Total synthesis of eupomatilones 1, 2, and 5 by enantioselective [2,3]-wittig rearrangement

Article abstract of DOI:10.1002/ejoc.201201247

In this study, the asymmetric total synthesis of eupomatilones 1, 2, and 5 has been accomplished. These compounds are lignan congeners containing a biaryl system bearing an α-methylene γ-lactone. They were isolated from the Australian shrub Eupomatia benn

Full text of DOI:10.1002/ejoc.201201247

FULL PAPER
DOI: 10.1002/ejoc.201201247
Total Synthesis of Eupomatilones 1, 2, and 5 by Enantioselective [2,3]-Wittig
Rearrangement
Yoshimi Hirokawa,[a] Maria Kitamura,[a] Makoto Mizubayashi,[a] Rie Nakatsuka,[a]
Yuya Kobori,[a] Chiharu Kato,[a] Yuki Kurata,[a] and Naoyoshi Maezaki*[a]
Keywords: Asymmetric synthesis / Total synthesis / Enantioselectivity / Rearrangement / Natural products / Lignans
In this study, the asymmetric total synthesis of eupomatilones
1, 2, and 5 has been accomplished. These compounds are
lignan congeners containing a biaryl system bearing an α-
methylene γ-lactone. They were isolated from the Australian
shrub Eupomatia bennettii. Two chiral centers were con-
structed enantioselectively by the asymmetric [2,3]-Wittig
rearrangement of highly oxygenated biaryl compounds,
using a bis(oxazoline) chiral ligand. Optimization of the key
reaction using nBuLi as the base and ether as the co-solvent
increased the enantioselectivity to 88–91% ee.
biaryl structure causes hindered rotation around the biaryl
linkage, and eupomatilones 5–7 exist as a mixtures of in-
separable atropisomers.
Introduction
In 1991, Carroll and Taylor isolated structurally new lig-
nans from the Australian shrub Eupomatia bennettii, which
is found in the tropical and subtropical forests of New
South Wales and Queensland, and elucidated their stereo-
structures.[1] The stereochemistry of eupomatilone 6 was re-
vised later by Coleman et al.[2] The eupomatilone 1–7 fam-
ily of lignans (Figure 1) possess an unusual biaryl skeleton
with a γ-lactone ring, and the compounds are presumably
formed by phenolic oxidative coupling and cleavage of a
propyl chain from the aromatic ring. The highly oxygenated
Eupomatilones 1, 2, and 5 are members of the eupomati-
lone family that contain an α-methylene γ-lactone, and they
are expected to form covalent bonds with biomolecules by
Michael addition, and thus, to exhibit biological activity.[3]
Although syntheses of eupomatilones containing a satu-
rated C-3 substituent have been reported,[4] there have been
few studies on the total syntheses of these natural products.
One paper describes the synthesis of racemic eupomatilones
2 and 5 using an allylindium reagent,[5] and another reports
the asymmetric synthesis of eupomatilones using a chiral
methoxycarbonylcrotyl boronate reagent.[2] In the latter
work, the enantioselectivity was still moderate (76–88% ee),
Figure 1. Structures of eupomatilones 1–7.
[a] Faculty of Pharmacy, Osaka Ohtani University,
3-11-1 Nishikiori-Kita, Tondabayashi, Osaka 584-8540, Japan
Fax: +81-721-24-9541
E-mail: maezan@osaka-ohtani.ac.jp
Homepage: http://www3.osaka-ohtani.ac.jp/ph/9/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201247.
Scheme 1. Synthetic plan for the synthesis of eupomatilones 1, 2,
and 5.
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N. Maezaki et al.
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and the formation of an inseparable diastereoisomer of eu-
pomatilone 1 remained as a problem to be solved.
We have investigated the highly enantioselective asym-
metric [2,3]-Wittig rearrangement of allyl benzyl ether de-
rivatives, using an external chiral ligand.[6] The application
of this methodology with highly oxygenated biarylmethyl
ethers as substrates was considered for the synthesis of eu-
pomatilone 2 (1), eupomatilone 5 (2), and eupomatilone 1
(3).[7] The synthetic plan is shown in Scheme 1. The two
stereogenic centers would be constructed stereoselectively
by the asymmetric [2,3]-Wittig rearrangement, and the re-
sulting homoallylic alcohol would be used for the construc-
tion of the α-methylene γ-lactone moiety.
Previously,[7] we reported the asymmetric total synthesis
of eupomatilone 2. In this paper, we report full details of
our research into the synthesis of eupomatilones 1, 2, and 5.
Scheme 3. Synthesis of biarylmethyl alcohols 8, 10, and 13.
Results and Discussion
bromide 11 was treated with boronic acid 7 under the same
conditions.[12] Ester 14 was then reduced with DIBAL in
Synthesis of Substrates for [2,3]-Wittig Rearrangement
In preliminary research, we found that simple biaryl- toluene to give alcohol 13 in 88% yield.
methyl ether 4 underwent the [2,3]-Wittig rearrangement to
The substrates for the [2,3]-Wittig rearrangement were
give 5 in 95% yield with high enantioselectivity and dia- synthesized by Williamson ether synthesis from biarylmeth-
stereoselectivity (92% ee, syn only), as shown in yl alcohols 8, 10, and 13 with allylic bromide 15[6] in the
Scheme 2.[6,8] The promising results encouraged us to apply presence of tBuOK, resulting in the formation of the biaryl-
this strategy to highly oxygenated biaryl-type substrates.
methyl ethers 16, 17, and 18 in 71, 84, and 66% yields,
respectively (Scheme 4).
Scheme 2. Model study of the key step.
The synthesis of congested biarylmethyl ethers, which are
key intermediates in the synthesis of the eupomatilones, is
shown in Scheme 3. Buchwald’s modified Suzuki coupling[9]
was used for the construction of the highly congested biaryl
moiety of eupomatilones 1, 2, and 5.
The Suzuki coupling of 2-bromo-3,4,5-trimethoxybenzyl
alcohol (6)[10] and 3,4,5-trimethoxyphenylboronic acid (7)
in the presence of Pd(OAc)2 (2 mol-%), (tBu)2(Biphenyl)P
(2 mol-%), and KF in THF at 50 °C for 7 h gave the cou-
pling product in 6% yield. However, the use of Pd(OAc)2,
(cHex)2(Biphenyl)P, and K3PO4 in toluene at 80 °C for 7 h,
gave biarylmethyl alcohol 8 in an increase in the yield to
76%. Suzuki coupling of bromide 6 and 3,4-(methylene-
dioxy)phenylboronic acid (9) furnished coupling product
Scheme 4. Synthesis of biarylmethyl ethers 16–18.
Synthesis of Racemic Eupomatilone 2
To establish the synthetic route to the eupomatilones be-
10 in 62% yield under the optimized conditions. The biaryl- fore the asymmetric synthesis was investigated, efforts were
methyl alcohol (i.e., 13) required for the synthesis of eupo- directed towards the conversion of biarylmethyl ether 16
matilone 1 was prepared from bromo ester 11[11] by DIBAL into racemic eupomatilone 2. On treatment of 16 with
(diisobutylaluminium hydride) reduction in toluene (99%) tBuLi (5 equiv.) in THF at –78 °C, the [2,3]-Wittig re-
and subsequent Suzuki coupling of the resulting bromo arrangement proceeded smoothly to give rac-19 in 85%
alcohol (i.e., 12) with boronic acid 7 (63%). We found that yield. Formation of the [1,2]-Wittig rearranged product was
the yield of the Suzuki coupling was improved to 94% when not observed.
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Total Synthesis of Eupomatilones
The relative stereochemistry of the resulting alcohol (i.e., potentially suitable chiral bis(oxazoline) ligands revealed
rac-19) was assumed to be syn based on the coupling con- that the enantiomeric excess was significantly dependent on
stant between the two methine protons at the C-1 and C-2 the structure of the ligand. Bulkiness at the C-4 position
positions (J1,2 = 3.2 Hz).[13] After deprotection of the TIPS was important for a high ee (entries 1 and 2), while bulk-
(triisopropylsilyl) group with TBAF (tetrabutylammonium iness at the C-5 position and on the methylene bridge re-
fluoride), the resulting diol (i.e., rac-20) was converted to duced both the yield and the enantioselectivity (entries 3–
rac-eupomatilone 2 (rac-1) by TEMPO (2,2,6,6-tetramethyl- 5). The best ligand of those examined was bis(oxazoline)
1-piperidinyloxy) oxidation in the presence of PhI(OAc)2 as L1 [(S,S)-Box-tBu]. However, the ee was moderate (68%
a co-oxidant[14] in 85% yield over two steps (Scheme 5). The ee), despite the high yield (92%). In contrast, the simple
1
spectroscopic data (IR, H and 13C NMR) were consistent biphenylmethyl ether with no methoxy substituents (i.e., 4)
with those reported for the natural product.[1,2]
had reacted under these conditions with excellent enantio-
selectivity (92% ee, see Scheme 2).
During attempts to improve the enantioselectivity, it was
found that highly oxygenated substrate 16 underwent slow
[2,3]-Wittig rearrangement, even with bases weaker than
tBuLi. Importantly, sBuLi and nBuLi showed better
enantioselectivity than tBuLi, but gave reduced yields of the
product (Table 2, entries 1–3). The yield was improved to
77% when the reaction ran for 4 h (entry 4). The co-solvent
also plays an important role in accelerating the reaction
rate. When toluene was used as the co-solvent, the reaction
was complete within 2 h, and the rearranged product (i.e.,
19) was obtained in 92% yield and with 80% ee (entry 5).
Finally, optimal selectivity was obtained when ether was
added as the co-solvent, and both the yield and the enantio-
selectivity were optimized to 98 and 89%, respectively (en-
try 6). The selectivity did not improve further, even when
the proportion of ether in the solvent mixture was in-
creased, but this resulted in a decrease in the yields (entries
8 and 9). Addition of the more polar THF suppressed the
reaction significantly, and resulted in a lower yield and
selectivity (entry 7). The addition of THF presumably inter-
fered with the coordination of the chiral ligand to nBuLi,
thus preventing the formation of a reactive chiral base.
Scheme 5. Synthesis of racemic eupomatilone 2.
Asymmetric [2,3]-Wittig Rearrangement
Next, we examined the asymmetric [2,3]-Wittig re-
arrangement, using 16 as substrate and a bis(oxazoline) as
the external chiral ligand.[6,15] The results are summarized
in Table 1.
Table 1. Effect of the chiral ligand on the asymmetric [2,3]-Wittig
rearrangement.[a]
Table 2. Effect of base and solvent on the asymmetric [2,3]-Wittig
rearrangement.[a]
Entry Conditions
Yield [%][b] ee [%][c]
Entry Ligand
R1
R2
R3
Yield [%][b] ee [%][c]
1
2
tBuLi, hexane
sBuLi, hexane
92
50
46
77
92
98
7
68
71
77
77
80
89
5
1
2
3
4
5
L1
L2
L3
L4
L5
tBu
iPr
tBu
iPr
H
H
Me
Me
H
Me
Me
Me
Me
Et
92
72
0
68
38
–
22
12
3
nBuLi, hexane
nBuLi, hexane
4[d]
5
38
43
nBuLi, hexane/toluene (4:1)[e]
nBuLi, hexane/ether (4:1)[e]
nBuLi, hexane/THF (4:1)[e]
nBuLi, hexane/ether (1:1)[e]
nBuLi, ether
tBu
6
7
8
9
[a] The reactions were performed in the presence of chiral ligand
(1 equiv.) and tBuLi (5 equiv.) in dry hexane at –78 °C for 2 h under
Ar atmosphere unless otherwise stated. [b] Isolated yields. [c] De-
termined by chiral HPLC.
83
26
89
87
[a] Reactions were carried out in the presence of chiral ligand L1
(1 equiv.) and base (5 equiv.) in dry solvent at –78 °C for 2 h under
Ar atmosphere, unless otherwise stated. [b] Isolated yields. [c] De-
termined by chiral HPLC. [d] The reaction was run for 4 h. [e] The
Arylmethyl ether 16 was subjected to the asymmetric
[2,3]-Wittig rearrangement, using 1 equiv. of the chiral li-
gand and 5 equiv. of base at –78 °C for 2 h. Investigation of solvent ratio before the addition of nBuLi solution is indicated.
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Confirmation of the absolute configuration at the chiral Total Synthesis of Eupomatilones 1, 2, and 5
center of the secondary alcohol was then attempted using
The construction of the α-methylene γ-lactone moiety of
the eupomatilones (Scheme 7) was the final task. For the
completion of the total synthesis, alcohol 19 was subjected
to deprotection with TBAF in THF, followed by selective
oxidation in the presence of a primary alcohol using a cata-
lytic amount of TEMPO and PhI(OAc)2 as the co-oxi-
dant.[14] This process provided eupomatilone 2 (1) in 95%
yield over two steps. Similarly, alcohol 21 was converted
into eupomatilone 5 (2) in 68% yield over two steps. Eupo-
matilone 1 (3) was also synthesized in 78% yield over two
steps.
the modified Mosher method,[16] but owing to the arbitrary
distribution of the ΔδSR sign, an assignment was difficult.[17]
Thus, the modified Mosher method was not suitable for this
compound. However, we assumed the absolute configura-
tion to be (1R,2S) by analogy to our previous results for
the asymmetric [2,3]-Wittig rearrangement.[18] This as-
sumed assignment was later confirmed by transformation
of 16 to the natural product.
Next, the optimum reaction conditions described above
were applied to the rearrangement of synthetic intermedi-
ates 17 and 18 (Scheme 6). The intermediate (i.e., 17) for
eupomatilone 5 gave rearranged product 21 in 74% yield
and with 91% ee. The signals due to the protons around
the biaryl moiety in the 1H and 13C NMR spectra were
doubled, indicating the existence of atropisomers.
Scheme 7. Asymmetric total synthesis of eupomatilones 1, 2, and
5.
1
The H and 13C NMR spectroscopic data for these syn-
Scheme 6. Asymmetric [2,3]-Wittig rearrangement.
thetic eupomatilones were identical to the reported data.[1,2]
Eupomatilone 5 was found to exist as a 1:1 mixture of
However, the reaction of intermediate 18 was sluggish, atropisomers, as reported. The optical purity of the syn-
and a considerable amount of starting material was reco- thetic eupomatilones was determined by chiral HPLC
vered, despite the use of 10 equiv. of nBuLi. When the (Daicel CHIRALPAK® AD-H), and was in agreement with
stronger bases sBuLi and tBuLi were used, a decrease in that of the corresponding [2,3]-Wittig products.[19] The
the ee and yield was observed, due to decomposition. This signs of the specific rotations of all of the [2,3]-Wittig prod-
problem was solved to some extent by using 10 equiv. of ucts and diols were negative, and the signs were reversed to
nBuLi and a longer reaction time (8 h); also, the quantity positive after formation of the γ-lactone moiety in eupoma-
of hexane was reduced to maintain the final solvent ratio tilones 2 and 5. The signs of the specific rotations of syn-
and concentration of substrate 18 after addition of the thetic eupomatilones 2 and 5 matched those of the natural
nBuLi hexane solution. Under these conditions, product 22 products, and the values were greater than those reported
was obtained in 54% yield (77% based on consumed 18) in previous studies [eupomatilone 2: [α]2D5 = +12.0 (c = 0.60,
and with 88% ee. All of the rearranged products were CHCl3), ref.[1] [α]D = +3.3 (c = 0.5, CHCl3); eupomatilone
formed as single diastereomers with coupling constants of 5: [α]2D4 = +26.4 (c = 1.04, CHCl3), ref.[1] [α]D = +6.5 (c =
approximately 3 Hz between the two methine protons at the 1.50, CHCl3)]. On the other hand, the specific rotation of
C-1 and C-2 positions.[13] This indicates a syn relationship our synthetic eupomatilone 1 was very small, despite its
between the hydroxy and methyl substituents at the C-1 and high optical purity [eupomatilone 1: [α]2D5 = –0.77 (c = 0.80,
C-2 positions, respectively.
CHCl3), ref.[1] [α]D = –10.0 (c = 0.50, CHCl3)].
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Total Synthesis of Eupomatilones
2.67 mmol) was added to a solution of biarylmethyl alcohol 8
(720 mg, 1.98 mmol) and bromide 15 (640 mg, 1.98 mmol) in dry
Conclusions
We have accomplished the total synthesis of eupomati- THF (10 mL) with stirring at room temp. under Ar. After stirring
for 1 d, the reaction was quenched with saturated NH4Cl. The mix-
ture was partitioned between EtOAc and water. The organic phase
was separated, and the aqueous phase was extracted with EtOAc.
The combined organic extracts were washed with water and brine
prior to drying and solvent evaporation. The residue was purified
by chromatography on silica gel with hexane/EtOAc (4:1) to give
ether 16 (860 mg, 71%) as a colorless powder. M.p. 51–52 °C (hex-
ane). 1H NMR: δ = 1.00–1.10 (m, 21 H), 1.64 (d, J = 7.1 Hz, 3 H),
3.67 (s, 3 H), 3.84 (s, 6 H), 3.899 (s, 3 H), 3.903 (s, 3 H), 3.91 (s, 3
H), 4.00 (s, 2 H), 4.18 (s, 2 H), 4.23 (m, 2 H), 5.76 (q, J = 7.1 Hz,
1 H), 6.47 (s, 2 H), 6.87 (s, 1 H) ppm. 13C NMR: δ = 11.98 (3 C),
13.01, 17.97 (6 C), 55.88, 56.02 (2 C), 60.86 (2 C), 61.19, 65.38,
65.41, 69.63, 107.13, 107.20 (2 C), 123.57, 128.31, 131.53, 132.32,
135.67, 136.89, 141.39, 151.10, 152.68 (2 C), 152.77 ppm. IR (KBr):
lones 1, 2, and 5 using the asymmetric [2,3]-Wittig re-
arrangement of highly oxygenated biaryl compounds as the
key reaction. The [2,3]-Wittig rearrangement proceeded,
even though the substrates were highly oxygenated, to give
the rearranged products with high diastereo- and enantio-
selectivities. This concise synthetic route should be appli-
cable to the synthesis of other congeners and unnatural de-
rivatives.
Experimental Section
General Remarks: Optical rotations were measured with a JASCO
P-1020 digital polarimeter. 1H and 13C NMR spectra were recorded
in CDCl3 solution at 400 and 100 MHz, respectively, with a JEOL
JNM-AL-400 spectrometer. Chemical shifts in 1H NMR spectra
are expressed in ppm downfield from tetramethylsilane as an in-
ternal standard (δ = 0 ppm). Chemical shifts in 13C NMR spectra
are expressed as ppm using CDCl3 as an internal standard (δ =
77 ppm). IR absorption spectra (FT: diffuse reflectance spec-
troscopy) were recorded with KBr powder with a JASCO FT-6300
IR spectrophotometer, and only noteworthy absorptions (cm–1) are
listed. Mass spectra were obtained with a JEOL GC-Mate II mass
spectrometer. Purification of the crude products was carried out by
flash column chromatography. Fuji Silysia Silica Gel BW-300 was
used as the adsorbent for column chromatography. For preparative
TLC (PTLC), silica gel 60F254 (Merck) was used. All air- or moist-
ure-sensitive reactions were carried out in flame-dried glassware
under an atmosphere of Ar or N2. All organic extracts were dried
with anhydrous MgSO4, filtered, and concentrated under reduced
pressure with a rotary evaporator, unless otherwise stated.
ν = 1583 cm– 1. MS (FAB): m/z = 605 [M + H]+. HRMS (FAB):
˜
calcd. for C33H53O8Si [M + H]+ 605.3510; found 605.3500.
C33H52O8Si: calcd. C 65.53, H 8.67; found C 65.30, H 8.52.
General Procedure for the [2,3]-Wittig Rearrangement Without a
Chiral Ligand
(1RS,2SR)-1-(3Ј,4,4Ј,5,5Ј,6-Hexamethoxybiphenyl-2-yl)-2-methyl-3-
[(triisopropylsilyloxy)methyl]but-3-en-1-ol (rac-19): tBuLi (1.59 m in
pentane; 2.10 mL, 3.30 mmol) was added dropwise to a suspension
of ether 16 (400 mg, 0.66 mmol) in THF (3.3 mL) with stirring at
–78 °C under Ar. Stirring was continued at this temperature for
2 h. Then the reaction was quenched with saturated NH4Cl, and
the mixture was partitioned between EtOAc and water. The organic
phase was separated, and the aqueous phase was extracted with
EtOAc. The combined organic extracts were washed with water
and brine prior to drying and solvent evaporation. The residue was
purified by chromatography on silica gel with hexane/EtOAc (2:1)
to give alcohol rac-19 (340 mg, 85%) as a colorless powder. M.p.
1
94–95 °C (hexane). H NMR: δ = 0.96 (d, J = 7.1 Hz, 3 H), 1.00–
General Procedure for Suzuki Coupling
1.10 (m, 21 H), 2.35 (qd, J = 7.1, 3.2 Hz, 1 H), 3.50 (br., 1 H), 3.67
(s, 3 H), 3.80 (s, 3 H), 3.85 (s, 3 H), 3.82 (d, J = 12.7 Hz, 1 H),
3.89 (s, 6 H), 3.93 (s, 3 H), 4.03 (d, J = 12.7 Hz, 1 H), 4.52 (s, 1
H), 4.77 (d, J = 3.2 Hz, 1 H), 4.97 (d, J = 1.2 Hz, 1 H), 6.42 (d, J
= 1.7 Hz, 1 H), 6.47 (d, J = 1.7 Hz, 1 H), 7.04 (s, 1 H) ppm. 13C
NMR: δ = 11.16, 11.86 (3 C), 17.85 (6 C), 43.80, 55.93, 55.97,
56.16, 60.77, 60.84, 61.25, 65.09, 72.61, 105.74, 106.59, 108.01,
113.05, 127.31, 131.92, 136.39, 136.94, 140.86, 150.51, 150.96,
(3Ј,4,4Ј,5,5Ј,6-Hexamethoxybiphenyl-2-yl)methanol (8): Pd(OAc)2
(20 mg, 0.093 mmol, 1.0 mol-%), 2-(dicyclohexylphosphanyl)bi-
phenyl (65 mg, 0.186 mmol, 2.0 mol-%), 2-bromo-3,4,5-trimeth-
oxybenzyl alcohol (6; 2.57 g, 9.30 mmol), (3,4,5-trimethoxyphenyl)-
boronic acid (7; 2.97 g, 14.0 mmol), and K3PO4 (3.95 g, 18.6 mmol)
were placed in an oven-dried three-necked flask. After the flask
was evacuated and backfilled with Ar, dry toluene (26 mL) was
added to the mixture. The suspension was then sonicated, evacu-
ated, and backfilled with Ar, and this cycle was repeated three
times. The flask was then heated at 80–90 °C with stirring for 10 h.
After cooling, the reaction mixture was diluted with diethyl ether
and washed with NaOH (1 n). The aqueous phase was extracted
twice with ether, and the combined organic extracts were washed
with brine prior to drying and solvent evaporation. The residue
was purified by chromatography on silica gel with hexane/EtOAc
152.39, 152.79, 153.00 ppm. IR (KBr): ν = 3477, 3097, 1586 cm–1.
˜
MS (FAB): m/z = 605 [M + H]+. HRMS (FAB): calcd. for
C
33H53O8Si [M + H]+ 605.3510; found 605.3528. C33H52O8Si:
calcd. C 65.53, H 8.67; found C 65.58, H 8.62.
General Procedure for the [2,3]-Wittig rearrangement with a Chiral
Ligand
(1R,2S)-1-(3Ј,4,4Ј,5,5Ј,6-Hexamethoxybiphenyl-2-yl)-2-methyl-3-
[(triisopropylsilyloxy)methyl]but-3-en-1-ol (19): nBuLi (1.6 m in hex-
ane; 1.25 mL, 2.00 mmol) was added dropwise to a suspension of
ether 16 (240 mg, 0.40 mmol) and bis(oxazoline) ligand L1
(118 mg, 0.40 mmol) in a mixture of dry hexane (1.6 mL) and dry
ether (0.4 mL) with stirring at –78 °C under Ar. Stirring was con-
tinued at this temperature for 2 h. The reaction was then quenched
with saturated NH4Cl, and the mixture was partitioned between
EtOAc and water. The organic phase was separated, and the aque-
ous phase was extracted with EtOAc. The combined organic ex-
tracts were washed with water and brine prior to drying and solvent
evaporation. The residue was purified by chromatography on silica
1
(1:2) to give 8 (2.57 g, 76%) as a colorless oil. H NMR: δ = 1.63
(t, J = 5.6 Hz, 1 H), 3.69 (s, 3 H), 3.84 (s, 6 H), 3.90 (s, 3 H), 3.91
(s, 3 H), 3.93 (s, 3 H), 4.44 (d, J = 5.6 Hz, 2 H), 6.48 (s, 2 H), 6.90
(s, 1 H) ppm. 13C NMR: δ = 56.00, 56.04 (2 C), 60.83, 60.85, 61.22,
63.00, 106.95, 107.05 (2 C), 127.86, 131.41, 134.48, 136.93, 141.43,
151.23, 152.83 (2 C), 152.87 ppm. IR (KBr): ν = 3496, 3066,
˜
1584 cm–1. MS (FAB): m/z = 365 [M + H]+. HRMS (FAB): calcd.
for C19H25O7 [M + H]+ 365.1600; found 365.1583.
General Procedure for Williamson Ether Synthesis
(E)-1-[(3Ј,4,4Ј,5,5Ј,6-Hexamethoxybiphenyl-2-yl)methoxy]-2-(tri-
isopropylsilyloxymethyl)but-2-ene (16): tBuOK (300 mg, gel with hexane/EtOAc (1:1) to give alcohol 19 (235 mg, 98%) as
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N. Maezaki et al.
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a colorless oil. ee 89% (column: Daicel CHIRALPAK® AD-H, 3.88 (s, 3 H), 3.91 (s, 3 H), 5.44 (d, J = 7.3 Hz, 0.5 H), 5.53 (d, J
iPrOH/hexane = 98:2, flow rate: 1 mL/min, λ = 254 nm). [α]2D5
–21.2 (c = 0.72, CHCl3).
=
= 7.1 Hz, 0.5 H), 5.54 (d, J = 2.2 Hz, 1 H), 6.017 (br. s, 0.5 H),
6.024 (br. s, 0.5 H), 6.028 (br. s, 0.5 H), 6.043 (br. s, 0.5 H), 6.24
(d, J = 2.2 Hz, 1 H), 6.59 (dd, J = 7.8, 1.5 Hz, 0.5 H), 6.64 (d, J =
1.2 Hz, 0.5 H), 6.69 (s, 1 H), 6.70 (dd, J = 7.8, 1.2 Hz, 0.5 H), 6.73
(d, J = 1.5 Hz, 0.5 H), 6.87 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR:
δ = 17.03 (0.5 C), 17.21 (0.5 C), 38.14 (0.5 C), 38.32 (0.5 C), 56.11,
60.85, 61.10 (0.5 C), 61.16 (0.5 C), 79.29 (0.5 C), 79.35 (0.5 C),
101.16 (0.5 C), 101.20 (0.5 C), 104.78 (0.5 C), 104.83 (0.5 C), 108.18
(0.5 C), 108.51 (0.5 C), 109.91 (0.5 C), 110.54 (0.5 C), 121.94,
122.72 (0.5 C), 123.31 (0.5 C), 127.12, 128.97, 130.03 (0.5 C),
130.06 (0.5 C), 141.06 (0.5 C), 141.14 (0.5 C), 141.83 (0.5 C), 146.94
(0.5 C), 147.04, 147.64 (0.5 C), 147.72 (0.5 C), 151.47, 152.90,
General Procedure for TIPS Deprotection
(1R,2S)-1-(3Ј,4,4Ј,5,5Ј,6-Hexamethoxybiphenyl-2-yl)-2-methyl-3-
methylenebutane-1,4-diol (20): Tetrabutylammonium fluoride (1 m
in THF, 1.54 mL, 1.54 mmol) was added to a solution of 19
(310 mg, 0.51 mmol) in THF (5 mL) at room temp. under Ar, and
the mixture was stirred for 2 h. The reaction was then quenched
with saturated aqueous NH4Cl, and the mixture was partitioned
between EtOAc and water. The organic phase was separated, and
the aqueous phase was extracted with EtOAc. The combined ex-
tracts were washed with saturated aqueous NH4Cl, water, and brine
prior to drying and solvent evaporation. The crude residue was
purified by chromatography on silica gel with hexane/EtOAc (1:2)
to give diol 20 (228 mg, quant.) as a colorless oil. [α]2D6 = –30.5 (c
= 0.54, CHCl3). 1H NMR: δ = 0.95 (d, J = 7.0 Hz, 3 H), 2.41 (qd,
J = 7.0, 2.6 Hz, 1 H), 3.69 (s, 3 H), 3.70 (d, J = 12.7 Hz, 1 H), 3.82
(d, J = 12.7 Hz, 1 H), 3.82 (s, 3 H), 3.86 (s, 3 H), 3.89 (s, 3 H),
3.90 (s, 3 H), 3.93 (s, 3 H), 4.60 (s, 1 H), 4.77 (d, J = 2.6 Hz, 1 H),
4.97 (s, 1 H), 6.44 (d, J = 1.7 Hz, 1 H), 6.47 (d, J = 1.7 Hz, 1 H),
7.02 (s, 1 H) ppm. 13C NMR: δ = 10.53, 43.21, 55.91, 56.02, 56.14,
60.71, 60.80, 61.18, 64.12, 72.32, 105.63, 106.65, 108.12, 113.12,
127.05, 131.85, 136.26, 136.85, 140.77, 150.77, 150.81, 152.30,
170.11 (0.5 C), 170.15 (0.5 C) ppm. IR (KBr): ν = 1767 cm–1. MS
˜
(FAB): m/z = 399 [M + H]+. HRMS (FAB): calcd. for C22H23O7
[M + H]+ 399.1444; found 399.1422.
(–)-Eupomatilone 1 (3): (–)-Eupomatilone 1 (3) was prepared in a
manner similar to that described for the preparation of (+)-eupom-
atilone 2 (1). Yield 85%. ee 88% (column: Daicel CHIRALPAK®
AD-H, iPrOH/hexane = 60:40, flow rate: 1 mL/min, λ = 254 nm).
1
Colorless oil. [α]2D5 = –0.77 (c = 0.80, CHCl3). H NMR: δ = 0.88
(d, J = 7.3 Hz, 3 H), 2.86–2.98 (m, 1 H), 3.84 (s, 3 H), 3.845 (s, 3
H), 3.847 (s, 3 H), 3.91 (s, 3 H), 5.44 (d, J = 7.6 Hz, 1 H), 5.53 (d,
J = 2.3 Hz, 1 H), 6.00 (s, 2 H), 6.25 (d, J = 2.3 Hz, 1 H), 6.33 (d,
J = 1.7 Hz, 1 H), 6.43 (d, J = 1.7 Hz, 1 H), 6.56 (br. s, 1 H) ppm.
13C NMR: δ = 16.42, 38.27, 56.09, 56.18, 59.98, 60.86, 79.26,
100.77, 101.37, 106.60, 107.61, 121.84, 127.37, 128.88, 130.97,
136.58, 137.26, 140.64, 140.89, 148.79, 152.99, 153.26, 170.07 ppm.
152.80, 152.95 ppm. IR (KBr): ν = 3450, 3070, 1583 cm–1. MS
˜
(FAB): m/z
= 471 [M +
Na]+. HRMS (FAB): calcd. for
C24H32O8Na [M + Na]+ 471.1995; found 471.1985.
General Procedure for TEMPO Oxidation
IR (KBr): ν = 1766, 1618, 1583 cm–1. MS (FAB): m/z = 429 [M +
˜
H]+. HRMS (FAB): calcd. for C23H25O8 [M + H]+ 429.1549; found
429.1556.
(+)-Eupomatilone
(TEMPO; 6.7 mg, 0.043 mmol) and PhI(OAc)2 (156 mg,
0.47 mmol) were added to solution of diol 20 (192 mg,
2
(1): 2,2,6,6-Tetramethyl-1-piperidinyloxy
a
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data of synthetic intermediates of eupomati-
lone 1 and 5, and 1H and 13C NMR spectra of all new compounds.
0.43 mmol) in dry CH2Cl2 (2.2 mL) with stirring at room temp.
under Ar. After continued stirring at room temp. for 1 h, additional
PhI(OAc)2 (227 mg, 0.68 mmol) was added to the mixture. The en-
tire mixture was then stirred at room temp. for 3.5 h. Next, the
mixture was diluted with CHCl3, and the resulting solution was
stirred with saturated Na2S2O3. Then the organic phase was sepa-
rated, and the aqueous phase was extracted with CHCl3. The com-
bined organic extracts were washed with saturated NaHCO3 and
brine prior to drying over Na2SO4 and solvent evaporation. The
residue was purified by chromatography on silica gel with hexane/
EtOAc (2:1) to give (+)-eupomatilone 2 (1; 180 mg, 95%) as a pale
yellow oil. ee 89% (column: Daicel CHIRALPAK® AD-H,
Acknowledgments
This study was supported by a Grant-in-Aid for Scientific Research
(C) from the Japan Society for the Promotion of Science (grant
number 21590032) and the Osaka Ohtani University Research
Fund (Pharmaceutical Sciences).
iPrOH/hexane = 85:15, flow rate: 1 mL/min, λ = 254 nm). [α]2D3
=
[1] A. R. Carroll, W. C. Taylor, Aust. J. Chem. 1991, 44, 1705–
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1
+12.0 (c = 0.60, CHCl3). H NMR: δ = 0.84 (d, J = 7.3 Hz, 3 H),
2.88 (qnt, J = 7.3, 2.2 Hz, 1 H), 3.70 (s, 3 H), 3.85 (s, 3 H), 3.86
(s, 3 H), 3.88 (s, 3 H), 3.92 (s, 6 H), 5.52 (d, J = 7.3 Hz, 1 H), 5.55
(d, J = 2.2 Hz, 1 H), 6.26 (d, J = 2.2 Hz, 1 H), 6.37 (d, J = 1.7 Hz,
1 H), 6.46 (d, J = 1.7 Hz, 1 H), 6.69 (s, 1 H) ppm. 13C NMR: δ =
16.86, 38.31, 56.12, 56.16, 56.25, 60.88, 60.92, 61.37, 79.26, 104.86,
106.42, 107.42, 122.07, 127.64, 129.86, 131.02, 137.28, 140.90,
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˜
3097, 1767, 1664, 1592 cm–1. MS (FAB): m/z = 445 [M + H]+.
HRMS (FAB): calcd. for C24H29O8 [M + H]+ 445.1862; found
445.1853.
(+)-Eupomatilone 5 (2): (+)-Eupomatilone 5 (2) was prepared in a
manner similar to that described for the preparation of (+)-eupom-
atilone 2 (1). Yield 90%. ee 91% (column: Daicel CHIRALPAK®
AD-H, iPrOH/hexane = 80:20, flow rate: 1 mL/min, λ = 254 nm).
Colorless oil. 1:1 Mixture of rotamers. [α]2D4 = +26.4 (c = 1.04,
CHCl3). 1H NMR: δ = 0.80 (d, J = 7.6 Hz, 1.5 H), 0.82 (d, J =
7.3 Hz, 1.5 H), 2.81–2.92 (m, 1 H), 3.64 (s, 1.5 H), 3.65 (s, 1.5 H),
726
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 721–727

Total Synthesis of Eupomatilones
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[16]
[17]
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alcohols with a (1R,2S)-configuration, which was confirmed by
their transformation into known compounds or by the modi-
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constants between the C-1- and C-2-methine protons. The val-
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corresponding anti isomers have larger values of around 8 Hz.
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[19] The enantiomeric excesses of the synthetic eupomatilones 1, 2,
and 5 was confirmed by chiral HPLC to be 88, 89, and 91%
ee, respectively.
Received: September 19, 2012
Published Online: December 10, 2012
Eur. J. Org. Chem. 2013, 721–727
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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