Synthesis of coronafacic acid via TBAF-assisted elimination of the mesylate and its conversion to the isoleucine conjugate

Article abstract of DOI:10.1021/ol201576c

An aldol reaction followed by elimination of the derived mesylate was used to construct the side chain that was designed to afford the cyclohexene ring of coronafacic acid via intramolecular alkylation. Elimination of the mesylate proceeded with TBAF. The

Full text of DOI:10.1021/ol201576c

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4232–4235
Synthesis of Coronafacic Acid
via TBAF-Assisted Elimination of
the Mesylate and Its Conversion
to the Isoleucine Conjugate
Yusuke Kosaki, Narihito Ogawa, Qian Wang, and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, Box B52,
Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Received June 13, 2011
ABSTRACT
An aldol reaction followed by elimination of the derived mesylate was used to construct the side chain that was designed to afford the
cyclohexene ring of coronafacic acid via intramolecular alkylation. Elimination of the mesylate proceeded with TBAF. The alkylation was
achieved with t-BuOK in THF, and then hydrolysis afforded coronafacic acid, which upon condensation with unprotected L-isoleucine using
ClCO2Bui furnished coronafacoyl-L-isoleucine, the L-Ile conjugate.
Coronatine 1a is a phytotoxin isolated from Pseudomo-
nas syrigae pv atropurpurea as a chlorosis-inducing factor
against Italian ryegrass leaves,1 and biosynthesis of 1a has
been elucidated2 (Figure 1). Structurally similar com-
pounds such as 1bꢀd have been found as well.3 Although
it isa phytotoxin, 1a shows biochemical activities similar to
those of some jasmonoids,4 which regulate plant physiol-
ogy and defense responses against environmental and
pathogenic stressors.5 Since 1a is highly potent and che-
mically more stable than the jasmonoids, 1a has been
utilized as a stable probe to find the coronatine insensitive
proteins 1 (COI1 proteins), which are the SCF proteins
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Mysore, K. S.; Bender, C. L. Mol. Plant-Microbe Interact. 2007, 20, 955–
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Howe, G. A.; Jander, G. Annu. Rev. Plant Biol. 2008, 59, 41–66. (h)
Browse, J. Annu. Rev. Plant Biol. 2009, 60, 183–205.
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10.1021/ol201576c
Published on Web 07/18/2011
2011 American Chemical Society

targeting the repressor JAZ proteins.6 Recently, 1a and
epi-jasmonoyl-L-isoleucine 4 were found to highly activate
COI1 proteins binding to JAZ proteins,7 whereas jasmo-
noyl-L-isoleucine, the C7 stereoisomer, was less active.8
Quite recently, the crystal structure of the complex con-
sisting of 4, COI1, and JAZ was published.9 A similar
complex with 1aoccupying the site for 4 was also disclosed.
The phenyl group of Phe89 is definitely responsible for the
stereospecificity of the site to the stereogenic centers on the
cyclopentane ring of 4 and 1a and to the Et group of 1a as
well. To elucidate the mechanism, which translates the
binding signals by 1a and 4 in different ways, a method of
conveniently supplying these molecules and analogues
should be established. Recently, we succeeded in synthe-
sizing 4 and other amino acid conjugates of epi-jasmonic
acid 5.10 Herein, we report the synthesis of coronafacic
acid 2, the known precursor to 1a, and its conversion to
coronafacoyl-L-isoleucine 1c under protective group-free
conditions.
stereoselective construction of the C6 stereogenic center
possessing the Et group and total yield. In our preliminary
experiments (Figure 2), each pair of keto esters (3a and 3a0)
and hydroxyl esters (6a and 6a0) was nearly coeluted on
TLC (hexane/EtOAc) (synthesis not shown). In considera-
tion of the close mobility between the diastereomers we
envisaged a synthesis of 2 through aldol reaction of 8 with
aldehyde 9 followed by elimination of the derived mesylate
7 and intramolecular alkylation (Scheme 1). As described
below, the elimination proceeded under unexpected con-
ditions and, besides, with the desired (E)-stereoselectivity.
The ester 8 for the aldol reaction was expected to be
obtained through palladium-catalyzed allylic substitution
of the corresponding acetate13 with malonate, while alde-
hyde 9 was prepared according to the literature method.14
Figure 2. TLC mobility of the two sets of the diastereomeric
mixtures.
Scheme 1. Retrosynthesis of Coronafacic Acid
Figure 1. Coronatine, its derivatives, and (epi-jasmonoyl)-L-
isoleucine.
Since the previous asymmetric syntheses of 211,12 suffer
from low selectivity, we focused our attention mainly on
(9) Sheard, L. B.; Tan, X.; Mao, H.; Withers, J.; Ben-Nissan, G.;
Hinds, 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.
(10) Ogawa, N.; Kobayashi, Y. Amino Acids 2011, DOI: 10.1007/
s00726-011-0925-z.
(11) (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., Perkin Trans. 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.; Ichihara, A. Biosci. Biotech. Biochem. 1997, 61, 752–753. (f) Ohira, S.
Bull. Chem. Soc. Jpn. 1984, 57, 1902–1907. (g) Nakayama, M.; Ohira, S.
Agric. Biol. Chem. 1983, 47, 1689–1690.
As summarized in Scheme 2 the TBS-protected acetate
11, derived from monoacetate 1013 with 99% ee, was
subjected to the palladium-catalyzed allylic substitution
with methyl malonate 12a according to the method pub-
lished by us15 to produce 13a, which upon decarboxylation
with KI at 140 °C afforded ester 8a in 81% yield from 11.
(13) (a) Sugai, T.; Mori, K. Synthesis 1988, 19–22. (b) Laumen, K.;
Schneider, M. P. J. Chem. Soc., Chem. Commun. 1986, 1298–1299. (c)
Curran, T. T.; Hay, D. A.; Koegel, C. P. Tetrahedron 1997, 53, 1983–
2004.
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1363.
(12) Cf. Recent synthesis in a racemic form: (a) Moreau, B.; Ginisty,
M.; Alberico, D.; Charette, A. B. J. Org. Chem. 2007, 72, 1235–1240. (b)
Okada, M.; Egoshi, S.; Ueda, M. Biosci. Biotechnol. Biochem. 2010, 74,
2092–2095. (c) Okada, M.; Ito, S.; Matsubara, A.; Iwakura, I.; Egoshi,
S.; Ueda, M. Org. Biomol. Chem. 2009, 7, 3065–3073. (d) Sono, M.;
Hashimoto, A.; Nakashima, K.; Tori, M. Tetrahedron Lett. 2000, 41,
5115–5118.
(15) Acharya, H. P.; Kobayashi, Y. Tetrahedron2006, 62, 3329–3343.
Org. Lett., Vol. 13, No. 16, 2011
4233

Scheme 2. Synthesis of Coronafacic Acid (a series, R = Me; b series, R = Et)
The next stage was aldol reaction followed by elimination
of the hydroxyl group to afford the (E)-olefin, which was
expected to be derived from the syn aldol isomer on the
basis of well-accepted anti elimination. With the above
consideration in mind aldol reaction of 8a with alde-
hyde 9 (96% ee),16 prepared by the literature method,14
was attempted under the syn selective conditions using
Bu2BOTf and i-Pr2NEt.17,12a However, no reaction
took place, suggesting the cyclopentene ring of 8a being
a big obstacle. On the other hand, aldol reaction of
lithium enolate18 derived from 8a in THF/HMPA (4:1)
with 9 afforded 14a as a mixture of the syn/anti stereo-
isomers (four isomers).19 Note that boron-mediated
aldol reaction of model ester 19 with achiral aldehyde
20 afforded 21 stereoselectively (Scheme 3, eq 1), whereas
another set of aldol reactions (real ester 8a and 20) was
unsuccessful.
Scheme 3. Model Study of Aldol Reaction (eq 1) and
Elimination (eqs 2, 3)
(16) Prepared as shown below. Enantiomeric excess (ee) of 9 was
calculated from the diastereomeric ratio of the intermediate i. Yields and
diastereoselectivity were comparable with those in the literature.14
(17) Inoue, T.; Liu, J.-F.; Buske, D. C.; Abiko, A. J. Org. Chem. 2002,
67, 5250–5256.
(18) (a) Mondal, S.; Malik, C. K.; Ghosh, S. Tetrahedron Lett. 2008,
49, 5649–5651. (b) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.;
Pirrung, M. C.; Sohn, J. E.; Lampe, J. J. Org. Chem. 1980, 45, 1066–
1081. (c) Meyers, A. I.; Reider, P. J. J. Am. Chem. Soc. 1979, 101, 2501–
2502. (d) See ref 11d.
(19) Multiplicity of the resonances in the 1H NMR spectrum pre-
vented calculation of a syn/anti ratio and assignment of the signals to the
syn and anti isomers by coupling constants.
4234
Org. Lett., Vol. 13, No. 16, 2011

Without determination of the syn/anti ratio, aldol 14a
was converted to diol 15a and then to mesylate 7ain a good
yield. Next, desilylation of mesylate 7a was attempted with
TBAF (1.2 equiv) in THF at 0 °C to rt for 2 h. To our
surprise, no desilylation took place. Instead, elimination of
the mesyloxy group proceeded to furnish 16a in 61% yield
with 90% (E)-selectivity over the (Z)-isomer as a conse-
quence of deprotonation at the R-position of the ester
group.20 The reagents (Et3N, Al2O3,15,21 and DBU22) used
for elimination of the mesylates derived from ketone aldols
afforded the olefin marginally.
To understand the selective formation of (E)-olefin from
the syn/anti mixture of aldol 14a, the model mesylate 22
(syn/anti = 45:55), synthesized by aldol reaction of the
lithium enolate of 19 with 20 (Scheme 3, eq 1) followed by
mesylation, was treated with TBAF under similar condi-
tions (0 °Cꢀrt, 2 h) to afford a mixture of (E)-23, (Z)-23,
and anti-22 in a 60:5:35 ratio by 1H NMR spectroscopy.
The product was fractionalized by chromatography togive
a mixture of (E)- and (Z)-23 in 55% yield and anti-22 in
33% yield. The result indicates that anti elimination of
anti-22, which should afford (Z)-23, was retarded by the
steric repulsion between the Bu and CHEt2 groups in the
transition state, whereas anti elimination of syn-isomer 22
took place without difficulty. In accord with the result,
unusual syn elimination of the recovered anti-22 started at
rt slowly to afford, after 8 h, a mixture of (E)-23, (Z)-23,
and anti-22 in a ratio given in eq 3.
Intramolecular alkylation of 18b was carried out with
t-BuOK in THF at 0 °C to afford 3b in a higher yield
of 62% (Table 1, entry 5). Finally, hydrolysis of 3b
under the reported acidic conditions afforded coronafacic
acid 2 in 85% yield. The 1H and 13C NMR spectra and
mp were consistent with those reported (see Supporting
Information).23
Table 1. Intramolecular Alkylation Using t-BuOK
entry
ketone
conditionsa
yieldb
31%
1
2
3
4
5
18a
18a
18a
18a
18b
THF, 0 °C
THF, ꢀ20 °C
t-BuOH, rt
t-BuOH/THF,c 0 °C
THF, 0 °C
23%
29%ꢀ57%
27%
62%
a t-BuOK (1.2ꢀ2.0 equiv). b Isolated yield. c 1:1.
Finally, coronafacic acid 2 was transformed successfully
to coronafacoyl-L-isoleucine 1c with unprotected L-isoleucine
as shown in eq 4 by using the method recently developed for
condensation of epi-jasmonic acid with amino acids.10 This
method would be applicable to condensation of 2 and its
analogues with other amino acids.
The TBS group in 16a was removed under acidic condi-
tions, and the resulting alcohol 17a was oxidized to ketone
18a, which was subjected to intramolecular alkylation with
t-BuOK as a base. In THF at 0 °C, 3a was produced with
unidentified polar products and an isolated yield of 3a was
only 31% (Table 1, entry 1). The polar compounds were
produced even at lower temperature (entry 2). Sufficiently
protic conditions were examined next using t-BuOH as a
solvent at rt due to the mp of t-BuOH (entry 3). The
reaction was, however, capricious producing 29ꢀ57%
yields of 3a. Use of t-BuOH/THF (1:1) at 0 °C was un-
successful (entry 4).
Based on the assumption that attack to the ester carbonyl
group in 18a and/or 3a was responsible for the formation of
polar compounds, intramolecular alkylation of 18b with
the slightly bigger ethyl ester was examined next. Synthesis
was accomplished in a similar way to methyl ester 18a
starting with acetate 10 and ethyl malonate 12b as summar-
ized in Scheme 2. Except for decarboxylation of 13b, which
was accomplished at 180 °C, the other steps of trans-
formation including stereoselective elimination of me-
sylate 7b to olefin 16b20 proceeded without any event.
In summary, we achieved stereoselective synthesis of
coronafacic acid 2, the known key intermediate for
synthesis of coronatine 1a, through intramolecular
cyclization of 18b to 3b. The total yield from 10 to 2
was 23.9% in 12 steps. During the synthesis we found
TBAF-assisted elimination of the mesyloxy group in
mesylate 7b, which proceeded stereoselectively and
faster than desilylation of the TBS group in it, furnished
the desired (E)-olefin 16b. Furthermore, condensation of
2 and unprotected L-isoleucine were achieved successfully
to afford the isoleucine conjugate 1c.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports, and Culture, Japan.
Supporting Information Available. Experimental pro-
cedures and spectral data of compounds described herein.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Chemical shifts (δ, ppm) of the diagnostic olefin proton ap-
peared as a doublet (J = ca. 10 Hz): 16a, 6.33; the (Z)-isomer of 16a,
5.59; 16b, 6.27; the (Z)-isomer of 16b, 5.51.
(21) Kobayashi, Y.; Murugesh, M. G.; Nakano, M.; Takahisa, E.;
Usmani, S. B.; Ainai, T. J. Org. Chem. 2002, 67, 7110–7123.
(22) In the case of an aldol derived from ester and R,β-enal, elimina-
tion of the derived mesylate proceeds with DBU.11d A similar tendency
was observed by us.15
(23) The specific rotations ([R]D) in MeOH reported earlier are ca.
120, whereas those reported recently are 104ꢀ109. Our data are con-
sistent with the latter. See Supporting Information.
Org. Lett., Vol. 13, No. 16, 2011
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