Synthetic studies toward clavilactone A: A concise access to,-substituted -butenolides by metathesis

Article abstract of DOI:10.3987/com-06-s(w)42

Synthetic studies toward clavilactone A (1), using olefin metathesis as key steps, have been described. The ring-opening/ring-closing metathesis of 3bromo-2-[1-(1-cyclobutenyl)carboxyl-2-propenyl]-1,4-dimethoxybenzene (9) constructed a -arylated butenoiid

Full text of DOI:10.3987/com-06-s(w)42

HETEROCYCLES, Vol. 70, 2006
135
HETEROCYCLES, Vol. 70, 2006, pp. 135 - 141. © The Japan Institute of Heterocyclic Chemistry
Received, 4th September, 2006, Accepted, 23rd October, 2006, Published online, 24th October, 2006. COM-06-S(W)42
SYNTHETIC STUDIES TOWARD CLAVILACTONE A: A CONCISE
ACCESS TO α,γ-SUBSTITUTED γ-BUTENOLIDES BY METATHESIS‡
Hiroyuki Yasui, Shun Yamamoto, Ken-ichi Takao, and Kin-ichi Tadano*
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
tadano@applc.keio.ac.jp
Abstract – Synthetic studies toward clavilactone A (1), using olefin metathesis as
key steps, have been described. The ring-opening/ring-closing metathesis of 3-
bromo-2-[1-(1-cyclobutenyl)carboxyl-2-propenyl]-1,4-dimethoxybenzene
(9)
constructed a γ-arylated butenolide (11). The ring-opening/ring-closing/cross
metathesis of 2-[1-(1-cyclobutenyl)carboxyl-2-propenyl-1,4-dimethoxybenzene
(19) in the presence of methallyl acetate (20) provided 2-[4-((E)-5-acetoxy-
4-methyl-3-pentenyl)-5-oxo-2,5-dihydrofuran-2-yl]-1,4-dimethoxybenzene (21).
The π-allyl palladium complex-mediated intramolecular cyclization of 21 for
construction of the 11-membered lactone moiety in the clavilactones was also
explored.
Clavilactones A (1), B (2) and C (3) (Figure 1) were isolated from cultures of the fungus
Basidiomycetous Clitocybe clavipes.1 Their relative structures were deduced based on NMR studies and
finally determined by a single-crystal X-ray analysis of the dimethyl ether derivative of 1. These natural
products consist of a 1,4-dihydroxybenzene or a 1,4-benzoquinone connected with a 11-membered
lactone, which shares with an α,β-epoxy-γ-lactone ring. Later, structurally resembling clavilactones D
(4) and E (5) were isolated from C. clavipes by using different culture conditions.2 Clavilactones A (1),
B (2) and C (3) exhibited antifungal and antibacterial activity and inhibited the germination of Lepidium
sativum.1 In addition, compounds (1), (2) and (4) exhibited potent inhibitory activity against epidermal
growth factor receptor (EGF-R) tyrosine kinase.2,3 Herein, we describe our synthetic studies toward the
clavilactone A (1), which are characterized by tandem olefin metathesis.
‡ This paper is dedicated to Professor Steven M. Weinreb (The Pennsylvania State University), with
respect and admiration, on the occasion of his 65th birthday.

136
HETEROCYCLES, Vol. 70, 2006
O
OH
OH
OH
R
R
O
O
O
O
O
O
O
O
O
O
OH
clavilactone B (2): R=H
clavilactone D (4): R=OH
clavilactone C (3): R=OH
clavilactone E (5): R=OMe
clavilactone A (1)
Figure 1. Structures of the clavilactones
During this decade, progress in olefin metathesis has brought significant benefit in the field of natural
product synthesis.4 We have reported some total syntheses of biologically intriguing natural products by
using olefin metathesis for the construction of their core skeletons.5-8 In the first total synthesis of natural
(+)-mycoepoxydiene, a structurally unique natural product having a 9-oxabicyclo[4.2.1]nona-2,4-diene
core skeleton, we have developed the one-pot ring-opening/cross/ring-closing metathesis of
7-oxanorbornene.6 For the total synthesis of 1, we planned the use of two metathesis approaches, i.e.,
ring-opening/ring-closing metathesis or ring-opening/ring-closing/cross metathesis for concise synthesis
of the functionalized butenolides such as 11 and 21 as a clue to the 11-membered lactone formation.
The first approach was commenced with known trisubstituted benzaldehyde (6)9 (Scheme 1).
Compound (6) was converted to allylic alcohol (7)10 by addition of vinylmagnesium bromide.
Esterification of the allylic alcohol (7) in the presence of lithium hexamethyldisilazide [LiN(TMS)2] with
a mixed anhydride (8), prepared from cyclobutenecarboxylic acid11 and pivaloyl chloride, provided ester
MeO
OMe
MeO
RuLn
Br
O
c
Br
Br
a
b
O
PCy3
CHO
CO2Piv
MeO
Cl
Cl
Ph
Ru
PCy3
OMe
MeO
RuLn
OH
O
O
8
9
7
6
i
10
MeO
MeO
MeO
MeO
Br
d
O
SnBu3
O
O
O
O
O
12
11
ii
13
Reagents and conditions: a) CH2=CHMgBr, THF, 83%; b) LiN(TMS)2, THF, -78 ºC, then 8, 94%; c) 10
(10 mol%), benzene, reflux, 27% after 4 cycles; d) 12, Pd(PPh3)4, CsF, 1,2-dichloroethane, 80 ºC, 58%.
Scheme 1. Preparation of 13 via the ROM/RCM of 9
(9). We explored the one-pot ring-opening/ring-closing metathesis (ROM/RCM) of 9 using 1st
generation Grubbs catalyst (10).12 This metathesis reaction was quenched when half amount of 9 was

HETEROCYCLES, Vol. 70, 2006
137
consumed owing to that prolonged reaction time decreased the yield of 11 significantly. The unreacted
9 was recovered for reuse. As a result, 2-(3-butenyl)-1,4-butenolide (11) was obtained in 27% yield
after three recycles. 13 As concerns the reaction mechanism for the formation of 11, we consider that the
allylic olefin reacts first with the Grubbs catalyst producing a ruthenium carbene complex (i),14 which is
converted to complex (ii) by a ring-opening/ring-closing process (Scheme 1). Then, another 9 reacts
with ii, producing 11 with generation of i, which resumes the second catalytic cycle. The Stille coupling
of bromobenzene (11) and methallyltributylstannane (12)15 in the presence of CsF provided the
methallylated product (13).16 The addition of CsF was required for this coupling to maintain good
yields.17
With substrate (13) in hand, we examined the RCM of 13 under a variety of conditions for the formation
of the 11-membered lactone part of 1 (Scheme 2). We examined the following reaction conditions: 1)
the Grubbs catalyst (10) in refluxing CH2Cl2 or benzene, 2) the Grubbs 2nd generation catalyst (15)18 in
refluxing CH2Cl2 or benzene, and 3) the 2nd generation Hoveyda-Grubbs catalyst19 in refluxing benzene.
Unfortunately, none of the conditions employed provided the desired RCM product (14). In most cases,
an undesired dimerized product and/or a cross metathesis product with styrene were obtained. On the
other hand, when 13 was treated with a high loading of the Grubbs catalyst (15) in refluxing benzene,
1,4-dimethoxy-6-methylnaphthalene (16)20 was obtained. This conversion can be explained by the
mechanism shown in Scheme 2. The ROM/RCM reaction occurred between the carbene derived from the
methallyl olefin and the butenolide olefin in iii, which followed aromatization of the resulting iv
accompanied by elimination of the carboxylic acid (v).
MeO
Mes N
Cl
N Mes
Ph
RCM
Ru
13
Cl
PCy3
15
O
O
MeO
RuLn
14
MeO
H
O
MeO
MeO
MeO
a
13
RuLn
MeO
RuLn
O
MeO
HO
O
O
16
iv
iii
O
v
Reagents and conditions: a) 15 (71 mol%), benzene (0.003 M), reflux, 24%.
Scheme 2. The attempted RCM of 13.
We next investigated another access to the clavilactone core structure by an intramolecular Friedel-Crafts
allylation using allylic acetate (21) via a π-allyl palladium complex21 (Scheme 3). For the synthesis of

138
HETEROCYCLES, Vol. 70, 2006
21, commercially available 17 was converted to 19 via allylic alcohol (18) by the reaction sequence
analogous to that shown in Scheme 1. The tandem metathesis of 19 was carried out using the Grubbs
catalyst (15) in the presence of methallyl acetate (20), which provided an α,γ-substituted butenolide (21)
in a yield of 22%.22 This reaction started with the ROM/RCM reactions of 19 leading to intermadiate
(vi), followed by the cross metathesis (CM) with 20. We examined first the use of the Grubbs 1st
generation catalyst (10) (30 mol%) in benzene for this tandem metathesis. Under these conditions, we
observed the formation of the ROM/RCM product (vi), which was characterized by comparison with an
authentic sample prepared in a separate experiment. However, the CM of vi with 20 did not proceed
using 10. On the other hand, treatment of the ROM/RCM product vi with 20 in the presence of 15
afforded 21. Consequently, we used the Grubbs catalyst (15) for the tandem metathesis of 19.
With the substrate (21) in hand, we explored the possibility of the attack of the electron-rich aromatic
carbon neighboring the methoxy group in 21 to the π-allyl palladium species, generated from the
methallyl acetate moiety, to construct the desired 11-membered lactone ring. In contrast to our
expectation, brief treatment of 21 with a catalytic amount of Pd(PPh3)4 in the presence of K2CO3 at 80 °C
produced a 2-oxospiro[4.5]decane-type compound (22)23 in 59% yield as a sole product.24 As shown in
Scheme 3, oxidative addition of the methallyl acetate moiety to a Pd(0) complex and base-mediated
deprotonation of the γ-proton in the butenolide ring provide an intermediary dienolate (vii). Then the
nucleophilic α-carbon of the dienolate attacks to the π-allyl palladium species regioselectively to produce
22, accompanying regeneration of the Pd(0) catalyst.25
MeO
MeO
MeO
MeO
MeO
a
b
c
CO2Piv
CHO
MeO
O
OAc
OH
19
8
O
17
20
18
AcO
MeO
MeO
MeO
MeO
MeO
AcO Pd
d
!
O
O
O
MeO
O
O
O
O
vi
O
22
vii
21
E / Z = 4 : 1
Reagents and conditions: a) CH2=CHMgBr, THF, 95%; b) LiN(TMS)2, THF, -78 ºC, then 8, 69%; c) 20,
15 (10 mol%), benzene, reflux, 22%; d) Pd(PPh3)4, K2CO3, DMF, 80 ºC, 59%.
Scheme 3. Preparation of 21 and formation of 22 by a Pd(0)-catalyzed intramolecular alkylation

HETEROCYCLES, Vol. 70, 2006
139
In conclusion, we have developed concise syntheses of 1,4-dimethyoxybenzenes (11), (13) and (21),
which possess a functionalized butenolide ring at C-2. These synthetic approaches rely on the
ROM/RCM or ROM/RCM/CM strategy for the construction of the γ-arylated butenolide moiety.
Further synthetic studies toward the total synthesis of clavilactones are in progress in this laboratory.
ACKNOWLEDGEMENTS
This work was supported by Grant-in-Aid for the 21st Century COE program "KEIO Life Conjugate
Chemistry" from MEXT, Japan.
REFERENCES AND NOTES
1. A. Arnone, R. Cardillo, S. V. Meille, G. Nasini, and M. Tolazzi, J. Chem. Soc., Perkin Trans. 1,
1994, 2165.
2. L. Merlini, G. Nasini, L. Scaglioni, G. Cassinelli, and C. Lanzi, Phytochemistry, 2000, 53, 1039.
3. G. Cassinelli, C. Lanzi, T. Pensa, R. A. Gambetta, G. Nasini, G. Cuccuru, M. Cassinis, G. Pratesi, D.
Polizzi, M. Tortoreto, and F. Zunino, Biochem. Pharmacol., 2000, 59, 1539.
4. K. C. Nicolaou, P. G. Bulger, and D. Sarlah, Angew. Chem. Int. Ed., 2005, 44, 4490.
5. K. Takao, G. Watanabe, H. Yasui, and K. Tadano, Org. Lett., 2002, 4, 2941.
6. K. Takao, H. Yasui, S. Yamamoto, D. Sasaki, S. Kawasaki, G. Watanabe, and K. Tadano, J. Org.
Chem., 2004, 69, 8789.
7. H. Yasui, K. Hirai, S. Yamamoto, K. Takao, and K. Tadano, Heterocycles, 2006, 67, 123.
8. H. Yasui, K. Hirai, S. Yamamoto, K. Takao, and K. Tadano, J. Antibiot., 2006, 59, 456.
9. C. Li, E. Lobkovsky, and J. A. Porco, Jr., J. Am. Chem. Soc., 2000, 122, 10484.
10. All new compounds were fully characterized by spectroscopic means [1H-NMR (270 MHz in
13
CDCl3), C-NMR (68 MHz in CDCl3), IR] and gave satisfactory HRMS (EI). Yields referred to
homogeneous samples obtained by chromatographic purification on silica gel.
11. Commercially available cyclobutanecarboxylic acid was converted to cyclobutenecarboxylic acid
according to a previous report: A. Campbell and H. N. Rydon, J. Chem. Soc., 1953, 3002.
12. (a) P. Schwab, M. B. France, J. W. Ziller, and R. H. Grubbs, Angew. Chem., Int. Ed. Engl., 1995, 34,
2039. (b) P. Schwab, R. H. Grubbs, and J. W. Ziller, J. Am. Chem. Soc., 1996, 118, 100.
13. Synthesis of 11: To a stirred solution of 9 (516 mg, 1.46 mmol) in benzene (150 mL) was added a
solution of Grubbs catalyst (10) (117 mg, 0.142 mmol) in benzene (0.5 mL). The mixture was
refluxed for 2 h, quenched with a few drops of DMSO, and evaporated in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/hexane, 1:10 to 1:5) to provide 55.7 mg
(11%) of 11 and 245 mg of 9 was recovered. The recovered 9 (245 mg) was subjected to the same

140
HETEROCYCLES, Vol. 70, 2006
reaction conditions using 10 (71.7 mg) to provide 45.6 mg (19%) of 11 and 159 mg of 9 was
recovered. The recovered 9 (159 mg) was subjected to the same reaction conditions using 10 (52.8
mg) to provide 24.9 mg (16%) of 11 and 112 mg of 9 was recovered. Again the recovered 9 (112
mg) was subjected to the same reaction conditions using 10 (26.4 mg) to provide 12.8 mg (11%) of
11 and 67.2 mg of 9 was recovered. After the three recycles, totally 139 mg (27%) of 11 was
obtained from 516 mg of 9. Compound (11): TLC Rf 0.31 (EtOAc/hexane, 1:2); IR (neat) 2920,
1750 cm-1; 1H NMR (270 MHz, CDCl3) δ 2.32-2.50 (m, 4H), 3.69 (s, 3H), 3.86 (s, 3H), 5.02 (dt, 1H,
J = 11.4, 1.8 Hz), 5.08 (dt, 1H, J = 17.0, 1.8 Hz), 5.85 (ddt, 1H, J = 11.4, 17.0, 6.2 Hz), 6.63 (m, 1H),
6.81 (d, 1H, J = 9.2 Hz), 6.89 (d, 1H, J = 9.2 Hz), 7.02 (m, 1H);13C NMR (68 MHz, CDCl3) δ 24.5,
31.3, 56.5, 56.9, 80.4, 111.4, 112.9, 115.1, 115.5, 122.6, 133.6, 137.0, 145.9, 150.4, 153.5, 174.6;
HRMS calcd for C16H17O4Br (M+) m/z 352.0310, found 352.0309.
14. For reports on metathesis applying to cyclobutene derivatives: (a) M. Mori, H. Wakamatsu, K.
Tonogaki, R. Fujita, T. Kitamura, and Y. Sato, J. Org. Chem., 2005, 70, 1066. (b) M. L. Randall, J.
A. Tallarico, and M. L. Snapper, J. Am. Chem. Soc., 1995, 117, 9610.
15. Y. Naruta, Y. Nishigaichi, and K. Maruyama, Org. Synth., 1993, 71, 118.
16. Compound (13) was obtained as a colorless oil: TLC Rf 0.65 (EtOAc/hexane, 1:2); IR 2940, 1750
cm-1; 1H NMR δ 1.79 (s, 3H), 2.34-2.52 (m, 4H), 3.37 (d, 1H, J = 16.9 Hz), 3.55 (d, 1H, J = 16.9 Hz),
3.65 (s, 3H), 3.76 (s, 3H), 4.30 (s, 1H), 4.77 (s, 1H), 4.99-5.11 (m, 2H), 5.84 (m, 1H), 6.08 (br s, 1H),
6.72 (d, 1H, J = 9.0 Hz), 6.86 (d, 1H, J = 9.0 Hz), 6.98 (br s, 1H); 13C NMR δ 17.9, 23.2, 31.5, 33.3,
56.1, 56.5, 78.1, 110.5, 110.7, 112.3, 126.0, 127.0, 128.0, 137.3, 144.8, 147.7, 147.8, 151.9, 153.3,
174.8; HRMS (EI) calcd for C20H24O4 (M+) m/z 328.1675, found 328.1675.
17. (a) A. F. Littke and G. C. Fu, Angew. Chem. Int. Ed. Engl., 1999, 38, 2411. (b) A. F. Littke, L.
Schwarz, and G. C. Fu, J. Am. Chem. Soc., 2002, 124, 6343.
18. M. Scholl, S. Ding, C. W. Lee, and R. H. Grubbs, Org. Lett., 1999, 1, 953.
19. S. B. Garber, J. S. Kingsbury, B. L. Gray, and A. H. Hoveyda, J. Am. Chem. Soc., 2000, 122, 8168.
20. Compound 16 was obtained as amorphous solid:1H NMR δ 2.52 (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H),
6.62 (d, 1H, J = 8.1 Hz), 6.67 (d, 1H, J = 8.1 Hz), 7.33 (d, 1H, J = 8.4 Hz), 7.98 (s, 1H), 8.09 (d, 1H,
13
J = 8.4 Hz): C NMR δ 21.8, 55.6, 55.7, 102.2, 103.3, 120.8, 121.7, 124.5, 126.4, 127.9, 135.6,
149.0, 149.6. These data were identical with those reported for 16 in the following paper: B. K.
Mehta, O. Barun, H. Ila, and H. Junjappa, Synthesis, 1998, 1483.
21. An analogous intermolecular Pd(0)-catalyzed allylation of aromatic rings, see: B. Nay, J.-F. Peyrat,
and J. Vercauteren, Eur. J. Org. Chem. 1999, 2231.
22. Synthesis of 21: To a stirred solution of 19 (12.6 mg, 45.9 µmol) in benzene (4.6 mL) were added
methallyl acetate (56 µL, 460 µmol) and a solution of the Grubbs catalyst (15) (11.7 mg, 4.6 µmol)

HETEROCYCLES, Vol. 70, 2006
141
in benzene (0.5 mL). The mixture was heated under reflux for 22 h, quenched with a few drops of
DMSO, and evaporated in vacuo. The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:6) to give 3.7 mg (22%) of 21 (E/Z = ca. 4:1, based on 1H NMR analysis) as a
1
colorless oil: TLC Rf 0.31 (EtOAc/hexane, 1:2); IR 2940, 1730 cm-1; H NMR for E-isomer δ 1.64
(br s, 3H), 2.01 (s, 3H), 2.32-2.39 (m, 4H), 3.74 (s, 3H), 3.85 (s, 3H), 4.43 (br s, 2H), 5.43 (m, 1H),
6.20 (d, 1H, J = 1.1 Hz), 6.75-6.84 (m, 3H), 7.20 (d, 1H, J = 1.1 Hz), for Z-isomer δ 1.73 (br s, 3H),
2.07 (s, 3H), 2.32-2.39 (m, 4H), 3.76 (s, 3H), 3.81 (s, 3H), 4.56 (br s, 2H), 5.38 (m, 1H), 6.20 (d, 1H,
J = 1.1 Hz), 6.75-6.84 (m, 3H), 7.20 (d, 1H, J = 1.1 Hz);13C NMR for E-isomer δ 14.0, 20.9, 24.9,
25.5, 55.8, 55.9, 69.7, 77.8, 111.5, 111.6, 114.1, 124.5, 127.4, 131.6, 132.0, 148.4, 150.4, 153.9,
170.8, 174.0; HRMS calcd for C20H24O6 (M+) m/z 360.1573, found 360.1577.
23. To a stirred solution of 21 (30.6 mg, 85.0 µmol) in DMF (17 mL) were added a solution of Pd(PPh3)4
(4.9 mg, 4.2 µmol) in DMF (0.5 mL) and K2CO3 (23.5 mg, 170 µmol). The mixture was stirred for
2 h at 80 °C, diluted with Et2O (20 mL), and washed with saturated aqueous NaCl (20 mL). The
organic layer was dried and concentrated in vacuo. The residue was purified by chromatography
on silica gel (EtOAc/hexane, 1:30) to provide 15.0 mg (59%) of 22 as a colorless oil: TLC Rf 0.67
(EtOAc/hexane, 1:2); IR 2930, 1790, 1500 cm-1; 1H NMR δ 1.72 (s, 3H), 1.75-2.57 (m, 6H), 3.80 (s,
13
3H), 3.88 (s, 3H), 5.55 (br s, 1H), 6.30 (s, 1H), 6.88 (s, 2H), 7.26 (s, 1H); C NMR δ 22.4, 23.6,
29.9, 37.3, 48.3, 55.7, 55.9, 111.9, 112.0, 113.1, 116.0, 117.5, 120.3, 130.7, 147.9, 151.7, 153.4,
181.2; HRMS calcd for C18H20O4 (M+) m/z 300.1362, found 300.1374.
24. We examined the conversion of 21 to 22 using the following two conditions; 1) Pd(PPh3)4, i-Pr2NEt,
THF, rt to reflux (decomposition of 21); 2) Pd(PPh3)4, i-Pr2NEt, DMF, 80 °C (27% yield of 22).
25. We consider that the conversion of 21 to 22 seems to be an intramolecular variant of the Tsuji-Trost
reaction, see the following seminal papers; 1) J. Tsuji, Tetrahedron, 1986, 42, 4361. 2) B. M. Trost,
Angew. Chem., Int. Ed. Engl.,1989, 28, 1173.