Total synthesis of (+)-eupomatilone 2 via asymmetric [2,3]-Wittig rearrangement of highly oxygenated biphenylmethyl ethers

Article abstract of DOI:10.1016/j.tetlet.2010.11.126

We have achieved the total synthesis of (±)- and (+)-eupomatilone 2 isolated from the Australian shrub Eupomatia bennettii. The key reaction was an asymmetric [2,3]-Wittig rearrangement employing a bis(oxazoline) chiral ligand. Although the highly oxygena

Full text of DOI:10.1016/j.tetlet.2010.11.126

Tetrahedron Letters 52 (2011) 581–583
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Total synthesis of (+)-eupomatilone 2 via asymmetric [2,3]-Wittig
rearrangement of highly oxygenated biphenylmethyl ethers
⇑
Yoshimi Hirokawa, Maria Kitamura, Chiharu Kato, Yuki Kurata, Naoyoshi Maezaki
Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tondabayashi, Osaka 584-8540, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have achieved the total synthesis of ( )- and (+)-eupomatilone 2 isolated from the Australian shrub
Eupomatia bennettii. The key reaction was an asymmetric [2,3]-Wittig rearrangement employing a
bis(oxazoline) chiral ligand. Although the highly oxygenated biphenylmethyl ether exhibited consider-
ably lowered enantioselectivity as compared with the non-substituted biphenylmethyl ether, the selec-
tivity was improved to 89% ee by using n-BuLi and ether as the base and the co-solvent, respectively.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 29 October 2010
Revised 22 November 2010
Accepted 24 November 2010
Available online 27 November 2010
Keywords:
Asymmetric synthesis
Natural product
[2,3]-Wittig rearrangement
Bis(oxazoline) ligand
1. Introduction
asymmetric
[2,3]-Wittig
Me
TIPSO
In 1991, structurally unique lignans named eupomatilones were
isolated from the Australian shrub Eupomatia bennettii by Carroll
and Taylor. This degraded lignan possesses an oxygenated biaryl
TIPSO
Me
*
HO
OMe
OMe
OMe
OMe
O
rearrangement
*
MeO
MeO
MeO
MeO
OMe
OMe
skeleton with a
of a dimeric phenylpropane precursor.1 Eupomatilone 2 is a conge-
ner having six methoxy groups and is characterized by an -meth-
ylene- -lactone group, which is expected to interact with
c-lactone ring constructed via the rearrangement
MeO
MeO
Me
4
a
3
c
O
OMe
OMe
O
5
biomolecules. Although many syntheses of congeners bearing a
saturated C3 substituent have been reported,2 there are few total
syntheses of this natural product. Examples include synthesis of
the racemate by using an allylindium reagent3 and an asymmetric
synthesis by using a chiral carbomethoxycrotyl boronate reagent
with moderate enantioselectivity (76% ee).4
MeO
MeO
OMe
eupomatilone 2
MeO
Scheme 1. Synthetic plan of eupomatilone 2.
We were interested in this natural product for its unique struc-
ture and unexplored biological activity. We planned to synthesize
eupomatilone 2 by employing an asymmetric [2,3]-Wittig rear-
rangement of arylmethyl ether in the presence of an external chiral
ligand (Scheme 1). During preliminary research, we found that the
simple biarylmethyl ether rearranged with high enantio- and dia-
stereoselectivity.5 This success encouraged us to apply this strat-
egy to the synthesis of highly oxygenated biaryl-type natural
products.
2. Result and discussion
As shown in Scheme 2, the highly congested biaryl moiety
of eupomatilone 2 was constructed using the modified Suzuki
coupling of 2-bromo-3,4,5-trimethoxybenzyl alcohol 16 and
3,4,5-trimethoxyphenylboronic acid 2, utilizing the o-(dicyclohex-
ylphosphine)biphenyl ligand, as developed by Buchwald.7 The
coupling reaction proceeded smoothly to give the biaryl product
3 in 76% yield [Pd(OAc)2, (c-Hex)2(Biphenyl)P, K3PO4, toluene, at
80 °C]. The resulting alcohol 3 underwent the Williamson ether
synthesis with allylic bromide 45 in the presence of t-BuOK, giving
the biarylmethyl ether 5 in 71% yield.
Herein, we report the enantioselective total synthesis of eup-
omatilone 2 by employing the asymmetric [2,3]-Wittig rearrange-
ment as the key reaction.
After obtaining the required substrate 5, we investigated the
[2,3]-Wittig rearrangement with t-BuLi (5 equiv) in THF at
⇑
Corresponding author. Tel./fax: +81 721 24 9541.
E-mail address: maezan@osaka-ohtani.ac.jp (N. Maezaki).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.126

582
Y. Hirokawa et al. / Tetrahedron Letters 52 (2011) 581–583
Pd(OAc)2
(c-Hex)2(Biphenyl)P
K3PO4, toluene
80°C, 7 h
OMe
OMe
HO
OMe
OMe
MeO
MeO
B(OH)2
HO
Br
MeO
MeO
+
OMe
OMe
MeO
(76%)
MeO
3
1
2
2 Me
TIPSO
Me
Br
TIPSO
TIPSO
Me
J = 3.2 Hz
4
OMe
OMe
t-BuLi (5 equiv)
THF, −78°C, 2 h
OMe
O
HO
1
t-BuOK
THF, rt, 1 d
(71%)
MeO
MeO
MeO
MeO
OMe
OMe
5
OMe
( )-6
(85%)
MeO
MeO
Scheme 2. Synthesis of alcohol ( )-6.
ꢀ78 °C. Fortunately, regioselective deprotonation proceeded pre-
dominately at the benzylic position in the presence of allylic pro-
tons, and the [2,3]-Wittig rearranged product ( )-6 was obtained
in 85% yield. Formation of the [1,2]-Wittig rearranged product
was not observed.
The reaction afforded a sole diastereoisomer, and the relative
stereochemistry of the resulting alcohol ( )-6 was assumed to be
a syn relationship based on the coupling constant between the
two methine protons at the C1 and C2 positions (J = 3.2 Hz).8
The total synthesis of ( )-eupomatilone 2 in 85% yield was
accomplished in two steps by deprotecting the TIPS group with
TBAF and subsequent primary alcohol selective TEMPO oxidation
in the presence of PhI(OAc)2 as a co-oxidant9 (Scheme 3). Spectral
data (IR, 1H and 13C NMR) were consistent with those reported for
the natural product.1,4
Table 1
Asymmetric [2,3]-Wittig rearrangement of 5
bis(oxazoline)
base
solvent, −78°C, 2 h
Me
TIPSO
OMe
OMe
HO
5
MeO
MeO
OMe
MeO
(−)-6
Entry
Conditionsa
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
L1, t-BuLi, hexane
L2, t-BuLi, hexane
L3, t-BuLi, hexane
L4, t-BuLi, hexane
L5, t-BuLi, hexane
L1, s-BuLi, hexane
L1, n-BuLi, hexane
L1, n-BuLi, hexaned
L1, n-BuLi, hexane/toluene (4/1)
L1, n-BuLi, hexane/ether (4/1)
L1, n-BuLi, hexane/ether (1/1)
L1, n-BuLi, hexane/THF (4/1)
92
72
0
68
38
—
38
43
50
46
77
92
98
83
7
22
12
71
77
77
80
89
89
5
Next, we examined the asymmetric [2,3]-Wittig rearrangement
of 5 by using bis(oxazoline) as an external chiral ligand.10 The re-
sults are summarized in Table 1.
The reactions were performed using 1 equiv of the chiral ligand
and 5 equiv of the base at ꢀ78 °C for 2 h. The enantiomeric excess
was significantly dependent on the structure of the bis(oxazoline)
ligand (Fig. 1). Bulkiness at the C4 position was important to
achieve high ee (entries 1 and 2), but bulkiness at the C5 position
and on the methylene bridge reduced both the yield and enantiose-
lectivity (entries 3–5). The ligand L1 achieved the best yield and
selectivity, although ee was moderate (68% ee). It is in sharp con-
trast that the simple biphenylmethyl ether with no methoxy sub-
stituent showed excellent selectivity (92% ee).5
We observed that the highly oxygenated substrate slowly
underwent the [2,3]-Wittig rearrangement even with bases weaker
than t-BuLi. To our delight, s-BuLi and n-BuLi exhibited better
enantioselectivity than t-BuLi but in reduced yield (entries 6 and
7). The yield improved to 77% when the reaction progressed for
4 h (entry 8). Interestingly, the addition of toluene as a co-solvent
accelerated the reaction time and the reaction was completed
within 2 h. The rearranged product (ꢀ)-6 was obtained in 92% yield
10
11
12
a
The reactions were carried out in the presence of chiral ligand (1 equiv) and
base (5 equiv) in dry solvent at ꢀ78 °C for 2 h under Ar atmosphere unless stated
otherwise.
b
Isolated yield.
c
Determined by chiral HPLC (Column: CHIRALPAK AD-H, solvent: hexane–i-
PrOH = 98:2, flow rate: 1 mL/min).
d
The reaction was carried out for 4 h.
R3 R3
R2
R2
R2
R2
O
4
5
O
N
N
R1
R1
L1: R1=t-Bu, R2=H, R3=Me
L2: R1=i-Pr, R2=H, R3=Me
L3: R1=t-Bu, R2=Me, R3=Me
L4: R1=i-Pr, R2=Me, R3=Me
L5: R1=t-Bu, R2=H, R3=Et
Me
HO
TBAF, THF
rt, 2 h
OMe
OMe
HO
MeO
MeO
( )-6
OMe
( )-7
Me
(90%)
MeO
Figure 1. Chiral bis(oxazoline) ligands L1–L5.
cat. TEMPO
PhI(OAc)2
CH2Cl2, rt, 1.5 h
O
OMe
OMe
OMe
with 80% ee (entry 9). Finally, when ether was added as a co-sol-
vent, both the yield and enantioselectivity were optimized up to
98% and 89% ee, respectively (entry 10).11 The selectivity did not
further improve even on increasing the ratio of ether (entry 11).
In contrast, addition of the more polar THF suppressed the reaction
significantly and both the yield and selectivity decreased dramati-
cally (entry 12). Presumably, the addition of THF interfered with
O
MeO
MeO
(94%)
MeO
( )-eupomatilone 2
Scheme 3. Synthesis of racemic eupomatilone 2.

Y. Hirokawa et al. / Tetrahedron Letters 52 (2011) 581–583
583
Rainka, M. P.; Milne, J. E.; Buchwald, S. L. Angew. Chem. Int. Ed. 2005, 44, 6177–
6180; (c) Yu, S. H.; Ferguson, M. J.; McDonald, R.; Hall, D. G. J. Am. Chem. Soc.
2005, 127, 12808–12809; (d) Gurjar, M. K.; Karumudi, B.; Ramana, C. V. J. Org.
Chem. 2005, 70, 9658–9661; (e) Coleman, R. S.; Gurrala, S. R. Org. Lett. 2004, 6,
4025–4028; (f) Gurjar, M. K.; Cherian, J.; Ramana, C. V. Org. Lett. 2004, 6, 317–
319; (g) Hutchison, J. M.; Hong, S.-P.; McIntosh, M. C. J. Org. Chem. 2004, 69,
4185–4191; (h) Hong, S.-P.; McIntosh, M. C. Org. Lett. 2002, 4, 19–21.
3. Kabalka, G. W.; Venkataiah, B. Tetrahedron Lett. 2005, 46, 7325–7328.
4. Mitra, S.; Gurrala, S. R.; Coleman, R. S. J. Org. Chem. 2007, 72, 8724–8736.
5. (a) Kitamura, M.; Hirokawa, Y.; Maezaki, N. Chem. Eur. J. 2009, 15, 9911–9917;
(b) Hirokawa, Y.; Kitamura, M.; Maezaki, N. Tetrahedron: Asymmetry 2008, 19,
1167–1170.
6. Mont, N.; Mehta, V. P.; Appukkuttan, P.; Beryozkina, T.; Toppet, S.; Van Hecke,
K.; Van Meervelt, L.; Voet, A.; DeMaeyer, M.; Van der Eycken, E. J. Org. Chem.
2008, 73, 7509–7516.
7. Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
9550–9561.
8. The relative relationship was able to speculate from the coupling constants
between the C1- and C2-methin protons. The values of syn-isomers are ranged
around 4 Hz. Instead, those of the corresponding anti-isomers exhibit the larger
value around 8 Hz. A similar empirical rule was also reported by Nakai, see;
Mikami, K.; Kimura, Y.; Kishi, N.; Nakai, T. J. Org. Chem. 1983, 48, 279–281.
9. Mico, A. D.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974–6977.
10. For asymmetric [2,3]-Wittig rearrangement employing an external chiral
ligand, see: (a) Tomooka, K. Chem. Organolithium Compd. 2004, 2, 749–828; (b)
Hiersemann, M.; Abraham, L.; Pollex, A. Synlett 2003, 1088–1095; (c) Tsubuki,
M.; Takahashi, K.; Honda, T. J. Org. Chem. 2003, 68, 10183–10186; (d)
McGowan, G. Aust. J. Chem. 2002, 55, 799; (e) Tomooka, K.; Komine, N.;
Nakai, T. Chirality 2000, 12, 505–509; (f) Tomooka, K.; Komine, N.; Nakai, T.
Tetrahedron Lett. 1998, 39, 5513–5516; (g) Manabe, S. Chem. Pharm. Bull. 1998,
46, 335–336; (h) Nakai, T.; Tomooka, K. Pure Appl. Chem. 1997, 69, 595–600; (i)
Manabe, S. Chem. Commun. 1997, 737–738; (j) Nakai, T.; Mikami, K. Org. React.
1994, 46, 105–209; (k) Marshall, J. A. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 3, pp 975–1014; (l)
Kang, J.; Cho, W. O.; Cho, H. G.; Oh, H. J. Bull. Korean Chem. Soc. 1994, 15, 732–
739.
Me
HO
TBAF,THF
rt, 2 h
OMe
OMe
HO
MeO
MeO
-6
(−)
OMe
-7
(quant)
MeO
(−)
Me
cat.
TEMPO
PhI(OAc)2
CH2Cl2, rt, 1.5 h
O
OMe
OMe
O
MeO
MeO
OMe
(95%)
MeO
(+)-eupomatilone 2
Scheme 4. Conversion to (+)-eupomatilone 2.
the coordination of the chiral ligand to n-BuLi that prevented the
formation of a reactive chiral base.
We attempted to confirm the absolute configuration at the chi-
ral center of the secondary alcohol by using the modified Mosher
method,12 but the arbitrary distribution of the
D
dSR sign made
the appropriate assignment difficult.13 The modified Mosher meth-
od was, therefore, considered unsuitable for this compound. Con-
sequently, we abandoned our attempt to confirm the absolute
configuration at this stage and decided to determine it by derivati-
zation of the natural product.
Finally, we transformed the product (ꢀ)-6 into chiral eupomat-
ilone 2, as shown in Scheme 4. After deprotecting the TIPS group
with TBAF, the resulting diol (ꢀ)-7 was selectively oxidized using
catalytic TEMPO in the presence of PhI(OAc)2 as co-oxidant.9 Thus,
(+)-eupomatilone 2 in 95% yield was obtained in two steps.14,15 The
sign of specific rotation was reversed on the formation of
tone. Thus, the sign of the synthetic eupomatilone 2 matched that
of the natural product; however, its value was greater than that re-
11. Procedure of asymmetric [2,3]-Wittig rearrangement (Table 1, entry 10). n-
BuLi (1.6 M in hexane, 1.25 mL, 2.00 mmol) was added dropwise to
a
suspension of ether (240 mg, 0.40 mmol) and bis(oxazoline) ligand L1
5
(118 mg, 0.40 mmol) in a 4:1 mixture of dry hexane and dry ether (2 mL) with
stirring at ꢀ78 °C under Ar. The stirring continued at this temperature for 2 h.
The reaction was quenched with saturated NH4Cl (8 mL) and the mixture was
partitioned between EtOAc (40 mL) and water (20 mL). The organic layer was
separated and the aqueous layer was extracted with EtOAc (20 mL). Prior to
drying and solvent evaporation, the combined organic layer was washed with
water (20 mL) and brine (20 mL). The residue was chromatographed on silica
gel with hexane–EtOAc (3:1) to give alcohol (ꢀ)-6 (235 mg, 98%, 89% ee) as a
c-lac-
ported in literature [½a D25
ꢁ
+12.0 (c 0.60, CHCl3); lit. ½a D
ꢁ
+3.3 (c 0.5,
CHCl3)].1 The 1H and 13C NMR spectra were identical to those in the
reported data.1,4
colorless oil. ½a D25
ꢁ
ꢀ21.2 (c 0.72, CHCl3); 1H NMR d: 0.96 (d, J = 7.1 Hz, 3H),
In conclusion, we have achieved the total synthesis of ( )- and
(+)-eupomatilone 2 by employing a [2,3]-Wittig rearrangement
as the key reaction. We optimized the enantioselectivity up to
89% ee by using the bisoxazoline ligand L1 and n-BuLi in a solvent
mixture of n-hexane and ether, and obtained (+)-eupomatilone 2 in
50% overall yield from alcohol 1 in five steps. This strategy contrib-
utes to our knowledge of the synthesis of eupomatilone congeners
and their derivatives as well as related biological research. The
application of this method to other congeners will follow in due
course.
1.00–1.10 (21H), 2.35 (qd, J = 7.1, 3.2 Hz, 1H), 3.50 (br, 1H), 3.67 (s, 3H), 3.80 (s,
3H), 3.85 (s, 3H), 3.82 (d, J = 12.7 Hz, 1H), 3.89 (s, 6H), 3.93 (s, 3H), 4.03 (d,
J = 12.7 Hz, 1H), 4.52 (s, 1H), 4.77 (d, J = 3.2 Hz, 1H), 4.97 (d, J = 1.2 Hz, 1H), 6.42
(d, J = 1.7 Hz, 1H), 6.47 (d, J = 1.7 Hz, 1H), 7.04 (s, 1H); 13C NMR d: 11.16, 11.85
(3C), 17.85 (6C), 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, 152.39, 152.79, 153.00; IR (KBr) cmꢀ1: 3477, 3097, 1586; MS (FAB) m/z:
605 [M+H]+; HRMS (FAB) m/z: calcd for C33H52O8Si: 605.3510, found: 605.3528
[M+H]+.
12. Ohtani, I.; Kusumi, K.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092–4096.
13. There are other examples where was not possible to apply a modified Mosher
method because of the arbitrary distribution of the
D
dSR sign, see: (a) Seco, J.
M.; Quiñoá, E.; Riguera, R. Chem. Rev. 2004, 104, 17–117; (b) Seco, J. M.; Quiñoá,
E.; Riguera, R. Tetrahedron: Asymmetry 2000, 11, 2781–2791.
14. The enantiomeric excess of the synthetic (+)-eupomatilone 2 was confirmed as
89% ee by chiral HPLC (Column: CHIRALPAK AD-H, solvent: hexane–i-PrOH =
9:1, flow rate: 1 mL/min).
Acknowledgments
We acknowledge the financial support of the Grant-in-Aid for
Scientific Research (C) from the Japan Society for the Promotion
of Science (No. 21590032) and the Osaka Ohtani University
Research Fund (Pharmaceutical Sciences).
15. Spectral data of synthetic (+)-eupomatilone 2: ½a D23
ꢁ
+12.02 (c 0.60, CHCl3); 1H
NMR d: 0.84 (d, J = 7.3 Hz, 3H), 2.88 (qnt, J = 7.3, 2.1 Hz, 1H), 3.70 (s, 3H), 3.85
(s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 3.92 (s, 6H), 5.52 (d, J = 7.3 Hz, 1H), 5.55 (d,
J = 2.0 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 6.37 (d, J = 1.7 Hz, 1H), 6.46 (d, J = 1.7 Hz,
1H), 6.69 (s, 1H); 13C NMR d: 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, 131.01, 137.28,
140.90, 141.90, 151.25, 152.98, 153.06, 153.24, 170.14; IR (KBr) cmꢀ1: 3097,
1767, 1664, 1592; MS (FAB): m/z 445 [M+H]+; HRMS (FAB): m/z calcd for
References and notes
1. Carroll, A. R.; Taylor, W. C. Aust. J. Chem. 1991, 44, 1705–1714.
2. For synthesis of congeners of eupomatilone 2, see: (a) Johnson, J. B.; Bercot, E.
A.; Williams, C. M.; Rovis, T. Angew. Chem. Int. Ed. 2007, 46, 4514–4518; (b)
C
24H28O8: 445.1862, found: 445.1853 [M+H]+.