects of temperature and re-
action time were examined. An obvious increase in the yield
was obtained when the reaction was performed at 1008C for
26 h (Table 2, entry 6). Further research demonstrated that
lower temperature (Table 2, entry 7) or reduced catalyst
loading (Table 2, entry 8) resulted in decreased yields, while
attempts to improve the yield by altering the reaction time
were unsuccessful (Table 2, entries 9 and 10).
As a high diastereomeric ratio of the product was detect-
ed by NMR spectroscopy (>20:1), our attention next
moved to assignment of the stereochemistry of the spiroke-
tal 11a. The relative configuration of 11a was finally estab-
lished to be cis by NOE analysis,[16] which was exactly oppo-
site to that obtained with Reissigꢁs protocol.[8 h] Because in-
termolecular hydrogen bonding in asymmetric Diels–Alder
cycloadditions has been demonstrated by both theoretical
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Chem. Asian J. 2012, 7, 903 – 906

Asymmetric Hetero-Diels–Alder Cycloaddition Cascade
calculations and several experimental results,[17] we believe
that a transition state involving a hydrogen-bonding interac-
tion between the 3’-hydroxy group and the carbonyl of the
o-QM could account for the observed stereochemistry
(Scheme 4).
yields and excellent diastereoselectivities. This methodology
achieves a high degree of complexity from two simple and
readily available open-chain starting materials in just one
operative step. Importantly, the diastereoselective hetero-
Diels–Alder cycloaddition which proceeds via a novel H-
bonded transition state is of great interest in stereocon-
trolled synthesis and may be widely used in the future. This
cis-stereoselectivity nicely complements the anti-stereoselec-
tivity developed by other groups. In addition, the tolerance
of various substituents on the aromatic rings makes this pro-
tocol highly practical for diversity-oriented synthesis. The
application of the new method to the total synthesis of natu-
ral products and the biological evaluation of these bis(ben-
zannelated) spiroketals are underway in our laboratory.
Scheme 4. Proposed transition state for the hetero-Diels–Alder cycload-
dition.
Under the optimized reaction conditions, the scope and
generality of this new one-pot process were then explored.
As shown in Scheme 5, the cascade reaction proceed with-
out any problems for a wide range of substrates bearing
electron-donating or electron-withdrawing substituents on
the aryl ring, providing spiroketals in good yields and excel-
lent diastereoselectivities (>20:1 d.r. in all cases). In partic-
ular, the sterically hindered bis(ortho-methoxy)-substituted
spiroketal 11q was obtained in good yield, indicating that
steric hindrance had no obvious influence on the efficiency
of our method.
Experimental Section
General procedure for the preparation of the aromatic spiroketals
A reaction tube was charged with 2-(1-hydroxyprop-2-ynyl)phenol (7,
0.1 mmol), o-methyleneacetoxyphenol (8, 0.12 mmol), CuI (0.005 mmol),
PPh3 (0.005 mmol), and CHCl3 (0.5 mL). The tube was filled with argon,
sealed, and heated at 1008C for 26 h in a drying oven. The resulting reac-
tion mixture was cooled to ambient temperature, diluted with CH2Cl2,
washed with water, purified by flash silica gel chromatography using n-
hexane/ethyl acetate (4:1) as eluent to give the desired spiroketal.
In conclusion, we have developed a novel, convenient,
and efficient method to construct diversely functionalized
aromatic spiroketals by a one-pot domino process with good
Acknowledgements
We are grateful for the financial support of the National Natural Science
Foundation of China (Grant No. 20872053).
Keywords: cycloaddition
· diastereoselectivity · domino
reactions · hydrogen bonding · spiroketals
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Jijun Xue, Ying Li et al.
COMMUNICATION
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Received: December 29, 2011
Published online: February 15, 2012
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Chem. Asian J. 2012, 7, 903 – 906