First total synthesis of (+)-heteroplexisolide e

Article abstract of DOI:10.1016/j.tetlet.2012.04.065

In this study, we achieved the first total synthesis of (+)-heteroplexisolide E. The synthetic highlights of our approach include a one-pot regioselective methylation method and the transformation of a β-methallyl alcohol moiety to a prenyl group using palladium-catalyzed hydrogenolysis.

Full text of DOI:10.1016/j.tetlet.2012.04.065

Tetrahedron Letters 53 (2012) 3274–3276
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First total synthesis of (+)-heteroplexisolide E
⇑
⇑
Noriki Kutsumura , Akito Kiriseko, Takao Saito
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, we achieved the first total synthesis of (+)-heteroplexisolide E. The synthetic highlights of
our approach include a one-pot regioselective methylation method and the transformation of a b-meth-
allyl alcohol moiety to a prenyl group using palladium-catalyzed hydrogenolysis.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 26 December 2011
Revised 29 March 2012
Accepted 13 April 2012
Available online 21 April 2012
Keywords:
Heteroplexisolide E
Total synthesis
One-pot regioselective methylation
Aldol condensation
Palladium-catalyzed hydrogenolysis
In 2009, Shi and co-workers isolated a novel diterpene lactone,
(+)-heteroplexisolide E (1), from an ethanolic extract of Heteroplex-
is micocephala (Compositae family), together with almost 50 other
We began the total synthesis of (+)-1 starting from the known
chiral building block (+)-2, which can be easily prepared from com-
mercially available 1,4-pentadien-3-ol in three steps.3,4 The allyl
alcohol derivative (+)-2 was successfully converted into (+)-3 in
excellent yield in a single-pot operation (Scheme 2). This three-
step key reaction was based on the one-pot methodology for tan-
dem/sequential bromination of allyl alcohol derivatives, regiose-
lective HBr-elimination, and C–C coupling, which was developed
recently by our group.2 After much effort, we achieved the methyl-
ation of (+)-6 by Negishi coupling using excess amounts of dimeth-
ylzinc with addition of THF in the presence of the precatalyst
PEPPSI™-IPr5 in the same pot.6
Next, an aldol reaction between (+)-3 and aldehyde 7 in the
presence of LDA followed by dehydration gave only E-alkene (+)-
8 in good yield.7,8 Consecutive removal of the p-methoxybenzyl
(PMB) group with 1,2-dichloro-4,5-dicyanobenzoquinone (DDQ)
and the acetal group using pyridinium p-toluenesulfonate (PPTS)
from (+)-8 provided the desired (+)-4 in good yield in a single oper-
ation. Conversions of (+)-4 into 9a–d were then performed using
the methods of (a)–(d): (a) acetic acid anhydride, pyridine, and
DMAP for (+)-9a; (b) ethyl chloroformate, pyridine, and DMAP
(+)-9b; (c) methanesulfonyl chloride, triethylamine, and tetra-
methylethylenediamine (TMEDA)9 for (+)-9c; and (d) tetrabro-
momethane and triphenylphosphine for (+)-9d.
compounds.1 The structural features of (+)-1 include a
c-lactone
core, a side chain of unsaturated ketone, and a branched prenyl
group. Heteroplexis micocephala, which grows in the limestone ter-
rains of Longzhou and Yangshuo, Guangxi Province, China, is tradi-
tionally used as a folk medicine for the treatment of indigestion
and dropsy. Shi and co-workers investigated various biological
activities of Heteroplexis micocephala such as selective cytotoxicity,
inhibition of HIV-1 replication, and antioxidation in vitro. However,
(+)-1 was found to be inactive, and to date, the active components
in traditional Chinese medicines using Heteroplexis micocephala
have not been reported. In order not only to achieve the first total
synthesis of (+)-1 but also to synthetically provide enough
amounts of (+)-1 for the exact evaluation of its additional activities,
we started a synthetic study of (+)-1. Thus we reveal herein the
first total synthesis of (+)-1 from the known chiral building block
(+)-2.
As shown in Scheme 1, the retrosynthetic analysis indicated
that the branched prenyl group of (+)-1 can be transformed from
the corresponding b-methallyl alcohol moiety at the final stage.
Allyl alcohol (+)-4 can be derived from compound (+)-3 via aldol
condensation of the side-chain aldehyde. The compound (+)-3
can be synthesized from the known chiral building block (+)-2
using one-pot chemoselective methylation.2
At the final stage, the conversions of the allylic compound 9 into
(+)-1 were examined (Table 1). Palladium-catalyzed hydrogenoly-
sis10 of 9 with 1.1 equiv of Bu3SnH as a hydride source was initi-
ated using the allylic acetate (+)-9a (Entries 1 and 2). The
reaction succeeded in providing the desired (+)-1, albeit in a low
yield. In addition, the ratio of (+)-1 was increased with increasing
⇑
Corresponding authors. Fax: +81 3 5261 4631.
E-mail addresses: nkutsu@rs.kagu.tus.ac.jp (N. Kutsumura), tsaito@rs.kagu.tus. ac.jp
(T. Saito).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.065

N. Kutsumura et al. / Tetrahedron Letters 53 (2012) 3274–3276
3275
Scheme 1. Retrosynthesis of (+)-1.
Scheme 3. Synthesis of 9 from (+)-3.
Scheme 2. Bromine addition/regioselective elimination/Negishi coupling in one-
pot operation.
Scheme 4. Improved process for the Appel reaction and the sequential palladium-
catalyzed hydrogenolysis
Moreover, we also improved the synthesis at the last stage
(Scheme 4). The Appel reaction11 of the sterically hindered second-
ary alcohol (+)-4 gave the bromide (+)-9d in moderate yield (61%
yield, Scheme 3), together with SN20 isomeric product 9d0.12 As
the isomer 9d0 was assumed to be a precursor of (+)-1, the entire
mixture of products was exposed to palladium-catalyzed hydrog-
enolysis. Gratifyingly, the final two-step yield was increased to
98% as a mixture of (+)-1 and 10,13,14 which were finally separated
by preparative TLC on silica gel.15
In summary, the first total synthesis of (+)-1 was achieved from
the known chiral building block (+)-2. Highlights include a one-pot
regioselective methylation method and the transformation of a b-
methallyl alcohol moiety to a prenyl group using palladium-cata-
lyzed hydrogenolysis.
Table 1
Total synthesis of (+)-heteroplexisolide E (1)
Entry
X
Conditions
Yielda /%
Ratiob (1:10)
1c
2c
3
4
5
6
7
8
OAc
OAc
THF, 60 °C
toluene, 100 °C
THF, 60 °C
toluene, 100 °C
THF, 60 °C
toluene, 100 °C
THF, 60 °C
13d
15e
64
32
92
95
94
96
1:1
3:1
1.7:1
1.6:1
1:9
1:3
7:1
8:1
OCO2Et
OCO2Et
OMs
OMs
Br
Acknowledgments
Br
toluene, 100 °C
We thank Dr. Tadaaki Ohgiya (Manager, Organic Chemistry
Department, Organic Chemistry Group 1, Tokyo New Drug
Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd.)
for chemical discussions. This work was partly supported by the
Sasakawa Scientific Research Grant from The Japan Science
Society.
a
b
c
Isolated yield of the mixture (1 + 10).
Ratio was determined by 1H NMR.
Reaction time was 1.5 h.
The starting material (+)-9a was recovered (80%).
The starting material (+)-9a was recovered (74%).
d
e
References and notes
temperature (Entry 2). The transformation of the ethyl carbonate
(+)-9b (Entries 3 and 4) or the mesylate (+)-9c (Entries 5 and 6)
proceeded (+)-1, but was still accompanied by byproduct 10 in
appreciable amounts. Finally, the reaction of allylic bromide (+)-
9d in toluene at 100 °C gave excellent yields and sufficient selectiv-
ity (Entry 8).
1. Fan, X.; Zi, J.; Zhu, C.; Xu, W.; Cheng, W.; Yang, S.; Guo, Y.; Shi, J. J. Nat. Prod.
2009, 72, 1184.
2. Kutsumura, N.; Niwa, K.; Saito, T. Org. Lett. 2010, 12, 3316.
3. (a) Zhu, L.; Mootoo, D. R. Org. Lett. 2003, 5, 3475; (b) Kutsumura, N.; Yokoyama,
T.; Ohgiya, T.; Nishiyama, S. Tetrahedron Lett. 2006, 47, 4133; (c) Yokoyama, T.;
Kutsumura, N.; Ohgiya, T.; Nishiyama, S. Bull. Chem. Soc. Jpn. 2007, 80, 578.

3276
N. Kutsumura et al. / Tetrahedron Letters 53 (2012) 3274–3276
4. Compound (+)-2 was prepared from commercially available 1,4-pentadien-
8. To a solution containing diisopropylamine (0.20 mL, 1.42 mmol) in THF
3-ol.3a,c
(4.0 mL) under argon at ꢀ78 °C was added n-butyllithium (0.53 mL,
1.42 mmol, 2.69 M sol. of hexane). Stirring at ꢀ78 °C was continued for
10 min, followed by the addition of (+)-3 (223.2 mg, 0.808 mmol) in THF
(2.0 mL). The mixture was stirred at ꢀ78 °C for 1 h, followed by the addition of
7 (234.1 mg, 1.62 mmol) in THF (2.0 mL). Stirring was continued at ꢀ78 °C for
30 min and then at room temperature for 30 min, followed by the addition of a
saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc,
washed with brine, and dried over MgSO4. The residue obtained after the
evaporation of the solvent was dissolved in 1,2-dichloroethane (8.1 mL), then
pyridine (0.26 mL, 3.22 mmol), DMAP (10.2 mg, 0.0834 mmol), and acetic acid
anhydride (0.30 mL, 3.17 mmol) were added at 0 °C, and solution was stirred at
room temperature for 2 h. DBU (0.61 mL, 4.03 mmol) was added, and the
mixture was stirred at 70 °C for 2 h. The reaction was quenched with
a
saturated aqueous NH4Cl solution at 0 °C. The mixture was extracted with
EtOAc, washed with brine, dried over MgSO4, concentrated in vacuo, and
purified by silica gel column chromatography (hexane/EtOAc = 2/1–3/2, then
CHCl3/acetonitrile = 20/1) to afford (+)-8 (247.4 mg, 76% from (+)-3) as the sole
product and (+)-3 (30.4 mg, 14% recovered).
9. Yoshida, Y.; Shimonishi, K.; Sakakura, Y.; Okada, S.; Aso, N.; Tanabe, Y. Synthesis
1999, 1633.
10. Tsuji, J.; Mandai, T. Synthesis 1996, 1.
11. Khan, S.; Kato, N.; Hirama, M. Synlett 2000, 1494.
12. (a) Bohlmann, F.; Steinmeyer, A. Tetrahedron Lett. 1986, 27, 5359; (b) Bouillon,
M. E.; Meyer, H. H. Tetrahedron 2007, 63, 2712.
5. (a) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Org. Lett. 2005, 7,
3805; (b) O’Brien, C. J.; Kantchev, E. A. B.; Chass, G. A.; Hadei, N.; Hopkinson, A.
C.; Organ, M. G.; Setiadi, D. H.; Tang, T.-H.; Fang, D.-C. Tetrahedron 2005, 61,
9723; (c) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. J. Org. Chem.
2005, 70, 8503; (d) Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E.
A. B.; O’Brien, C. J.; Valente, C. Chem. Eur. J. 2006, 12, 4749.
13.
A mixture of (+)-4 (10.3 mg, 0.0429 mmol), tetrabromomethane (29.1 mg,
0.0877 mmol), and triphenylphosphine (23.0 mg, 0.0877 mmol) in
dichloromethane (0.43 mL) was stirred at room temperature for 22 h. After
evaporation, the residue was purified by silica gel column chromatography
(hexane/EtOAc = 1/1) to afford a mixture of (+)-9d and the isomeric product. To
the mixture in toluene (0.43 mL) was added tetrakis(triphenylphosphine)
palladium (2.5 mg, 0.00216 mmol) and then heated to 100 °C. Tributyltin
6. A mixture of (+)-2 (1.09 g, 4.17 mmol) and pyridinium bromide perbromide
(1.47 g, 4.58 mmol) in acetonitrile (41.7 mL) was stirred at room temperature
for 15 h. DBU (1.96 mL, 12.9 mmol) was added to the reaction mixture at 0 °C
and the system was then stirred at 60 °C for 2.5 h. After confirming
consumption of (+)-6 by a thin layer chromatography (TLC), THF (10.5 mL),
PEPPSI™-IPr (283 mg, 0.427 mmol), and dimethyl zinc (24.0 mL, 25.0 mmol,
1.0 M sol. of hexane) were added to the reaction mixture at 0 °C without
evaporation, and the system was then stirred at 60 °C for 1 h. The reaction was
quenched with H2O at 0 °C and the reaction mixture was extracted with EtOAc,
washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by
silica gel column chromatography (hexane/EtOAc = 3/2) to afford (+)-3 (1.00 g,
87%).
7. (a) Tanaka, M.; Mukaiyama, C.; Mitsuhashi, H.; Maruno, M.; Wakamatsu, T. J.
Org. Chem. 1995, 60, 4339; (b) Choi, Y.; Kang, J.-H.; Lewin, N. E.; Blumberg, P.
M.; Lee, J.; Marquez, V. E. J. Med. Chem. 2003, 46, 2790; (c) Edmonds, D. J.; Muir,
K. W.; Procter, D. J. J. Org. Chem. 2003, 68, 3190; (d) Peng, X.-S.; Wong, H. N. C.
Chem. Asian. J. 2006, 1–2, 111; (e) Berger, G. O.; Tius, M. A. J. Org. Chem. 2007, 72,
6473.
hydride (13 lL, 0.0483 mmol) was added and the system was stirred for 10 min.
After being cooled to room temperature, the solvent was removed under
reduced pressure, and the residue was purified by column chromatography
(10% w/w anhydrous K2CO3-silica;14 hexane/EtOAc = 2/1–1/1) to afford the
mixture of (+)-1 and 10 (9.3 mg, (+)-1/10 = 8/1, 98% in 2 steps).14
14. Harrowven, D. C.; Curran, D. P.; Kostiuk, S. L.; Wallis-Guy, I. L.; Whiting, S.;
Stenning, K. J.; Tang, B.; Packard, E.; Nanson, L. Chem. Commun. 2010, 46, 6335.
15. Spectral data of the synthetic (+)-heteroplexisolide E (1, 19.0 mg), which were
partially separated (7.6 mg) by preparativeTLC (Silica gel 60 F254, 0.5 mm, Merck,
dichloromethane/2-propanol = 2/1) ꢁ 6 times, were identical to those of the
natural product in all respects. In addition, a 2:1 mixture of (+)-1 and 10 was also
separated (5.4 mg).½a D20
ꢂ
+74.0 (c 0.38, MeOH); lit.1 a 2D0
½ ꢂ +15.6 (c 0.27, MeOH).