Stereoselective synthesis of epi-jasmonic acid, tuberonic acid, and 12-oxo-PDA

Article abstract of DOI:10.1039/c0ob00218f

epi-Jasmonic acid (epi-JA) and tuberonic acid (TA) were synthesized from the key aldehyde, all cis-2-(2-hydroxy-5-vinylcyclopentyl)acetaldehyde (14), which was in turn prepared stereoselectively from the (1R)-acetate of 4-cyclopentene-1,3-diol (10) through S_N2-type allylic substitution with CH₂CHMgBr followed by Mitsunobu inversion, Eschenmoser-Claisen rearrangement, and regioselective Swern oxidation of the corresponding bis-TES ether (13). Wittig reaction of the aldehyde 14 with [Ph₃P(CH ₂)Me]⁺Br^- followed by oxidation afforded epi-JA (3) stereoselectivity over the trans isomer. Similarly, TA (5) was synthesized. Furthermore, the above findings were applied successfully to improve the total efficiency of the previous synthesis of 12-oxo-PDA (1).

Full text of DOI:10.1039/c0ob00218f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective synthesis of epi-jasmonic acid, tuberonic acid, and
12-oxo-PDA†
Hisato Nonaka, Narihito Ogawa, Noriaki Maeda, Yong-Gang Wang and Yuichi Kobayashi*
Received 6th June 2010, Accepted 6th August 2010
DOI: 10.1039/c0ob00218f
epi-Jasmonic acid (epi-JA) and tuberonic acid (TA) were synthesized from the key aldehyde, all
cis-2-(2-hydroxy-5-vinylcyclopentyl)acetaldehyde (14), which was in turn prepared stereoselectively
from the (1R)-acetate of 4-cyclopentene-1,3-diol (10) through SN2-type allylic substitution with
CH2 CHMgBr followed by Mitsunobu inversion, Eschenmoser–Claisen rearrangement, and
regioselective Swern oxidation of the corresponding bis-TES ether (13). Wittig reaction of the aldehyde
14 with [Ph3P(CH2)Me]+Br- followed by oxidation afforded epi-JA (3) stereoselectivity over the trans
isomer. Similarly, TA (5) was synthesized. Furthermore, the above findings were applied successfully to
improve the total efficiency of the previous synthesis of 12-oxo-PDA (1).
Introduction
Plants metabolize linolenic acid to a class of cyclopentanones and
-enones, which possess the two side chains at the a and b positions
(Fig. 1).1 Different from the well-known prostaglandins, the side
chains are projected to the same direction (defined herein as the
cis configuration),2 which renders the metabolites susceptible to
isomerization at the a carbon to produce the thermodynami-
cally more stable trans isomers. Indeed, the metabolites isolated
from natural sources through multi-step purifications have been
contaminated with the trans isomers in varying ratios, whereas
these materials have been used for biological studies.3 The ther-
modynamic instability also restricts reactions for stereocontrolled
synthesis of these metabolites. For example, the enolate reaction is
ill-suited. Strongly acidic and basic conditions should be avoided
as well. Consequently, stereoselective synthesis of the metabolites
is a challenging subject in modern organic chemistry.4
Recently, we have established regio- and stereoselective allylic
substitution of the monoacetate of cis-4-cyclopentene-1,3-diol
with copper and borane reagents derived from organometallics
such as RMgX and RLi.5,6 This substitution was utilized to
construct the intermediates with the upper chain of 12-oxo-PDA
(1), OPC-8:0 (2), and related compounds, while the lower chain
was attached through the Claisen rearrangement.7 Later, 12-oxo-
PDA was used to identify a peroxisomal acyl-activating enzyme8
and to elucidate the expression of the specific DNA.9
Afterwards, we focused our attention on the synthesis of epi-
JA (3) and TA (5). The former is the junction in the metabolic
cascade leading to Me epi-JA (4)1,2,10 and amino acid conjugates
7,11,12 though a mechanism regulating the two pathways is not
fully clarified. The lack of a method to obtain epi-JA seems
responsible for. So far, optically active epi-JA was once synthesized
from diol 8 as a mixture with lactone 9 [eqn (1)].13 On the other
hand, several syntheses of optically active Me epi-JA have been
reported,13,14 though reaction conditions for hydrolysis to epi-JA
Fig.
1
The linolenic acid cascade in plants. 12-oxo-PDA,
(15Z)-12-oxo-10,15-phytodienoic acid; OPC-8:0, (3-oxo-2-((2Z)-
pentenyl)cyclopentyl)octanoic acid; epi-JA, epi-jasmonic acid; Me epi-JA,
methyl epi-jasmonate; TA, tuberonic acid; TAG, tuberonic acid glucoside.
Department of Biomolecular Engineering, Tokyo Institute of Technology,
B52, Nagatsuta-cho 4259, Midori-ku, Yokohama, 226-8501, Japan. E-mail:
ykobayas@bio.titech.ac.jp
† Electronic supplementary information (ESI) available: Spectral data for
the compounds described herein. See DOI: 10.1039/c0ob00218f
are not established. Instead, chemically stable analogues of epi-
JA has been synthesized.15 TA (5)16 and TAG (6)17 have been
isolated from the leaves of potato as the promoters of the tuber
formation. The cis configuration for the two side chains of TAG
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was determined by Koda on the basis of the time-dependent loss
of the biological activity.18,19 The assignment is consistent with the
stereochemistry that is created by the cascade. By analogy, the cis
configuration was assigned to TA (5). Previously, the methyl ester
of TA has been synthesized as optically active and racemic forms
by Kitahara20 and Kiyota,21 respectively. In these syntheses, they
observed isomerization to the trans isomer during the removal of
the THP, EE (ethoxyethyl), and TBDPS (t-BuPh2Si) groups under
acidic conditions, and hence changed these groups to the very
unstable CF3CO and TMS groups, respectively. Importantly, as
was in the case of Me epi-JA, hydrolysis of the ester to TA is not
reported.
previous synthesis of 12-oxo-PDA (1) to improve the efficiency.
Herein, we present a full account of the investigation.
Results and discussion
Synthesis of the key intermediate 14
(1R)-Acetate 10 (>99% ee by chiral HPLC analysis) was prepared
by the PPL-assisted hydrolysis of the corresponding diacetate
(PPL, pig pancreatic lipase).25 Allylic substitution of 10 with
CH2 CHMgBr was performed in the presence of CuCN and LiCl
to afford 11 with 93% regioselectivity over the anti SN2¢ isomer and
with complete stereoselectivity (Scheme 2).6c,d,26 Since the product
is highly volatile, the 93 : 7 mixture was subjected to Mitsunobu
inversion27 with AcOH and DIAD in toluene at -78 ◦C to produce
acetate 15 as a single product in 63% yield from 10. Under
these conditions the minor alcohol (regioisomer of 11) remained
unreacted probably due to the vinyl group obstacle. Acetate of 10
(stereoisomer of 15) was not detected by 1H NMR analysis (15, d
3.21–3.32 ppm; acetate of 11, d 3.40–3.52 ppm). Hydrolysis of 15
afforded alcohol 16, which was subjected to Claisen rearrangement
using excess CH2 CHOEt and Hg(OAc)2 (cat.) in benzene at
(1)
With the above information on the stability in mind, we planed
a synthesis of epi-JA (3) and TA (5), which is summarized in
Scheme 1 with several key reactions. Aldehyde 14 was designed
as a common key intermediate to be converted to targets 3
and 5 by using a Wittig reaction. The vinyl group chosen
as a CH2CO2H equivalent22 was expected to reduce steps for
protection/deprotection manipulation. The realization of this
strategy was communicated with the synthesis of 5,23 in which
the conversion of lactone 12 to aldehyde 14 was accomplished
quite efficiently and with operationally simple way through
regioselective Swern oxidation24 of bis-TES ether 13. In addition,
conversion of 11 to 12 was improved by using the Escenmosher–
Claisen rearrangement, which is the mercury free version of the
rearrangement. We then accomplished synthesis of epi-JA (3)
along this line. Furthermore, the method was applied to the
◦
180–200 C according to the previous procedure.7a However, the
reaction took place slowly to give, after 60 h, a mixture of aldehyde
17b (22% yield) and alcohol 16 as minor and major components.
Coordination of the vinyl group to the mercury catalyst is a likely
reason for the low yield.28 The Eschenmoser method29 was next
examined with MeC(OMe)2NMe2 in xylene under reflux. The
reaction completed within 1 h to afford amide 17a, which was
then subjected to iodolactonization with I2 in aqueous THF to
Scheme 1 An approach to epi-JA and TA.
Scheme 2 Synthesis of the key intermediate 14.
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produce iodolactone 18 in 45% yield from acetate 15. Inevitable
loss of the volatile alcohol 16 during the isolation/purification
might be responsible for the somewhat low yield (45%). The iodo
group was then removed with Bu3SnH and AIBN to afford lactone
12 without causing damage to the vinyl moiety.
Previously, lactone 20 was converted to aldehyde 22 in the
synthesis of OPC-8:0 through the hydroxy methyl ester 21 in four
steps (Scheme 3), in which 21 was quickly semi-purified for the
next reaction in order to prevent lactonization back to 20.7a This
conversion was also successful with a similar lactone leading to 12-
oxo-PDA (1). However, the present hydroxy ester 23 derived from
lactone 12 underwent rapid lactonization to 12 (Scheme 4), which
led us to investigate another sequence of reactions. As delineated
in Scheme 2, reduction of lactone 12 with LiAlH4 followed by bis-
silylation of the resulting diol 19 afforded bis-TES ether 13 in 82%
yield from iodolactone 18. Swern oxidation24 of 13 at the primary
TESOCH2 group proceeded regioselectively to afford aldehyde 14
as a sole product. This conversion is one-step shorter than the
attempted sequence through 23 (Scheme 4) and, furthermore, the
overall yield is acceptable (77% yield at the stage of 24). In addition,
the intermediates in this three-step sequence are chemically quite
stable to allow easy handling.
Scheme 5 Synthesis of epi-JA (3).
(1)) was not detected. To confirm the structure of 3, especially
the cis configuration, 3 was converted (Scheme 6) to Me epi-JA
1
(4) and the trans isomer (i.e., JA), and the H and 13C NMR
spectra of the products were found to be consistent with those
reported.13,14b,d,30 The chemical purity of 3 over the trans isomer was
98% by 1H NMR spectroscopy (3, d 2.77–2.91 ppm; the isomer, d
2.71–2.83 ppm) (see page S13 of the ESI†).
Scheme 3 The previous conversion of lactone 20 to aldehyde 22.
Scheme 6 Conversion of 3 to the known compounds.
Synthesis of TA
Two phosphonium salts 26a,b with PMB (p-MeOC6H4CH2) and
THP protective groups received attention as a Wittig partner of
aldehyde 14. Among them, 26a was not examined for a specific
reason found in a preliminary study using a model PMB ether
derived from racemic Me JA.31
Scheme 4 An attempted conversion of lactone 12 to aldehyde 14.
Synthesis of epi-JA
[Ph3P(CH2 )3OR]+ Br-
26 for R; a, PMB; b, THP
Aldehyde 14 prepared above was transformed to epi-JA (3) as
delineated in Scheme 5. Wittig reaction with an ylide derived
from [Ph3P(CH2)2Me]+Br- and NaHMDS (NaN(TMS)2) in THF–
DMF afforded cis olefin 24 stereoselectively. Hydroboration of 24
with Cy2BH (Cy: c-C6H11) was regioselective to produce alcohol
25 in 65% yield after oxidative workup. Finally, desilylation of
the TES group followed by Jones oxidation of the resulting diol
As shown in Scheme 7, Wittig reaction of aldehyde 14 with an
anion derived from the THP ether 26b afforded cis olefin 27, which,
upon hydroboration with Cy2BH followed by oxidative workup,
produced alcohol 28 in 67% yield. The remaining reactions at this
stage were oxidation of the C1 and C6 carbons and deprotection
of the THP group. First, desilylation of 28 afforded diol 29 in 75%
yield. Jones oxidation was attempted between -40 and -30 ◦C in
order to prevent unwanted deprotection of the THP protective
group.32 However, a mixture of products was produced. Next, the
◦
8 at 0 C furnished epi-JA (3) in 62% yield from 25. The lactone
9 produced previously13 from 8 by the oxidation with PDC (eqn
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Scheme 7 Synthesis of TA (5).
keto aldehyde 31 derived from diol 29 was subjected to Jones
oxidation at -30 ◦C to give another mixture, whereas no oxidation
took place at -40 ◦C. Oxidation of 31 with NaClO2 proceeded
with isomerization to afford a 70 : 30 mixture of 30 and the trans
isomer 32.33
The above results clearly suggested a sequential oxidation first at
C1 and then at C6 is inevitable to prevent the competitive reactions
and/or the isomerization. To this end, oxidation of alcohol
28 with SO3·pyridine gave the corresponding aldehyde, which,
upon further oxidation with NaClO2 under neutral conditions,34
afforded acid 33 in good yield. Selective removal of the TES group
from 33 was accomplished with PPTS (ca. 0.3 equiv) in EtOH
(rt, 1 h) to produce the acid alcohol 34 in 90% yield.35 Finally,
Jones oxidation of alcohol 34 at -40 ◦C produced the keto acid 30
without any cleavage of the THP group and isomerization to the
trans isomer.
isomer (12-hydroxy-JA),33 while exposure to 0.1 N HCl (5 mol%)
in MeOH at 0 ◦C afforded a 27 : 73 mixture of TA (5) and the trans
isomer. The facile isomerization is consistent with that reported
previously for the deprotection of the THP, EE, and TBDPS ethers
of the TA methyl ester in 70% AcOH at 60 ◦C and with HF in
aqueous MeCN at -20 ◦C.20,21 We then examined several protocols
to finally find that MgBr2 (3 equiv) in Et2O36 at room temperature
for 2 h provided TA (5) in high yield with a minimum level of the
isomerization (ratio of 5 to the trans isomer = 92 : 8 by 1H NMR
spectroscopy) (see page S23 of the ESI†). This step was repeated
several times with similar selectivities.
Isomerization of TA
Time-dependency of the isomerization of TA (5) to the trans
isomer was studied at room temperature in CD3OD by monitoring
the protons at d 2.74–2.88 and 2.60–2.71 ppm for 5 and the trans
isomer,33 respectively. In contrast to the fairly rapid isomerization
under acidic conditions (see above) and basic conditions,33 little
To remove the THP group the keto acid 30 was exposed to dry
HCl (5 mol%; derived from AcCl) in MeOH at room temperature,
which unfortunately induced complete isomerization to the trans
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Scheme 8 Synthesis of 12-oxo-PDA (1).
isomerization was detected even after 21 days! We then added
K2CO3 (heterogeneous in CD3OD), which catalyzed isomerization
slowly to produce a 40 : 60 mixture after 7 days.
under neutral conditions to establish no isomerization over an
extended period. The stability of 5 established herein will be quite
informative for modifying the isolation of 5 (and probably 3) from
the natural sources.
Synthesis of 12-oxo-PDA
Due to the demand for the biological study of 12-oxo-PDA,8,9
the above findings were applied to the previous synthesis of 12-
oxo-PDA.7a, cf. 37 As shown in Scheme 8 Eschenmoser–Claisen
rearrangement of alcohol 357a in xylene afforded amide 36 in
82% yield, which was subjected to iodolactonization with I2 in
aqueous THF and subsequent reaction with DBU to produce
lactone 38 in 83% yield. In addition to the advantage of using the
mercury-free method, the present method is superior in terms of
yield, reaction time, operation, and steps to the original procedure
[(1) CH2 CHOEt/Hg(OAc)2 cat., 170 ◦C, 61 h, a sealed tubing;
(2) Jones oxidation of the resulting aldehyde to acid 37 in 79%
yield over two steps]. Lactone 38 was converted successfully to
aldehyde 41 through Swern oxidation of the bis-TES ether 40.
Subsequently, Wittig reaction and desilylation afforded diol 42
in 85% yield from lactone 38. Finally, Jones oxidation of diol 42
furnished 12-oxo-PDA (1) in 63% yield. Diastereomeric purity of
1 was >95% by 1H NMR spectroscopy, which was identical to that
obtained previously. The overall yield of 1 from 35 was improved
to be 36% (previously 19%).38
Experimental
General remarks
Infrared (IR) spectra are reported in wave numbers (cm-1). The 1H
NMR (300 MHz) and 13C NMR (75 MHz) spectra were measured
in CDCl3 using SiMe4 (d = 0 ppm) and the center line of CDCl3
triplet (d = 77.1 ppm) as internal standards, respectively. Signal
patterns are indicated as br s, broad singlet; s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet. Coupling constants (J) are given
in hertz (Hz). In some cases chemical shifts of carbons accompany
plus (for C and CH2) and minus (for CH and CH3) signs of APT
(Attached Proton Test) experiments. (1R)-acetate 10 of >99% ee
(by chiral HPLC analysis) was prepared according to the literature
procedure.25 The following solvents were distilled before use: THF
(from Na/benzophenone), Et2O (from Na/benzophenone), and
CH2Cl2 (from CaH2).
(1R,4R)-4-Vinylcyclopent-2-enyl ethanoate (15). To an ice-
cold solution of LiCl (1.20 g, 28.3 mmol) in THF (2.5 mL)
was added CH2 CHMgBr (30 mL, 0.70 M in THF, 21 mmol)
dropwise. After 20 min at 0 ◦C, CuCN (189 mg, 2.11 mmol) was
added. The mixture was stirred at 0 ◦C for 15 min, and a solution
of monoacetate 10 (1.0 g, 7.03 mmol, >99% ee) in THF (2.5 mL)
was added. The reaction was carried out for 30 min and quenched
by addition of saturated NH4Cl and 28% NH4OH with vigorous
stirring. The resulting mixture was extracted with Et2O twice. The
combined extracts were washed with brine, dried over MgSO4, and
Conclusions
We have established a synthesis epi-JA (3) and TA (5), for the
first time. Furthermore, the mercury-free Claisen rearrangement
and the new method for conversion of lactone 12 to aldehyde
14 was applied to the previous synthesis of 12-oxo-PDA (1) to
establish a new method to 1. In addition, stability of 5 was studied
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concentrated to give alcohol 11 and the regioisomer in a 93 : 7 ratio,
which was used for the next reaction without further purification:
Rf (hexane–EtOAc 3 : 1) = 0.28 and 0.08 for 11 and 10; 1H NMR
(300 MHz, CDCl3) d = 1.65–2.05 (m, 3 H), 3.53 (br q, J = 7.5 Hz,
1 H), 4.89 (br s, 1 H), 4.93 (ddd, J = 10, 2, 1 Hz, 1 H), 5.03 (ddd,
J = 17, 2, 1.5 Hz, 1 H), 5.66 (ddd, J = 17, 10, 8 Hz, 1 H), 5.88 (br
s, 2 H).
A solution of the above alcohol and MeC(OMe)2NMe2
(5.90 mL, 90% purity, 36.3 mmol) in xylene (24 mL) was stirred at
150 ◦C (oil bath temperature) for 1 h, cooled to room temperature,
and concentrated. The residue was passed through a short column
of silica gel (hexane–EtOAc) to give amide 17a, which was used for
the next reaction without further purification: Rf (hexane–EtOAc
1 : 1) = 0.35 and 0.57 for 17a and 16; [a]2D6 = -62.8 (c 1.13, CHCl3);
IR (neat) 1645, 1398, 1140 cm-1; 1H NMR (300 MHz, CDCl3) d =
2.15 (dd, J = 16, 9 Hz, 1 H), 2.17–2.30 (m, 1 H), 2.35 (dd, J =
16, 7 Hz, 1 H), 2.43–2.58 (m, 1 H), 2.94 (s, 3 H), 2.97 (s, 3 H),
3.21–3.32 (m, 1 H), 4.96–5.08 (m, 2 H), 5.75 (br s, 1 H), 5.81 (ddd,
J = 17, 10, 8 Hz, 1 H).
To an ice-cold solution of the above amide in THF (5 mL)
were added I2 (1.80 g, 7.09 mmol) and H2O (5 mL). The resulting
mixture was stirred at room temperature overnight and diluted
with aqueous Na2S2O3 and EtOAc. The organic phase was
separated, and the aqueous phase was extracted with EtOAc
twice. The combined organic layers were washed with brine, dried
over MgSO4, and concentrated to afford a residue, which was
purified by chromatography (hexane–EtOAc) to give iodolactone
18 (889 mg, 45% from 15): Rf (hexane–EtOAc 3 : 1) = 0.45 and 0.15
for 18 and 17a; [a]2D5 = +11 (c 1.16, CHCl3); IR (neat) 3079, 1781,
1167, 1010 cm-1; 1H NMR (300 MHz, CDCl3) d = 1.97 (ddd, J =
15, 12, 5 Hz, 1 H), 2.12 (dd, J = 15, 7 Hz, 1 H), 2.54 (dd, J = 19,
4 Hz, 1 H), 2.58 (dd, J = 19, 9 Hz, 1 H), 3.15–3.27 (m, 1 H), 3.34–
3.49 (m, 1 H), 4.49 (d, J = 5 Hz, 1 H), 5.12 (dt, J = 17, 1.5 Hz, 1 H),
5.22 (dt, J = 10.5, 1.5 Hz, 1 H), 5.28 (d, J = 6.5 Hz, 1 H), 5.77 (ddd,
J = 17, 10.5, 6.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) d = 27.7
(-), 29.8 (+), 38.4 (+), 39.6 (-), 44.1 (-), 92.4 (-), 118.0 (+), 135.5
(-), 176.4 (+). HRMS (FAB) calcd for C9H11IO2Na [(M+Na)+]
300.9701, found 300.9699.
To a solution of the above mixture in toluene (8 mL) at
◦
-78 C were added PPh3 (3.70 g, 14.1 mmol), AcOH (0.81 mL,
14.1 mmol), and DIAD (2.95 mL, 15.0 mmol). The mixture was
stirred at -78 ◦C for 5 min, and diluted with saturated NaHCO3
and hexane. The resulting mixture was filtered through a pad of
Celite. The filtrate was washed with brine, dried over MgSO4,
and concentrated to afford a residue, which was purified by
chromatography (hexane–EtOAc) to give acetate 15 (676 mg, 63%
from 10): Rf (hexane–EtOAc 3 : 1) = 0.70 and 0.27 for 15 and 11;
1
[a]2D3 = -53 (c 1.57, CHCl3); IR (neat) 3079, 1738, 1239 cm-1; H
NMR (300 MHz, CDCl3) d = 1.57 (dt, J = 14, 5 Hz, 1 H), 2.04 (s,
3 H), 2.60 (dt, J = 14, 8 Hz, 1 H), 3.21–3.32 (m, 1 H), 4.98 (ddd,
J = 10, 2, 1 Hz, 1 H), 5.07 (dt, J = 17, 1.5 Hz, 1 H), 5.61–5.68 (m,
1 H), 5.77 (ddd, J = 17, 10, 8 Hz, 1 H), 5.84 (dt, J = 5.5, 2 Hz, 1 H),
5.94 (ddd, J = 5.5, 2, 1 Hz, 1 H); 13C NMR (75 MHz, CDCl3) d =
21.4 (-), 36.9 (+), 48.1 (-), 79.8 (-), 114.2 (+), 130.0 (-), 139.4 (-),
141.2 (-), 171.0 (+).
(1S,4R)-4-Vinylcyclopent-2-enyl ethanoate (acetate of 11). Ac-
cording to the above procedure, a solution of monoacetate 10
(500 mg, 3.52 mmol) in THF (2 mL) was added to an ice-cold
mixture of CH2 CHMgBr (16 mL, 0.66 M in THF, 11 mmol),
CuCN (95 mg, 1.1 mmol), and LiCl (597 mg, 14.1 mmol) in THF
◦
(2 mL). The reaction was carried out at 0 C for 1.5 h to afford
alcohol 11, which was used for the next reaction without further
purification.
(1R,2S,3R)-2-(2-Hydroxyethyl)-3-vinylcyclopentanol (19).
A
A solution of the above alcohol 11 and Ac2O (0.50 mL,
5.3 mmol) in pyridine (2 mL) was stirred at room temperature
overnight, and diluted with CH2Cl2 and 1 N NaOH with vigorous
stirring. The organic phase was separated, and the aqueous
phase was extracted with CH2Cl2 twice. The combined organic
layers were washed with 1 N HCl and brine, dried over MgSO4,
and concentrated to afford a residue, which was purified by
chromatography (hexane–EtOAc) to give acetate of 11 (403 mg,
75% from 10): Rf (hexane–EtOAc 3 : 1) = 0.70 and 0.27 for the
solution of iodolactone 18 (650 mg, 2.24 mmol), Bu3SnH (1.20 mL,
4.47 mmol), and◦AIBN (4 mg, 0.024 mmol) in benzene (5 mL)
was stirred at 85 C (oil bath temperature) for 30 min, cooled to
room temperature, and diluted with CH2Cl2. The solution was
washed with 1 N NaOH and with brine. The aqueous solutions
used were extracted with CH2Cl2 twice. The CH2Cl2 solutions
were combined, dried over MgSO4, and concentrated. The residue
was passed through a short column of silica gel (hexane–EtOAc)
to give lactone 12, which was used for the next reaction without
further purification: Rf (hexane–EtOAc 3 : 1) = 0.43 for 12 and 18;
1H NMR (300 MHz, CDCl3) d = 1.39–1.58 (m, 1 H), 1.62–1.80
(m, 2 H), 1.99 (dd, J = 13, 7 Hz, 1 H), 2.36 (dd, J = 19, 5 Hz, 1 H),
2.43 (dd, J = 19, 10.5 Hz, 1 H), 2.53–2.67 (m, 1 H), 2.90–3.03 (m,
1 H), 4.95–5.03 (m, 1 H), 5.01 (dt, J = 17, 1.5 Hz, 1 H), 5.08 (dt,
J = 11, 1.5 Hz, 1 H), 5.71 (ddd, J = 17, 11, 6.5 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) d = 26.9 (+), 29.7 (+), 32.7 (+), 40.9 (-), 46.1
(-), 85.8 (-), 116.7 (+), 136.9 (-), 177.7 (+).
To an ice-cold suspension of LiAlH4 (255 mg, 6.71 mmol) in
THF (6 mL) was added the above lactone in THF (6 mL) dropwise.
After 5 min of stirring at 0 ◦C, excess hydride was quenched with
H2O. The resulting mixture was diluted with EtOAc and 1 N
HCl, and stirred vigorously at room temperature until the layers
became clear. The organic layer was separated and washed with
brine. The combined aqueous layers were extracted with EtOAc
twice. The organic layers were combined, dried over MgSO4, and
concentrated to give diol 19, which was used for the next reaction
1
acetate and 11; H NMR (300 MHz, CDCl3) d = 1.95 (s, 3 H),
1.85–2.14 (m, 2 H), 3.40–3.52 (m, 1 H), 4.90 (d, J = 10 Hz, 1 H),
4.98 (dt, J = 17, 1.5 Hz, 1 H), 5.53–5.67 (m, 2 H), 5.81 (dt, J = 6,
2 Hz, 1 H), 5.91 (dd, J = 6, 2 Hz, 1 H).
(3aS,4R,6S,6aS )-6-Iodo-4-vinylhexahydro-2H -cyclo-penta-
[b]furan-2-one (18). To a solution of acetate 15 (1.10 g,
7.22 mmol) in MeOH (7 mL) was added 3 N NaOH (7 mL). The
mixture was stirred at room temperature for 15 min and diluted
with Et2O. The organic layer was separated, and the aqueous layer
was extracted with Et2O twice. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated to give
alcohol 16, which was used for the next reaction without further
1
purification: H NMR (300 MHz, CDCl3) d = 1.47 (dt, J = 14,
5 Hz, 1 H), 2.55 (ddd, J = 14, 8, 7 Hz, 1 H), 3.22 (br q, J = 7 Hz,
1 H), 4.77–4.85 (m, 1 H), 4.97 (d, J = 10 Hz, 1 H), 5.05 (dt, J = 17,
1.5 Hz, 1 H), 5.77–5.93 (m, 3 H); 13C NMR (75 MHz, CDCl3) d =
40.6, 48.0, 65.9, 113.7, 134.2, 137.1, 142.2.
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without further purification. The reaction was repeated to obtain
analytically pure 19: Rf (hexane–EtOAc 1 : 1) = 0.24 and 0.66 for
19 and 12; 1H NMR (300 MHz, CDCl3) d = 1.52–1.99 (m, 7 H),
2.54–2.68 (m, 1 H), 3.61 (ddd, J = 10, 9, 4.5 Hz, 1 H), 3.78 (dt,
J = 10, 5 Hz, 1 H), 3.89 (br s, 2 H), 4.23–4.33 (m, 1 H), 4.87–
4.99 (m, 2 H), 5.89 (dt, J = 18, 9 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) d = 28.5 (+), 29.5 (+), 33.2 (+), 46.0 (-), 47.2 (-), 62.2 (+),
74.4 (-), 113.9 (+), 141.8 (-). HRMS (FAB) calcd for C9H16O2Na
[(M+Na)+] 179.1048, found 179.1050.
3 H), 0.96 (t, J = 8 Hz, 9 H), 1.56–1.80 (m, 4 H), 1.80–1.93 (m,
1 H), 1.96–2.19 (m, 4 H), 2.59 (dq, J = 4, 18 Hz, 1 H), 4.16–4.21
(m, 1 H), 4.80–4.91 (m, 2 H), 5.26–5.45 (m, 2 H), 5.94 (dt, J = 17,
10 Hz, 1 H); 13C NMR (75 MHz, CDCl3) d = 5.1 (+), 7.0 (-), 14.4
(-), 20.8 (+), 23.9 (+), 30.1 (+), 34.7 (+), 45.6 (-), 50.1 (-), 75.4
(+), 113.1 (+), 129.0 (-), 131.5 (-), 143.3 (-). HRMS (EI) calcd for
C18H34OSi [M+] 294.2379, found 294.2382.
2-((1R,2S,3R)-2-((Z)-Pent-2-enyl)-3-(triethylsilyloxy)-cyclo-
pentyl)ethanol (25). To an ice-cold solution of olefin 24 (40 mg,
0.136 mmol) in THF (2 mL) was added freshly prepared◦Cy2BH
(0.82 mL, 0.5 M in THF, 0.41 mmol). After 15 min at 0 C, 3 N
NaOH (2 mL) and 35% H2O2 (2 mL) were added to the solution.
The resulting mixture was stirred at room temperature for 1 h
and diluted with EtOAc. The organic phase was separated, and
the aqueous phase was extracted EtOAc twice. The combined
organic phases were washed with brine, dried over MgSO4,
and concentrated. The residue was purified by chromatography
(hexane–EtOAc) to give alcohol 25 (27 mg, 65%): Rf (hexane–
EtOAc 5 : 1) = 0.33 and 0.74 for 25 and 24; [a]2D4 = -2 (c 1.45,
(1R,2S,3R)-1-(Triethylsilyloxy)-2-(2-(triethylsilyloxy)-ethyl)-
3-vinylcyclopentane (13). A solution of the above diol, TESCl
(1.13 mL, 6.70 mmol), and imidazole (610 mg, 8.96 mmol) in
DMF (1.1 mL) was stirred at room temperature overnight and
directly subjected to chromatography (hexane–EtOAc) to give the
TES ether 13 (704 mg, 82% from 18): Rf (hexane–EtOAc 1 : 1) =
0.95 and 0.25 for 13 and 19; [a]2D5 = -6 (c 0.99, CHCl3); IR (neat)
1
3079, 1414, 1239, 1095 cm-1; H NMR (300 MHz, CDCl3) d =
0.53–0.64 (m, 12 H), 0.94 (t, J = 8 Hz, 18 H), 1.50–1.94 (m, 7 H),
2.57 (dq, J = 4, 9 Hz, 1 H), 3.62 (t, J = 7 Hz, 2 H), 4.12–4.19 (m,
1 H), 4.80–4.90 (m, 2 H), 5.92 (dt, J = 17, 10 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) d = 4.5 (+), 5.1 (+), 6.9 (-), 7.0 (-), 29.4 (+),
30.2 (+), 34.7 (+), 45.26 (-), 45.34 (-), 62.0 (+), 75.8 (-), 113.1
(+), 143.4 (-). HRMS (FAB) calcd for C21H44O2Si2Na [(M+Na)+]
407.2778, found 407.2781.
1
CHCl3); IR (neat) 3350, 1053, 1016 cm-1; H NMR (300 MHz,
CDCl3) d = 0.57 (q, J = 8 Hz, 6 H), 0.95 (t, J = 8 Hz, 9 H), 0.97 (t,
J = 7.5 Hz, 3 H), 1.18–1.87 (m, 8 H), 1.93–2.28 (m, 5 H), 3.51–3.62
(m, 1 H), 3.67 (ddd, J = 10.5, 8, 5 Hz, 1 H), 4.11–4.19 (m, 1 H),
5.28–5.50 (m, 2 H); 13C NMR (75 MHz, CDCl3) d = 5.0 (+), 7.0
(-), 14.3 (-), 20.8 (+), 22.7 (+), 28.6 (+), 33.8 (+), 35.0 (+), 35.9
(-), 48.8 (-), 62.5 (+), 75.3 (-), 129.3 (-), 131.6 (-). HRMS (FAB)
calcd for C18H37O2Si [(M+H)+] 313.2563, found 313.2570.
(1R,2S,3R)-1-(Triethylsilyloxy)-2-((Z)-pent-2-enyl)-3-vinyl-
cyclopentane (24). To a solution of (COCl)2 (0.11 mL, 1.26 mmol)
in CH2Cl2 (2 mL) was added DMSO (0.19 mL, 2.68 mmol) at
-78 ◦C. After 15 min, TES ether 13 (100 mg, 0.260 mmol) in
CH2Cl2 (3 mL) was added dropwise. The suspension was stirred
below -60 ◦C for 40 min, and Et3N (0.36 mL, 2.60 mmol) was
added. The resulting mixture was stirred vigorously below -60 ◦C
for 20 min and then at room temperature for 10 min before
dilution with CH2Cl2. The solution thus obtained was washed with
saturated NaHCO3 and then with brine. The aqueous solutions
were extracted with CH2Cl2 twice. The extracts were combined,
dried over MgSO4, and concentrated to give aldehyde 14, which
epi-Jasmonic acid (3). To an ice-cold solution of alcohol 25
(32 mg, 0.102 mmol) in THF (1 mL) was added TBAF (0.30 mL,
1 M in THF, 0.30 mmol). The solution was stirred at room
temperature for 2 h and concentrated. The residue was passed
through a short column of silica gel (hexane–EtOAc) to give diol 8,
which was used for the next reaction without further purification:
Rf (hexane–EtOAc 1 : 1) = 0.27; 1H NMR (300 MHz, CDCl3) d =
0.98 (t, J = 8 Hz, 3 H), 1.1–1.9 (m, 9 H), 1.97–2.21 (m, 4 H),
2.22–2.35 (m, 1 H), 3.59 (dt, J = 10, 7 Hz, 1 H), 3.70 (ddd, J = 10,
8, 5 Hz, 1 H), 4.17–4.26 (m, 1 H), 5.35–5.47 (m, 2 H); 13C NMR
(75 MHz, CDCl3) d = 14.3 (-), 20.8 (+), 22.9 (+), 28.9 (+), 33.3
(+), 34.8 (+), 36.1 (-), 47.8 (-), 62.2 (+), 75.1 (-), 128.4 (-), 132.4
(-). These data were consistent with those reported.13
1
was used for the next reaction without further purification: H
NMR (300 MHz, CDCl3) d = 0.56 (q, J = 8 Hz, 6 H), 0.92 (t, J =
8 Hz, 9 H), 1.56–1.88 (m, 4 H), 2.33–2.58 (m, 3 H), 2.62–2.74 (m,
1 H), 4.22–4.28 (m, 1 H), 4.84–4.94 (m, 2 H), 5.79 (ddd, J = 17,
11, 9 Hz, 1 H), 9.79 (br s, 1 H); 13C NMR (75 MHz, CDCl3) d =
4.9 (+), 6.9 (-), 28.7 (+), 33.9 (+), 40.7 (+), 43.6 (-), 44.7 (-), 75.1
(-), 114.6 (+), 141.7 (-), 203.0 (-).
To an ice-cold solution of the above diol in acetone (0.5 mL)
was added Jones reagent (4 M solution) dropwise until the color
of the reagent persisted (a few drops). After 30 min of stirring at
0 ◦C, i-PrOH was added, and the mixture was diluted with Et2O.
The organic layer was passed through a plug of silica gel with
Et2O. The filtrate was concentrated, and the residue was purified
by chromatography (CH2Cl2–MeOH) to furnish epi-JA (3) (13 mg,
62% from 25), which was 98% pure over the trans isomer (see below
To an ice-cold suspension of [Ph3P(CH2)2Me]+Br- (331 mg,
0.859 mmol) in THF (3 mL) was added NaHMDS (0.78 mL, 1 M
in THF, 0.78 mmol). The resulting orange-red mixture was stirred
at room temperature for 40 min and cool to -78 ◦C. To this solution
were added DMF (0.5 mL) and a solution of the above aldehyde
in THF (3 mL) dropwise. The resulting solution was stirred at
-78 ◦C for 2 h, allowed to warm to room temperature, and stirred
overnight. Saturated NH4Cl and EtOAc were added with vigorous
stirring. The mixture was separated, and the aqueous layer was
extracted with EtOAc twice. The combined organic layers were
dried over MgSO4 and concentrated to afford a residue, which
was purified by chromatography (hexane–EtOAc) to give olefin
1
for preparation) by H NMR spectroscopy: Rf (hexane–EtOAc
1 : 1) = 0.17 and 0.26 for 3 and 8; [a]3D0 = +24 (c 1.08, CHCl3); IR
(neat) 3100, 1738, 1712 cm-1; 1H NMR (300 MHz, CDCl3) d = 0.97
(t, J = 7.5 Hz, 3 H), 1.89 (ddt, J = 13, 8, 5.5 Hz, 1 H), 1.97–2.45 (m,
9 H), 2.49 (dd, J = 16, 5.5 Hz, 1 H), 2.77–2.91 (m, 1 H), 5.26–5.52
(m, 2 H); 13C NMR (75 MHz, CDCl3) d = 14.1, 20.8, 23.1, 25.8,
33.7, 35.4, 35.5, 52.6, 125.4, 133.8, 177.7, 218.8.
24 (59 mg, 77% from 13): Rf (hexane–EtOAc 5 : 1) = 0.76; [a]D22
=
To confirm the structure, epi-JA (3) (7 mg, 0.033 mmol, 98%
purity) in Et2O (0.3 mL) was treated with excess CH2N2 for 5 min,
and the solution was passed through a short column of silica gel
1
-18 (c 0.98, CHCl3); IR (neat) 3073, 1075, 1005 cm-1; H NMR
(300 MHz, CDCl3) d = 0.59 (q, J = 8 Hz, 6 H), 0.95 (t, J = 7.5 Hz,
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with Et2O as an eluent to give Me epi-JA (4) (91% purity over the
trans isomer (Me JA)): Rf (hexane–EtOAc 1 : 1) = 0.70 and 0.16
for the ester and 3; 1H NMR (300 MHz, CDCl3) d = 0.96 (t, J =
7.5 Hz, 3 H), 1.76–1.89 (m, 1 H), 1.94–2.48 (m, 10 H), 2.77–2.91
(m, 1 H), 3.69 (s, 3 H), 5.24–5.58 (m, 2 H); 13C NMR (75 MHz,
CDCl3) d = 14.1, 20.7, 23.0, 25.7, 33.8, 35.3, 35.6, 51.8, 52.8, 125.5,
133.6, 173.0, 219.0 ppm. The 1H NMR and 13C NMR spectra were
identical to the data reported.13,14b,d,30
2-((1R,2S,3R)-2-((Z)-5-(Tetrahydro-2H-pyran-2-yl-oxy)pent-2-
enyl)-3-(triethylsilyloxy)cyclopentyl)ethanol (28). To an ice-cold
solution of olefin 27 (77 mg, 0.195 mmol) in THF (2 mL) was
adde◦d Cy2BH (1.2 mL, 0.5 M in THF, 0.60 mmol). After 15 min
at 0 C, 3 N NaOH (2 mL) and 35% H2O2 (2 mL) were added.
The resulting mixture was stirred at room temperature for 2 h and
diluted with EtOAc. The organic phase was separated, and the
aqueous phase was extracted with EtOAc twice. The combined
organic layers were washed with brine and concentrated. The
residue was purified by chromatography (hexane–EtOAc) to give
alcohol 28 (53 mg, 67%): Rf (hexane–EtOAc 5 : 1) = 0.22 and 0.76
for 28 and 27; 1H NMR (300 MHz, CDCl3) d = 0.57 (q, J = 8 Hz,
6 H), 0.94 (t, J = 8 Hz, 9 H), 1.45–2.08 (m, 15 H), 2.10–2.30
(m, 2 H), 2.33–2.49 (m, 2 H), 3.45–3.94 (m, 6 H), 4.10–4.20 (m,
1 H), 4.46–4.65 (m, 1 H), 5.31–5.60 (m, 2 H); 13C NMR (75 MHz,
CDCl3) d = 5.5 (+), 7.0 (-), 19.60 (+) and 19.63 (+), 22.9 (+), 25.5
(+), 28.1 (+) and 28.2 (+), 28.6 (+), 30.7 (+), 33.7 (+), 35.0 (+),
35.9 (-), 48.6 (-), 62.33 (+), 62.37 (-), 67.0 (+) and 67.2 (+), 75.3
(-), 98.7 (-) and 98.9 (-), 125.4 (-) and 125.5 (-), 132.0 (-) and
132.03 (-).
Isomerization of epi-jasmonic acid (3) to jasmonic acid.
A
mixture of epi-JA (3) (10 mg, 0.048 mmol) in MeOH (2 mL)
and 6 N NaOH (0.5 mL) was stirred at room temperature for 3 h,
neutralized with AcOH (0.1 mL), and concentrated to afford a
residue, which was purified by chromatography (CH2Cl2–MeOH)
to give JA (10 mg, 100%): Rf (hexane–EtOAc 1 : 1) = 0.17 for JA
and 3; 1H NMR (300 MHz, CDCl3) d = 0.96 (t, J = 7.5 Hz, 3 H),
1.43–1.63 (m, 1 H), 1.86–2.46 (m, 10 H), 2.71–2.83 (m, 1 H), 5.20–
5.33 (m, 1 H), 5.41–5.53 (m, 1 H); 13C NMR (75 MHz, CDCl3) d =
14.2, 20.7, 25.6, 27.3, 37.81, 37.83, 38.8, 53.9, 124.9, 134.3, 178.1,
219.0. The 1H NMR and 13C NMR data were identical with those
reported.39
2-((1R,2S,3R)-2-((Z)-5-(Tetrahydro-2H-pyran-2-yloxy)-pent-
2-enyl)-3-(triethylsilyloxy)cyclopentyl)ethanoic acid (33). To an
ice-cold solution of alcohol 28 (80 mg, 0.194 mmol) in
CH2Cl2/DMSO (1 : 1, v/v, 2 mL) were added Et3N (0.14 mL,
1.01 mmol) and SO3·pyridine (123 mg, 0.773 mmol). After being
stirred at 0 ◦C for 20 min, the mixture was diluted first with H2O
and then with saturated NH4Cl and EtOAc. The organic phase was
separated, and the aqueous phase was extracted EtOAc twice. The
combined organic layers were dried over MgSO4 and concentrated
to afford a residue, which was passed through a short column
of silica gel (hexane–EtOAc) to give the corresponding aldehyde,
which was used for the next reaction without further purification:
Rf (hexane–EtOAc 3 : 1) = 0.63 and 0.26 for the aldehyde and 28;
1H NMR (300 MHz, CDCl3) d = 0.58 (q, J = 8 Hz, 6 H), 0.95 (t,
J = 8 Hz, 9 H), 1.43–1.96 (m, 12 H), 2.04–2.27 (m, 2 H), 2.37 (q,
J = 7 Hz, 2 H), 2.42–2.62 (m, 2 H), 3.42 (ddt, J = 10, 2, 7 Hz, 1 H),
3.45–3.56 (m, 1 H), 3.75 (ddt, J = 10, 2.5, 7 Hz, 1 H), 3.87 (ddd,
J = 11, 7, 3.5 Hz, 1 H), 4.12–4.22 (m, 1 H), 4.56–4.64 (m, 1 H),
5.34–5.57 (m, 2 H), 9.75 (s, 1 H); 13C NMR (75 MHz, CDCl3) d =
5.0 (+), 7.0 (-), 19.7 (+), 23.5 (+), 25.5 (+), 28.2 (+), 29.5 (+), 30.8
(+), 33.6 (-), 34.2 (+), 47.1 (+), 48.5 (-), 62.4 (+), 67.0 (+), 75.2
(-), 98.8 (-), 126.4 (-), 130.8 (-), 203.7 (-).
(1R,2S,3R)-1-Triethylsilyloxy-2-((Z)-5-(tetrahydro-2H-pyran-
2-yloxy)pent-2-enyl)-3-vinylcyclopentane (27). To a solution of
(COCl)2 (0.11 mL, 1.26 mmol) in CH2Cl2 (2 mL) was added
DMSO (0.19 mL, 2.68 mmol) at -78 ◦C, and, after 15 min, a
solution of TES ether 13 (100 mg, 0.260 mmol) in CH2Cl2 (2 mL).
After 40 min of stirring below -60 ◦C, Et3N (0.36 mL, 2.58 mmol)
was added to the mixture, which was stirred vigorously at the
same temperature for 20 min and at room temperature for 10 min.
The mixture was diluted with CH2Cl2 and washed with saturated
NaHCO3 and with brine. The aqueous solutions were combined
and extracted with CH2Cl2 twice. The combined extracts were
dried over MgSO4 and concentrated to give aldehyde 14, which
was used for the next reaction without further purification.
To a suspension of [Ph3P(CH2)3OTHP]+Br- (26b) (416 mg,
0.857 mmol) in THF (3 mL) at 0 ◦C was added NaHMDS
(0.78 mL, 1 M in THF, 0.78 mmol). The resulting orange-red
mixture was stirred at room temperature for 40 min and cooled
◦
to -78 C. DMF (0.5 mL) and a solution of the above aldehyde
in THF (3 mL) were added to the mixture. The reaction was
conducted at -78 ◦C for 2 h and at room temperature overnight and
quenched with saturated NH4Cl. The product was extracted with
EtOAc three times. The combined extracts were washed with brine,
dried over MgSO4, and concentrated. The residue was purified
by chromatography (hexane–EtOAc) to give olefin 27 (100 mg,
97% from 13): Rf (hexane–EtOAc 5 : 1) = 0.76; [a]2D2 = -20.3 (c
To a solution of the above aldehyde in t-BuOH (2 mL)
were added 2-methyl-2-butene (0.21 mL, 1.98 mmol), phosphate
buffer (1 mL, pH 7), and aqueous NaClO2 (33 mg, 80% purity,
0.292 mmol) dissolved in H2O (1 mL). After being stirred at
room temperature for 1 h, the mixture was acidified to pH 6
with 1 N HCl and the product was extracted with EtOAc three
times. The combined extracts were washed with brine, dried over
MgSO4, and concentrated to afford a residue, which was purified
by chromatography (hexane–EtOAc) to give acid 33 (63 mg, 77%
from 28): Rf (hexane–EtOAc 3 : 1) = 0.38 and 0.61 for 33 and the
aldehyde; [a]2D6 = -2 (c 1.66, CHCl3); IR (neat) 3000, 1707, 1077,
1
1.43, CHCl3); IR (neat) 3073, 3008, 1077, 1034 cm-1; H NMR
(300 MHz, CDCl3) d = 0.59 (q, J = 8 Hz, 6 H), 0.95 (t, J = 8 Hz,
9 H), 1.43–1.92 (m, 11 H), 1.88–2.21 (m, 2 H), 2.35 (q, J = 7 Hz,
2 H), 2.59 (dq, J = 17, 4 Hz, 1 H), 3.40 (dt, J = 9, 7 Hz, 1 H),
3.44–3.55 (m, 1 H), 3.72 (dt, J = 9, 7 Hz, 1 H), 3.87 (ddd, J = 11,
7.5, 3.5 Hz, 1 H), 4.15–4.22 (m, 1 H), 4.57–4.63 (m, 1 H), 4.80–4.91
(m, 2 H), 5.30–5.58 (m, 2 H), 5.93 (dt, J = 17, 10 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) d = 5.0 (+), 7.0 (-), 19.6 (+), 24.1 (+),
25.6 (+), 28.2 (+), 30.0 (+), 30.8 (+), 34.6 (+), 45.5 (-), 50.0 (-),
62.3 (+), 67.1 (+), 75.3 (-), 98.7 (-), 113.1 (+), 125.4 (-), 131.6
(-), 143.2 (-). HRMS (FAB) calcd for C23H42O3SiNa [(M+Na)+]
417.2801, found 417.2805.
1
1034 cm-1; H NMR (300 MHz, CDCl3) d = 0.58 (q, J = 8 Hz,
6 H), 0.96 (t, J = 8 Hz, 9 H), 1.46–1.96 (m, 12 H), 2.06–2.27 (m,
2 H), 2.28–2.54 (m, 4 H), 3.36–3.57 (m, 2 H), 3.69–3.81 (m, 1 H),
3.83–3.94 (m, 1 H), 4.12–4.22 (m, 1 H), 4.58–4.66 (m, 1 H), 5.34–
5.58 (m, 2 H); 13C NMR (75 MHz, CDCl3) d = 5.0 (+), 7.0 (-),
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19.55 (+) and 19.58 (+), 23.3 (+), 25.5 (+), 28.2 (+), 29.3 (+), 30.7
(+), 34.0 (+), 36.0 (-), 36.9 (+), 48.6 (-), 62.2 (+) and 62.3 (+),
67.0 (+) and 67.1 (+), 75.3 (-), 98.7 (-) and 98.8 (-), 126.26 (-)
and 126.30 (-), 130.9 (-), 180.1 (+) and 180.2 (+).
d = 1.44–1.64 (m, 1 H), 1.93–2.04 (m, 1 H), 2.08 (ddd, J = 18, 11,
9 Hz, 1 H), 2.17–2.45 (m, 8 H), 2.60–2.71 (m, 1 H), 3.55 (t, J =
7 Hz, 2 H), 5.37–5.54 (m, 2 H); 13C NMR (75 MHz, CDCl3) d =
26.4, 28.3, 31.8, 38.7, 39.6, 55.3, 62.6, 128.9, 129.2, 222.2. The 1H
and 13C NMR spectra were consistent with the data reported in
the literature.7a,19c
2-((1R,2S,3R)-3-Hydroxy-2-((Z)-5-(tetrahydro-2H-pyran-2-
yloxy)pent-2-enyl)cyclopentyl)ethanoic acid (34). A solution of
acid 33 (30 mg, 0.0648 mmol) and PPTS (5 mg, 0.02 mmol) in
EtOH (1 mL) was stirred at room temperature for 1 h. Et3N
(0.30 mL, 2.15 mmol) was added and the solution was concen-
trated to afford a residue, which was purified by chromatography
(hexane–EtOAc) to give alcohol 34 (18 mg, 90%): Rf (hexane–
EtOAc 1 : 1) = 0.22 and 0.64 for 34 and 33; 1H NMR (300 MHz,
CDCl3) d = 1.4–2.8 (m, 19 H), 3.34–3.58 (m, 2 H), 3.73–3.94 (m,
2 H), 4.10–4.24 (m, 1 H), 4.55–4.66 (m, 1 H), 5.34–5.60 (m, 2 H);
13C NMR (75 MHz, CDCl3) d = 19.5 (+) and 19.6 (+), 23.5 (+)
and 23.6 (+), 25.4 (+), 28.1 (+), 29.8 (+) and 30.0 (+), 30.36 (+)
and 30.45 (+), 33.2 (+) and 33.3 (+), 36.46 (-) and 36.52 (-), 36.8
(+), 47.7 (-), 62.3 (+) and 62.6 (+), 67.0 (+) and 67.4 (+), 73.9 (-),
99.0 (-) and 99.5 (-), 127.4 (-), 130.5 (-) and 130.7 (-), 179.4 (+).
2-((1S,5S)-5-(8-(tert-Butyldiphenylsilyloxy)octyl)cyclopent-2-
enyl)-N,N-dimethyl acetamide (36). A solution of alcohol 35
(190 mg, 0.422 mmol) and MeC(OMe)2NMe2 (0.34 mL, 90%
purity, 2.1 mmol) in xylene (5 mL) was stirred at 150 ◦C for 5 h,
cooled to room temperature, and concentrated. The residue was
purified by chromatography (hexane–EtOAc) to afford amide 36
(181 mg, 82%): Rf (hexane–EtOAc 5 : 1) = 0.16 and 0.32 for 36 and
35; [a]2D6 = –73 (c 1.16, CHCl3); IR (neat) 1654, 1395, 1112, 823
cm-1; 1H NMR (300 MHz, CDCl3) d = 1.05 (s, 9 H), 1.2–1.5 (m,
11 H), 1.50–1.62 (m, 2 H), 1.96 (ddq, J = 16, 8, 2 Hz, 1 H), 2.12
(dd, J = 14, 10 Hz, 1 H), 2.21–2.46 (m, 4 H), 2.95 (s, 3 H), 2.98
(s, 3 H), 3.04–3.16 (m, 1 H), 3.66 (t, J = 6 Hz, 2 H), 5.67–5.77
(m, 1 H), 5.79–5.86 (m, 1 H), 7.34–7.46 (m, 6 H), 7.65–7.72 (m,
4 H); 13C NMR (75 MHz, CDCl3) d = 19.3 (+), 25.8 (+), 26.9
(-), 28.8 (+), 29.4 (+), 29.7 (+), 29.9 (+), 30.6 (+), 32.6 (+), 33.2
(+), 35.5 (-), 37.3 (+), 37.5 (-), 41.4 (-), 43.6 (-), 64.0 (+), 127.6
(-), 129.5 (-), 130.4 (-), 134.2 (+), 135.6 (-), 135.7 (-), 172.8 (+).
HRMS (FAB) calcd for C33H50NO2Si [(M+H)+] 520.3611, found
520.3610.
2-((1R,2S)-3-Oxo-2-((Z)-5-(tetrahydro-2H -pyran-2-yloxy)-
pent-2-enyl)cyclopentyl)ethanoic acid (30). To a solution of alco-
hol 34 (6 mg, 0.019 mmol) in acetone (0.2 mL) was added Jones
reagent (1 drop, 4 M solution) at -40 ◦C. The mixture was stirred at
-40 ◦C for 30 min and excess reagent was quenched by addition of
i-PrOH. The mixture was stirred at -40 ◦C for 10 min and diluted
with Et2O. The organic layer was passed through a plug of silica
gel with Et2O. Concentration of the filtrate afforded a residue,
which was purified by chromatography (hexane–EtOAc) to give
keto acid 30 (6 mg, 92%): Rf (EtOAc) = 0.30; [a]2D7 = +10 (c 1.43,
(3aS,4S,6aR)-4-(8-(tert-Butyldiphenylsilyloxy)octyl)-3,3a,4,6a-
tetrahydro-2H-cyclopenta[b]furan-2-one (38).
A
mixture of
amide 36 (369 mg, 0.710 mmol) and I2 (360 mg, 1.42 mmol) in
THF (5 mL) and H2O (5 mL) was stirred at room temperature for
5 h and diluted with aqueous Na2S2O3 and EtOAc. The organic
phase was separated, and the aqueous phase was extracted
with EtOAc twice. The combined organic layers were washed
with brine, dried over MgSO4, and concentrated to give the
corresponding iodolactone, which was used for the next reaction
without further purification: Rf (hexane–EtOAc 5 : 1) = 0.44 and
0.17 for the iodolactone and 36; 1H NMR (300 MHz, CDCl3) d =
1.05 (s, 9 H), 1.17–1.74 (m, 15 H), 2.03–2.16 (m, 1 H), 2.42–2.78
(m, 3 H), 3.01–3.20 (m, 1 H), 3.66 (t, J = 6.5 Hz, 2 H), 4.45 (d, J =
5 Hz, 1 H), 5.26 (d, J = 7 Hz, 1 H), 7.29–7.51 (m, 6 H), 7.63–7.78
(m, 4 H); 13C NMR (75 MHz, CDCl3) d = 19.4, 25.9, 27.0, 28.4,
28.6, 28.7, 29.4, 29.6, 29.8, 30.2, 32.7, 39.0, 40.3, 40.5, 64.0, 92.8,
1
CHCl3); IR (neat) 3000, 1733, 1031 cm-1; H NMR (300 MHz,
CDCl3) d = 1.3–2.6 (m, 17 H), 2.78–2.93 (m, 1 H), 3.35–3.58 (m,
2 H), 3.67–3.95 (m, 2 H), 4.56–4.66 (m, 1 H), 5.32–5.62 (m, 2H);
13C NMR (75 MHz, CDCl3) d = 19.6 and 19.7, 23.16 and 23.21,
25.5, 25.90 and 25.93, 28.1 and 28.2, 30.7 and 30.8, 34.1, 35.39
and 35.44, 35.6 and 35.7, 52.6, 62.4 and 62.6, 66.8 and 67.1, 98.8
and 99.0, 99.2, 127.8 and 128.0, 128.2 and 128.3, 177.0 and 177.1,
218.9.
Tuberonic acid (5). To a solution of the keto acid 30 (7 mg,
0.023 mmol) in Et2O (0.5 mL) was added MgBr2 (13 mg,
0.071 mmol). The solution was stirred at room temperature for
2 h and diluted with Et2O and MeOH. Most of the solvents were
removed to afford a residue, which was purified by chromatog-
raphy (CH2Cl2–MeOH) to furnish TA (5) (5 mg, 96%), which
was 92% pure over the trans isomer (12-hydroxy-JA) by 1H NMR
spectroscopy: Rf (CH2Cl2–MeOH 9 : 1) = 0.17 and 0.51 for 5 and
30; [a]2D5 = +11 (c 0.26, MeOH); 1H NMR (300 MHz, CD3OD) d =
1.77–1.95 (m, 1 H), 1.9–2.5 (m, 10 H), 2.74–2.88 (m, 1 H), 3.55 (t,
J = 7 Hz, 2 H), 5.37–5.62 (m, 2 H); 13C NMR (75 MHz, CD3OD)
d = 24.1, 26.6, 31.8, 36.1, 41.8, 62.5, 132.3.
1
127.5, 129.5, 134.1, 135.5, 176.4. The H and 13C NMR spectra
were identical to those reported.7a
A solution of the above iodolactone and DBU (0.28 mL,
1.9 mmol) in THF (7 mL) was heated under reflux for 7 h, cooled to
room temperature, and diluted with saturated NH4Cl. The mixture
was extracted with EtOAc three times. The combined extracts were
washed with brine and concentrated to leave an oil, which was
purified by chromatography (hexane–EtOAc) to afford lactone 38
(288 mg, 83% from amide 36); Rf (hexane–EtOAc 5 : 1) = 0.26 and
0.44 for 38 and the iodolactone; 1H NMR (300 MHz, CDCl3) d =
1.05 (s, 9 H), 1.18–1.63 (m, 14 H), 2.42 (dd, J = 15, 9 Hz, 1 H), 2.49
(dd, J = 15, 9 Hz, 1 H), 2.74–2.88 (m, 1 H), 3.19 (tt, J = 9, 8 Hz,
1 H), 3.66 (t, J = 6.5 Hz, 2 H), 5.46 (dm, J = 8 Hz, 1 H), 5.82 (ddd,
J = 6, 2.5, 1.5 Hz, 1 H), 5.95 (dt, J = 6, 1 Hz, 1 H), 7.32–7.48 (m,
6 H), 7.64–7.73 (m, 4 H); 13C NMR (75 MHz, CDCl3) d = 19.4,
25.9, 27.0, 28.3, 29.4, 29.5, 29.6, 29.7, 31.2, 32.7, 39.9, 46.5, 64.1,
Isomerization of TA (5) to the trans isomer, 12-hydroxy-JA.
Additionally, TA (5) (14 mg, 0.062 mmol) was subjected to
isomerization with 6 N NaOH (0.6 mL) in MeOH (2 mL) at room
temperature for 2 h. The mixture was neutralized with AcOH
(0.1 mL), and most of the solvents were evaporated. A residue
thus obtained was purified by chromatography (CH2Cl2–MeOH)
to afford 12-hydroxy-JA (11 mg, 79%): Rf (CH2Cl2–MeOH 9 : 1) =
1
0.17; IR (neat) 1722, 1119 cm-1; H NMR (300 MHz, CD3OD)
5220 | Org. Biomol. Chem., 2010, 8, 5212–5223
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1
89.1, 127.5, 128.1, 129.5, 134.1, 135.5, 140.0, 177.2. The H and
NMR spectrum was thus revised, while the 13C NMR spectrum
was identical to that reported.7a
13C NMR spectra were identical to those reported.7a
To an ice-cold suspension of [Ph3P(CH2)2Me]+Br- (220 mg,
0.571 mmol) in THF (5 mL) was added NaHMDS (0.63 mL,
1.0 M in THF, 0.63 mmol). The resulting orange-red mixture was
stirred at room temperature for 1 h and cooled to -78 ◦C. To this
solution was added a solution of the above aldehyde in THF (2 mL)
dropwise. The resulting solution was stirred at -78 ◦C for 2 h and
then at room temperature for 12 h, diluted with saturated NH4Cl
and EtOAc with vigorous stirring. The mixture was separated, and
the aqueous layer was extracted with EtOAc twice. The combined
organic layers were dried over MgSO4 and concentrated to afford
olefin, which was passed through a short silica gel before the next
reaction: Rf (hexane–EtOAc 5 : 1) = 0.85 and 0.68 for the olefin
and 41; 1H NMR (300 MHz, CDCl3) d = 0.57 (q, J = 8 Hz, 6 H),
0.95 (q, J = 8 Hz, 9 H), 0.98 (t, J = 7 Hz, 3 H), 1.05 (s, 9 H),
1.14–1.62 (m, 14 H), 1.91–2.30 (m, 5 H), 2.34–2.46 (m, 1 H), 3.65
(t, J = 6.5 Hz, 2 H), 4.50 (dd, J = 6, 3 Hz, 1 H), 5.26–5.58 (m,
2 H), 5.78–5.94 (m, 1 H), 6.12 (dd, J = 6, 3 Hz, 1 H), 7.32–7.47
(m, 6 H), 7.64–7.73 (m, 4 H); 13C NMR (75 MHz, CDCl3) d = 5.4,
7.2, 14.5, 19.4, 21.0, 23.4, 26.0, 27.0, 28.2, 29.6, 29.8, 30.2, 32.6,
32.8, 46.2, 47.4, 64.1, 76.4, 127.5, 128.7, 129.5, 131.6, 132.7, 134.2,
135.6, 140.2. The 1H and 13C NMR spectra were identical to those
reported.7a
To a solution of the above olefin in THF (5 mL) was added
TBAF (1.0 mL, 1.0 M in THF, 1.0 mmol). The solution was
stirred at 55 ◦C for 1 h, cooled to room temperature, and diluted
with saturated NH4Cl. The mixture was extracted with EtOAc
three times. The combined extracts were washed with brine, dried
over MgSO4, and concentrated. The residue was purified by
chromatography (hexane–EtOAc) to give diol 42 (49 mg, 85%
from the TES ether 40): Rf (hexane–EtOAc 5 : 1) = 0.05 and 0.87
for 42 and the olefin; 1H NMR (300 MHz, CDCl3) d = 0.99 (t, J =
7.5 Hz, 3 H), 1.16–1.68 (m, 15 H), 1.96–2.39 (m, 6 H), 2.42–2.54
(m, 1 H), 3.63 (t, J = 6.5 Hz, 2 H), 4.51 (dd, J = 6, 2 Hz, 2 H),
5.33–5.59 (m, 2 H), 5.96 (ddd, J = 6, 4, 2 Hz, 1 H), 6.23 (dd, J =
6, 3 Hz, 1 H); 13C NMR (75 MHz, CDCl3) d = 14.4, 20.9, 23.2,
25.9, 28.2, 29.5, 29.7, 30.0, 32.9, 33.7, 46.2, 46.3, 63.1, 76.7, 127.9,
132.0, 132.4, 141.7. The 1H and 13C NMR spectra were identical
to those reported.7a
(3R,4S,5S)-5-(8-(tert-Butyldiphenylsilyloxy)octyl)-3-triethyl-
silyloxy-4-(2-(triethylsilyloxy)ethyl)cyclopent-1-ene (40). To an
ice-cold suspension of LiAlH4 (60 mg, 1.6 mmol) in Et2O (7 mL)
was added lactone 38 (260 mg, 0.530 mmol) in Et2O (3 mL)
dropwise. The mixture was stirred at room temperature for 1 h,
and excess hydride was quenched by addition of 10% NaOH. The
resulting mixture was filtered through a pad of Celite, and the
filtrate was concentrated to afford diol 39, which was used for
the next reaction without further purification: Rf (hexane–EtOAc
3 : 1) = 0.21 and 0.66 for 39 and 38; 1H NMR (300 MHz, CDCl3)
d = 1.05 (s, 9 H), 1.16–1.46 (m, 10 H), 1.48–1.98 (m, 6 H), 2.00–
2.30 (m, 3 H), 2.42–2.52 (m, 1 H), 3.65 (t, J = 6.5 Hz, 2 H), 3.76
(ddd, J = 10, 9, 4 Hz, 1 H), 3.89 (t, J = 10, 5 Hz, 1 H), 4.61 (dd, J =
6, 2.5 Hz, 1 H), 5.96 (dm, J = 6 Hz, 1 H), 6.20 (dd, J = 6, 2.5 Hz,
1 H), 7.32–7.47 (m, 6 H), 7.63–7.71 (m, 4 H). The spectrum was
identical to that reported.7a
A solution of the above diol, TESCl (0.27 mL, 1.6 mmol), and
imidazole (144 mg, 2.12 mmol) in DMF (10 mL) was stirred at
room temperature overnight and diluted with saturated NaHCO3
with vigorous stirring. The product was extracted with EtOAc
three times. The combined extracts were washed with brine, dried
over MgSO4, and concentrated to afford an oil, which was purified
by chromatography (hexane–EtOAc) to give bis-TES ether 40
(381 mg, 99% from lactone 38): Rf (hexane–EtOAc 3 : 1) = 0.86
and 0.19 for 40 and 39; [a]D26 = 0 (c 1.03, CHCl3); IR (neat) 1238,
1112, 1008, 739 cm-1; 1H NMR (300 MHz, CDCl3) d = 0.51–0.66
(m, 12 H), 0.90–1.01 (m, 18 H), 1.04 (s, 9 H), 1.1–1.9 (m, 16 H),
1.98–2.13 (m, 1 H), 2.31–2.42 (m, 1 H), 3.55–3.75 (m, 4 H), 4.70
(dd, J = 6, 2 Hz, 1 H), 5.83 (dq, J = 6, 1 Hz, 1 H), 6.12 (dd, J =
6, 3 Hz, 1 H), 7.34–7.46 (m, 6 H), 7.64–7.72 (m, 4 H); 13C NMR
(75 MHz, CDCl3) d = 4.5 (+), 5.3 (+), 6.9 (-), 7.0 (-), 19.3 (+),
25.9 (+), 27.0 (-), 28.1 (+), 28.9 (+), 29.5 (+), 29.7 (+), 30.1 (+),
32.7 (+), 42.9 (-), 46.2 (-), 62.2 (+), 64.1 (+), 76.3 (-), 127.6 (-),
129.5 (-), 132.7 (-), 134.3 (-), 135.7 (+), 140.4 (-). HRMS (FAB)
calcd for C43H73O3Si3 [(M - H)+] 721.4868, found 721.4885.
(1R,4S,5S)-4-(8-Hydroxyoctyl)-5-((Z)-pent-2-enyl)cyclo-pent-
2-enol (42). To a solution of (COCl)2 (0.087 mL, 0.10 mmol) in
CH2Cl2 (3 mL) was added DMSO (0.14 mL, 2.0 mmol) at -78 ◦C.
After 40 min, TES ether 40 (144 mg, 0.199 mmol) in CH2Cl2 (2 mL)
was added dropwise. The suspension was stirred at -78 ◦C for 1 h,
and Et3N (0.28 mL, 2.0 mmol) was added. The resulting mixture
was stirred vigorously at -78 ◦C for 20 min and then at room
temperature for 1 h, and diluted with saturated NaHCO3. The
mixture was extracted with CH2Cl2 twice. The combined extracts
were dried over MgSO4 and concentrated to give aldehyde 41,
which was used for the next reaction without further purification:
Rf (hexane–EtOAc 5 : 1) = 0.16 and 0.60 for 41 and 40; 1H NMR
(300 MHz, CDCl3) d = 0.57 (q, J = 8 Hz, 6 H), 0.94 (t, J = 8 Hz,
9 H), 1.05 (s, 9 H), 1.15–1.63 (m, 14 H), 2.38 (dd, J = 15, 4 Hz,
1 H), 2.48–2.60 (m, 1 H), 2.61–2.82 (m, 2 H), 3.65 (t, J = 6.5 Hz,
2 H), 4.68 (dm, J = 6 Hz, 1 H), 5.77 (dt, J = 6, 2 Hz, 1 H), 5.98
(dd, J = 6, 2 Hz, 1 H), 7.33–7.48 (m, 6 H), 7.63–7.72 (m, 4 H),
9.87 (t, J = 1 Hz, 1 H); 13C NMR (75 MHz, CDCl3) d = 5.2, 7.1,
19.4, 26.0, 27.0, 28.1, 29.5, 29.7, 30.0, 32.3, 32.7, 40.2, 41.7, 45.9,
64.1, 76.8, 127.5, 129.4, 132.6, 134.2, 135.6, 138.1, 202.8. The 1H
12-oxo-PDA (1). To an ice-cold solution of diol 42 (9.8 mg,
0.053 mmol) in acetone (1 mL) was added Jones reagent (4.0 M
solution) dropwise until the color of the reagent persisted (four
drops). After 30 min of stirring at 0 ◦C, i-PrOH was added to
quench the remaining reagent. The mixture was passed through
a plug of silica gel with hexane–EtOAc (1 : 1). The filtrate was
concentrated, and the residue was purified by chromatography
(hexane–EtOAc) to furnish 12-oxo-PDA (1) (6.3 mg, 63%),
1
which was of >95% purity over the trans isomer by H NMR
spectroscopy (d = 7.74 (dd, J = 6, 3 Hz, 1 H) for 1; 7.61 (dd, J = 6,
2.5 Hz, 1 H) for the trans isomer). Rf (hexane–EtOAc 1 : 1) = 0.377
and 0.48 for 1 and 42; 1H NMR (300 MHz, CDCl3) d 0.97 (t, J =
7.5 Hz, 3 H), 1.04–1.82 (m, 12 H), 1.97–2.22 (m, 3 H), 2.35 (t, J =
7.5 Hz, 2 H), 2.39–2.57 (m, 2 H), 2.92–3.04 (m, 1 H), 5.26–5.54 (m,
2 H), 6.19 (dd, J = 6, 1.5 Hz, 1 H), 7.74 (dd, J = 6, 3 Hz, 1 H); 13
C
NMR (75 MHz, CDCl3) d 14.2, 20.9, 23.9, 24.8, 27.7, 29.1, 29.2,
29.7, 30.9, 34.1, 44.4, 50.0, 126.9, 132.4, 132.9, 167.2, 179.4, 210.9.
The 1H and 13C NMR spectra were identical to those reported.40,7a
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Acknowledgements
Racemic Me JA was kindly provided by Zeon Co. Ltd., Japan. This
work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports, and Culture,
Japan. The authors thank Ms. M. Ishikawa of Center for Ad-
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28 Claisen rearrangement of alcohol i under the same conditions produced
aldehyde ii in 80% yield.
5222 | Org. Biomol. Chem., 2010, 8, 5212–5223
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33 The authentic trans isomers, 32 and 12-hydroxy-JA (iv), were synthe-
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aqueous MeOH. The diagnostic signals for 30 vs. 32 and for 5 vs. iv in
the 1H NMR spectra (300 MHz, the former two in CDCl3 and the latter
two in CD3OD) are (d, ppm): 30, 2.78–2.93; 32, 2.54–2.73; 5, 2.74–2.88;
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31 Deprotection of iii with DDQ in wet CH2Cl2 proceeded as usual.
However, separation of 12-hydroxy-JA (iv) and aldehyde v by chro-
matography on silica gel was unsuccessful due to the close mobilities.
In contrast, a mixture of ethyl ester of iv and v produced from ethyl
ester of iii was separated easily, affording the ethyl ester in 79% yield.
with that reported19c
.
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35 The use of TBAF (6 equiv) in THF (rt, 4 h) produced 34 in 71% yield.
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38 Overall yields and steps involved in the syntheses: 26.7% and 12
steps from acetate 10 by us; 4.9% and 8 steps from benzoquinone-
cyclopentadiene adduct by Grieco;37a 6.5% and 11 steps from cyclopen-
tenyl chloride by Helmchen37b
.
39 K. Weinges, H. Getho¨ffer, U. Huber-Patz, H. Rodewald and H.
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40 S. W. Baertschi, C. D. Ingram, T. M. Harris and A. R. Brash,
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The Royal Society of Chemistry 2010
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