First total synthesis of tuberonic acid

Article abstract of DOI:10.1016/j.tetlet.2007.01.035

A vinyl group as an acetic acid side chain was attached to the optically active monoacetate of 4-cyclopentene-1,3-diol with CH₂{double bond, long}CHMgBr, LiCl, and a CuCN catalyst to produce the S_N2-type product, from which the full carbon skeleton of tuberonic acid was constructed through Mitsunobu inversion, Claisen rearrangement, and Wittig reaction. At the last stage, the THP protective group was removed with MgBr₂ in Et₂O. The diastereomeric ratio of tuberonic acid and the trans isomer was 92:8 by ¹H NMR spectroscopy.

Full text of DOI:10.1016/j.tetlet.2007.01.035

Tetrahedron Letters 48 (2007) 1745–1748
First total synthesis of tuberonic acid
Hisato Nonaka, Yong-Gang Wang and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, Box B52, Nagatsuta-cho 4259,
Midori-ku, Yokohama 226-8501, Japan
Received 22 November 2006; revised 2 January 2007; accepted 9 January 2007
Available online 12 January 2007
Abstract—A vinyl group as an acetic acid side chain was attached to the optically active monoacetate of 4-cyclopentene-1,3-diol
with CH
2
N
@CHMgBr, LiCl, and a CuCN catalyst to produce the S 2-type product, from which the full carbon skeleton of tuberonic
acid was constructed through Mitsunobu inversion, Claisen rearrangement, and Wittig reaction. At the last stage, the THP protec-
tive group was removed with MgBr in Et O. The diastereomeric ratio of tuberonic acid and the trans isomer was 92:8 by H NMR
1
2
2
spectroscopy.
Ó 2007 Elsevier Ltd. All rights reserved.
Depicted in Figure 1 are some of the a-linolenic acid
metabolites, which regulate important events of plants.
used for the synthesis of these metabolites. In fact,
1
epi-jasmonic acid (1) was only synthesized as a mixture
3
The common structural features of these metabolites are
the cis orientation of the two side chains on the ring and
attachment of the pentenyl chain to the a position of the
carbonyl group. Consequently, the metabolites in gen-
eral tend to undergo epimerization to the more stable
trans isomers. In fact, there have been reports that
with the lactone, while methyl epi-jasmonate biosynthe-
sized from epi-jasmonic acid by the carboxyl methyl-
4
3,5
transferase has been synthesized by several groups
probably due to its neutral property as an ester form.
On the other hand, we have established the synthesis
of metabolites with a long acid chain such as 12-oxo-
PDA and OPC-8:0 starting with the monoacetate of 4-
cyclopentene-1,3-diol (4 in Scheme 1), to which the
2
describe the isolation of the trans isomers.
The instability mentioned above and the existence of the
acid moiety have restricted reactions and reagents to be
C(1)–C(8) chain was attached by using the highly S 2
directing reagent system of RMgCl/CuCN (cat.). With
N
6
1
2-oxo-PDA Howe has characterized the enzymes for
7
the b-oxidation, and Ohta elucidated the specific
1
0
CO H
2
S 2 type
vinylation
1
2-oxo-PDA
double bond at C10,11)
OPC-8:0
single bond at C10,11)
N
CH=CH2
OAc
(
12
O
(
HO
4
1
) iodo-
lactonization
COX
CO H
2
2
) Wittig
1
2
) inversion
5
epi-jasmonic acid (1), R = H
tuberonic acid (2), R = OH
β-D-glucopyranosyltuberonic acid (3),
R = O-glucose
) Claisen rearr.
O
R
1
2
[O]
[
O]
1
Figure 1. Some of the metabolites of linolenic acid.
2
6
1
R O
OR2
Keywords: Tuberonic acid; Total synthesis; Stereoselective; Mono-
acetate of 4-cyclopentene-1,3-diol.
OH
6
12
*
Corresponding author. Tel./fax: +81 45 924 5789; e-mail: ykobayas@
bio.titech.ac.jp
Scheme 1. An approach to tuberonic acid.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.035

1746
H. Nonaka et al. / Tetrahedron Letters 48 (2007) 1745–1748
8
DNA induced by 12-oxo-PDA. These studies strongly
suggest that other metabolites should possess their
own biological role(s) in plants.
rion of this approach. Herein, we present the results
along this line and the first total synthesis of tuberonic
acid.
With the above implication in mind, we have been inter-
The first step of our synthesis is CuCN-catalyzed vinyla-
ested in the synthesis of tuberonic acid (2). This mole-
tion of (1R)-acetate 4 (>99% ee by chiral HPLC analy-
9
cule is a natural product as such and an aglycone of
sis) with CH @CHMgBr in the presence of LiCl
2
1
0
b-D-glucopyranosyltuberonic acid (3), both of which
(Scheme 2), which afforded 7 with a high regioselectivity
1
6,17
are isolated from the leaves of potato as tuber-forming
(93:7) and complete stereoselectivity.
This vinyl
1
1
18
substances. Previously, synthesis of the trans isomer
group was chosen as a –CH CO H equivalent. With-
2
2
1
2
of 2 in the racemic form has been reported while the
methyl ester of 2 in an optically active and a racemic
out purification due to the volatile property, the hydr-
oxyl group of 7 was inverted by using the Mitsunobu
reaction with AcOH and DIAD. Acetate 8 obtained in
a 63% yield from 4 was free of the stereoisomer, that
1
3
14
form has been reported by Kitahara and Kiyota,
respectively. In the last step, the CF CO (TFA) and
3
1
TMS protective groups of the hydroxyl group at C12
have been removed under mild conditions without epi-
merization (in MeOH at rt; HFpyridine at ꢀ40 °C).
However, due to their unstable nature even under
slightly acidic and basic conditions, these groups are
incompatible with transformations of the standard class.
On the other hand, the authors have mentioned that the
unwanted epimerization took place with deprotection of
the more stable THP, EE, and TBDPS protective groups
is, the acetate of 7, by 300 MHz H NMR analysis (8,
d 3.21–3.32; acetate of 7, d 3.40–3.52). Hydrolysis of 8
afforded alcohol 9, which was subjected to Claisen rear-
rangement under the standard conditions (excess
CH @CHOEt, Hg(OAc) (cat.), benzene, 180–200 °C,
2
2
60 h). However, the reaction was slow to produce the
corresponding aldehyde 10b only in a 22% yield with
the recovered alcohol. Coordination of the terminal ole-
fin to the mercury catalyst is a likely reason for the low
yield because Claisen rearrangement of alcohol 20 under
the same conditions produced aldehyde 21 in an 80%
yield (Eq. 1). Alternatively, we investigated an Esc-
1
3
14
in 70% AcOH or with HF.
With the limited positive information for an epimeriza-
1
9
tion-free approach to acid 2, we decided, as presented in
henmoser variant, which was performed simply by
heating a xylene solution of alcohol 9 and MeC(O-
Me) NMe under reflux for 1 h to afford amide 10a.
6
,15
Scheme 1, to apply our strategy
developed for the
synthesis of 12-oxo-PDA and OPC-8:0 in order (1) to
construct the full carbon framework as 6 with minimum
effort starting with monoacetate 4 through 5; (2) to con-
centrate much time upon oxidative manipulation of 6 at
C1 (to COOH) and C6 (to C@O) and thereafter
2
2
Without purification the amide was subjected to iodo-
lactonization with I in aqueous THF to produce iodo-
2
lactone 11 in a 45% yield from acetate 8. The iodo group
was then removed with Bu SnH and AIBN to produce
3
2
20
unmasking of the OR group at C12 without the epimer-
lactone 12 without participation of the olefin moiety
ization. We found that the THP group meets the crite-
in the reaction.
R
OAc
MgBr
CuCN (cat.), LiCl
AcOH
MeC(OMe)2NMe2
xylene, Δ
I2
X
1
. LiAlH4
HO
X
COX
2. TESCl, Im
THF/H O
O
2
4
10a, X = NMe2
cf 10b, X = H
O
7
8
, X = β-OH
, X = α-OAc
63% from 4
>
99% ee
DIAD, PPh3
1
1
1, X = I
Bu SnH
NaOH
aq MeOH
3
4
5% from 8
AIBN (cat.)
9, X = α-OH
2, X = H
+
–
(COCl)2
[Ph P(CH ) OTHP] Br
Cy2BH
3
2 3
CHO
DMSO
NaHMDS
THF/DMF, –78 °C–rt
then H O , 3 N NaOH
OTES
2
2
Et N
OTES
OTES
OTHP
OTES
3
67%
14
15
1
3
9
7% from 13
8
2% from 11
OH
+
1
. SO ·Py, DMSO, Et N
CO H
CrO , H
CO2H
MgBr2
3
3
2
3
2
2
. NaClO , MeCH=CMe
–40 °C
Et O
2
2
2
O
OTES
phosphate buffer
OR
92%
OTHP
96%
OTHP
OTHP
7
7%
1
1
7, R = TES
8, R = H
1
6
19
PPTS (cat.)
EtOH
9
0%
Scheme 2. Synthesis of tuberonic acid (2).

H. Nonaka et al. / Tetrahedron Letters 48 (2007) 1745–1748
1747
OH
CHO
CH =CHOEt
OTBS
2
OTBS
CHO
OH
O
HO
OTHP
OTHP
Hg(OAc) , Δ
2
23
24
8
0%
20
21
ð1Þ
After unsuccessful deprotection of the THP group of 19
2
5
under various conditions,
we found that MgBr2
In the synthesis of 12-oxo-PDA and OPC-8:0,6a the lac-
tone carbonyl moiety was converted to the aldehyde
2
6
(
3 equiv) in Et O at room temperature for 2 h provided
2
2
in high yield with minimum epimerization (2 over the
ꢀ
1
20
through a four-step sequence of (i) HO ; (ii) CH N ;
2
2
trans isomer = 92:8 by H NMR spectroscopy).
(
iii) TESCl; (iv) DIBAL, in which the products of steps
i and ii were isolated and semi-purified as fast as possible
to prevent lactonization back to 12. In the present study,
we investigated another sequence of reactions involving
Time-dependency of the epimerization of tuberonic acid
2) was studied at room temperature in CD OD with a
(
3
9
0:10 mixture of 2 and the trans isomer by monitoring
2
4
direct conversion of a primary TESOCH moiety to an
2
the protons for 2 and the trans isomer. In contrast
2
1
aldehyde group by Swern oxidation. Thus, the reduc-
to the fairly rapid epimerization under the acidic condi-
2
5
tion of lactone 12 with LiAlH followed by bissilylation
4
tions, detectable epimerization was not observed for
over 21 days! On the other hand, epimerization took
place, but slowly, in the presence of K CO (hetero-
afforded 13 in an 82% yield from iodolactone 11. Swern
oxidation of 13 proceeded selectively at the primary car-
bon to afford aldehyde 14, which could be used for the
next Wittig reaction without chromatographic purifica-
tion. As expected, the intermediates in this shorter
sequence (three-step) were chemically quite stable to
allow easy handling.
2
3
geneous in CD OD) to produce a 40:60 mixture after
3
7
days. Now, scientists working in this area are free of
the fear of autoepimerization by its own acidity that
1
4
was suggested by Kiyota et al.
In summary, we have established for the first time a
method for obtaining tuberonic acid (2), which was of
a 92% purity over the trans isomer. Furthermore, we
confirmed the stable nature of 2 under neutral condi-
tions over an extended period. The stability established
herein will be quite informative for modifying the isola-
tion of 2 in future, and thus facilitate research in this
field.
Two phosphonium salts 22a,b with different protective
2
groups (R = PMB (p-MeOC H CH ), THP) were con-
6
4
2
ceived as a Wittig partner of 14. Among them, 22a with
the PMB group was eliminated due to the reason found
in a preliminary study using a model acid derived from
2
2
racemic methyl jasmonate.
2
þ
ꢀ
2
½
Ph PðCH Þ OR ꢁ Br
22 for R ; a; PMB; b; THP
3
2
3
Acknowledgments
The crude aldehyde 14 (vide supra) upon Wittig reaction
with the anion derived from the THP ether 22b and
Racemic methyl jasmonate was kindly provided by Zeon
Co. Ltd., Japan. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Edu-
cation, Science, Sports, and Culture, Japan.
2
0
NaHMDS (NaN(TMS) ) afforded olefin 15 (= 6 with
2
1
2
R = TES; R = THP in Scheme 1) stereoselectively in a
high yield. Hydroboration of 15 with Cy BH (Cy: c-
2
C H ) followed by oxidative workup produced alcohol
6
11
1
6, which upon oxidation first with SO Æpyridine and
3
2
3
References and notes
then with NaClO under neutral conditions afforded
2
acid 17 in a 52% yield from olefin 15. Selective removal
of the TES group in 17 was accomplished under two
conditions with PPTS (0.3 equiv) in EtOH (rt, 1 h) and
with TBAF (6 equiv) in THF (rt, 4 h) to produce alcohol
1
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1
8
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ꢀ
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furnished a 70:30 mixture of 19 and the trans isomer.

1748
H. Nonaka et al. / Tetrahedron Letters 48 (2007) 1745–1748
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(
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1H), 3.72 (dt, J = 9, 7 Hz, 1H), 3.87 (ddd, J = 11, 7.5,
3.5 Hz, 1H), 4.15–4.22 (m, 1H), 4.57–4.63 (m, 1H), 4.80–
4.91 (m, 2H), 5.30–5.58 (m, 2H), 5.93 (dt, J = 17, 10 Hz,
(
1
1
3
6
7
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(ꢀ), 62.3 (+), 67.1 (+), 75.3 (ꢀ), 98.7 (ꢀ), 113.1 (+), 125.4
2
1
(ꢀ), 131.6 (ꢀ), 143.2 (ꢀ). Compound 18: H NMR
(CDCl ) d 1.4–2.8 (m, 19H), 3.34–3.58 (m, 2H), 3.73–3.94
3
(m, 2H), 4.10–4.24 (m, 1H), 4.55–4.66 (m, 1H), 5.34–5.60
1
3
(m, 2H); C NMR 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 (+). Compound 19:
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8
2
D
7
1
½
aꢁ +10 (c 1.43, CHCl ); H NMR (CDCl ) d 1.3–2.6 (m,
3
3
9
. (a) Koda, Y.; Omer, E.-S. A.; Yoshihara, T.; Shibata, H.;
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2
1
7H), 2.78–2.93 (m, 1H), 3.35–3.58 (m, 2H), 3.67–3.95 (m,
13
H), 4.56–4.66 (m, 1H), 5.32–5.62 (m, 2H); C NMR d
1047–1051; (b) Yoshihara, T.; Omer, E.-S. A.; Koshino,
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3
9
2
5.7, 52.6, 62.4 and 62.6, 66.8 and 67.1, 98.8 and 99.0,
9.2, 127.8 and 128.0, 128.2 and 128.3, 177.0 and 177.1,
25
1
18.9. Compound 2: ½aꢁ +11 (c 0.26, MeOH); H NMR
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1
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1
0H), 2.74–2.88 (m, 1H), 3.55 (t, J = 7 Hz, 2H), 5.37–5.62
(
m, 2H).
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2
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7
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1
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1
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2
1
O
OR
1
1
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OMe
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iii
1
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2
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4. Upon alkaline treatment in aqueous MeOH, acids 19 and
2 underwent epimerization to trans isomers iv and v,
1
1
1
1
8
1
0
7. In the absence of LiCl, the S 2 product 7 and anti S 2
N
N
isomer was produced in a ratio of 63:37.
8. Tsuji, J.; Kobayashi, Y.; Kataoka, H.; Takahashi, T.
Tetrahedron Lett. 1980, 21, 1475–1478.
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respectively. The diagnostic signals for 19, iv, 2, and v in
1
the H NMR spectra (300 MHz, the former two in CDCl
3
and the latter two in CD
3
OD) are (d): 19, 2.78–2.93; iv,
2
.54–2.73; 2, 2.74–2.88; v, 2.60–2.71 ppm. In addition, the
1
H NMR spectrum of v was consistent with that
reported.
10c
4
11–414.
1
13
2
0. [a]
D
, H NMR (300 MHz, CDCl
) data of the intermediates. Com-
pound 12: H NMR (CDCl ) d 1.39–1.58 (m, 1H), 1.62–
3
or CD
3
OD), and/or
C
CO H
2
NMR (75 MHz, CDCl
3
1
3
iv, R = THP
OR v, R = H
1
5
1
.80 (m, 2H), 1.99 (dd, J = 13, 7 Hz, 1H), 2.36 (dd, J = 19,
Hz, 1H), 2.43 (dd, J = 19, 10.5 Hz, 1H), 2.53–2.67 (m,
H), 2.90–3.03 (m, 1H), 4.95–5.03 (m, 1H), 5.01 (dt,
O
J = 17, 1.5 Hz, 1H), 5.08 (dt, J = 11, 1.5 Hz, 1H), 5.71
25. For example, deprotection with HCl (cat.) in MeOH at
room temperature produced a 27:73 mixture of 2 and the
trans isomer in an 81% yield.
26. Kim, S.; Park, J. H. Tetrahedron Lett. 1987, 28, 439–
440.
1
3
(
(
(
(
ddd, J = 17, 11, 6.5 Hz, 1H); C NMR d 26.9 (+), 29.7
+), 32.7 (+), 40.9 (ꢀ), 46.1 (ꢀ), 85.8 (ꢀ), 116.7 (+), 136.9
1
ꢀ), 177.7 (+). Compound 15: H NMR (CDCl
3
) d 0.59
q, J = 8 Hz, 6H), 0.95 (t, J = 8 Hz, 9H), 1.43–1.92 (m,