Total synthesis of (+)-heteroplexisolide E

Article abstract of DOI:10.3987/COM-12-S(N)91

Total synthesis of (+)-heteroplexisolide E has been demonstrated. The synthetic approach exploits the one-pot regioselective Negishi coupling (methylation) and transformation of a β-methallyl alcohol moiety to a branched prenyl group via palladium-catalyzed hydrogenolysis. For the introduction of the 4-oxo-pentylidene side chain, two independent methods were devised: olefin cross metathesis (CM) (route A) and aldol condensation (route B).

Full text of DOI:10.3987/COM-12-S(N)91

HETEROCYCLES, Vol. 86, No. 2, 2012
1367
HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1367 - 1378. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 6th July, 2012, Accepted, 10th August, 2012, Published online, 24th August, 2012
DOI: 10.3987/COM-12-S(N)91
TOTAL SYNTHESIS OF (+)-HETEROPLEXISOLIDE E‡
Noriki Kutsumura,* Akito Kiriseko, and Takao Saito*
Department of Chemistry, Faculty of Science, Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Email: nkutsu@rs.kagu.tus.ac.jp; tsaito@rs.kagu.tus.ac.jp
‡This paper is dedicated to Professor Ei-ichi Negishi on celebration of his 77th
birthday.
Abstract – Total synthesis of (+)-heteroplexisolide E has been demonstrated. The
synthetic approach exploits the one-pot regioselective Negishi coupling
(methylation) and transformation of a β-methallyl alcohol moiety to a branched
prenyl group via palladium-catalyzed hydrogenolysis. For the introduction of the
4-oxo-pentylidene side chain, two independent methods were devised: olefin cross
metathesis (CM) (route A) and aldol condensation (route B).
INTRODUCTION
Heteroplexisolide E (1) is a novel diterpene lactone. It is isolated from an ethanolic extract of
Heteroplexis micocephala (Compositae family) that grows in the limestone terrains of Longzhou and
Yangshuo in the Guangxi Province of China.1 This γ-lactonic natural product possesses a
4-oxo-pentylidene side chain and a branched prenyl group. No significant biological activity has been
reported so far for this compound. Therefore, we initiated a synthetic study of (+)-1 to acquire sufficient
quantities for a biological activity test. In this study, we disclose the first total synthesis of (+)-1 from the
known starting material (+)-2 with an overall yield of 62%.2
Scheme 1. Planned synthetic routes of (+)-1 from (+)-2

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HETEROCYCLES, Vol. 86, No. 2, 2012
RESULTS AND DISCUSSION
As shown in Scheme 1, our synthetic strategy involving known γ-lactone (+)-2 as a key starting
material2,3 can serve in the diversity-oriented synthesis of various optically active γ-lactonic derivatives
that can be studied further in terms of their chemical biology.4 In this context, Nishiyama and co-workers
reported the total syntheses of ()-muricatacin and ()-(R,R)-sapinofuranone B by using compound
()-2.3b,3c From our perspective, a straightforward strategy for the synthesis of (+)-1 would entail the
development of methods for both the introduction of the 4-oxo-pentylidene side chain and the
transformation of the allyl alcohol moiety to the branched prenyl group. For the introduction of the side
chain, we envisaged two possible methods: (1) route A: olefin cross metathesis (CM) between the
α-methylene-γ-lactone moiety and the corresponding terminal olefin and (2) route B: aldol condensation
of the γ-lactone moiety with the corresponding aldehyde. On the other hand, the transformation to the
prenyl group would be achieved through several steps, including a one-pot regioselective Negishi
coupling.
i) Pyr.-HBr3
O
(1.1 equiv)
3 stepsref. 2,3
O
Br
MeCN, rt
2
(+)-
OH
Br
> 99% ee
PMBO
3
iii) Me2Zn (6 equiv)
PEPPSITM-IPr
(10 mol%)
ii) DBU
O
O
(3.1 equiv)
O
O
60 °C
THF, 60 °C
Br
94% in one pot
87% in one pot
PMBO
(+)-5
PMBO
(+)-4
2
2
(from (+)- )
(f rom (+)- )
Scheme 2. Syntheses of (+)-4 and (+)-5 from (+)-2 in a one-pot manner
The total synthesis of (+)-1 was achieved using a known chiral building block (+)-2, which was prepared
in three steps from 1,4-pentadiene-3-ol (Scheme 2).2,3 The allyl alcohol derivative (+)-2 was converted
into (+)-4 in a two-step sequential, one-pot bromination (i. bromine addition, ii. DBU-promoted
elimination),5 or into (+)-5 in a three-step sequential, one-pot methylation (i. bromine addition, ii.
DBU-promoted elimination, and iii. PEPPSI (Pyridine-enhanced precatalyst, preparation, stabilization,
and initiation)TM-IPr (diisopropylphenylimidazolium derivative)6-catalyzed Negishi coupling).
Our first approach to introducing the alkyl side chain was through chemoselective olefin CM of
α-methylene-γ-butyrolactone (+)-67 derived from (+)-4 using a terminal alkene 7 or 8 in the presence of
2,6-dichlorobenzoquinone and Grubbs 2nd or Hoveyda‒Grubbs 2nd generation catalyst (Scheme 3).8

HETEROCYCLES, Vol. 86, No. 2, 2012
1369
Grubbs 2nd cat.
Hoveyda–Grubbs 2nd cat.
1) Eschenmoser's salt (5 equiv)
TMSOTf (2.2 equiv)
O
O
or
O
DIPEA (5 equiv)/CH2Cl2, –5 ºC
2,6-dichlorobenzoquinone cat.
O
(+)-4
2) mCPBA (4 equiv)/CH2Cl2, rt
7
( )
Br
Br
O
PMBO
or
/CH2Cl2
PMBO
X
69%, 2 steps
(+)-6
(8)
O
O
9: X = O
10
: X =
OCH2CH2O
Scheme 3. Chemoselective CM utilizing the poor reactivity of vinyl bromide (route A)
This challenging reaction was based on the expectation that the exo-methylene moiety would be much
more reactive than the anomalously low reactive vinyl bromide toward CM in general.9 Unfortunately,
however, the expected products 9 or 10 were detected only in trace amounts under all reaction conditions
attempted.10 This is probably because of the rapid decomposition of the ruthenium monohalomethylidene
intermediate, as explained by Johnson and co-workers.11
O
Cl
S
DDQ
nBu3SnH
AIBN/toluene
100 ºC
O
O
O
O
CH2Cl2-Buffer
rt
DMAP/MeCN
rt
O
O
O
O
5
(+)-
+
95%
92%
68% (1 : 1)
PhO(S=)CO
12
HO
13
(desired)
14
11
(+)-
(+)-
(undesired)
O
CBr4, PPh3
CH2Cl2, rt
nBu3SnH, Pd(PPh3)4
toluene, 100 ºC
O
13
(desired)
14
+
(undesired)
68%
72% (11 : 1)
Br
(–)-15
i) NaH, HCO2Et, EtOH
THF, rt
8
(1.5 equiv)
Hoveyda–Grubbs 2nd (10 mol%)
O
O
ii) (HCHO)n/THF, 60 ºC
2,6-dichlorobenzoquinone (0.1 equiv)
complex mixtures
(N.D.)
O
O
+
CH2Cl2, 40 ºC
31%
16
17
(desired)
(undesired)
Scheme 4. Chemoselective CM by differentiating the two olefins (route A)
An alternative pathway attempted is illustrated in Scheme 4. After the deprotection of the
p-methoxybenzyl ether (PMB) group of (+)-5, the hydroxy lactone (+)-11 was derivatized to the desired
prenyl-substituted lactone 13 in two ways: (1) a Barton‒McCombie-type transformation12 via the
thiocarbonate (+)-12 (68%, 13:14 = 1:1) and (2) the Appel reaction13 and the sequential

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HETEROCYCLES, Vol. 86, No. 2, 2012
palladium-catalyzed hydrogenolysis14 of ()-15 (72%, 13:14 = 11:1). After the methylenation of the
lactones 13 and 14, chemoselective CM based on differentiation of the olefins between the resulting
mixtures 16/17 and 8 was attempted. However, this approach was also unsuccessful, giving an
unidentified complex mixture (Scheme 4).
O
H
O
O
i) DDQ
CH2Cl2-H2O, rt
ii) PPTS
acetone, 50 ºC
18
(
)
, THF, –78 ºC
1) LDA,
2) Ac2O, pyr., DMAP
(CH2Cl)2, rt
O
O
O
O
then DBU, 70 ºC
(+)-5
90% in one pot
86%, 2 steps
O
PMBO
HO
O
O
19
20
(+)-
(+)-
Scheme 5. Aldol condensation pathway (route B)
A different approach (route B) to carbon-chain elongation was a much more secure and conservative
pathway. An aldol reaction between (+)-5 and aldehyde 18 in the presence of lithium diisopropylamide
(LDA) followed by dehydration gave only E-alkene (+)-19 in good yield (Scheme 5).15 Consecutive
removal of the PMB group with 2,3-dichloro-4,5-dicyano-1,4-benzoquinone (DDQ) and the acetal group
with pyridinium p-toluenesulfonate (PPTS) from (+)-19 in a one-pot process afforded the desired (+)-20 in
excellent yield.
nBu3SnH (1.1 equiv)
O
O
CBr4, PPh3
CH2Cl2, rt
Pd(PPh3)4 (5 mol%)
O
O
toluene, 100 ºC, 10 min
Br
20
(+)-
+
Br
O
O
SN2 product (+)-21
SN2' product 21'
(ca. 6 : 4 mixture)
O
O
O
Pd(OCOCF3)2 (10 mol%)
toluene, 100 ºC, 10 h
O
(+)-1
+
94%
as a single product !
O
O
[ ]D20 +74.0 (c 0.38, MeOH)
(+)-1
(+)-22


98% (8:1 mixture)
2 steps
1
lit. [ ]D20 +15.6 (c 0.27, MeOH)
(from (+)-20)
Scheme 6. Total synthesis of (+)-heteroplexisolide E (1)

HETEROCYCLES, Vol. 86, No. 2, 2012
1371
To efficiently transform the β-methallyl alcohol moiety of (+)-20 into the prenyl group at the final stage,
we examined various allylic compounds,2 such as the acetate, ethyl carbonate, mesylate, and bromide, for
the palladium-catalyzed hydrogenolysis.14 After many attempts, we finally found the optimal method. The
Appel reaction of the sterically hindered secondary alcohol (+)-20 gave a mixture of bromide (+)-21 and
the SN2′ isomeric product 21′ (Scheme 6),16 both of which were reasonably assumed to be a good
precursor of (+)-1. Therefore, the mixture was exposed to the palladium-catalyzed hydrogenolysis to
furnish an 8:1 mixture of (+)-1 and undesired product (+)-22 in excellent yield. Fortunately, the minor
isomeric product (+)-22 was completely converted into (+)-1 by the reaction of palladium trifluoroacetate
in toluene at 100 C, even in the presence of the major product (+)-1.
In conclusion, the first total synthesis of (+)-1 from the known chiral building block (+)-2 was achieved
with an overall yield of 62%. Synthetic highlights include the one-pot regioselective Negishi coupling
(methylation) and the transformation of a β-methallyl alcohol moiety to a branched prenyl group by the
palladium-catalyzed hydrogenolysis. The 4-oxo-pentylidene side chain was constructed through the aldol
condensation pathway.
EXPERIMENTAL
1
General. Infrared spectra were recorded on a Horiba FT-710 spectrophotometer. H and 13C NMR
spectroscopic data were obtained with a Bruker AV 600, a JEOL JNM-EX 500, or a Bruker BioSpin DPX
1
300 instrument. Chemical shifts (δ) are quoted in ppm using tetramethylsilane (TMS, δ = 0 ppm) for H
13
NMR spectroscopy, and CDCl3 (δ = 77.0 ppm) for C NMR spectroscopy, as references. Mass spectra
were measured on a Bruker Daltonics microTOF or a Hitachi double-focusing M-80B spectrometer.
Column chromatography was conducted on silica gel (Kanto Chemical). All reactions were performed
under an argon atmosphere.
Synthesis of (+)-5 from (+)-2 in a one-pot manner. A mixture of (+)-2 (1.09 g, 4.17 mmol) and
pyridinium bromide perbromide (1.47 g, 4.58 mmol) in MeCN (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 (+)-3 by a thin layer chromatography (TLC),
THF (10.5 mL), PEPPSITM-IPr (283 mg, 0.427 mmol), and dimethylzinc (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. The combined extracts were washed with brine, dried over Na2SO4, concentrated
in vacuo, and purified by silica gel column chromatography (hexane/EtOAc = 3/2) to afford (+)-5 (1.00 g,

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HETEROCYCLES, Vol. 86, No. 2, 2012
87% in three steps). Compound (+)-5: []D +53.4 (c 1.00, CHCl3); IR (neat) 2947, 1774, 1612 cm-1; 1H
NMR (500 MHz, CDCl3, ) 1.77 (m, 3H), 1.93 (m, 1H), 2.14 (m, 1H), 2.44 (m, 1H), 2.55 (m, 1H), 3.73
(d, J = 5.7 Hz, 1H), 3.80 (s, 3H), 4.25 (d, J = 11.7 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.56 (ddd, J = 7.0,
7.0, 5.7 Hz, 1H), 5.03 (m, 1H), 5.12 (m, 1H), 6.87 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H); 13C NMR
(126 MHz, CDCl3, ) 18.0, 24.5, 28.3, 55.2, 69.9, 81.2, 84.2, 113.8, 113.8, 116.5, 129.4, 129.4, 129.8,
141.0, 159.2, 177.2; HRMS-ESI (m/z) [M+Na]+ Calcd for C16H20O4Na: 299.1254, Found: 299.1254.
Synthesis of (+)-6 from (+)-4. To a mixture of (+)-4 (583 mg, 1.70 mmol), Eschenmoser’s salt (1.58 g,
8.52 mmol), and DIPEA (1.50 mL, 8.61 mmol) in CH2Cl2 (17.0 mL) was added TMSOTf (0.70 mL, 3.87
mmol) slowly at 5 C and then stirred for 5 min. The reaction was quenched with a saturated aqueous
NaHCO3 solution at 0 C and the reaction mixture was extracted with EtOAc. The combined extracts
were dried over MgSO4 and concentrated in vacuo to afford a crude product as an oil. The crude product
was dissolved in CH2Cl2 (17.0 mL) and then mCPBA (1.57 g, 6.83 mmol) was added slowly at room
temperature. After being stirred at the same temperature for 1 h, the reaction was quenched with a
saturated aqueous Na2SO3 solution and the reaction mixture was extracted with EtOAc. The combined
extracts were washed with a saturated aqueous NaHCO3 solution, dried over MgSO4, concentrated in
vacuo, and purified by silica gel column chromatography (hexane/EtOAc = 3/12/11/1) to afford (+)-6
(414 mg, 69% in two steps). Compound (+)-6: []D +56.1 (c 1.00, CHCl3); IR (neat) 2931, 2862, 1766,
1
1666, 1612, 1511 cm-1; H NMR (300 MHz, CDCl3, ) 2.61 (dddd, J = 17.3, 8.4, 2.7, 2.6 Hz, 1H), 2.94
(dddd, J = 17.3, 5.4, 2.7, 2.6 Hz, 1H), 3.81 (s, 3H), 3.84 (d, J = 4.8 Hz, 1H), 4.32 (d, J = 11.6 Hz, 1H),
4.68 (d, J = 11.6 Hz, 1H), 4.75 (ddd, J = 8.4, 5.4, 4.8 Hz, 1H), 5.59 (dd, J = 2.6, 2.6 Hz, 1H), 5.87 (d, J =
1.9 Hz, 1H), 6.06 (d, J = 1.9 Hz, 1H), 6.22 (dd, J = 2.7, 2.7 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.25 (d, J =
8.7 Hz, 2H); 13C NMR (126 MHz, CDCl3, ) 29.8, 55.3, 70.6, 76.0, 83.0, 113.9, 113.9, 121.6, 121.7,
128.1, 128.8, 129.8, 129.8, 133.9, 159.6, 169.9; HRMS-ESI (m/z) [M+Na]+ Calcd for C16H1779BrO4Na:
375.0202, Found: 375.0205; HRMS-ESI (m/z) [M+Na]+ Calcd for C16H1781BrO4Na: 377.0184, Found:
377.0179.
Synthesis of (+)-11 from (+)-5. A mixture of (+)-5 (38.2 mg, 0.14 mmol) and DDQ (37.7 mg, 0.17
mmol) in CH2Cl2 (1.4 mL)  phosphate buffer (pH 6.86 ± 0.02, 0.35 mL) was stirred at 0 C for 15 min,
then at room temperature for 1.5 h. The reaction was quenched with a saturated aqueous NaHCO3
solution and the reaction mixture was extracted with EtOAc. The combined extracts were dried over
MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc = 1/1)
to afford (+)-11 (20.5 mg, 95%). Compound (+)-11: []D +38.5 (c 1.00, CHCl3); IR (neat) 3448, 1759

HETEROCYCLES, Vol. 86, No. 2, 2012
1373
cm-1; 1H NMR (500 MHz, CDCl3, δ) 1.80 (s, 3H), 2.09 (m, 1H), 2.21 (m, 1H), 2.502.65 (m, 2H), 2.75 (d,
J = 4.3 Hz, 1H), 4.07 (dd, J = 5.7, 4.3 Hz, 1H), 4.59 (ddd, J = 7.3, 7.3, 5.7 Hz, 1H), 5.01 (m, 1H), 5.06 (m,
13
1H); C NMR (126 MHz, CDCl3, ) 18.3, 24.0, 28.4, 77.6, 81.5, 114.3, 142.6, 177.1; HRMS-ESI (m/z)
[M+Na]+ Calcd for C8H12O3Na: 179.0679, Found: 179.0674.
Barton‒McCombie-type transformation via the thiocarbonate (+)-12. A mixture of (+)-11 (13.1 mg,
0.0839 mmol), DMAP (30.8 mg, 0.252 mmol), and o-phenylchlorothionoformate (17 µL, 0.126 mmol) in
MeCN (0.84 mL) was stirred at room temperature for 17 h. After the evaporation of the solvent, the
residue was purified by silica gel column chromatography (CHCl3/MeCN = 50/1) to afford (+)-12 (22.6
mg, 92%). Compound (+)-12: []D +91.5 (c 0.14, CHCl3); IR (neat) 2924, 1774, 1188, 1103, 748 cm-1;
1H NMR (500 MHz, CDCl3, δ) 1.87 (s, 3H), 2.12 (m, 1H), 2.33 (m, 1H), 2.532.67 (m, 2H), 4.83 (ddd, J
= 7.3, 7.3, 6.0 Hz, 1H), 5.20 (m, 1H), 5.22 (m, 1H), 5.72 (d, J = 6.0 Hz, 1H), 7.12 (d, J = 7.7 Hz, 2H),
7.30 (dd, J = 7.4, 7.4 Hz, 1H), 7.42 (dd, J = 7.7, 7.4 Hz, 2H); 13C NMR (126 MHz, CDCl3, ) 19.2, 24.0,
28.0, 79.0, 87.2, 117.6, 121.8, 121.8, 126.7, 129.6, 129.6, 137.8, 153.3, 176.1, 194.0; HRMS-ESI (m/z)
[M+Na]+ Calcd for C15H16O4SNa: 315.0662, Found: 315.0662.
A mixture of (+)-12 (22.6 mg, 0.0773 mmol), tributyltin hydride (13 µL, 0.101 mmol), and
azobisisobutyronitrile (1.3 mg, 0.00792 mmol) in toluene (0.77 mL) was stirred at 100 C for 5.5 h. After
the evaporation of the solvent, the residue was purified by column chromatography (10% w/w anhydrous
K2CO3-silica;17 hexane/EtOAc = 5/1) to afford a 1:1 mixture of 13 and 14 (8.0 mg, 68%). Compound
13: 1H NMR (300 MHz, CDCl3, δ) 1.74 (d, J = 1.1 Hz, 3H), 1.78 (d, J = 1.0 Hz, 3H), 1.93 (m, 1H), 2.36
(m, 1H), 2.55 (m, 2H), 5.22 (m, 1H), 5.22 (m, 1H); 13C NMR (126 MHz, CDCl3, ) 18.3, 25.7, 29.1, 29.3,
1
77.6, 122.8, 139.8, 177.2. Compound 14: H NMR (300 MHz, CDCl3, δ) 1.78 (s, 3H), 1.91 (m, 1H),
2.262.38 (m, 2H), 2.452.57 (m, 3H), 4.66 (dddd, J = 14.4, 13.4, 7.7, 6.7 Hz, 1H), 4.80 (m, 1H), 4.88
(m, 1H); 13C NMR (126 MHz, CDCl3, ) 22.8, 27.6, 28.6, 43.4, 79.1, 113.7, 140.4, 177.0.
Synthesis of ()-15. A mixture of (+)-11 (55.2 mg, 0.353 mmol), tetrabromomethane (211 mg, 0.636
mmol), and triphenylphosphine (166 mg, 0.634 mmol) in CH2Cl2 (3.5 mL) was stirred at room
temperature for 3.5 h. After the evaporation of the solvent, the residue was purified by silica gel column
chromatography (hexane/EtOAc = 3/1) to afford ()-15 (52.4 mg, 68%). Compound ()-15: []D 17.2
1
(c 1.00, CHCl3); IR (neat) 1782, 640 cm-1; H NMR (500 MHz, CDCl3, δ) 1.90 (s, 3H), 2.17 (m, 1H),
13
2.522.67 (m, 3H), 4.48 (d, J = 8.9 Hz, 1H), 4.73 (m, 1H), 5.06 (m, 1H), 5.18 (m, 1H); C NMR (126
MHz, CDCl3, ) 18.0, 27.0, 28.5, 59.3, 79.2, 117.5, 140.9, 176.1; HRMS-ESI (m/z) [M+Na]+ Calcd for
C8H1179BrO2Na: 240.9835, Found: 240.9840; HRMS-ESI (m/z) [M+Na]+ Calcd for C8H1181BrO2Na:

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HETEROCYCLES, Vol. 86, No. 2, 2012
242.9815, Found: 242.9816.
Palladium-catalyzed hydrogenolysis of ()-15. To a solution of ()-15 (31.9 mg, 0.146 mmol) and
Pd(PPh3)4 (8.6 mg, 0.0074 mmol) in toluene (1.5 mL) was added tributyltin hydride (50 µL, 0.186 mmol)
slowly at 100 C. After being stirred at the same temperature for 20 min, the solvent was removed under
reduced pressure, and the residue was purified by column chromatography (10% w/w anhydrous
K2CO3-silica;17 hexane/EtOAc = 4/12/1) to afford the mixture of 13 and 14 (14.7 mg, 13:14 = 11:1,
72%).
Synthesis of 16 and 17. To a solution of an 11:1 mixture of 13 and 14 (14.8 mg, 0.106 mmol) in THF
(1.1 mL) was added NaH (60% dispersion in mineral oil, 7.6 mg, 0.174 mmol) at 0 C. After being stirred
at 0 C for 10 min, ethyl formate (17.5 µL, 0.217 mmol) in EtOH (1 drop) was added and the system was
stirred at room temperature for 4 h. The browny crystals were collected by filtration with a suction filter
and dissolved in THF (1.1 mL). Paraformaldehyde (14.3 mg, 0.477 mmol) was added to the stirred
suspension and the system was stirred at 60 C for 1 h. The reaction was quenched with a saturated
aqueous K2CO3 solution and the reaction mixture was extracted with EtOAc. The combined extracts were
dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography
1
(hexane/EtOAc = 2/1) to afford an 11:1 mixture of 16 and 17 (5.0 mg, 31%). Compound 16: H NMR
(300 MHz, CDCl3, δ) 1.76 (s, 3H), 1.78 (s, 3H), 2.63 (dddd, J = 16.8, 6.0, 2.9, 2.6 Hz, 1H), 3.12 (dddd, J
= 16.8, 7.2, 2.9, 2.6 Hz, 1H), 5.22 (m, 1H), 5.22 (m, 1H), 5.62 (dd, J = 2.6, 2.6 Hz, 1H), 6.22 (dd, J = 2.9,
2.9 Hz, 1H).
Aldol reaction: synthesis of (+)-19. To a solution containing diisopropylamine (0.57 mL, 4.06 mmol) in
THF (8.0 mL) under argon at 78 C was added n-butyllithium (1.6 mL, 4.06 mmol, 2.54 M sol. of
hexane). Stirring at 78 C was continued for 10 min, followed by the addition of (+)-5 (668 mg, 2.42
mmol) in THF (8.0 mL) via a cannula. The mixture was stirred at 78 C for 45 min, followed by the
addition of aldehyde 18 (702 mg, 4.87 mmol) in THF (8.0 mL) via a cannula. Stirring was continued at
78 C for 1 h and then at 0 C for 15 min, followed by the addition of a saturated aqueous NH4Cl
solution. The mixture was extracted with EtOAc. The combined extracts were washed with brine, and
dried over MgSO4. The residue obtained after the evaporation of the solvent was dissolved in
1,2-dichloroethane (24 mL), then pyridine (0.77 mL, 9.54 mmol), DMAP (31.3 mg, 0.256 mmol), and
acetic anhydride (0.91 mL, 9.63 mmol) were added at 0 C, and solution was stirred at room temperature
for 14.5 h. DBU (1.8 mL, 11.9 mmol) was added, and the mixture was stirred at 70 C for 6 h. The

HETEROCYCLES, Vol. 86, No. 2, 2012
1375
reaction was quenched with a saturated aqueous NH4Cl solution at 0 C. The mixture was extracted with
EtOAc and the combined extracts were washed with brine, dried over MgSO4, concentrated in vacuo, and
purified by silica gel column chromatography (hexane/EtOAc = 3/21/1) to afford (+)-19 (837 mg, 86%
from (+)-5) as the sole product. Compound (+)-19: []D +54.4 (c 1.00, CHCl3); IR (neat) 2939, 2877,
1
1759, 1682, 1612, 1511 cm-1; H NMR (300 MHz, CDCl3, ) 1.32 (s, 3H), 1.77 (s, 3H), 1.80 (m, 2H),
2.24 (m, 2H), 2.53 (m, 1H), 2.76 (m, 1H), 3.72 (d, J = 6.2 Hz, 1H), 3.80 (s, 3H), 3.94 (m, 4H), 4.26 (d, J
= 11.7 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.60 (ddd, J = 8.4, 6.2, 5.8 Hz, 1H), 5.03 (brs, 1H), 5.14 (dd, J
= 1.5, 1.5 Hz, 1H), 6.69 (tdd, J = 7.5, 2.8, 2.8 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H);
13C NMR (126 MHz, CDCl3, ) 18.0, 23.8, 24.7, 27.6, 37.1, 55.2, 64.7, 64.7, 69.9, 77.8, 84.0, 109.2,
113.7, 113.7, 116.8, 125.9, 129.3, 129.3, 129.8, 139.6, 140.8, 159.1, 170.6; HRMS-ESI (m/z) [M+Na]+
Calcd for C23H30O6Na: 425.1935, Found: 425.1931.
Synthesis of (+)-20. A mixture of (+)-19 (449 mg, 1.11 mmol) and DDQ (320 mg, 1.41 mmol) in CH2Cl2
(8.0 mL)  H2O (2.0 mL) was stirred at room temperature for 6 h. To the reaction mixture were added
H2O (3.0 mL), acetone (5.0 mL), and PPTS (84.0 mg, 0.334 mmol) and the system was stirred at 50 C
for 4 h. After the evaporation of the solvent, the reaction was quenched with a saturated aqueous NaHCO3
solution and the reaction mixture was extracted with EtOAc. The combined extracts were dried over
MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc =
1/21/3) to afford (+)-20 (241 mg, 90%). Compound (+)-20: []D +32.2 (c 1.00, CHCl3); IR (neat) 3455,
3078, 1751, 1712, 1681 cm-1; 1H NMR (300 MHz, CDCl3, ) 1.82 (brs, 3H), 2.16 (s, 3H), 2.33 (brm, 1H),
2.42 (dt, J = 7.1, 7.1 Hz, 2H), 2.65 (t, J = 7.1 Hz, 2H), 2.73 (m, 1H), 2.92 (m, 1H), 4.04 (dd, J = 6.0, 6.0
Hz, 1H), 4.61 (ddd, J = 8.3, 6.0, 6.0 Hz, 1H), 5.05 (brm, 1H), 5.08 (brs, 1H), 6.60 (tdd, J = 7.1, 2.9, 2.9
13
Hz, 1H); C NMR (126 MHz, CDCl3, ) 18.3, 24.0, 27.7, 29.9, 41.3, 78.0, 78.4, 114.9, 127.0, 138.8,
142.3, 170.2, 206.7; HRMS-ESI (m/z) [M+Na]+ Calcd for C13H18O4Na: 261.1097, Found: 261.1097.
Synthesis of a mixture of (+)-1 and (+)-22 utilizing bromination and sequential hydrogenolysis. A
mixture of (+)-20 (10.3 mg, 0.0429 mmol), tetrabromomethane (29.1 mg, 0.0877 mmol), and
triphenylphosphine (23.0 mg, 0.0877 mmol) in CH2Cl2 (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 (+)-21 and the isomeric product 21'. Compound (+)-21: []D +10.4 (c 0.62,
CHCl3); IR (neat) 2924, 1759, 1712, 1682, 640 cm-1; 1H NMR (300 MHz, CDCl3, ) 1.91 (brs, 3H), 2.17
(s, 3H), 2.45 (m, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.87 (m, 1H), 3.19 (m, 1H), 4.46 (d, J = 8.8 Hz, 1H), 4.76
(ddd, J = 8.8, 5.5, 5.5 Hz, 1H), 5.07 (m, 1H), 5.17 (s, 1H), 6.64 (tdd, J = 7.0, 2.9, 2.9 Hz, 1H); 13C NMR

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HETEROCYCLES, Vol. 86, No. 2, 2012
(126 MHz, CDCl3, ) 18.1, 24.1, 30.0, 30.8, 41.3, 60.1, 76.3, 117.7, 126.6, 139.6, 140.9, 169.9, 206.4;
HRMS-ESI (m/z) [M+Na]+ Calcd for C13H1779BrO3Na: 323.0253, Found: 323.0256; HRMS-ESI (m/z)
[M+Na]+ Calcd for C13H1781BrO3Na: 325.0234, Found: 325.0239.
To the mixture in toluene (0.43 mL) was added Pd(PPh3)4 (2.5 mg, 0.00216 mmol) and then heated to 100
C. Tributyltin hydride (13 µL, 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;17 hexane/EtOAc = 2/11/1) to
afford the mixture of (+)-1 and (+)-22 (9.3 mg, (+)-1:(+)-22 = 8:1, 98% in two steps). Heteroplexisolide
1
E (1): []D +74.0 (c 0.38, MeOH); IR (neat) 2978, 2922, 1755, 1720, 1684 cm-1; H NMR (600 MHz,
acetone-d6, ) 1.75 (s, 3H), 1.75 (s, 3H), 2.10 (s, 3H), 2.37 (dt, J = 7.5, 7.1 Hz, 2H), 2.55 (m, 1H), 2.70 (t,
J = 7.1 Hz, 2H), 3.17 (m, 1H), 5.25 (m, 1H), 5.25 (m, 1H), 6.49 (tdd, J = 7.5, 2.9, 2.9 Hz, 1H); 1H NMR
(500 MHz, CDCl3, ) 1.73 (s, 3H), 1.76 (s, 3H), 2.15 (s, 3H), 2.40 (dt, J = 7.5, 7.2 Hz, 2H), 2.54 (m, 1H),
2.62 (t, J = 7.2 Hz, 2H), 3.10 (m, 1H), 5.21 (m, 1H), 5.21 (m, 1H), 6.56 (tdd, J = 7.5, 2.9, 2.9 Hz, 1H); 13C
NMR (150 MHz, acetone-d6, ) 18.2, 24.6, 25.7, 30.2, 32.8, 41.6, 74.7, 125.2, 128.8, 138.5, 139.2, 170.8,
206.8; 13C NMR (126 MHz, CDCl3, ) 18.4, 24.1, 25.7, 30.0, 32.5, 41.5, 74.4, 123.7, 127.9, 137.9, 139.6,
170.8, 206.6; HRMS-ESI (m/z) [M+Na]+ Calcd for C13H18O3Na: 245.1148, Found: 245.1152.
1
Compound (+)-22: []D +31.4 (c 0.26, CHCl3); IR (neat) 1751, 1712 cm-1; H NMR (300 MHz, CDCl3,
) 1.78 (s, 3H), 2.16 (s, 3H), 2.28 (dd, J = 14.4, 7.1 Hz, 1H), 2.42 (m, 2H), 2.52 (dd, J = 14.4, 6.6 Hz, 1H),
2.57 (m, 1H), 2.64 (t, J = 7.1 Hz, 2H), 3.02 (m, 1H), 4.70 (m, 1H), 4.80 (brs, 1H), 4.89 (brs, 1H), 6.60
13
(tdd, J = 7.1, 2.9, 2.9 Hz, 1H); C NMR (126 MHz, CDCl3, ) 22.8, 24.0, 30.0, 30.9, 41.4, 44.3, 75.9,
113.9, 127.5, 138.5, 140.3, 170.6, 206.6; HRMS-ESI (m/z) [M+Na]+ Calcd for C13H18O3Na: 245.1148,
Found: 245.1146.
Palladium-catalyzed conversion into (+)-1. To a solution of a 8:1 mixture of (+)-1 and (+)-22 (3.5 mg,
0.0157 mmol) in toluene (0.16 mL) was added Pd(OCOCF3)2 (0.5 mg, 0.00150 mmol) at room
temperature. After being stirred at 100 C for 10 h, the solvent was removed under reduced pressure, and
the residue was purified by column chromatography (hexane/EtOAc = 3/2) to afford (+)-1 (3.3 mg, 94%)
as a single product.
ACKNOWLEDGEMENTS
This work was partly supported by the Sasakawa Scientific Research Grant from The Japan Science
Society and by MEXT-Supported Program for the Strategic Research Foundation at Private Universities,
2012-2016.

HETEROCYCLES, Vol. 86, No. 2, 2012
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8
O
O
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O
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(+)-6
+
(+)-6 (recovered, 91%)
+
CH2Cl2, 40 ºC, 19 h
Br
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PMBO
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