Synthesis of multi-substituted cyclobutenes: Cyclic strategy for [2?+?2] cycloaddition of ketene silyl acetals with propiolates

Article abstract of DOI:10.1016/j.tetlet.2017.06.039

Cyclic ketene silyl acetals were utilized for [2?+?2] cycloaddition with propiolates to prevent an undesired electrocyclic ring opening reaction. Trimethylaluminum catalyzed this cycloaddition to afford the cyclobutene derivatives in high yields. The adva

Full text of DOI:10.1016/j.tetlet.2017.06.039

Accepted Manuscript
Synthesis of multi-substituted cyclobutenes: Cyclic strategy for [2+2] cycload-
diton of ketene silyl acetals with propiolates
Yousuke Yamaoka, Motoki Ueda, Tohru Yamashita, Kazuma Shimoda, Ken-
ichi Yamada, Kiyosei Takasu
PII:
S0040-4039(17)30761-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.039
TETL 49031
Reference:
Tetrahedron Letters
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10 June 2017
13 June 2017
Please cite this article as: Yamaoka, Y., Ueda, M., Yamashita, T., Shimoda, K., Yamada, K-i., Takasu, K., Synthesis
of multi-substituted cyclobutenes: Cyclic strategy for [2+2] cycloadditon of ketene silyl acetals with propiolates,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.06.039
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Synthesis of multi-substituted cyclobutenes:
Cyclic strategy for [2+2] cycloadditon of
ketene silyl acetals with propiolates
Leave this area blank for abstract info.
Yousuke Yamaoka,* Motoki Ueda, Tohru Yamashita, Kazuma
Shimoda, Ken-ichi Yamada, and Kiyosei Takasu*

1
Tetrahedron Letters
Synthesis of multi-substituted cyclobutenes: Cyclic strategy for [2+2] cycloadditon of
ketene silyl acetals with propiolates
Yousuke Yamaoka,  Motoki Ueda, Tohru Yamashita, Kazuma Shimoda, Ken-ichi Yamada, and Kiyosei
Takasu
aGraduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Cyclic ketene silyl acetals were utilized for [2+2] cycloaddition with propiolates to prevent an
undesired electrocyclic ring opening reaction. Trimethylaluminum catalyzed this cycloaddition
to afford the cyclobutene derivatives in high yields. The advantage of this reaction was
highlighted by the successful application of -substituted propiolates to afford the multi-
substituted cyclobutenes. Furthermore, we applied this methodology to the late stage
functionalization of natural product artemisinin.
Available online
Keywords:
[2+2]cycloaddition
cyclobutenes
2009 Elsevier Ltd. All rights reserved.
cyclobutanes
ketenesilylacetals
Introduction
Accordingly, we investigated [2+2] cycloaddition of ketene
silyl acetals (KSA) with propiolates for the synthesis of highly
Four-membered carbocycles, such as cyclobutenes and
cyclobutanes, have been utilized as synthetic intermediates,
because of their ring strain.1,2 In addition, they are sometimes
found in bioactive natural products (Figure 1).3 The simple route
for functionalized cyclobutene derivatives is [2+2] cycloaddition
of alkynes and alkenes, although the photoactivation is usually
required.4 We have recently developed a Brønsted acid-catalyzed
[2+2] cycloadditon of silyl enol ethers with acrylates and
propiolates to afford cyclobutane and cyclobutene derivatives,
respectively.5 This reactions can be carried out without the
activation which is required special equipment.
functionalized and oxidized cyclobutene and cyclobutane for the
purpose to synthesis these natural products above.6,7 Although
there are some reports of [2+2] cycloaddition of ketene silyl
acetals with propiolates, to the best of our knowledge, [2+2]
cycloaddition of -aryl ketene silyl acetals has not been
reported.8
Scheme 1. Preliminary results of synthesis of a cyclobutene
bearing an aromatic ring.
Figure 1. Natural products containing a cyclobutane/cyclobutene
scaffold.
At the outset of our study, [2+2] cycloaddition of KSA
derived from methyl phenylacetate with ethyl propiolate was
———
 Corresponding author. Tel.: +81-75-753-4563; fax: +81-75-753-4604; e-mail: yyamaoka@pharm.kyoto-u.ac.jp
 Corresponding author. Tel.: +81-75-753-4553; fax: +81-75-753-4604; e-mail: kay-t@pharm.kyoto-u.ac.jp

2
Tetrahedron
6
7
8
9
TIPS (1c)
TIPS (1c)
TIPS (1c)
TIPS (1c)
Me3Al (20)
Me3Al (10)
Tf2NH (2)
Tf2NH (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
89 (3ca)
54 (3ca)
47 (3ca)
40 (3ca)
investigated (Scheme 1a). The reaction catalyzed by various
Brønsted acids or Lewis acids failed to give the desired
cyclobutene because of its thermal ring opening reaction.
Bloomfield et al. reported that bicyclo[4.2.0]octene can undergo
thermal ring opening at high temperature to give cis,trans-
cyclooctadiene, but this compound could not be isolated because
of a rapid reverse reaction to the starting material.9 Thus, we
hypothesized that the use of cyclic KSA from isochromanone
would prevent the thermal ring opening reaction. As expected,
[2+2] cycloaddtion of cyclic KSA 1a from 3-isochromanone with
ethyl propiolate (2a) promoted by an equimolar amount of
trimethylaluminum afforded the desired cyclobutene 3aa bearing
an aromatic ring in 32% yield (Scheme 1b). Herein we wish to
report [2+2] cycloaddtion of cyclic KSAs of 3-isochromanone
with propiolates to afford the cyclobutene derivatives bearing an
aromatic ring. Furthermore, we investigated the generality of
[2+2] cycloaddtion with simple KSAs, and the late stage
a Condition: KSA 1 (0.55 mmol), 2a (0.5 mmol) in solvent (0.25 M) at 0
to 23 °C. b isolated yield.
Table 2. Substrate scope of propiolates.a
functionalization of
transformations of cyclobutene derivatives.
a
natural product10 and further
entry
2
R1
H
R2
Me
Ph
Et
yield (%)b
74 (3cb)
1
2
3
4
5
2b
2c
2d
2e
2f
H
63 (3cc)
Results and Discussion
Et
81 (90)c (3cd)
Ph
Et
67 (3ce)
We first optimized reaction conditions for cycloaddition of
isochromanone-derived KSA 1a with ethyl propiolate (2a) (Table
1). We found that the chemical yield could be improved to 60%,
when the temperature was gradually raised from 0 to 23 °C (entry
1). After screening several Lewis acids, trimethylaluminium was
a best catalyst.11 Then a series of solvents were examined, and
dichloromethane was a suitable solvent for this reaction to
improve the chemical yield (entries 1-3). Gratifyingly, a catalytic
amount of trimethylaluminum (20 mol%) gave the desired
product in almost the same yield (entry 4). The effects of silyl
substituents on KSA were evaluated (entries 4-6). Finally, the use
of triisopropylsilyl group (1c) as a protecting group gave the best
result (89% yield). The amount of trimethylaluminum could be
reduced to 10 mol%, although the yield was decreased to 54%
(entry 7). When 2 mol% of triflic imide (Tf2NH) was used
instead of trimethylaluminum, higher catalyst turnover numbers
were observed and the product was produced in 47% yield (entry
8). However, increasing the amount of the catalyst did not
improve the chemical yield (entry 9). Thus, the optimized
conditions entailed the use of 20 mol% of trimethylaluminum as
a catalyst and triisopropylsilyl group as a protecting group in
CH2Cl2 (entry 6).
CO2Et
Et
95 (3cf)
a Condition: KSA 1c (0.55 mmol), 2 (0.5 mmol), and Me3Al (20 mol%) in
CH2Cl2 (0.25 M) at 0 to 23 °C. b isolated yield. c 18.5 mmol scale.
With the optimized conditions in hand, we turned to examine
the substrate scope of propiolates with KSA 1c (Table 2). Both
alkyl (2b) and aryl (2c) esters of propiolic acid afforded the
desired cyclobutenes in good yields (entries 1 and 2). Next, we
investigated the [2+2] cycloaddition with propiolates bearing a β-
8e, 12
substituent.8b,
The reactions of 1c with internal ynoates
having an alkyl (2d) and an aromatic (2e) group gave the desired
products (3cd and 3ce) in good yields under the standard
conditions, respectively (entries 3 and 4). A
to
afford the desired product 3cd in 90% yield (7.7 g). The reaction
with diethyl acetylenedicarboxylate (2f) also gave the desired
product (3cf) in 95% yield (entry 5). Although we also conducted
[2+2] cycloadditon with acrylate to give the cyclobutane as in the
previous paper,5c the reaction of 1c with ethyl acrylate led only to
recover the starting material.
Next, substrate scope of various KSAs was examined (Table
3). KSA 1d gave almost no desired product due to its less
reactivity (entry 1). KSA 1e, prepared from 4,5-
dihydrobenzo[d]oxepin-2-one, gave 3ea in 79% yield (entry 2).
The [2+2] cycloaddition of monocyclic KSAs also worked well.
5-7 Membered KSAs reacted with ethyl propiolate to give the
corresponding cyclobutenes (3fa-3ha) in moderate to good yields
(entries 3-5). It is noteworthy that this methodlogy is superior to
the previous reports, in term of chemical yields.7c, 7d Furthermore,
KSAs bearing an alkyl or an aryl group at the -position were
applicable to this reaction to afford multi-substituted
cyclobutenes (3ia and 3ja) in high yields (entries 6 and 7).
Table 1. Optimization of reaction conditions.a
entry
Si
acid (mol%)
Me3Al (100)
Me3Al (100)
Me3Al (100)
Me3Al (20)
Me3Al (20)
solvent
toluene
CH2Cl2
THF
yield (%)b
60 (3aa)
73 (3aa)
0 (3aa)
The synthetic utility of the method was demonstrated by late
stage construction of a cyclobutene ring onto a biologically
active compound. Artemisinin is a peroxide-containing lactone
isolated from the antimalarial plant Artemisia annua.13 The low
bioavailability and low aqueous solubility of artemisinin have
prompted synthetic efforts to potent analogues compared to the
parent molecule.14 Thus, we investigated the late stage
1
2
3
4
5
TBS (1a)
TBS (1a)
TBS (1a)
TBS (1a)
TES (1b)
CH2Cl2
CH2Cl2
70 (3aa)
0 (3ba)

3
functionalization of artemisinin using the developed
methodology with its biologically crucial endoperoxide group
retained. The [2+2] cycloaddition of ethyl propiolate with the
lactone moiety proceeded without any problems to afford its
analogue 4 in 95% yield in two steps (Scheme 2).
concave face, probably to avoid the bulky TIPS group.
Reduction of the ester group and deprotection of the silyl group
afforded the desired product 8. The structure of 8 was
unambiguously determined by X-ray crystallographic analysis.
Finally, protection of the primary alcohol and PCC oxidation of
the acetal moiety gave cyclobutanone 9 in high yield (eq 2). We
observed an unique skeleton rearrangement of 10 under an acidic
deprotection condition to gave the compound 11 in 66% yield (eq
3).
Table 3. Substrate scope of KSAs.a
Scheme 3. Further transformations of cyclobutene 3cd.
Conclusions
In conclusion, we have developed trimethylaluminum-
catalyzed [2+2] cycloaddition of ketene silyl acetals with
propiolates to provide several cyclobutene derivatives in high
yield. Especially, we succeeded in the [2+2] cycloaddition of -
aryl ketene silyl acetals with propiolates by use of cylic ketene
silyl acetals. Furthermore, we applied this methodology to the
late stage functionalization of natural product artemisinin. The
synthetic utility of the protocol was exemplified in a number of
transformations to access multi-functionalized cyclobutenes and
cyclobutanes. Further applications to the synthesis of the natural
products are ongoing in our laboratory.
a
Condition: KSA 1 (0.55 mmol), 2a (0.5 mmol), and Me3Al (20 mol%)
in CH2Cl2 (0.25 M) at 0 to 23 °C. b isolated yield.
Scheme 2. Late stage installation of a cyclobutene moiety
onto natural product artemisinin.
Acknowledgments
This work was supported by JSPS KAKENHI Grant Number
16K18842, 16H05073, MEXT KAKNHI Grant Number
JP16H01147 in Middle Molecular Strategy, and AMED Platform
for Drug Discovery, Informatics, and Structural Life sciences.
We explored further transformations of cyclobutene 3cd
(Scheme 3). Hydrogenation of cyclobutene 3cd with palladium
on carbon in MeOH under hydrogen atmosphere gave the
undesired cyclobutene ring opened product 5 (eq 1). Gratifyingly,
the solvent replacement of MeOH with THF prevented the side
reaction and gave the desired product 6 in 92% yield as a single
diastereomer. Interestingly, the hydrogenation occurred from the
A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at ......

4
Tetrahedron
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5
1, Cyclic ketene silyl acetals were utilized for [2+2]
cycloaddition with propiolates.
2, Me3Al catalyzed [2+2] cycloaddition afforded
cyclobutenes in high yields.
3, Multi-substituted cyclobutenes could be synthesized.