Stereoselective Syntheses of all the Possible Stereoisomers of Coronafacic Acid

Article abstract of DOI:10.1002/open.202000210

An efficient and stereoselective syntheses of all the possible stereoisomers of coronafacic acid (CFA) has been developed. The stereochemistries of C3a and C7a were controlled in a diastereoselective Diels-Alder type cycloaddition using a chiral auxiliary. CFA and 6-epi-CFA were synthesized by hydrogenation of a common intermediate. During the synthesis of 6-epi-CFA, we established that its cis-fused configuration is important for the introduction of C4-C5 double bond by dehydration. This report is the first practical synthesis of both 6-epi-CFA, and its enantiomer.

Full text of DOI:10.1002/open.202000210

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Stereoselective Syntheses of all the Possible Stereoisomers
of Coronafacic Acid
Raku Watanabe,[a] Nobuki Kato,*[b] Kengo Hayashi,[b] Sho Tozawa,[b] Yusuke Ogura,[c]
Shigefumi Kuwahara,[c] and Minoru Ueda*[a, b]
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An efficient and stereoselective syntheses of all the possible
stereoisomers of coronafacic acid (CFA) has been developed.
The stereochemistries of C3a and C7a were controlled in a
diastereoselective Diels-Alder type cycloaddition using a chiral
auxiliary. CFA and 6-epi-CFA were synthesized by hydrogenation
of a common intermediate. During the synthesis of 6-epi-CFA,
we established that its cis-fused configuration is important for
the introduction of C4-C5 double bond by dehydration. This
report is the first practical synthesis of both 6-epi-CFA, and its
enantiomer.
1. Introduction
Jasmonate, an oxylipin-type plant hormone, plays important
roles in the life cycle of plants,[1–3] and (+)-(3R, 7R)-jasmonoyl-L-
isoleucine (JA-Ile, 1)[4] is a significant endogenous bioactive
jasmonate which causes myriad of plant biological responses
including those associated with defense, response to wounds,
fertility, senescence, secondary metabolite production, and
growth inhibition (Figure 1). Hormone 1 has been used as an
important chemical tool in the field of jasmonate biology.
However, (3R, 7R)-JA-Ile is unsuitable for use in biological
studies due to its tendency to isomerize into the biologically
inactive (3R, 7S)-form,[4] and therefore coronatine (COR, 2), a
more stable structural and biological mimic of JA-Ile, is
generally used as a chemical tool in jasmonate research
instead.[5,6]
Recently, we found that NOPh (3), an oxime derivative of
COR, caused defense response against pathogenic infection
without undesired biological responses such as growth
inhibition.[7,8] This result is based on a slight difference in the 3D
shape of coronatine. Therefore, a chemical library composed of
all the possible 16 stereochemical isomers of COR could be
useful as a source of useful chemical tool in jasmonate biology.
COR is composed of coronafacic acid (CFA, 4) and unusual
Figure 1. JA-Ile (1), COR (2), NOPh (3), CFA (4) and CMA (5).
amino acid coronamic acid (CMA, 5). To date, the possible four
stereochemical isomers of CMA can be also accomplished by
Salaün,[9] Charette,[10] and Toshima & Ichihara,[11] and syntheses
of CFA have been accomplished by many groups[12,13] including
practical supply by Watson and Ueda.[14,15] However, no report
can be found for practical supply of 6-epi-CFA (6) and its
enantiomer (ent-6) (Scheme 1). Here, we report the first
syntheses of 6 and ent-6. We synthesize both of CFA and 6-epi-
CFA from the common intermediates (9) by switching the
stereoselectivity in hydrogenation (Scheme 1).
We previously obtained enantiopure samples of 4 and ent-4
by separation of (�)-4, but this is not practical on large scales.
Therefore, we planned to develop practical stereoselective
syntheses of all stereoisomers of 4 based on our previous
synthetic route.[16]
Enol 7 was proposed as a possible starting material for all
stereoisomers of 4 (Scheme 1). A diastereoselective Diels-Alder
type reaction between 7 and 8/ent-8 could be used to establish
the desired absolute configurations at C3a and C7a, and the
stereochemistry at C6 could be catalytically controlled in a
stereoselective hydrogenation – we have previously reported
that the palladium-catalyzed hydrogenation of 9 selectively
[a] R. Watanabe, Prof. M. Ueda
Graduate School of Life Science, Tohoku University, 6–3, Aramaki-Aza-Aoba,
Aoba-ku, Sendai 980-8578, (Japan)
E-mail: minoru.ueda.d2@tohoku.ac.jp
[b] Dr. N. Kato, K. Hayashi, S. Tozawa, Prof. M. Ueda
Graduate School of Science, Tohoku University, 6–3, Aramaki-Aza-Aoba,
Aoba-ku, Sendai 980-8578, (Japan)
E-mail: nobuki.kato.e7@tohoku.ac.jp
[c] Dr. Y. Ogura, Prof. S. Kuwahara
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricul-
tural Science, Tohoku University, Sendai 980–8572, (Japan)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.202000210
© 2020 The Authors. Published by Wiley-VCH GmbH. This is an open access
article under the terms of the Creative Commons Attribution Non-Com-
mercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for
commercial purposes.
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Scheme 1. Systematic strategy used to synthesize all stereoisomers of 4.
afforded 10 having the naturally occurring C6 configuration,[16]
but by using Crabtree’s catalyst (which coordinates to the
lactone carbonyl group), 11 with the unnatural C6 configuration
was obtained.[17] The resulting 11 can be converted to 6-epi-CFA
(6). The enantiomers ent-4 and ent-6 were obtained from ent-9
using the same method.
selectivity was obtained with the 6-membered cyclic acetal 8
(entry 2).
Next, we examined the effect of temperature on the
reaction outcome (Table 2). When the reaction was conducted
°
at À 20 C, the selectivity decreased compared with at room
temperature, though we do not have any reason to explain the
decrease in selectivity (entries 1 and 2). On the other hand,
°
conducting the reaction at À 40 C for 5 d gave the desired
2. Results and Discussion
product 12b in 64% yield with higher selectivity (entry 3). The
desired compound 12b and its diastereomer 13b were readily
separable by silica-gel column chromatography.
At first, we investigated the diastereoselective Diels-Alder type
reaction (Table 1).[18] Using a variety of chiral dienophile acetals
(14, 8, 15),[19] the ring-opened compounds (12a–c and 13a–c)
were obtained - the result of Diels-Alder type reaction and
subsequent cyclic acetal opening by β-elimination (entries 1–3).
Only the exo cyclization products were obtained; no endo
cyclization products were observed.[20] The best yield and
The stereoselectivity of this reaction can be explained by
the model depicted in Figure 2. The six-membered ring of
compound 8 can exist in two possible conformations (A and B),
of which A predominates as B is destabilized by steric repulsion
Table 2. Effects of temperature on the diastereoselective Diels-Alder type
reaction.
Table 1. Screening of chiral auxiliaries on the diastereoselective Diels-Alder
type reaction.
Entry
Condition
rt, 24 h
Result
12b:13b
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2
3
12b (59%), 13b (17%)
12b (52%), 13b (18%)
12b (64%), 13b (14%)
3.5:1
2.9:1
4.6:1
°
À 20 C, 40 h
°
À 40 C, 5 d
Entry
Dienophile
Result
12:13
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3
14
8
15
12a (42%), 13a (33%)
12b (59%), 13b (17%)
12c (56%), 13c (21%)[a]
1.3:1
3.5:1
2.7:1[b]
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[a] The yield was determined by H NMR. [b] The ratio was determined by
1H NMR.
Figure 2. Proposed model for observed facial selectivity.
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°
°
Scheme 2. Reagents and conditions: (a) PivCl, pyridine, quant.; (b) BH3·THF, THF, 0 C; HCl aq., 93%; (c) TFA, THF, 0 C, 75%; (d) H2, Pd/C, toluene, 10 (71%), 11
°
(23%); (e) NaOMe, MeOH; (f) H2, Pd/C, MeOH; (g) TMSCHN2, benzene MeOH, 70% (3 steps); (h) POCl3, pyridine, 0 C, 91%; (i) HCl, H2O, reflux, quant.
between the axial methyl and cyclopentenone methylene
groups. This is consistent with NOE studies which revealed a
correlation between the axial methyl group and β-proton of the
cyclopentenone in 8. Attack of conformation A by diene 7 is
anticipated to proceed from the equatorial methyl face
opposite the axial methyl group.
Our synthesis of CFA (4) is summarized in Scheme 2. Diels-
Alder type reaction product 12b was treated with PivCl and
pyridine to afford 16. BH3 reduction of the ketone of 16, and
spontaneous transesterification between the C7 and C3 hydroxy
groups gave lactone 18. In the BH3 reduction of 12b, the
desired lactone was not obtained and instead the undesired 19
was generated as a result of conjugate addition of hydroxy
group and subsequent reduction of ketone. Lactone 18 was
treated with TFA to afford α,β-unsaturated enone 9, the
common intermediate of 4 and 6, via hydroxy carboxylic acid
20. Hydrogenation of
9 with Pd/C resulted in stepwise
°
Scheme 3. Reagents and conditions: (a) ent-8, Et3N, CH2Cl2, À 60 C, 63%; (b)
reductions to give the desired monoketone 10 (having the
naturally occurring 6S configuration) and its C6 epimer 11 in
yields of 71% and 23% respectively. Fortunately, 10 and 11
were easily separated by silica-gel column chromatography.
Ring-opening of 10 by β-elimination and subsequent hydro-
genolysis afforded cis-23. The observed H3a-H7a coupling
constant (3J3a,7a =6.2 Hz) is consistent with a cis-fused config-
uration. Finally, methyl esterification of cis-23, dehydration of
the resulting 24 with phosphorus oxychloride, and hydrolysis
under acidic conditions gave optically pure CFA (4) in 17 steps
and 7% overall yield from 12. ent-CFA (ent-4) was also obtained
from 7 and ent-8 by the same method (Scheme 3). The optical
purities of 4 and ent-4 were determined by chiral HPLC analyses
°
°
PivCl, pyridine; (c) BH3·THF, THF, 0 C; HCl aq.; (d) TFA, THF, 0 C, 41%
(3 steps); (e) H2, Pd/C, toluene, 68%; (f) NaOMe, MeOH; (g) H2, Pd/C, MeOH,
°
68%; (h) TMSCHN2, benzene MeOH; (i) POCl3, pyridine, 0 C, 67% (4 steps); (j)
HCl, H2O, reflux, quant.
on a Chiralpak IA after methyl esterification with trimethylsilyl
diazomethane. Chiral HPLC analysis of synthetic 4 and ent-4
gave optical purities of >99.5% ee.
Next, we synthesized 6-epi-CFA (6) (Scheme 4). Hydrogena-
tion of the common intermediate 9 using Crabtree’s catalyst
proceeded from the lactone side as expected, to give the
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Scheme 5. Reagents and conditions: (a) NaOMe, MeOH; (b) TMSCHN2,
benzene MeOH; (c) H2, Pd/C, MeOH, 70% (3 steps); (d) see, Table 4; (e) HCl,
H2O, reflux, quant.
Scheme 4. Reagents and conditions: (a) H2, [Ir(cod)(py)(PCy3)]PF6, CH2Cl2, 11
(76%), 10 (16%); (b) NaOMe, MeOH; (c) H2, Pd/C, MeOH; (d) TMSCHN2,
benzene MeOH, 70% (3 steps); (e) see, Table 3.
Table 4. Dehydration of cis-27.
Entry
Condition
28
29
1
2
3
4
Martin sulfurane, CH2Cl2, rt, 1 h
POCl3, pyridine, rt, 7 h
0%
78%
10%
8%
desired 6R ketone 11 stereoselectively. Interestingly, ring-open-
ing by β-elimination, hydrogenation, and methyl esterification
afforded trans-fused 27 but not the C6 epimer of the cis-fused
23, the intermediate in the synthesis of CFA (4). The coupling
constant (3J3a,7a =14.3 Hz) is consistent with trans-configuration.
Then, we investigated the dehydration of trans-27 (Table 3).
Phosphorus oxychloride (which was used for the synthesis of 4
and ent-4) was tested first (entry 1). The desired α.β-unsaturated
ester 28 was obtained as a result of dehydration and isomer-
ization, though the reaction yield was low. When trans-27 was
treated with Martin sulfurane[21] to afford only a trace amount of
28 and cyclopropane 29 (entry 2). Neither the Burgess dehy-
dration reaction[22] nor the Chugaev elimination,[23] (a syn-
elimination) were efficient either (entries 3 and 4). Although the
ketone of trans-27 was masked with an acetal to prevent
cyclopropanation, the dehydration reaction was not improved.
Due to the poor yields obtained for the dehydration of
trans-27, we planned to dehydrate cis-27 (Scheme 5). The
hydrogenation of cyclic compounds using Pd/C is known to
proceed from the opposite side of the ring to the meth-
oxycarbonyl groups.[24 Therefore, hydrogenation was conducted
after methyl esterification to obtain cis-27. The configuration of
cis-27 was determined by the 3JAB-based configurational 1H NMR
analysis (3J3a,7a =6.0 Hz). Then, we investigated the dehydration
of cis-27 (Table 4). The highest yield was obtained using
87%
54%
55%
°
SOCl2, pyridine, 0 C, 3 h
Burgess reagent, toluene, reflux, 1 h
32%
phosphorus oxychloride (entry 2). Finally, hydrolysis under the
acidic condition gave 6-epi-CFA (6) stereoseletively in 17 steps
and 7% overall yield from 12. ent-6-epi-CFA (ent-6) was also
obtained from ent-9 by the same method (Scheme 6). The
optical purities of 6 and ent-6 were determined by chiral HPLC
analyses on a Chiralpak IA after methyl esterification with
trimethylsilyl diazomethane. Chiral HPLC analysis of synthetic 6
and ent-6 gave optical purities of >97% ee.
Table 3. Dehydration of trans-27.
Entry
Condition
28
29
1
2
3
4
POCl3, pyridine, rt, 12 h
Martin sulfurane, CH2Cl2, rt, 24 h
Burgess reagent, toluene, reflux, 6 h
1) NaH, imidazole, CS2, THF; MeI, 0 C
2) toluene, reflux, 20 h
21%
trace
25%
trace
0%
12%
6%
Scheme 6. Reagents and conditions: (a) H2, [Ir(cod)(py)(PCy3)]PF6, CH2Cl2, 73%;
(b) NaOMe, MeOH; (c) TMSCHN2, benzene MeOH, 91% (2 steps); (d) H2, Pd/C,
°
trace
°
MeOH, 98%; (e) POCl3, pyridine, 0 C, 75%; (f) HCl, H2O, reflux, quant.
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3. Conclusions
Synthesis of Diels-Alder Type Reaction Product 12b
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To a solution of 7 (1.46 g, 10.4 mmol) and 8 (2.71 g, 14.9 mmol) in
CH2Cl2 (70 mL) was added Et3N (1.5 mL, 10.8 mmol) at room
temperature under argon atmosphere. The reaction mixture was
stirred at room temperature for 24 h. After evaporation, the residue
was purified by silica gel column chromatography (n-hexane/
EtOAc=5/1) to give 12b (1.99 g, 6.14 mmol, 59%) as a colorless oil
and the diastereomer 13b (575 mg, 1.77 mmol, 17%) as a colorless
Efficient and stereoselective syntheses of all four possible
stereoisomers of CFA have been developed; key reactions are
the diastereoselective Diels-Alder type reaction (to establish the
desired absolute configuration) and the catalyst-controlled
stereoselective hydrogenation. Our method is stereoselective
and the desired stereoisomers were obtained without using the
cumbersome separations of stereoisomers. Our method allows
practical supply of 6-epi-CFA and the enantiomer. Studies
towards the generation of a chemical library consisting of all
the possible 16 stereochemical isomers of COR, a useful
chemical tool in jasmonate chemical biology, are underway.
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oil; 12b: [α]D À 176.0 (c 0.75, CHCl3). H NMR (400 MHz, CDCl3) δH:
6.07 (q, J=1.9 Hz, 1H), 5.44 (d, J=0.7 Hz, 1H), 5.05 (t, J=1.9 Hz, 1H),
4.67 (dqd, J=9.3, 6.2, 2.8 Hz, 1H), 4.15 (brs, 1H), 3.94 (dqd, J=10.1,
6.3, 2.8 Hz, 1H), 3.19 (ddd, J=7.5, 1.9, 0.7 Hz, 1H), 2.79 (d, J=7.5 Hz,
1H), 2.32 (dqd, J=16.4, 7.3, 1.9 Hz, 1H), 2.26 (dqd, J=16.4, 7.3,
1.9 Hz, 1H), 1.86 (ddd, J=14.7, 9.3, 2.8 Hz, 1H), 1.70 (ddd, J=14.7,
10.1, 2.8 Hz, 1H), 1.37 (d, J=6.2 Hz, 3H), 1.24 (d, J=6.3 Hz, 3H), 1.12
(t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δC: 202.1, 185.9, 172.8,
145.2, 128.2, 107.4, 77.9, 77.1, 76.4, 63.5, 50.4, 48.2, 45.4, 24.8, 24.5,
20.0, 11.2; IR (film) cmÀ 1: 3419, 2970, 2933, 2883, 1770, 1677, 1579,
1457, 1373, 1341, 1186, 1116, 958, 912; HRMS (ESI, positive) m/z [M
+Na]+ Calcd. for C17H22NaO6: 345.1314, Found: 345.1314.
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Experimental Section
General
1
13b: [α]D22 +74.7 (c 0.75, CHCl3). H NMR (400 MHz, CDCl3) δH: 6.07
All chemical reagents and solvents were obtained from commercial
suppliers (Kanto Chemical Co. Ltd., Wako Pure Chemical Industries
Co. Ltd., Nacalai Tesque Co. Ltd., Tokyo Chemical Industry Co. Ltd.,
Sigma-Aldrich Co. LLC., GE Healthcare) and used without further
purification. All anhydrous solvents were either dried by standard
techniques and freshly distilled before use, or purchased in
anhydrous form and used as supplied. Reversed-phase high-
performance liquid chromatography (HPLC) was carried out on a
PU-4180 plus pump equipped with UV-4075 and MD-4010
detectors (JASCO, Tokyo, Japan). 1H and 13 C NMR spectra were
recorded on a JNM-ECS-400 spectrometer (JEOL, Tokyo, Japan) in
deuterated chloroform using TMS as an internal standard. Fourier
transform infrared (FT/IR) spectra were recorded on an FT/IR-4100
(JASCO, Tokyo, Japan). High-resolution (HR) electrospray ionization
(ESI)-mass spectrometry (MS) analyses were conducted using a
microTOF II (Bruker Daltonics Inc., Billerica, MA). Optical rotations
were measured using a JASCO P-2200 polarimeter (JASCO, Tokyo,
Japan). Flash chromatography was performed on an Isolera system
(Biotage Ltd., North Carolina, US). TLC analyses were performed on
Silica gel F254 (0.25 mm or 0.5 mm, MERCK, Germany) or RP-
18F254S (0.25 mm, MERCK). SiO2/K2CO3/H2O is a homogeneous
mixture of 400 g of SiO2, 40 g of K2CO3 and 120 mL of water. All
reactions were carried out under air unless stated otherwise.
(q, J=2.0 Hz, 1H), 5.44 (d, J=0.4 Hz, 1H), 5.04 (t, J=2.0 Hz, 1H), 4.66
(dqd, J=9.2, 6.4, 2.6 Hz, 1H), 3.94 (dqd, J=10.0, 6.4, 2.8 Hz, 1H),
3.19 (ddd, J=7.2, 2.0, 0.4 Hz, 1H), 2.77 (d, J=7.2 Hz, 1H), 2.32 (dqd,
J=17.2, 7.2, 2.0 Hz, 1H), 2.22 (dqd, J=17.2, 7.2, 2.0 Hz, 1H), 1.87
(ddd, J=15.0, 9.2, 2.8 Hz, 1H), 1.68 (ddd, J=15.0, 10.0, 2.6 Hz, 1H),
1.36 (d, J=6.4 Hz, 3H), 1.25 (d, J=6.4 Hz, 3H), 1.11 (t, J=7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) δC:202.1, 185.8, 172.5, 145.2, 128.0, 107.4,
77.5, 77.0, 76.1, 63.8, 50.3, 47.9, 45.2, 24.7, 24.4, 20.0, 11.1; IR (film)
cmÀ 1: 3460, 2968, 2935, 2914, 1774, 1681, 1581, 1456, 1374, 1345,
1300, 1248, 1184, 1121, 1111, 1043, 1003, 957, 913; HRMS (ESI,
positive) m/z [M+Na]+ Calcd. for C17H22NaO6: 345.1314, Found:
345.1309.
Synthesis of Piv Ester 16
To a solution of 12b (1.74 g, 5.40 mmol) in pyridine (20 mL) was
added PivCl (1.0 mL, 8.13 mmol) under an argon atmosphere. The
reaction mixture was stirred at room temperature. After 17 hr, the
reaction mixture was quenched with MeOH (3.0 mL), and the
mixture was co-evaporated with toluene. 1 M aqueous HCl was
added and the aqueous layer was extracted with EtOAc. Then the
organic layer was washed with saturated aqueous NaCl, dried over
Na2SO4, and filtered. After evaporation, the residue was purified by
silica gel column chromatography (n-hexane/EtOAc=1/1) to give
23
Synthesis of Chiral Acetal 8
16 (2.17 g, 5.35 mmol, 99%) as a white amorphous. [α]D À 127.4 (c
1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δH: 6.04 (q, J=1.9 Hz, 1H), 5.30
(d, J=0.8 Hz, 1H), 5.02 (t, J=1.9 Hz, 1H), 5.02–4.95 (m, 1H), 4.41
(dquintet, J=8.0, 6.1 Hz, 1H), 3.14 (ddd, J=7.7, 1.9, 0.8 Hz, 1H), 2.79
(d, J=7.7 Hz, 1H), 2.35 (dqd, J=16.8, 7.3, 1.9 Hz, 1H), 2.24 (dqd, J=
16.8, 7.3, 1.9 Hz, 1H), 1.99 (ddd, J=14.5, 8.0, 4.9 Hz, 1H), 1.96 (ddd,
J=14.5, 8.4, 6.1 Hz, 1H), 1.39 (d, J=6.2 Hz, 3H), 1.28 (d, J=6.1 Hz,
3H), 1.19 (s, 9H), 1.12 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δC: 201.9, 185.1, 177.4, 172.0, 145.4, 127.4, 107.1, 76.7, 76.4, 76.0,
To a solution of 4-cyclopentene-1,3-dione (2.77 g, 28.8 mmol) and
(2R,4R)-(À )-2,4-pentanediol (2.01 g, 19.3 mmol) in toluene (120 mL)
was added TsOH·H2O (731 mg, 3.84 mmol). The reaction mixture
was refluxed with stirring. After 1 h, the mixture was concentrated
in vacuo to give a residue, which was purified by silica gel column
chromatography (n-hexane/EtOAc=5/1) to give
8
(1.99 g,
6.14 mmol, 59%) as a colorless oil. [α]D23 +16.2 (c 1.0, CHCl3).1H
NMR (400 MHz, CDCl3) δH 7.47 (d, J=5.9 Hz, 1H), 6.20 (d, J=5.9 Hz,
1H), 4.18 (dquintet, J=7.7 Hz, 6.3 Hz, 1H), 4.06 (dquintet, J=8.2,
6.3 Hz, 1H), 2.68 (d, J=17.8 Hz, 1H), 2.59 (d, J=17.8 Hz, 1H), 1.75
(ddd, J=13.1, 8.2, 6.3 Hz, 1H), 1.72 (ddd, J=13.2, 7.7, 6.3 Hz, 1H),
1.28 (d, J=6.3 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H); 13C NMR(100 MHz,
CDCl3) δC 204.7, 157.4, 134.6, 104.8, 65.2, 65.0, 47.2, 39.6, 21.7, 21.3;
IR (film); 2975, 2933, 2878, 1727, 1457, 1384, 1340, 1268, 1150,
1024, 795 cmÀ 1; HRMS (ESI, positive) m/z [M+Na]+ Calcd. for
C10H14NaO3: 205.0835, Found: 205.0833.
66.4, 50.1, 47.9, 42.1, 38.6, 26.9, 24.5, 20.0, 19.0, 10.9; IR (film) cmÀ 1
3497, 2975, 2936, 2877, 1774, 1725, 1683, 1582, 1481, 1458, 1372,
1341, 1288, 1182, 1141, 1113, 1039, 914, 732; HRMS (ESI, positive)
m/z [M+Na]+ Calcd. for C22H30NaO7: 429.1889, Found: 429.1885.
:
Synthesis of Lactone 18
To a solution of 16 (436 mg, 1.07 mmol) in THF (20 mL) was added
BH3·THF solution (1 M in THF, 1.5 mL, 1.50 mmol) at 0 C under
argon atmosphere, and the reaction mixture was stirred at 0 C for
°
°
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5 h. The reaction mixture was quenched with saturated aqueous
NaHCO3 and the aqueous layer was extracted with EtOAc. The
organic layer was washed with saturated aqueous NaCl, dried over
Na2SO4, and filtered. After evaporation, the residue was purified by
silica gel column chromatography (n-hexane/EtOAc=2/3) to give
(110 mg, 150 μmol) under argon atmosphere. The atmosphere was
displaced with hydrogen, and then the reaction mixture was stirred
at room temperature for 11 h. After filtration through Celite, the
filtrate was evaporated. The residue was carried on to the next step
without further purification due to its adequate purity and high
polarity. To a solution of the residue in MeOH (2.5 mL) and benzene
(2.5 mL) was added TMS diazomethane solution (0.6 M in n-hexane,
1
2
3
4
5
6
7
8
9
18 (408 mg, 998 μmol, 93%) as
a white amorphous. Since
compound 18 was prone to decompose, it was used for the next
reaction immediately after 1H NMR analysis. 1H NMR (400 MHz,
CDCl3) δH: 5.61 (t, J=1.5 Hz, 1H), 5.45 (dd, J=7.0, 2.7 Hz, 1H), 5.02
(dqd, J=9.9, 6.2, 3.8 Hz, 1H), 4.78 (dd, J=2.6, 0.7 Hz, 1H), 4.40 (dd,
J=6.6, 4.2 Hz, 1H), 4.12 (dqd, J=9.1, 6.2, 4.0 Hz, 1H), 3.18 (d, J=
6.6 Hz, 1H), 3.09 (dd, J=9.3, 7.0 Hz, 1H), 3.00 (ddd, J=9.3, 4.2,
0.7 Hz, 1H), 2.72 (brs, 1H), 2.32 (dqd, J=9.0, 7.4, 1.7 Hz, 1H), 2.28
(dqd, J=9.1, 7.1, 1.6 Hz, 1H), 1.87 (ddd, J=14.7, 9.1, 3.8 Hz, 1H),
1.82 (ddd, J=14.7, 9.9, 4.0 Hz, 1H), 1.29 (d, J=6.2 Hz, 3H), 1.22 (d,
J=6.2 Hz, 3H), 1.15 (s, 9H), 1.11 (t, J=7.1 Hz, 3H).
°
1.2 mL, 0.72 mmol) at 0 C for 10 min. The reaction mixture was
concentrated under reduced pressure to afford cis-23 (70.1 mg).
The crude product was used for the next reaction without further
purification. To a solution of cis-23 in pyridine (3 mL) was added
°
phosphorus oxychloride (0.4 ml, 4.29 mmol) at 0 C under argon
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
atmosphere. The reaction mixture was gradually warmed to room
temperature with overnight stirring. The reaction mixture was
quenched with slow addition of cold H2O, and then extracted with
Et2O. The resulting organic layer was washed with saturated
aqueous NaCl, dried over Na2SO4, and filtered. After evaporation,
the residue was purified by silica gel column chromatography (n-
hexane/AcOEt=4/1) to give 24 (30.1 mg, 0.14 mmol, 47% in
4 steps) as a colorless oil. All spectral data of 24 were identical to
those reported.[25]
Synthesis of Enone 9
To a solution of 18 (93.5 mg, 229 μmol) in CH2Cl2 (3 mL) was added
°
TFA (50 μL, 653 μmol) at 0 C. After the reaction mixture was stirred
°
at 0 C for 30 min. After evaporation, the residue was purified by
silica gel column chromatography (n-hexane/EtOAc=5/1) to give 9
Synthesis of CFA (4)
(37.9 mg, 172 μmol, 75%) as a white crystal. [α]D21 +149.6 (c 1.18,
CHCl3). H NMR (400 MHz, CDCl3) δH: 7.77 (dd, J=5.8, 2.4 Hz, 1H),
1
A suspension of 24 (130 mg, 583 μmol) in 3 M aqueous HCl (8.0 mL)
was refluxed for 6 h. After the reaction mixture was quenched with
H2O, the mixture was extracted with EtOAc. The resulting organic
layer was washed with saturated aqueous NaCl, dried over Na2SO4,
6.37 (dd, J=5.8, 2.0 Hz, 1H), 6.06 (q, J=2.0 Hz, 1H), 5.21 (t, J=
2.0 Hz, 1H), 3.86 (brs, 1H), 3.43 (dt, J=7.2, 2.0 Hz, 1H), 2.74 (dd, J=
7.2, 2.4 Hz, 1H), 2.29 (dqd, J=18.8, 7.6, 2.0 Hz, 1H), 2.24 (dqd, J=
18.8, 7.6, 2.0 Hz, 1H), 1.10 (t, J=7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δC: 204.2, 173.9, 162.8, 145.7, 138.8, 128.4, 78.2, 77.7, 49.9,
49.1, 24.6, 11.0; IR (film) cmÀ 1: 3462, 2967, 2937, 2876, 1769, 1763,
1733, 1716, 1709, 1684, 1652, 1635, 1578, 1558, 1541, 1522, 1508,
1489, 1474, 1457, 1396, 1386, 1215, 1075, 987, 950, 895; HRMS (ESI,
positive) m/z [M+Na]+ Calcd. for C12H12NaO4: 243.0633, Found:
243.0613.
and filtered. After evaporation, coronafacic acid
4 (122 mg,
583 μmol, quant.) was obtained as a colorless crystalline solid. All
spectral data of 4 were identical to those reported.[25]
Synthesis of Chiral Acetal ent-8
To a solution of 4-cyclopentene-1,3-dione (2.30 g, 24.0 mmol) and
(2S,4S)-(+)-2,4-pentanediol (1.95 g, 18.7 mmol) in toluene (120 mL)
was added TsOH·H2O (351 mg, 1.85 mmol) and the reaction mixture
was stirred and refluxed for 1 h. After evaporation, the residue was
purified by silica gel column chromatography (n-hexane/EtOAc=5/
1) to give ent-8 (2.52 g, 13.8 mmol, 74%) as a colorless oil.
Synthesis of Ketone 10
To a solution of 9 (948 mg, 4.31 mmol) in toluene (200 mL) under
argon atmosphere was added 5% Pd/C (491 mg, 231 μmol). The
atmosphere was displaced with hydrogen, and the reaction mixture
was stirred at room temperature for 59 h. After filtration with Celite,
the filtrate was evaporated to dryness. The residue was purified by
silica gel column chromatography (n-hexane/EtOAc=1/1) to give
10 (686 mg, 3.06 mmol, 71%) as a colorless oil and 11 (222 mg,
24
1
[α]D À 16.4 (c 1.14, CHCl3). H NMR (400 MHz, CDCl3) δH: 7.46 (d, J=
5.8 Hz, 1H), 6.19 (d, J=5.8 Hz, 1H), 4.17 (dquintet, J=7.8, 6.1 Hz,
1H), 4.06 (dquintet, J=8.2, 6.1 Hz, 1H), 2.68 (d, J=17.9 Hz, 1H), 2.58
(d, J=17.9 Hz, 1H), 1.75 (ddd, J=13.2, 8.2, 6.1 Hz, 1H), 1.71 (ddd, J=
13.2, 7.8, 6.1 Hz, 1H), 1.27 (d, J=6.1 Hz, 3H), 1.26 (d, J=6.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δC: 204.9, 157.5, 134.8, 105.0, 65.4, 65.2,
47.3, 39.7, 21.8, 21.4; IR (film) cmÀ 1: 2974, 2927, 2878, 1737, 1463,
1379, 1346, 1276, 1161, 1022, 798; HRMS (ESI, positive) m/z [M+
Na]+ Calcd. for C10H14NaO3: 205.0841, Found: 205.0840.
1
991 μmol, 23%) as a colorless oil. [α]D22 +175.4 (c 0.93, CHCl3). H
NMR (400 MHz, CDCl3) δH: 4.86 (t, J=1.2 Hz, 1H), 3.50 (brs, 1H), 2.93
(ddd, J=10.8, 8.4, 4.8 Hz, 1H), 2.63 (dt, J=10.8, 1.2 Hz, 1H), 2.38–
2.14 (m, 4H), 1.94–1.80 (m, 2H), 1.55 (dquintet, J=14.4, 7.2 Hz, 1H),
1.45 (dd, J=13.4, 3.8 Hz, 1H), 1.41 (dquintet, J=14.4, 7.2 Hz, 1H),
0.95 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δC: 216.0, 176.8,
78.4, 72.6, 50.8, 41.7, 39.4, 37.6, 37.2, 26.5, 21.8, 11.2; IR (film) cmÀ 1
:
Synthesis of Diels-Alder Type Reaction Product ent-12b
3445, 2962, 2935, 2874, 1742, 1457, 1274, 1123, 1007, 959; HRMS
(ESI, positive) m/z [M+Na]+ Calcd. for C12H16NaO4: 247.0946, Found:
247.0936.
To a solution of 7 (1.46 g, 10.4 mmol) and ent-8 (2.71 g, 14.9 mmol)
°
in CH2Cl2 (70 mL) was added Et3N (1.5 mL, 10.7 mmol) at À 40 C
under argon atmosphere. The reaction mixture was stirred at
°
À 40 C for 1 d. After evaporation, the residue was purified by silica
gel column chromatography (n-hexane/EtOAc=2/3) to give ent-
12b (1.99 g, 6.17 mmol, 59%) as a white crystal and the diaster-
eomer ent-13b (575 mg, 0.78 mmol, 17%) as a white crystal. ent-
Synthesis of Methyl Ester 24
To a solution of 10 (64.3 mg, 287 μmol) in MeOH (3 mL) was added
NaOMe (64.0 mg, 1.18 mmol) at 0 C under argon atmosphere. After
12b: [α]D20 +176.9 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) δH: 6.07
1
°
the reaction mixture was stirred for 30 min, the reaction mixture
was quenched with 0.5 M aqueous HCl. The mixture was extracted
with EtOAc. The organic layer was washed with saturated aqueous
NaCl, dried over Na2SO4, and filtered. After evaporation, to a
solution of the residue in MeOH (21 mL) was added 10% Pd/C
(q, J=1.9 Hz, 1H), 5.43 (d, J=0.7 Hz, 1H), 5.05 (t, J=1.9 Hz, 1H), 4.67
(dqd, J=9.4, 6.2, 2.9 Hz, 1H), 4.13 (brs, 1H), 3.94 (dqd, J=9.9, 6.3,
2.8 Hz, 1H), 3.19 (ddd, J=7.6, 1.9, 0.7 Hz, 1H), 2.79 (d, J=7.6 Hz, 1H),
2.31 (dqd, J=17.6, 7.3, 1.9 Hz, 1H), 2.25 (dqd, J=17.6, 7.3, 1.9 Hz,
1H), 1.86 (ddd, J=14.7, 9.4, 2.8 Hz, 1H), 1.69 (ddd, J=14.7, 9.9,
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2.9 Hz, 1H), 1.38 (d, J=6.2 Hz, 3H), 1.24 (d, J=6.3 Hz, 3H), 1.12 (t,
J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δC: 202.1, 185.9, 172.8,
145.2, 128.2, 107.4, 77.9, 77.1, 76.4, 63.5, 50.4, 48.2, 45.4, 24.8, 24.5,
20.0, 11.2; IR (film) cmÀ 1: 3390, 2972, 2933, 2878, 1771, 1677, 1578,
1458, 1372, 1340, 1186, 1114, 957, 911; HRMS (ESI, positive) m/z [M
+Na]+ Calcd. for C17H22NaO6: 345.1314, Found: 345.1313. ent-13b:
[α]D À 75.1 (c 1.11, CHCl3). H NMR (400 MHz, CDCl3) δH: 6.06 (q, J
=2.0 Hz, 1H), 5.41 (d, J=0.8 Hz, 1H), 5.04 (t, J=2.0 Hz, 1H), 4.65
(dqd, J=9.2, 6.4, 2.8 Hz, 1H), 3.93 (dqd, J=10.0, 6.0, 3.2 Hz, 1H),
3.18 (ddd, J= 7.2, 2.0, 0.8 Hz, 1H), 2.79 (d, J=7.2 Hz, 1H), 2.32 (dqd,
J=16.4, 7.2, 2.0 Hz, 1H), 2.26 (dqd, J=16.4, 7.2, 2.0 Hz, 1H), 1.88
(ddd, J=14.8, 9.2, 2.8 Hz, 1H), 1.69 (ddd, J=14.8, 10.0, 3.2 Hz, 1H),
1.36 (d, J=6.4 Hz, 3H), 1.26 (d, J=6.0 Hz, 3H), 1.11 (t, J=7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) δC: 202.1, 185.8, 172.5, 145.2, 128.0, 107.5,
77.5, 77.0, 76.1, 63.9, 50.3, 47.9, 45.2, 24.7, 24.4, 19.5, 11.1; IR (film)
cmÀ 1: 3468, 2971, 2933, 2882, 1771, 1680, 1579, 1457, 1375, 1339,
1250, 1184, 1039, 999, 912, 861, 760; HRMS (ESI, positive) m/z [M+
Na]+ Calcd. for C17H22NaO6: 345.1314, Found: 345.1303.
2.32 (dqd, J=9.0, 7.4, 1.7 Hz, 1H), 2.28 (dqd, J=9.1, 7.1, 1.6 Hz, 1H),
1.87 (ddd, J=14.7, 9.1, 3.8 Hz, 1H), 1.82 (ddd, J=14.7, 9.9, 4.0 Hz,
1H), 1.29 (d, J=6.2 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H), 1.15 (s, 9H), 1.11
(t, J=7.1 Hz, 3H).
1
2
3
4
5
6
7
8
9
22
1
Synthesis of Enone ent-9
To a solution of ent-18 (22.0 mg, 53.9 μmol) in CH2Cl2 (3 mL) was
°
added TFA (2 μL, 261 μmol) at 0 C. After the reaction mixture was
°
stirred at 0 C for 1 h. After evaporation, the residue was purified by
silica gel column chromatography (n-hexane/EtOAc=2/3) to give
21
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
ent-9 (5.4 mg, 24.1 μmol, 45%) as a white crystal. [α]D À 155.3 (c
1
1.39, CHCl3). H NMR (400 MHz, CDCl3) δH: 7.75 (dd, J=5.8, 2.6 Hz,
1H), 6.37 (dd, J=5.8, 2.0 Hz, 1H), 6.06 (q, J=2.0 Hz, 1H), 5.21 (t, J=
2.0 Hz, 1H), 3.65 (brs, 1H), 3.43 (dt, J=6.8, 2.0 Hz, 1H), 2.73 (dd, J=
6.8, 2.6 Hz, 1H), 2.29 (dqd, J=17.2, 7.6, 2.0 Hz, 1H), 2.24 (dqd, 17.2,
7.6, 2.0 Hz, 1H), 1.10 (t, J=7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δC:
204.0, 174.0, 162.8, 145.8, 138.8, 128.4, 78.2, 77.7, 49.8, 49.1, 24.6,
11.0; IR (film) cmÀ 1: 3443, 2971, 2938, 2879, 1770, 1760, 1749, 1733,
1716, 1705, 1684, 1671, 1646, 1578, 1520, 1487, 1420, 1339, 1211,
1074, 999, 930, 893; HRMS (ESI, positive) m/z [M+Na]+ Calcd. for
C12H12NaO4: 243.0633. Found: 243.0613.
Synthesis of Piv Ester ent-16
To a solution of ent-12b (1.68 g, 5.21 mmol) in pyridine (20 mL) was
added PivCl (970 μL, 7.89 mmol) under argon atmosphere and the
reaction mixture was stirred at room temperature for 24 h. The
reaction mixture was quenched with MeOH (3.0 mL), and the
mixture was co-evaporated with toluene. 1 M aqueous HCl was
added and the aqueous layer was extracted with EtOAc. Then the
organic layer was washed with saturated aqueous NaCl, dried over
Na2SO4, and filtered. After evaporation, the residue was purified by
Synthesis of ketone ent-10
To a solution of ent-9 (391 mg, 1.78 mmol) in toluene (90 mL) under
argon atmosphere was added 5% Pd/C (37.6 mg, 17.7 μmol). The
atmosphere was displaced with hydrogen, and the reaction mixture
was stirred at room temperature for 48 h. After filtration with Celite,
the filtrate was evaporated to dryness. The residue was purified by
silica gel column chromatography (n-hexane/EtOAc=1/1) to give
ent-10 (269 mg, 1.20 mmol, 68%) as a colorless oil and ent-11
silica gel column chromatography (n-hexane/acetone=30/1–20/1)
20
to give ent-16 (2.10 g, 5.16 mmol, 99%) as a white crystal. [α]D
+
123.9 (c 1.06, CHCl3). 1H NMR (400 MHz, CDCl3) δH: 6.04 (q, J=1.9 Hz,
1H), 5.30 (d, J=0.8 Hz, 1H), 5.02 (t, J=1.9 Hz, 1H), 5.02–4.95 (m, 1H),
4.41 (dquintet, J=8.0, 6.1 Hz, 1H), 3.14 (ddd, J=7.7, 1.9, 0.8 Hz, 1H),
2.79 (d, 7.7 Hz, 1H), 2.35 (dqd, J=16.8, 7.3, 1.9 Hz, 1H), 2.24 (dqd,
J=16.8, 7.3, 1.9 Hz, 1H), 1.99 (ddd, J=14.5, 8.0, 4.9 Hz, 1H), 1.96
(ddd, J=14.5, 8.4, 6.1 Hz, 1H), 1.39 (d, J=6.2 Hz, 3H), 1.28 (d, J=
6.1 Hz, 3H), 1.19 (s, 9H), 1.12 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δC: 201.9, 185.1, 177.4, 172.0, 145.4, 127.4, 107.1, 76.7, 76.4,
76.0, 66.4, 50.1, 47.9, 42.1, 38.6, 26.9, 24.5, 20.0, 19.0, 10.9; IR (film)
cmÀ 1: 3493, 2975, 2937, 2876, 1773, 1725, 1683, 1583, 1481, 1458,
1378, 1341, 1328, 1288, 1181, 1142, 1114, 1038, 913, 732; HRMS
(ESI, positive) m/z [M+Na]+ Calcd. for C22H30NaO7: 429.1889, Found:
429.1889.
20
(94.8 mg, 423 μmol, 22%) as a colorless oil. [α]D À 168.0 (c 0.74,
CHCl3). 1H NMR (400 MHz, CDCl3) δH: 4.85 (t, J=1.2 Hz, 1H), 3.50
(brs, 1H), 2.93 (ddd, J=10.4, 9.2, 6.0 Hz, 1H), 2.63 (dt, J=10.4,
1.2 Hz, 1H), 2.38–2.12 (m, 4H), 1.94–1.80 (m, 2H), 1.55 (dquintet, J=
14.8, 7.2 Hz, 1H), 1.44 (dd, J=13.6, 4.4 Hz, 1H), 1.40 (dquintet, J=
14.8, 7.2 Hz, 1H), 0.95 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δC: 216.0, 176.9, 78.4, 72.6, 50.9, 41.7, 39.4, 37.6, 37.2, 26.5, 21.8,
11.2; IR (film) cmÀ 1: 3452, 2965, 2932, 2874, 1745, 1459, 1260, 1124,
1010, 960; HRMS (ESI, positive) m/z [M+Na]+ Calcd. for C12H16NaO4:
247.0946, Found: 247.0985.
Synthesis of Methyl Ester ent-24
Synthesis of Lactone ent-18
To a solution of ent-10 (202 mg, 901 μmol) in MeOH (9 mL) was
°
added NaOMe (69.3 mg, 1.28 mmol) at 0 C under argon atmos-
To a solution of ent-16 (2.10 g, 5.17 mmol) in THF (95 mL) was
phere. After the reaction mixture was stirred for 30 min, the
reaction mixture was quenched with 0.5 M aqueous HCl. The
mixture was extracted with EtOAc. The organic layer was washed
with saturated aqueous NaCl, dried over Na2SO4, and filtered. After
evaporation, to a solution of the residue in MeOH (10 mL) was
added 10% Pd/C (49.2 mg, 461 μmol) under argon atmosphere.
The atmosphere was displaced with hydrogen, and then the
reaction mixture was stirred at room temperature for 40 min. After
filtration with Celite, the filtrate was evaporated. The residue was
carried on to the next step without further purification because this
compound was pure enough and highly polar. To a solution of the
residue in MeOH (6 mL) and benzene (6 mL) was added TMS
diazomethane solution (0.6 M in n-hexane, 1.5 mL, 900 μmol) at
°
added BH3·THF solution (1 M in THF, 6.7 mL, 6.70 mmol) at 0 C
under argon atmosphere. After the reaction mixture was stirred at
°
0 C for 6 h. The reaction mixture was quenched with saturated
aqueous NaHCO3 and the aqueous layer was extracted with EtOAc.
The organic layer was washed with saturated aqueous NaCl, dried
over Na2SO4, and filtered. 1 M aqueous HCl was added and the
aqueous layer was extracted with EtOAc. Then the organic layer
was washed with saturated aqueous NaCl, dried over Na2SO4, and
filtered. After evaporation, the residue was purified by silica gel
column chromatography (n-hexane/acetone=30/1–20/1) to give
ent-18 (1.75 g, 4.28 mmol, 83%) as a white amorphous. Since
compound ent-18 was easily decomposed, it was used for the next
reaction immediately after H NMR analysis. H NMR δH (CDCl3) 5.61
(t, J=1.5 Hz, 1H), 5.45 (dd, J=7.0, 2.7 Hz, 1H), 5.02 (dqd, J=9.9, 6.2,
3.8 Hz, 1H), 4.78 (dd, J=2.6, 0.7 Hz, 1H), 4.40 (dd, J=6.6, 4.2 Hz, 1H),
4.12 (dqd, J=9.1, 6.2, 4.0 Hz, 1H), 3.18 (d, J=6.6 Hz, 1H), 3.09 (dd,
J=9.3, 7.0 Hz, 1H), 3.00 (ddd, J=9.3, 4.2, 0.7 Hz, 1H), 2.72 (brs, 1H),
1
1
°
0 C for 10 min. The reaction mixture was concentrated under
reduced pressure to afford ent-cis-23 (461 mg). The crude product
was used for the next reaction without further purification. To a
solution of ent-cis-23 in pyridine (8 mL) was added phosphorus
°
oxychloride (1.6 mL, 17.1 mmol) at 0 C under argon atmosphere.
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The reaction mixture was stirred at room temperature for 11 h. The
reaction mixture was quenched with slow addition of cold H2O, and
then extracted with Et2O. The resulting organic layer was washed
with saturated aqueous NaCl, dried over Na2SO4, and filtered. After
evaporation, the residue was purified by silica gel column
chromatography (n-hexane/acetone=4/1) to give ent-24 (132 mg,
595 μmol, 66% in 4 steps) as a colorless oil. All spectral data of ent-
24 were identical to those reported. [25]
Synthesis of Dehydration Reaction Precursor of cis-27
1
2
3
4
5
6
7
8
9
To a solution of 30 (29.7 mg, 125 μmol) in MeOH (5 mL) was added
5% Pd/C (14.0 mg, 6.5 μmol) under argon atmosphere. The
atmosphere was displaced with hydrogen, and then the reaction
mixture was stirred for 2 h at rt. After filtration with Celite, the
filtrate was evaporated and purified by silica gel column chroma-
tography (n-hexane/EtOAc=3/2) to give cis-27 (26.3 mg, 110 μmol,
88%) as a colorless oil. [α]D22 +82.7 (c 0.95, CHCl3). 1H NMR
(400 MHz, CDCl3) δH: 3.72 (s, 3H), 3.38 (s, 1H), 3.57–2.44 (m, 2H),
2.30-1.96 (m, 4H), 1.96–1.80 (m, 2H), 1.65 (ddddd, J=10.8, 10.5, 6.7,
Synthesis of ent-CFA (ent-4)
1
3.8 3.7 Hz, 1H), 1.38–1.18 (m, 4H), 0.89 (t, J=7.4 Hz, 3H); H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
A suspension of ent-24 (94.9 mg, 427 μmol) in 3 M aqueous HCl
(5.0 mL) was refluxed for 6 h. After the reaction mixture was
quenched with H2O, the mixture was extracted with EtOAc. The
resulting organic layer was washed with saturated aqueous NaCl,
dried over Na2SO4, and filtered. After evaporation, coronafacic acid
ent-4 (87.8 mg, 423 μmol, 99%) was obtained as a colorless
crystalline solid. All spectral data of ent-4 were identical to those
reported.[25]
(400 MHz, pyridine-d5) δH: 3.68 (s, 3H), 2.81 (td, J=8.4, 6.0 Hz, 1H),
2.68 (ddd, J=7.6, 6.0, 4.6 Hz, 1H), 2.37–2.14 (m, 4H), 2.30–1.96 (m,
4H), 2.10–1.95 (m, 2H), 1.82–1.70 (m, 1H), 1.63 (dd, J=13.5, 9.0 Hz,
1H), 1.47–1.30 (m, 3H), 0.83 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δC: 217.6, 176.1, 76.4, 52.3, 47.9, 44.9, 40.2, 35.3, 32.4, 29.1,
26.5, 21.4, 11.7; IR (film) cmÀ 1: 3471, 2954, 2870, 1736, 1454, 1246;
HRMS (ESI, positive) m/z [M+Na]+ Calcd. for C13H20NaO4: 263.1254,
Found: 263.1249.
Synthesis of Ketone 11
Synthesis of α,β-Unsaturated ester 28
To a solution of 9 (453 mg, 2.06 mmol) in CH2Cl2 (20 mL) was added
Crabtree’s catalyst (100 mg, 124 μmol) under argon atmosphere.
The atmosphere was displaced with hydrogen, and the reaction
mixture was stirred at room temperature for 5 days. After evapo-
ration, the residue was purified by silica gel column chromatog-
raphy (n-hexane/EtOAc=5/1) to give 11 (352 mg, 1.57 mmol, 76%)
as a colorless oil and 10 (76.2 mg, 340 μmol, 16%) as a colorless oil.
To a solution of cis-27 (62.1 mg, 259 μmol) in pyridine (2.8 mL) was
°
added phosphorus oxychloride (280 μL, 3.1 mmol) at 0 C under
argon atmosphere. The reaction mixture was gradually warmed to
room temperature with overnight stirring. The reaction mixture was
quenched with slow addition of cold H2O, and then extracted with
Et2O. The resulting organic layer was washed with saturated
aqueous NaCl, dried over Na2SO4, and filtered. After evaporation,
the residue was purified by silica gel short pass to give the mixture
of 28 and 29 (8:1, 50.6 mg, 87%) as a colorless oil. The mixture was
separated by silica gel column chromatography (n-hexane/EtOAc=
1
[α]D24 +156.5 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) δH: 4.79 (dd,
J=3.1, 1.9 Hz, 1H), 3.43 (brs, 1H), 2.87 (ddd, J=10.8, 8.9, 5.7 Hz, 1H),
2.74 (dt, J=10.8, 1.2 Hz, 1H), 2.36–2.15 (m, 4H), 2.08 (dd, J=12.8,
10.8 Hz, 1H), 1.87–1.78 (m, 1H), 1.58 (dd, J=12.8, 6.6 Hz, 1H), 1.45
(dsext, J=14.9, 7.5 Hz, 1H), 1.32 (dsext, J=14.9, 7.5 Hz, 1H), 0.99 (t,
J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δC: 217.2, 176.9, 79.3, 72.9,
46.7, 42.4, 39.5, 37.4, 37.3, 26.4, 22.0, 11.7; IR (film) cmÀ 1: 3457, 2964,
2933, 2872, 1742, 1458, 1261, 1128, 1009, 968; HRMS (ESI, positive)
m/z [M+Na]+ Calcd. for C12H16NaO4: 247.0946. Found: 247.0943.
1
9/1). 28: [α]D22 +157.7 (c 1.08, CHCl3). H NMR (400 MHz, CDCl3) δH:
6.98 (d, J=2.2 Hz, 1H), 3.77 (s, 3H), 3.32-3.23 (m, 1H), 2.49 (tdd, J=
7.5, 4.4, 1.0 Hz, 1H), 2.33–2.09 (m, 3H), 2.08–1.89 (m, 3H), 1.48–1.31
(m, 3H), 0.97 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δC: 221.4,
167.6, 145.5, 131.2, 51.9, 46.1, 37.0, 36.1, 34.9, 27.9, 27.2, 25.7, 11.7;
IR (film) cmÀ 1: 2954, 2877, 1716, 1643, 1442, 1257, 1146, 1080, 756;
HRMS (ESI, positive) m/z [M+Na]+ Calcd. for C13H18NaO3: 245.1148,
Found: 245.1168.
Synthesis of Methyl Ester 30
29: 1H-NMR (400 MHz, CDCl3) δH 3.68 (s, 3H), 2.72 (dd, J=13.6,
9.2 Hz, 1H), 2.66 (dd, J=13.6, 9.2 Hz, 1H), 2.41–2.15 (m, 5H), 2.10–
1.97 (m, 1H), 1.41 (dd, J=13.6, 7.9 Hz, 1H), 1.31 (q, J=6.8 Hz, 1H),
1.27–1.17 (m, 2H), 0.84 (t, J=7.4 Hz, 3H). 13C-NMR (400 MHz, CDCl3)
δC 212.7, 171.2, 55.3, 52.3, 49.0, 47.3, 45.1, 40.6, 37.0, 32.9, 29.2, 20.1,
12.9. ESI-MS m/z 245 (M+Na)+.
To a solution of 11 (79.8 mg, 356 μmol) in MeOH (4 mL) was added
°
NaOMe (54.3 mg, 1.81 mmol) at 0 C under argon atmosphere. After
the reaction mixture was stirred for 1 h, the reaction mixture was
quenched with 1 M aqueous HCl. The mixture was extracted with
EtOAc. The organic layer was washed with saturated aqueous NaCl,
dried over Na2SO4, and filtered. After evaporation, to a solution of
the residue in MeOH (4.0 mL) and benzene (4.0 mL) was added TMS
diazomethane solution (0.6 M in n-hexane, 2.0 mL, 1.2 mmol) at
Synthesis of 6-epi-CFA (6)
°
0 C. The reaction mixture was quenched with acetic acid (2 mL)
A suspension of 28 (34.9 mg, 15.6 μmol) in 3 M aqueous HCl
(840 μL) was refluxed for 6.5 h. After the reaction mixture was
quenched with H2O, the mixture was extracted with EtOAc. The
resulting organic layer was washed with saturated aqueous NaCl,
dried over Na2SO4, and filtered. After evaporation, 6-epi-CFA (6)
(32.3 mg, 15.5 μmol, quant.) was obtained as a colorless crystalline
solid. [α]D23 +133.9 (c 0.575, CHCl3). 1H NMR (400 MHz, CDCl3) δH:
7.15 (dd, J=3.1, 1.0 Hz, 1H), 3.27 (ddt, J=12.4, 6.6, 1.7, 1H), 2.51
(ddd, J=12.4, 6.2, 1.3 Hz, 1H), 2.30 (td, J=11.3, 7.0 Hz, 1H), 2.79 (d,
J=7.5 Hz, 1H), 2.32 (dqd, J=16.4, 7.3, 1.9 Hz, 1H), 2.26 (dqd, J=
16.4, 7.3, 1.9 Hz, 1H), 2.04 (qd, J=7.5, 5.8 Hz, 1H), 2.03 (ddd, J=12.4,
6.6, 5.5 Hz, 1H), 1.46 (dquint., J=14.6, 7.4 Hz, 1H), 1.43–1.41 (m, 1H),
1.38 (dquint., J=14.6, 7.4 Hz, 1H), 0.98 (t, J=7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δC: 221.2, 172.3, 148.2, 130.6, 45.9, 36.9, 35.8, 35.1,
27.7, 27.1, 25.5, 11.6; IR (film) cmÀ 1: 3039, 2962, 2933, 2876, 1739,
and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (n-hexane/EtOAc=3/
22
2) to give 30 (73.0 mg, 306 μmol, 86%) as a white crystal. [α]D
+
1
73.7 (c 1.04, CHCl3). H NMR (400 MHz, CDCl3) δH: 6.67 (dd, J=3.8,
3.0, 1H), 3.73 (s, 3H), 3.66 (s, 1H), 2.93 (ddd, J=14.8, 7.1, 3.8 Hz, 1H),
2.53 (tddd, J=10.7, 7.0, 6.0, 4.4, 3.0 Hz, 1H), 2.45–2.21 (m, 3H), 2.09
(dd, 13.8, 6.0 Hz), 1.63 (dd, J=13.8, 10.7 Hz, 1H), 1.55 (dquintet, J=
14.2, 7.0 Hz, 1H), 1.47 (dquintet, J=14.2, 7.0 Hz, 1H), 1.34–1.20 (m,
1H), 0.99 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δC: 205.4,
175.4, 136.7, 135.8, 76.4, 53.0, 47.4, 40.7, 38.9, 38.4, 27.8, 22.8, 11.5;
IR (film) cmÀ 1: 3456, 2962, 2870, 1724, 1655, 1454, 1219, 1107;
HRMS (ESI, positive) m/z [M+Na]+ Calcd. for C13H18NaO4: 261.1097,
Found: 261.1132.
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1685, 1636, 1461, 1406, 1275, 1233, 1146, 1054, 929, 890; HRMS
(ESI, negative) m/z [MÀ H]À Calcd. for C12H16NaO3: 231.0992, Found:
231.0993.
Synthesis of α,β-Unsaturated Ester ent-28
1
2
3
4
5
6
7
8
9
To a solution of ent-cis-27 (124.3 mg, 108 μmol) in pyridine (5.7 mL)
was added phosphorus oxychloride (480 μL, 5.17 mmol) at 0 C
°
under argon atmosphere. The reaction mixture was gradually
warmed to room temperature with overnight stirring. The reaction
mixture was quenched with slow addition of cold H2O, and then
extracted with Et2O. The resulting organic layer was washed with
saturated aqueous NaCl, dried over Na2SO4, and filtered. After
evaporation, the residue was purified by silica gel short pass to give
the mixture of ent-28 and ent-29 (6.3:1, 101.0 mg, 87%) as a
colorless oil. The mixture was separated by silica gel column
Synthesis of Ketone ent-11
To a solution of ent-9 (395 mg, 1,79 mmol) in CH2Cl2 (15 mL) was
added Crabtree’s catalyst (100 mg, 124 μmol). The atmosphere was
displaced with hydrogen, and the reaction mixture was stirred at
room temperature for 5 days. After evaporation, the residue was
purified by silica gel column chromatography (n-hexane/EtOAc=4/
6) to give ent-11 (299 mg, 1.33 mmol, 74%) as a colorless oil and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
22
chromatography (n-hexane/EtOAc=9/1). ent-28: [α]D À 160.5 (c
24
1
ent-10 (97.1 mg, 433 μmol, 25%) as a colorless oil. [α]D À 155.8 (c
1.08, CHCl3). H NMR (400 MHz, CDCl3) δH: 6.98 (d, J=2.2 Hz, 1H),
1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δH: 4.79 (dd, J=2.8, 1.2 Hz,
1H), 3.43 (brs, 1H), 2.88 (ddd, J=10.8, 9.2, 6.4 Hz, 1H), 2.76 (dt, J=
10.8, 1.2 Hz, 1H), 2.36–2.15 (m, 4H), 2.09 (dd, J=12.8, 10.4 Hz, 1H),
1.87–1.78 (m, 1H), 1.57 (dd, J=12.8, 6.4 Hz, 1H), 1.45 (dquintet, J=
14.8, 7.6 Hz, 1H), 1.33 (dquintet, J=14.8, 7.6 Hz, 1H), 0.98 (t, J=
7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δC: 217.2, 176.9, 79.3, 72.9,
46.7, 42.4, 39.5, 37.4, 37.3, 26.4, 22.0, 11.7; IR (film) cmÀ 1: 3457, 2964,
2936, 2878, 1744, 1458, 1265, 1132, 968 (ESI, positive) m/z [M+
Na]+ Calcd. for C12H16NaO4: 247.0946, Found: 247.0934.
3.77 (s, 3H), 3.32–3.23 (m, 1H), 2.49 (tdd, J=7.5, 4.4, 1.0 Hz, 1H),
2.33–2.09 (m, 3H), 2.08–1.89 (m, 3H), 1.48–1.31 (m, 3H), 0.97 (t, J=
7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δC: 221.4, 167.6, 145.5, 131.2,
51.9, 46.1, 37.0, 36.1, 34.9, 27.9, 27.2, 25.7, 11.7; IR (film) cmÀ 1: 2958,
2877, 1716, 1643, 1442, 1257, 1146, 1080, 756; HRMS (ESI, positive)
m/z [M+Na]+ Calcd. for C13H18NaO3: 245.1148, Found: 245.1165.
Synthesis of ent-6-epi-CFA (ent-6)
A suspension of ent-28 (125 mg, 559 μmol) in 3 M aqueous HCl
(8 ml) was refluxed for 6 h. After the reaction mixture was
quenched with H2O, the mixture was extracted with EtOAc. The
resulting organic layer was washed with saturated aqueous NaCl,
dried over Na2SO4, and filtered. After evaporation, ent-6-epi-CFA
(ent-6) (122 mg, 586 μmol, quant.) was obtained as a colorless
Synthesis of Methyl Ester ent-30
To a solution of ent-11 (54.6 mg, 244 μmol) in MeOH (3 mL) was
°
added NaOMe (54.3 mg, 1.0 mmol) at 0 C under argon atmosphere.
After the reaction mixture was stirred for 1 h, the reaction mixture
was quenched with 1 M aqueous HCl. The mixture was extracted
with EtOAc. The organic layer was washed with saturated aqueous
NaCl, dried over Na2SO4, and filtered. After evaporation, to a
solution of the residue in MeOH (3.0 mL) and benzene (3.0 mL) was
added TMS diazomethane solution (0.6 M in n-hexane, 1.5 mL,
22
crystalline solid. [α]D À 126.8 (c 0.69, CHCl3). 1H NMR (400 MHz,
CDCl3) δH: 7.15 (dd, J=3.2, 1.2 Hz, 1H), 3.27 (ddt, J=12.4, 6.6, 1.6,
1H), 2.51 (ddd, J=12.4, 6.4, 1.4 Hz, 1H), 2.31 (td, J=11.2, 7.0 Hz, 1H),
2.79 (d, J=7.6 Hz, 1H), 2.32 (dqd, J=16.4, 7.4, 2.0 Hz, 1H), 2.26 (dqd,
J=16.4, 7.4, 2.0 Hz, 1H), 2.04 (qd, J=7.6, 5.8 Hz, 1H), 2.03 (ddd, J=
12.4, 6.6, 5.6 Hz, 1H), 1.46 (dquint., J=14.6, 7.4 Hz, 1H), 1.43–1.41
°
0.9 mmol) at 0 C. The reaction mixture was quenched with acetic
(m, 1H), 1.37 (dquint., J=15.2, 7.6 Hz, 1H), 0.98 (t, J=7.6 Hz, 3H); 13
C
acid (2 mL) and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (n-
hexane/EtOAc=3/2) to give ent-30 (52.9 mg, 222 μmol, 91%) as a
NMR (100 MHz, CDCl3) δC: 221.0, 171.8, 148.1, 130.3, 45.7, 36.8, 35.7,
34.9, 27.5, 26.9, 25.3, 11.4; IR (film) cmÀ 1: 2963, 2933, 2878, 1741,
1684, 1634, 1458, 1418, 1274, 1220, 1147, 1051, 924, 887; HRMS
(ESI, negative) m/z [MÀ H]À Calcd. for C12H15O3: 207.1027, Found:
207.1054.
22
1
white crystal. [α]D À 76.6 (c 1.04, CHCl3). H NMR (400 MHz, CDCl3)
δH: 6.67 (dd, J=3.8, 3.0, 1H), 3.73 (s, 3H), 3.66 (s, 1H), 2.93 (ddd, J=
14.8, 7.1, 3.8 Hz, 1H), 2.53 (tddd, J=10.7, 7.0, 6.0, 4.4, 3.0 Hz, 1H),
2.45-2.21 (m, 3H), 2.09 (dd, 13.8, 6.0 Hz), 1.63 (dd, J=13.8, 10.7 Hz,
1H), 1.55 (dquintet, J=14.2, 7.0 Hz, 1H), 1.47 (dquintet, J=14.2,
7.0 Hz, 1H), 1.34–1.20 (m, 1H), 0.99 (t, J=7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δC: 205.4, 175.4, 136.7, 135.8, 76.4, 53.0, 47.4, 40.7,
38.9, 38.4, 27.8, 22.8, 11.5; IR (film) cmÀ 1: 3456, 2962, 2870, 1720,
1655, 1455, 1219, 1107; HRMS (ESI, positive) m/z [M+Na]+ Calcd.
for C13H18NaO4: 261.1097, Found: 261.1121.
Chiral HPLC analysis
Coronafacic Acid Methyl Ester 24and ent-24
Optical purities were determined by chiral HPLC analyses on a
Chiralpak IA Φ4.6×250 mm column (Daicel Co., Ltd., Japan) eluting
with 99% n-hexane containing 1% EtOH at 0.5 mL/min. Under
these conditions, good separation of each enantiomer was
achieved: coronafacic acid methyl ester 24 at Rt=28.3 min and ent-
24 at Rt 27.7 min. Enantiomeric excess was calculated from the ratio
of peak areas (mAu s) at 235 nm. Chiral HPLC analysis of 25 ng of
the synthetic 24 gave a ratio of 24: ent-24=9789214: 22582, which
corresponded to >99.5% ee. According to the above-mentioned
procedure, Chiral HPLC analysis of 45 ng of the synthetic ent-24
gave a ratio of 24: ent-24=29444: 14203903, which corresponded
to >99.5% ee.
Synthesis of Dehydration Reaction Precursor of ent-cis-27
To a solution of ent-30 (35.7 mg, 150 μmol) in MeOH (6 mL) was
added 5% Pd/C (15.0 mg, 7.0 μmol) under argon atmosphere. The
atmosphere was displaced with hydrogen, and then the reaction
mixture was stirred for 2 h at rt. After filtration with Celite, the
filtrate was evaporated and purified by silica gel column chroma-
tography (n-hexane/EtOAc=3/2) to give ent-cis-27 (35.1 mg,
22
146 μmol, 98%) as a colorless oil. [α]D À 79.6 (c 1.09, CHCl3). 1H
NMR (400 MHz, CDCl3) δH: 3.72 (s, 3H), 3.38 (s, 1H), 3.57–2.44 (m,
2H), 2.30-1.96 (m, 4H), 1.96–1.80 (m, 2H), 1.65 (ddddd, J=10.8, 10.5,
6.7, 3.8 3.7 Hz, 1H), 1.38-1.18 (m, 4H), 0.89 (t, J=7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δC: 217.6, 176.2, 76.4, 52.3, 47.9, 44.9, 40.2,
35.3, 32.4, 29.1, 26.6, 21.5, 11.7; IR (film) cmÀ 1: 3475, 2954, 2870,
1736, 1454, 1246; HRMS (ESI, positive) m/z [M+Na]+ Calcd. for
C13H20NaO4: 263.1254, Found: 263.1262.
C6-epi-Coronafacic Acid Methyl Ester 28and ent-28
Optical purities were determined by chiral HPLC analyses on a
Chiralpak IA Φ4.6×250 mm column (Daicel Co., Ltd., Japan) eluting
with 98% n-hexane containing 2% iPrOH at 1.0 mL/min. Under
these conditions, good separation of each enantiomer was
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[8] M. Ueda, T. Kaji, W. Kozaki, Int. J. Mol. Sci. 2020, 21, 1124.
[9] A. Gaucher, J. Ollivier, J. Marguerite, R. Paugam, J. Salaün, Can. J. Chem.
1994, 72, 1312–1327.
[10] A. B. Charette, B. Cote, J. Am. Chem. Soc. 1995, 117, 12721–12732.
[11] H. Toshima, A. Ichihara, Biosci. Biotechnol. Biochem. 1995, 59, 497–500.
[12] CFA has four stable stereoisomers. The stereochemistries at C7a of
achieved: C6-epi-coronafacic acid methyl ester 28 at Rt=9.0 min
and ent-28 at Rt 9.8 min. Enantiomeric excess was calculated from
the ratio of peak areas (mAu s) at 235 nm. Chiral HPLC analysis of
10 ng of the synthetic 28 gave a ratio of 28: ent-28=2320104:
2954, which corresponded to >99% ee. According to the above-
mentioned procedure, Chiral HPLC analysis of 15 ng of the
synthetic ent-28 gave a ratio of 28: ent-28=47987: 3347993, which
corresponded to 97.2% ee.
1
2
3
4
5
6
7
8
9
trans-stereoisomers, which have
a trans ring junction, are readily
epimerised to give cis stereoisomers.[13]
[13] M. M. Littleson, C. J. Russell, E. E. Frye, K. B. Ling, C. Jamieson, A. J. B.
Watson, Synthesis 2016, 48, 3429–3448, and references cited therein.
[14] M. M. Littleson, C. M. Baker, A. J. Dalencon, E. C. Frye, C. Jamieson, A. R.
Kennedy, K. B. Ling, M. M. McLachlan, M. G. Montgomery, C. J. Russell,
A. J. B. Watson, Nat. Commun. 2018, 9, 1105.
[15] N. Kato, S. Miyagawa, H. Nomoto, M. Nakayama, M. Iwashita, M. Ueda,
Chirality 2020, 32, in press.
Acknowledgements
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This work was financially supported by a Grant-in-Aid for Scientific
Research for MU from JSPS, Japan (nos. 17H06407, 18KK0162, and
20H00402), JSPS A3 Foresight Program (MU), and JSPS Core-to-
Core Program Asian Chemical Biology Initiative (MU), for NK (no.
19K06968), SUNBOR GRANT (NK).
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Conflict of Interest
The authors declare no conflict of interest.
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Keywords: natural products · phytochemistry · coronatine
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Manuscript received: July 29, 2020
Revised manuscript received: September 5, 2020
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