Efficient Synthesis of butenolide-medium ring ether hybrids by a [3 + 2] cyclization-ring-closing metathesis strategy

Article abstract of DOI:10.1021/ol006307k

A new strategy for the synthesis of bicyclic γ-alkylidenebutenolides, butenolide-medium ring ether hybrids, is reported which involves Me₃-SiOTf-catalyzed cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with oxalyl chloride, Mitsunobu reaction, and subsequent ring-closing metathesis.

Full text of DOI:10.1021/ol006307k

ORGANIC
LETTERS
2000
Vol. 2, No. 19
2991-2993
Efficient Synthesis of
Butenolide−Medium Ring Ether Hybrids
by a [3 + 2] Cyclization-Ring-Closing
Metathesis Strategy
Peter Langer,* Tobias Eckardt, and Martin Stoll
Institut fu¨r Organische Chemie der Georg-August-UniVersita¨t Go¨ttingen,
Tammannstrasse 2, 37077 Go¨ttingen, Germany
planger@uni-goettingen.de
Received July 9, 2000
ABSTRACT
A new strategy for the synthesis of bicyclic γ-alkylidenebutenolides, butenolide−medium ring ether hybrids, is reported which involves Me3-
SiOTf-catalyzed cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with oxalyl chloride, Mitsunobu reaction, and subsequent ring-closing
metathesis.
The development of new synthetic methods for the efficient
construction of biologically active compounds is an important
field in organic chemistry. In this context, natural products
are of particular importance as lead structures.1 However,
the isolation of new natural products is rather difficult and
time-consuming. Therefore, the concept of the synthesis of
natural product hybrids and analogues, containing two
different pharmacophoric subunits, has been recently de-
vised.2 This concept has been also used by nature in the
combined biosynthesis of vitamin E which is formed from
a terpene and shikimic acid.3 The hybrid vincristin is formed
from aspido sperma and an iboga alkaloid and represents an
important drug against blood cancer of children.4
Many natural products, including prominent compounds
such as freelingyne, tetrenolin, dihydroxerulin, and patulin,
belong to the pharmacologically important group of γ-alky-
lidenebutenolides.5,6 Similarly, medium-ring ethers are found
(3) (a) Netscher, T. Chimia 1996, 50, 563. (b) Furuya, T.; Yoshikawa,
T.; Kimura, T.; Kaneko, H. Phytochemistry 1987, 26, 2741. (c) Stocker,
A.; Fretz, H.; Frick, H.; Ru¨ttimann, A.; Woggon, W.-D. Bioorg. Med. Chem.
1996, 4, 1129.
(1) For the isolation of strobilurines, see: (a) Zapf, A.; Werle, A.; Anke,
T.; Klostermeyer, D.; Steffan, B.; Steglich, W. Angew. Chem. 1995, 107,
255; Angew. Chem., Int. Ed. Engl. 1995, 34, 196. For the isolation of
epothilones, see: (b) Ho¨fle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, P.;
Gerth, K.; Reichenbach, H. Angew. Chem. 1996, 108, 1671; Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1567.
(2) (a) Hoppen, S.; Emde, U.; Friedrich, T.; Grubert, L.; Koert, U. Angew.
Chem. 2000, 112, 2181; Angew. Chem., Int. Ed. 2000, 39, 2099. (b) Tietze,
L. F.; Schneider, G.; Wo¨lfling, J.; No¨bel, T.; Wulff, C.; Schubert, I.;
Ru¨beling, A. Angew. Chem. 1998, 110, 2644; Angew. Chem., Int. Ed. 1998,
37, 2469. (c) Wang, J.; De Clerq, P. J. Angew. Chem. 1995, 107, 1698;
Angew. Chem., Int. Ed. Engl. 1995, 34, 1749. (d) Depew, K. M.; Zeman,
M.; Boyer, S. H.; Denhart, D. J.; Ikemoto, N.; Crothers, D. M.; Danishefsky,
S. J. Angew. Chem. 1996, 108, 2972; Angew. Chem., Int. Ed. Engl. 1996,
35, 2797.
(4) (a) Magnus, P.; Mendoza, J. S.; Stamford, A.; Ladlow, M.; Willis,
P. J. Am. Chem. Soc. 1992, 114, 10232. (b) Bornmann, W. G.; Kuehne, M.
E. J. Org. Chem. 1992, 57, 1752.
(5) Reviews: (a) Rao, Y. S. Chem. ReV. 1976, 76, 625. (b) Pattenden,
G. Prog. Chem. Nat. Prod. 1978, 35, 133. (c) Knight, D. W. Contemp.
Org. Synth. 1994, 1, 287. (d) Negishi, E.-i.; Kotora, M. Tetrahedron 1997,
53, 6707.
(6) (a) Siegel, K.; Bru¨ckner, R. Chem. Eur. J. 1998, 4, 1116. (b) Goerth,
F.; Umland, A.; Bru¨ckner, R. Eur. J. Org. Chem. 1998, 1055. (c) Enders,
D.; Dyker, H.; Leusink, F. R. Chem. Eur. J. 1998, 4, 311. (d) Go¨rth, F. C.;
Bru¨ckner, R. Synthesis 1999, 1520. (e) Knight, D. W.; Pattenden, G. J.
Chem. Soc., Perkin Trans 1 1979, 62. (f) Ingham, C. F.; Massy-Westropp,
R. A.; Reynolds, G. D.; Thorpe, W. D. Aust. J. Chem. 1975, 28, 2499. (g)
Ohe, F. v. d.; Bru¨ckner, R. Tetrahedron Lett. 1998, 1909. (h) Hanisch, I.;
Bru¨ckner, R. Synlett 2000, 374.
10.1021/ol006307k CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/31/2000

in a number of biologically active marine natural products,
such as brevetoxins A and B, yessotoxin, ciguatoxin,
laurencin, and maitotoxin.7 We have recently reported8 a new
synthesis of R-hydroxy-γ-alkylidenebutenolides by the first
regio- and stereoselective cyclizations of 1,3-dicarbonyl
dianion equivalents with oxalic acid dielectrophiles. Herein,
we wish to report an efficient synthesis of 5,n bicyclic
butenolides (n ) 7-9) which can be regarded as hybrids of
the pharmacologically relevant subunits of γ-alkylidene-
butenolides and medium-ring ethers.
Scheme 1
Our starting point was the reaction of the dianion of ethyl
acetoacetate with allyl bromide which afforded ethyl 3-oxo-
hept-6-enoate 1 in 82% yield. Unfortunately, all attempts to
directly prepare â-allyl-γ-alkylidenebutenolide 5 by using
our dianion methodology8a failed: reaction of dilithiated ethyl
3-oxoheptenoate 1 with N,N′-dimethoxy-N,N′-dimethyl-
ethanediamide resulted in a complex mixture. This can be
explained by the lability of the dianion of 1. Therefore, we
have envisaged a Lewis acid-catalyzed synthesis of buteno-
lide 5 via the 1,3-bis(trimethylsilyloxy)-1,3-butadiene 3
which represents an electroneutral dianion equivalent.9 Bis-
silyl enol ether 3 was efficiently prepared by formation of
the silyl enol ether 2 (using Me3SiCl/NEt3) in 96% yield
(Scheme 1). Deprotonation of 2 with LDA at -78 °C and
subsequent addition of Me3SiCl afforded diene 3 in 90%
yield. To our satisfaction, Me3SiOTf-catalyzed cyclization
of 3 with oxalyl chloride 4 afforded the γ-alkylidenebuteno-
lide 5 in 76% yield with very good regioselectivity and
Z-selectivity.
The chemoselective alkylation of the R-hydroxy group
proved problematic: reaction of 5 with allyl bromide in the
presence of K2CO3 afforded the desired allylated butenolide
6a, however, in only 22% yield. The low yield can be
explained by the general base lability of the Michael position
of γ-alkylidenebutenolides.6f The use of 2-bromo-3-butene
resulted in formation of an inseparable mixture of products,
presumably due to decomposition and competing SN/SN′
reactions. The problem could be eventually solved by the
use of the Mitsunobu reaction: treatment of 5 with allylic
alcohol, 2-hydroxy-3-butene, and 3-hydroxy-1-pentene in the
presence of PPh3/DEAD afforded the corresponding allylated
butenolides 6a-c in good yields with very good chemose-
lectivities.10 The chemoselective alkylation of γ-alkylidene-
butenolides has to our knowledge not been reported so far.11
To our satisfaction, the ring-closing metathesis (RCM)12 of
6a-c using the Grubbs catalyst 7 proceeded uneventfully
(7) For medium-ring ethers, see: (a) Altenbach, H.-J. In Organic
Synthesis Highlights; Mulzer, J., Altenbach, H.-J., Braun, M., Krohn, K.,
Reissig, H.-U., Ed.; VCH: Weinheim, 1991. (b) Nicolaou, K. C.; Hwang,
C.-K.; Marron, B. E.; DeFrees, S. A.; Couladouros, E. A.; Abe, Y.; Carroll,
P. J.; Snyder, J. P. J. Am. Chem. Soc. 1990, 112, 3040 and cited literature.
(c) Overman, L. E. Acc. Chem. Res. 1992, 25, 358. (d) Brandes, A.;
Hoffmann, H. M. R. Tetrahedron 1995, 51, 145. (e) Alvarez, E.; Diaz, M.
T.; Perez, R.; Ravelo, J. L.; Regueiro, A.; Vera, J. A.; Zurita, D.; Martin,
J. D. J. Org. Chem. 1994, 59, 2848. (f) Robinson, R. A.; Clark, J. S.;
Holmes, A. B. J. Am. Chem. Soc. 1993, 115, 10400. (g) Paquette, L. A.;
Sweeney, T. J. Tetrahedron 1990, 46, 4487.
(8) Langer, P.; Stoll, M. Angew. Chem. 1999, 111, 1919; Angew. Chem.,
Int. Ed. 1999, 38, 1803. (b) Langer, P.; Krummel, T. Chem. Commun. 2000,
967. (c) Langer, P.; Eckardt, T. Synlett 2000, 844.
(9) (a) Krohn, K.; Ostermeyer, H.-H.; Tolkiehn, K. Chem. Ber. 1979,
112, 2640-2649. (b) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980,
102, 3534. (c) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993,
115, 830.
(10) Representative experimental procedure: To a degassed THF
solution (6 mL) of 5 (240 mg, 1.1 mmol), 3-hydroxy-1-pentene (114 mg,
1.32 mmol), and PPh3 (347 mg, 1.32 mmol) was added a THF solution (2
mL) of DEAD (0.205 mL, 1.32 mmol). The solution was stirred at 20 °C
for 14 h. The solvent was removed in vacuo, and the residue was purified
by chromatography (silica gel, ether: petroleum ether ) 1:3) to give 6c as
a light yellow oil (180 mg, 56%). 1H NMR (CDCl3, 250 MHz): 0.95, 1.28
(2 × t, J ) 7 Hz, 2 × 3 H, 2 × CH3), 1.75 (m, 2 H, CHCH2), 3.10 (m, 2
H, CCH2CHdCH), 4.22 (q, J ) 7 Hz, 2 H, OCH2CH3), 5.00-5.40 (m, 5
H, CHCdO, 2 × CHdCH2), 5.60-5.90 (m, 2 H, CHdCH2).13C NMR
(CDCl3, 62.5 MHz): δC 9.15, 14.16, 26.50, 28.03, 60.69, 82.99, 96.86,
117.56, 119.05, 129.61, 132.18, 136.27, 144.60, 155.46, 162.49, 163.37.
MS (70 eV, EI): 292 (20, M+). Anal. Calcd for C16H20O5: C 65.74, H
6.90. Found: C 65.56, H 7.10. All new compounds were characterized
spectroscopically and gave correct elemental analyses and/or high-resolution
mass spectra.
(11) For Mitsunobu reactions of tetronic acid derivatives, see: Bajwa,
J. S.; Anderson, R. C. Tetrahedron Lett. 1990, 48, 6973.
2992
Org. Lett., Vol. 2, No. 19, 2000

and afforded the bicyclic γ-alkylidenebutenolides 8a-c in
(95%) which was transformed into the 1,3-bis(trimethyl-
silyloxy)-1,3-butadiene 13 in 86% yield. Cyclization of 13
good yields (Scheme 1).13
The application of the RCM reaction to the formation of
medium-sized rings is of great current interest, and only a
few examples have been reported so far.14 Therefore, we have
studied the synthesis of butenolide-ring ether hybrids
containing medium-sized rings. Reaction of γ-alkylidene-
butenolide 5 with 1-hydroxy-3-butene and 1-hydroxy-4-
pentene afforded the cyclization precursors 9a and 9b,
respectively, in good yields. Ring-closing metathesis of 9a,b
afforded the bicyclic butenolides 10a,b containing an eight-
and a nine-membered ring, respectively, in acceptable yields
(Scheme 2).
Scheme 3
Scheme 2
with oxalyl chloride afforded the γ-alkylidenebutenolide 14
in 72% yield with very good regioselectivity and Z-
selectivity. Mitsunobu reaction of 14 with allylic alcohol
afforded the cyclization precursor 15. Ring-closing metathesis
of 15 using catalyst 7 afforded the medium-sized bicyclic
butenolide 16 which represents a positional isomer of
butenolide 10a.
Reaction of the dianion of ethyl acetoacetate with 1-bromo-
3-butene afforded ethyl 3-oxooct-7-enoate 11 in 88% yield
(Scheme 3). Silylation of 11 afforded the silyl enol ether 12
In summary, we have developed a new and efficient
synthesis of bicyclic butenolides containing a medium-sized
ring ether moiety. In this context, the first chemoselective
alkylation of γ-alkylidenebutenolides was developed. The
medium-sized rings were prepared in acceptable to good
yields by ring-closing metathesis. The bicyclic products
prepared represent hybrids of γ-alkylidenebutenolides and
medium-ring ethers. These substance classes are of phar-
macological relevance and occur in a variety of natural
products.
(12) Reviews: (a) Schuster, M.; Blechert, S. Angew. Chem. 1997, 109,
2124; Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (b) Armstrong, S. K.
J. Chem. Soc., Perkin Trans. 1 1998, 371. (c) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (d) Fu¨rstner, A. Synlett 1999, 1523.
(13) Representative experimental procedure: To a degassed benzene
solution (8 mL) of butenolide 6c (0.23 mmol, 66 mg) was added catalyst
7 (19 mg, 10 mol %). The solution was stirred for 12 h under argon and
for 4 h at the air. The solvent was removed in vacuo, and the residue was
purified by chromatography (silica gel, ether: petroleum ether ) 1:1) to
1
give 8c as a light yellow oil (28 mg, 60%). H NMR (CDCl3, 200 MHz):
δ 1.05, 1.31 (2 × t, J ) 7 Hz, 2 × 3 H, OCH2CH3), 1.85 (m, 2 H, CH2),
2.93 (dd, J ) 17 Hz, J ) 7 Hz, 1 H, CCH2CHdCH), 2.45 (dt, J ) 17 Hz,
J ) 3 Hz, 1 H, CCH2CHdCH), 4.22 (q, J ) 7 Hz, 2 H, OCH2CH3), 5.25
(s, 1 H, CHCdO), 5.85, 6.10 (2 × m, 2 × 1 H, CHdCH). 13C NMR (CDCl3,
62.5 MHz): δC 9.31, 14.21, 22.60, 27.62, 60.78, 80.14, 95.59, 120.57,
131.23, 131.86, 146.74, 156.30, 162.81, 163.44. MS (70 eV, EI): 264 (100,
M+). Anal. Calcd for C14H16O5: C 63.63, H 6.10. Found: C 63.35, H 6.32.
(14) For an account of the synthesis of medium-sized rings by RCM,
see: (a) Maier, M. E. Angew. Chem. 2000, 112, 2153; Angew. Chem., Int.
Ed. 2000, 39, 2073. See also: (b) Crimmins, M. T.; Choy, A. L. J. Am.
Chem. Soc. 1999, 121, 5653. (c) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.;
Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 2108.
Acknowledgment. P.L. thanks Professor A. de Meijere
for his support. Financial support from the Fonds der
Chemischen Industrie (Liebig-scholarship and funds for P.L.)
and the Deutsche Forschungsgemeinschaft is gratefully
acknowledged.
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