The total synthesis of eupomatilones 2 and 5

Article abstract of DOI:10.1016/j.tetlet.2005.08.140

Efficient and diastereocontrolled syntheses of natural lignans eupomatilone 2 (1) and 5 (2) are described. Biaryl coupling was achieved using Suzuki chemistry. The lactone moiety was constructed using allylmetal reagents, which were synthesized from Bayli

Full text of DOI:10.1016/j.tetlet.2005.08.140

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7325–7328
The total synthesis of eupomatilones 2 and 5
George W. Kabalka* and Bollu Venkataiah
Department of Chemistry, The University of Tennessee, Knoxville, TN 37996-1600, USA
Received 19 July 2005; revised 23 August 2005; accepted 25 August 2005
Available online 13 September 2005
Abstract—Efficient and diastereocontrolled syntheses of natural lignans eupomatilone 2 (1) and 5 (2) are described. Biaryl coupling
was achieved using Suzuki chemistry. The lactone moiety was constructed using allylmetal reagents, which were synthesized from
Baylis–Hillman adducts. Allylindium reagents were found to be most effective.
Ó 2005 Elsevier Ltd. All rights reserved.
The a-methylene-c-lactone moiety is widely found in
naturally occurring compounds.1 The ability of the
unsaturated lactone functionality to act as a highly reac-
tive Michael acceptor is the basis of its role as a physio-
logically important building block2 Eupomatilones are
structurally novel lignans, first isolated in 1991 by Car-
rol and Taylor from the shrub eupomatia bennettii and
are characterized by a biaryl system with a substituted
c-lactone ring system attached to one of the aryl rings.3
Three synthetic approaches to eupomatilone-6 (3) (in
which the olefin on the lactone moiety is hydrogenated)
have been reported; however there are no reports relat-
ing to the syntheses of eupomatilones that contain an a-
methylene-c-lactone.4 We wish to report the first total
syntheses of eupomatilones 2 (1) and 5 (2) (Fig. 1) using
Baylis–Hillman adducts as synthetic precursors.
OMe
OMe
MeO
MeO
MeO
MeO
O
O
O
O
MeO
OMe
O
OMe
O
eupomatilone 2
eupomatilone 5
1
2
OMe
MeO
MeO
O
The Baylis–Hillman reaction is an attractive method for
forming carbon–carbon bonds because it yields highly
functionalized products.5 In a continuation of our study
of reactions involving organoborane reagents,6 we re-
ported the cross-coupling of Baylis–Hillman adducts
and bis(pinacoloto)diboron in the presence of palladium
catalysts to generate 3-substituted-2-alkoxycarbonylal-
lylboronates.7 Reaction of these allylboronates with
aldehydes required relatively long reaction times. How-
ever, we recently observed that the allylation reaction is
accelerated in the presence of Lewis acids to generate
functionalized homoallylic alcohols, which can be cyc-
O
O
O
eupomatilone 6
3
Figure 1. Eupomatilone structures.
lized to a-methylene-c-lactones.8 These results encour-
aged us to investigate new approaches to the synthesis
of eupomatilones 2 (1) and 5 (2).
The synthesis is initiated with the synthesis of 5 from
commercially available 4.9 The key reaction involves
coupling an arylboronic acid 6 with 2-bromo-3,4,5-tri-
methoxybenzaldehyde (5) in the presence of 4 mol %
Keywords: Eupomatilone; Indium; Organoboron; Cross-coupling;
Baylis–Hillman.
*
Corresponding author. Tel.: +1 865 974 3250; fax: +1 865 974
2997; e-mail: kabalka@utk.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.140

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G. W. Kabalka, B. Venkataiah / Tetrahedron Letters 46 (2005) 7325–7328
Br
B(OH)2
OMe
MeO
MeO
CHO
MeO
MeO
b
+
R
OR2
CHO
OR2
OR1
OMe
5, 92%
R
R = OMe, R1 = R2 = Me, 6a
R = H, R1 = R2 = CH2 , 6b
OR1
a
R = OMe, R1 = R2 = Me, 7a 74%
MeO
MeO
CHO
R = H, R1 = R2 =
CH2 , 7b 79%
OMe
4
Scheme 1. Reagents and conditions: (a) NBS, CHCl3, reflux, 2 h; (b) PdCl2(PPh3)2 (4 mol %), toluene: H2O (10:1), KF (2 equiv).
of PdCl2(PPh3)2 (Scheme 1). The cross-coupling was
achieved without the use of an external ligand (KF
was used as the base) to obtain biaryl aldehydes 7a
and 7b in high yield.
(1:1).10a Homoallylic alcohols 10a and 10b formed as
the desired syn isomers (95:5) (minor amounts of the anti
isomers were observed, however, they were easily sepa-
rated from the desired product). Cyclization of alcohols
10a and 10b was achieved under mild acidic conditions
(PTSA, CH2Cl2) to form products 1 and 2 (Scheme 3).
The 1H NMR and 13C NMR spectra12 of 1 proved iden-
tical with those published for eupomatilone 2.3 The
spectra13 of 2 revealed the presence of a mixture of
non-separable atropisomers, which were identical to
natural eupomatilone 5.3
The lactone ring of eupomatilone 2 (1) was constructed
by the addition of 3-methyl-2-methoxycarbonylallylbor-
onate (9) to the biaryl aldehyde 7a. Allylboronate 9 was
prepared via reaction of Baylis–Hillman acetate adduct
8 with bis(pinacoloto)diboron in the presence of a palla-
dium catalyst as shown in Scheme 2.7 Since allylboro-
nates are moisture sensitive and can be difficult to
purify, allylboronate 9 was used directly in the prepara-
tion of 10a. A variety of conditions were employed but
the reaction yields were poor presumably due to steric
factors and the presence of the electron donating meth-
oxy groups on the aromatic ring of the aldehyde.
After successfully completing the total synthesis of the
two natural eupomatilones 2 (1) and 5 (2), reaction of
1 and 2 with 10% Pd/C and H2 in ethanol gave olefin
isomerized products 13a and 13b, respectively (Scheme
4). The conjugated unsaturated lactone 13b is an inter-
mediate in the Gurjar approach to the synthesis of 3-
epi-eupomatilone 6 (14) and on further hydrogenation
in the presence of Rh/Al2O3 in ethyl acetate at 60 psi
produces 3-epi-eupomatilone 6 (14).4c
Since the boronate-based coupling reactions generated
only modest yields of the desired products, we investi-
gated the use of indium moderated reactions developed
by Paquette and others.10 Allylbromide 12 was synthe-
sized from Baylis–Hillman adduct 11.11 Bromination
using N-bromosuccinimide and triphenylphosphine in
CH2Cl2 at room temperature occurred regioselectively
(with allylic rearrangement) to afford the thermodynam-
ically favored Z-isomer. The allylation of 7a and 7b with
12 was most efficiently carried out using powdered in-
dium in a mixture of water and tetrahydrofuran
In conclusion, we have successfully completed the syn-
theses of eupomatilones 2 and 5 using Suzuki coupling
and allylation reactions as the key steps. We have dem-
onstrated that eupomatilone 5 can be hydrogenated to
synthesize another biaryllignan 3-epi-eupomatilone 6.
Although no reports have appeared describing the bio-
logical activity of eupomatilones, our short and efficient
OMe
MeO
O
OAc O
O
B
a
b, c, or d
MeO
MeO
OMe
OMe
OMe
O
7a
OH
8
O
OMe
10a
OMe
9
Scheme 2. Reagents and conditions: (a) bis(pinacoloto)diboron (1.1 equiv), Pd2(dba)3 (3 mol %), toluene, 50 °C, 5 h; (b) Sc(OTf)3 (10 mol %), rt,
3 days, 12%; (c) BF3ÆSiO2,8d (300 mg) rt, 3 days, 15%; (d) 90 °C, 3 days, 19%.

G. W. Kabalka, B. Venkataiah / Tetrahedron Letters 46 (2005) 7325–7328
7327
OH
O
O
a
b
OMe
OMe
Br
11
12, 78%
OMe
OMe
MeO
MeO
MeO
MeO
O
OMe
c
OH
O
O
2
R
OR
2
R
OR
1
OR
1
OR
1
2
1
2
R = OMe, R = R = Me, 1, 94%
R = OMe, R = R = Me, 10a 68%
1
2
1
2
R = H, R = R =
CH
, 2, 93%
R = H, R = R =
CH
10b, 70%
2
2
Scheme 3. Reagents and conditions: (a) NBS, PPh3, rt, 12 h; (b) In, THF/H2O (1:1), 2 h; (c) PTSA (10 mol %), DCM, rt, 12 h.
OMe
OMe
OMe
MeO
MeO
MeO
MeO
MeO
MeO
a
b
O
O
O
Ref. 4c
O
O
O
OR2
R
OR2
R
O
OR1
OR1
O
1, 2
14, 89%
R = OMe, R1 = R2 = Me, 13a, 66%
R = H, R1 = R2 =
CH2 , 13b, 63%
Scheme 4. Reagents and conditions: (a) Pd/C, H2, EtOH, rt, 18 h; (b) Rh/Al2O3, H2, 60 psi, 20 h, Ref. 4c.
Org. Lett. 2004, 4, 19; (c) Gurjar, M. K.; Cherian, J.;
Ramana, C. V. Org. Lett. 2004, 6, 317; (d) Coleman, R. S.;
Gurrala, S. R. Org. Lett. 2004, 6, 4025.
strategy could serve as a catalyst for research in this
area.
5. For reviews on Baylis–Hillman reactions see: (a) Drewes,
S. E.; Ross, G. H. P. Tetrahedron 1988, 44, 4653; (b)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811.
6. (a) Yu, S.; Lim, N.-S.; Kabalka, G. W. J. Org. Chem.
1999, 64, 5822; (b) Kabalka, G. W.; Wu, Z.; Ju, Y. Org.
Lett. 2002, 4, 3415; (c) Kabalka, G. W.; Dong, G.;
Venkataiah, B. Org. Lett. 2003, 5, 893; (d) Kabalka, G.
W.; Guchhait, S. K. Org. Lett. 2003, 5, 4129.
Acknowledgment
We wish to thank the US Department of Energy and the
Robert H. Cole Foundation for support of this research.
References and notes
7. Kabalka, G. W.; Venkataih, B.; Dong, G. J. Org. Chem.
2004, 69, 5807.
1. Yoshioka, H.; Mabry, T. J.; Timmerman, B. N. Sesqui-
terpene Lactones; University of Tokyo Press: Tokyo, 1973.
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Giacobbe, T. J. Science 1970, 168, 376; (b) Kupchan, S.
M.; Eakin, M. A.; Thomas, A. M. J. Med. Chem. 1971, 14,
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Based on Natural Product Models; Cassady, J. M.,
Douros, J. D., Eds.; Academic: New York, 1980; Vol. 7,
pp 201–207.
8. For recent reports on the acceleration of allylboration
reaction in the presence of Lewis acids, see: (a) Kennedy,
J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 11586;
(b) Ishiyama, T.; Ahiko, T.-A.; Miyaura, N. J. Am. Chem.
Soc. 2002, 124, 12414; (c) Lachance, H.; Lu, X.; Gravel,
M.; Hall, D. G. J. Am. Chem. Soc. 2003, 125, 10160; (d)
Kabalka, G. W.; Venkataiah, B.; Dong, G. Tetrahedron
Lett. 2005, 46, 4209.
3. Carroll, A. R.; Taylor, W. C. Aust. J. Chem. 1991, 44,
1615.
9. Molander, G. A.; George, K. M.; Monovich, L. G. J. Org.
Chem. 2003, 68, 9533.
4. (a) Huthinson, J. M.; Hong, S.-P.; MIntosh, M. C. J. Org.
Chem. 2004, 69, 4185; (b) Hong, S.-P.; McIntosh, M. C.
10. (a) Mendez-Andiono, J.; Paquette, L. A. Adv. Synth.
Catal. 2002, 344, 303; (b) Mendez-Andiono, J.; Paquette,

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L. A. Org. Lett. 2000, 2, 1263; (c) Hirayama, L. C.;
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13C NMR (CDCl3); 16.6, 38.1, 55.9, 60.6, 61.1, 79.0, 104.4,
104.7, 106.3, 107.3, 121.7, 127.5, 129.7, 130.8, 137.1, 140.7,
141.7, 151.0, 152.7, 152.8, 169.8.
11. (a)Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: New York, 1995; (b)
Breotemsteom, B.; Liebaria, A.; Delgado, A. Tetrahedron
Lett. 2004, 45, 1511.
13. Eupomatilone 5 (2): mixture of non-separable atropiso-
mers. 1H NMR (CDCl3); 0.80 (d, J = 7.5, 3H), 0.83 (d,
J = 7.6, 3H), 2.87 (m, 2H), 3.64 (s, 3H), 3.65 (s, 3H),
3.88 (s, 6H), 3.91 (s, 6H), 5.44 (d, J = 7 Hz, 1H), 5.54 (d,
J = 2 Hz, 2H), 6.02 (m, 4H), 6.23 (d, J = 2 Hz, 2H), 6.58–
6.74 (m, 6H), 6.68 (d J = 8 Hz, 2H); 13C NMR (CDCl3)
17.2, 38.1, 38.3, 56.0, 60.8, 61.0, 79.3, 101.2, 104.8,
108.1, 108.4, 109.9, 110.5, 121.9, 122.7, 123.3, 127.1,
128.9, 130.0, 141.1, 141.8, 146.9, 147.0, 147.7, 151.4, 152.8,
169.9.
12. Eupomatilone 2 (1): 1H NMR (CDCl3); 1H NMR
(CDCl3); 0.85 (d, J = 7.5, 3H), 2.87 (m, 1H), 3.70 (s,
3H), 3.85 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 3.90 (s, 3H),
3.92 (s, 3H), 3.93 (s, 3H), 5.52 (d, J = 7.2 Hz, 1H), 5.56 (d,
J = 2.0 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 6.36 (d,
J = 1.5 Hz, 1H), 6.47 (d, J = 1.5 Hz, 1H), 6.69 (s, 1H);