Reinvestigation of palladium-catalyzed allylation of the monoacetate of 4-cyclopentene-1,3-diol and synthesis of the coronafacic acid ethyl ester

Article abstract of DOI:10.1016/j.tetlet.2013.10.052

A larger quantity of a β-keto ester that is 1.5-1.7 equiv more than the base (t-BuOK, NaH) was found to be essential in securing sufficient yields of the products in the palladium-catalyzed allylic substitution of the monoacetate of 4-cyclopentene-1,3-diol with β-keto esters. This requirement also works well for substitutions with the TBS ether of the monoacetate and the monoacetate of 2-cyclohexene-1,4-diol. As an application, the coronafacic acid ethyl ester was synthesized as an optically active form.

Full text of DOI:10.1016/j.tetlet.2013.10.052

Tetrahedron Letters 54 (2013) 7017–7020
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reinvestigation of palladium-catalyzed allylation of the monoacetate
of 4-cyclopentene-1,3-diol and synthesis of the coronafacic acid ethyl
ester
⇑
Wataru Kinouchi, Yusuke Kosaki, Yuichi Kobayashi
Department of Bioengineering, Tokyo Institute of Technology, Box B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A larger quantity of a b-keto ester that is 1.5–1.7 equiv more than the base (t-BuOK, NaH) was found to be
essential in securing sufficient yields of the products in the palladium-catalyzed allylic substitution of the
monoacetate of 4-cyclopentene-1,3-diol with b-keto esters. This requirement also works well for substi-
tutions with the TBS ether of the monoacetate and the monoacetate of 2-cyclohexene-1,4-diol. As an
application, the coronafacic acid ethyl ester was synthesized as an optically active form.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 16 August 2013
Revised 8 October 2013
Accepted 10 October 2013
Available online 21 October 2013
Keywords:
Palladium
Allylic substitution
4-Cyclopentene-1,3-diol monoacetate
b-Keto ester
Coronafacic acid
Owing to the reasonable availability as an optically active form
both enantiomers of the monoacetate of cis 4-cyclopentene-1,3-
diol have been a convenient starting material in organic synthe-
sis.1,2 Among the reactions applicable to the monoacetates, we
have used palladium-catalyzed allylic substitution with malonate
ester in the synthesis of
D
12-PGJ2,3 epoxyisoprostane-PC,4 epi-
jasmonates,5 quinine,6 and coronafacic acid.7 In continuous inves-
tigation, we encountered varying yields of 3 in the reaction of
monoacetate 1a and functionalized b-keto ester 2 as shown in
Scheme 1 even though complete consumption of 1a was confirmed
by TLC analysis. To the best of our knowledge, no reason was found
in the literatures. To pursue the project, the substitution was rein-
vestigated to establish a highly efficient and reproducible protocol
as presented herein. Furthermore, application of the allylic substi-
tution to the synthesis of the coronafacic acid ethyl ester is
described.
We have chosen two racemic substrates 1a and its TBS ether 1b,
which were subjected to reaction with a simple b-keto t-Bu ester 4
in the presence of a base and Pd(PPh3)4 (catalytic quantity) in THF
(Table 1). Initially, reaction of 1a (1 equiv) with 4 (3.0 equiv) was
studied using t-BuOK (2.0 equiv) and Pd(PPh3)4 (5 mol %) in THF
at rt according to the procedure developed for substitution with
malonate ester.3 The reaction completed within 1 h and afforded
5a in 81% yield (entry 1).8 Neither regioisomer nor stereoisomer
Scheme 1. A reaction that prompted the present investigation.
was detected by 1H NMR spectroscopy. In contrast, the use of an
excess quantity of t-BuOK over 4, which is probably a protocol in
a small scale reaction, resulted in no production of 5a (entry 2). In-
stead, diol 6a was isolated as the predominant product, whereas
production of 3- and/or 2-cyclopentenone9 was not detected in
the crude product.10 A significant effect of the ratio of the reactant
4 and t-BuOK on yield was also observed in the substitution of the
TBS ether 1b. In brief, the desired product 5b8 was obtained in 90%
yield with 2.5 equiv of 4 and 2.0 equiv of t-BuOK at 50–55 °C11 for
6 h (entry 3), whereas the use of 4 and t-BuOK in 2.0 and 3.0 equiv
under otherwise identical conditions produced 5b only in 3% NMR
yield and the diol monosilyl ether 6b was isolated as the major
product (entry 4). Similar results were also observed when NaH
was used as a base for the allylation (entries 5 and 6 for alcohol
1a; entries 7 and 8 for TBS ether 1b). Ethyl acetoacetate was not
an exception to result in the same outcome (entries 9 and 10).
⇑
Corresponding author.
E-mail address: ykobayas@bio.titech.ac.jp (Y. Kobayashi).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.052

7018
W. Kinouchi et al. / Tetrahedron Letters 54 (2013) 7017–7020
Table 1
Allylation of 1a and 1b with 4
Entry
1a or 1b (1 equiv)
4, equiva
Base (equiv)a
Temp (°C)
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1a
1a
1b
1b
1a
1a
3.0
2.0
2.5
2.0
3.4
2.0
3.0
2.0
t-BuOK (2.0)
t-BuOK (3.0)
t-BuOK (2.0)
t-BuOK (3.0)
NaH (2.0)
NaH (3.0)
NaH (2.0)
NaH (3.0)
t-BuOK (2.0)
t-BuOK (3.0)
rt
rt
50–55
50–55
rt
1
1
6
6
1
1
6
6
1
1
81
0b
90
<5c
86
0b
90
<5c
90
0b
rt
50–55
50–55
rt
3.0 (Et ester)d
2.0 (Et ester)d
10
rt
a
b
c
Based on 1 equiv of substrate 1a or 1b.
Diol 6a was produced.
The TBS ether 6b was isolated in 76% and 47% yields in entries 4 and 8, respectively.
Ethyl acetoacetate was used instead of the t-Bu ester 4.
d
To examine efficiency of the present protocol, several b-keto esters
7, 9, 11, and 5b were subjected to the allylation. In brief, reaction of
1a with b-keto ester 7 possessing the Et substituent afforded 8a in
71% yield (Scheme 2). Similarly, 7 underwent reaction with the TBS
ether 1b to produce 8b in high yield. A b-keto ester 9, which was
chosen as a model reactant of 2, smoothly participated in the reac-
tion with 1a and 1b to afford 10a and 10b in good yields, respec-
tively.
a-Methyl substituted b-keto ester 11 was also a good
reaction partner of 1a and 1b and furnished 12a and 12b. In the last
example, 5b (the product of Table 1, entry 3) was used as a b-keto
ester, and produced 13 as a mixture of the diastereomers in 64%
yield.
Reactions with methyl malonate (14) examined next afforded
15 in 87% yield with stereo- and regioselectivity when a larger
quantity of 14 than that of t-BuOK was used (Scheme 3). This result
definitely indicates that the b-keto ester 2 as such is not a reason
for varying yield mentioned in the introduction.
The present results of palladium-catalyzed allylation of 1a,b
with the reactants and those in the literatures3,7,12–14 are summa-
rized in Table 2, focusing reactant/base ratio. In the literatures, ra-
tios have been 1:1 or reactant excess, and no reason for the use of
the excess reactant over the base has been commented. Conse-
quently, the present finding is significantly important in organic
synthesis in securing reproducibility and high yields. Furthermore,
we noticed that the yields of the products derived from the TBS
ether 1b is higher than that from alcohol 1a, and thus 1b is recom-
mended as a substrate.
The proper ratio of b-keto ester and base elucidated above was
applied to the monoacetate of 2-cyclohexene-1,4-diol 16,15 which
was found to be less reactive toward the nucleophile derived from
4 and t-BuOK at rt.16 After several trials, the use of higher temper-
atures of 40–45 °C brought about complete reaction, giving 17 in a
reasonable yield with exclusive regioselectivity (Scheme 4).
As an application, synthesis of coronafacic acid, the acid part of
coronatine,17,18 is investigated starting with (1R)-1b of >99% ee
(Scheme 5). The b-keto ester 18 was prepared by a method delin-
eated in Scheme 6, in which TES ether 25 (>99% ds) was prepared
from 24 according to the method of Olivo19 and subjected to
Scheme 2. Examples of the Pd-catalyzed reaction with various b-keto esters.

W. Kinouchi et al. / Tetrahedron Letters 54 (2013) 7017–7020
7019
Scheme 3. Allylation with methyl malonate.
Table 2
Comparison of the present and previous results
Substrate/reactant/base
Ratio
Yield
Ref. no.a
1a/b-keto ester/t-BuOK
1:3:2
1:2:3
81
0
a
a
1a/b-keto ester/NaH
1:2.1:2.1
1:3.4:2
1:2:3
91
86
0
68
86
81
87
0
12
a
a
13
12
14
a
1a/b-keto ester/K2CO3
1a/malonate/NaH
1:1.06:1b
1:2:2
1:2:1
1:3:2
1:2:3
a
1b/b-keto ester/t-BuOK
1b/b-keto ester/NaH
1b/malonate/t-BuOK
1:2.5:2
1:2:3
1:3:2
1:2:3
1:2.2:2
1:2:1.1
90
<5
90
<5
93
99
a
a
a
a
3
7
Scheme 5. Synthesis of the coronafacic acid ethyl ester.
a
The results obtained in this study are indicated by a.
Speculation from the general procedure.
b
Scheme 6. Synthesis of the b-keto ester intermediate.
Scheme 4. Allylation of 16 with 4.
the monoacetate and the cyclohexene monoacetate. The substitu-
tion was applied successfully to synthesis of the coronafacic acid
ethyl ester.
Claisen condensation20 with an anion derived from CH2(CO2H)CO2-
Et and i-PrMgBr in a 1:2 ratio to afford 18 in 96% yield. Allylic sub-
stitution of (1R)-1b with 18 (1.5 equiv) using t-BuOK (1.2 equiv) at
65–70 °C proceeded cleanly and afforded 19 as a diastereomeric
mixture in 87% yield after chromatography. Hydride reduction of
19 with NaBH4 followed by hydrogenation gave a mixture of 20
and alcohol 21. Without separation the mixture was subjected to
desilylation with PPTS in EtOH to furnish diastereomeric diol 21
in 66% yield. Mesylation of 21 produced dimesylate 22, which
was converted to ethyl ester 23 in 41% yield according to the pre-
vious method.7 In the present synthesis the sequence from (1R)-1b
is one step shorter than the previous one though the overall yield is
lower. Furthermore, ketone 18 is less enolizable than the previous
aldehyde intermediate (R)-TESOCH2CH(Et)CHO. These advantages
would be useful in organic synthesis.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture,
Japan.
Supplementary data
Supplementary data (the 1H NMR spectra of 5a,b, 8a,b, 10a,b,
12a,b, 13, 17–19) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2013.10.052.
References and notes
In summary, we figured out that larger quantity of the reactant
(b-keto esters, malonate ester) than that of the base (t-BuOK, NaH)
is required to attain high yields in the palladium-catalyzed allylic
substitution of the monoacetate of cyclopentene-1,3-diol with b-
keto esters.21 This requirement is applicable to the TBS ether of
1. (a) Kobayashi, Y. In Modern Organonickel Chemistry; Tamaru, Y., Ed.; Wiley-
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Q.; Craney, C. L. Org. Synth. 1998, 6, 487–493; (c) Laumen, K.; Schneider, M. P. J.
Chem. Soc., Chem. Commun. 1986, 1298–1299; (d) Johnson, C. R.; Braun, M. P. J.

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Am. Chem. Soc. 1993, 115, 11014–11015; (e) Laumen, K.; Schneider, M.
Tetrahedron Lett. 1984, 25, 5875–5878; (f) Wang, Y.-F.; Chen, C.-S.; Girdaukas,
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T. R.; Kobayashi, Y.; Hsu, F.-F.; Sharon, M.; Browse, J.; He, S. Y.; Rizo, J.; Howe, G.
A.; Zheng, N. Nature 2010, 468, 400–405.
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4. Acharya, H. P.; Kobayashi, Y. Angew. Chem., Int. Ed. 2005, 44, 3481–3484.
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Chem. 2010, 8, 5212–5223; (b) Ogawa, N.; Kobayashi, Y. Amino Acids 2012, 42,
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Igarashi, J.; Katsukawa, M.; Wang, Y.-G.; Acharya, H. P.; Kobayashi, Y.
Tetrahedron Lett. 2004, 45, 3783–3786.
18. Asymmetric syntheses of coronafacic acid: (a) Taber, D. F.; Sheth, R. B.; Tian, W.
J. Org. Chem. 2009, 74, 2433–2437; (b) Mehta, G.; Reddy, D. S. J. Chem. Soc.,
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1 2001, 1153–1161; (c) Arai, T.; Sasai, H.; Yamaguchi, K.;
Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 441–442; (d) Nara, S.; Toshima, H.;
Ichihara, A. Tetrahedron 1997, 53, 9509–9524; (e) Toshima, H.; Nara, S.;
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8. The cis stereochemistry for the two substituents on the cyclopentene ring of 5a,
5b, and the products shown in Table 1 (entries 9 and 10) and Schemes 2 and 3
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was determined by 1H NMR spectroscopy on the basis of
D
d (ca. 1–1.1 ppm) of
21. General Procedure for allylation of alcohol 1a (Table 1, entry 1): To an ice-cold
solution of t-BuOK (82.7 mg, 0.737 mmol) in THF (2 mL) was added b-keto
ester 4 (0.180 mL, 1.13 mmol) under Ar atmosphere. After 30 min of stirring at
room temperature Pd(PPh3)4 (24.1 mg, 0.0203 mmol, 5 mol %) and a solution of
monoacetate 1a (53.7 mg, 0.378 mmol) in THF (0.7 mL) were added to the
solution, which was stirred at room temperature for 1 h. Saturated NH4Cl was
added to the solution and a resulting mixture was extracted with EtOAc three
times. The combined extracts were dried over MgSO4 and concentrated to
leave a residue, which was purified by chromatography on silica gel (hexane/
EtOAc) to afford 5a (82.3 mg, 81%): Rf = 0.44 (hexane/EtOAc, 1:1); 1H NMR
(300 MHz, CDCl3) d 1.35–1.57 (m, 1H), 1.47 (s, 9H), 2.04–2.22 (m, 1H), 2.24 (s,
3H), 2.48–2.61 (m, 1H), 3.17–3.32 (m, 1H), 3.43 (d, J = 9 Hz, 1H), 4.79 (br s, 1H),
5.76–5.95 (m, 2H). General Procedure for allylation of the TBS ether 1b (Table 1,
entry 3): To an ice-cold solution of t-BuOK (54.3 mg, 0.484 mmol) in THF
the methylene protons, which are generally >1 and <0.3 ppm for cis and trans
configurations, respectively: (a) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc.
1980, 102, 4730–4743; (b) Sable, H. Z.; Rltchey, W. M.; Nordlander, J. E.
Carbohydrate Res. 1965, 1, 10–21; (c) Couc, F. G.; Wolczunowicz, G.; Bors, L.;
Posternak, T. Helv. Chim. Acta 1970, 53, 739–749.
9. Suzuki, M.; Oda, Y.; Noyori, R. J. Am. Chem. Soc. 1979, 101, 1623–1625.
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diol 6a mostly remained in the aqueous layer was extracted repeatedly with
EtOAc and then CH2Cl2. The extraction was, however, insufficient and the yield
of 6a was not determined.
11. The reaction did not proceed at room temperature.
12. Deardorff, D. R.; Linde, R. G., II; Martin, A. M.; Shulman, M. J. J. Org. Chem. 1989,
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(1.2 mL) was added b-keto ester
4 (0.098 mL, 0.601 mmol) under Ar
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Helv. Chim. Acta 1989, 72, 1852–1859.
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16. Even after 5 h at rt, the reaction did not complete, and a ratio of 16 and 17 was
17:83 by 1H NMR spectroscopy.
17. Isolation and biology: (a) Ichihara, A.; Shiraishi, K.; Sato, H.; Sakamura, S.;
Nishiyama, K.; Sakai, R.; Furusaki, A.; Matsumoto, T. J. Am. Chem. Soc. 1977, 99,
636–637; (b) Ichihara, A.; Shiraishi, K.; Sakamura, S. Tetrahedron Lett. 1979,
atmosphere. After 30 min of stirring at room temperature Pd(PPh3)4
(14.1 mg, 0.0119 mmol, 5 mol %) and a solution of 1b (61.8 mg, 0.242 mmol)
in THF (0.8 mL) were added to the solution, which was stirred at 50–55 °C for
6 h. A similar workup and purification as above afforded 5b (76.8 mg, 90%):
Rf = 0.35 (hexane/EtOAc, 14:1); 1H NMR (300 MHz, CDCl3) d 0.03–0.08 (m, 6H),
0.87 and 0.88 (2 s, 9H), 1.16–1.28 and 1.34–1.44 (2 m, 1H), 1.46 (s, 9H), 2.22
and 2.23 (2 s, 1H), 2.35–2.48 (m, 1H), 3.12–3.25 (m, 1H), 3.36 (d, J = 6 Hz, 0.6H)
and 3.39 (d, J = 6 Hz, 0.4H), 4.75–4.84 (m, 1H), 5.68–5.83 (m, 2H).