Synthesis of furan-bridged 10-membered rings through [8 + 2]-cycloaddition of dienylfurans and acetylenic esters

Article abstract of DOI:10.1021/ol050416n

(Chemical Equation Presented) The coupling of various dienylfurans with dimethyl acetylenedicarboxylate (DMAD) has been examined. In most cases this reaction proceeds via [8 + 2]-cycloaddition to afford furan-bridged 10-membered ring systems as a single d

Full text of DOI:10.1021/ol050416n

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1665-1667
Synthesis of Furan-Bridged
10-Membered Rings through
[8
+ 2]-Cycloaddition of Dienylfurans
and Acetylenic Esters
Lei Zhang, Yu Wang, Clare Buckingham, and James W. Herndon*
New Mexico State UniVersity, Department of Chemistry and Biochemistry, MSC 3C,
Las Cruces, New Mexico 88003
jherndon@nmsu.edu
Received February 25, 2005
ABSTRACT
The coupling of various dienylfurans with dimethyl acetylenedicarboxylate (DMAD) has been examined. In most cases this reaction proceeds
via [8 2]-cycloaddition to afford furan-bridged 10-membered ring systems as a single diastereomer. Dienylfuran intermediates were generated
+
using either a chromium carbene-based method or aldol-based methods. Reaction of [8
selectively at the enol ether alkene.
+ 2]-cycloadducts with electrophilic reagents occurred
Furan-bridged 10-membered ring systems are commonly
found in a variety of coral-derived cytotoxic compounds.1
The most potent anticancer agent possessing this substructure
is eleutherobin (1, Scheme 1), which is active against a
variety of cancer cell lines at nanomolar concentrations and
operates through stabilization of microtubules. Eleutherobin
is obtained in low yield from a rare coral species,2 and two
elegant but lengthy total syntheses of eleutherobin have been
reported.3 Much of the drug development effort has centered
on evaluation of the minimal pharmacophore requirements
through examination of analogues4 and the preparation of
simpler analogues through organic synthesis.5 A recently
reported reaction, the [8 + 2]-cycloaddition reaction6 between
dienylisobenzofuran derivatives (e.g., 4) and dimethyl acety-
(3) (a) Nicolaou, K. C.; Ohshima, T.; Hosokawa, S.; Van Delft, F. L.;
Vourloumis, D.; Xu, J. Y.; Pfefferkorn, J.; Kim, S. J. Am. Chem. Soc. 1998,
120, 8674-8680. (b) Chen, X. T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge,
C. E.; Pettus, T. R. R.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121,
6563-6579. (c) A formal total synthesis has also been reported. Ritter, N.;
Metz, P. Synlett 2003, 2422-2424.
(4) (a) McDaid, H. M.; Bhattacharya, S. K.; Chen, X. T.; He, L.; Shen,
H. J.; Gutteridge, C. E.; Horwitz, S. B.; Danishefsky, S. J. Cancer
Chemother. Pharmacol. 1999, 44, 131-137. (b) Cinel, B.; Roberge, M.;
Behrisch, H.; van Ofwegen, L.; Castro, C. B.; Andersen, R. J. Org. Lett.
2000, 2, 257-260. (c) Roberge, M.; Cinel, B.; Anderson, H. J.; Lim, L.;
Jiang, X.; Xu, L.; Bigg, C. M.; Kelly, M. T.; Andersen, R. J. Cancer Res.
2000, 60, 5052-5058. (d) Britton, R.; Dilip de Silva, E.; Bigg, C. M.;
McHardy, L. M.; Roberge, M.; Andersen, R. J. J. Am. Chem. Soc. 2001,
123, 8632-8633. (e) Diederichsen, U. Org. Synth. Highlights V 2003, 317-
325.
(1) For a review, see: Bernardelli, P.; Paquette, L. A. Heterocycles 1998,
49, 531-556.
(2) (a) The yield is 0.01% dry weight. Lindel, T.; Jensen, P. R.; Fenical,
W.; Casazza, A. M.; Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997,
119, 8744-8745. (b) Production of eleutherobin through aquaculture has
recently been reported. Taglialatela-Scafati, O.; Deo-Jangra, U.; Campbell,
M.; Roberge, M.; Andersen, R. J. Org. Lett. 2002, 4, 4085-4088.
(5) (a) Chandrasekhar, S.; Jagadeshwar, V.; Narsihmulu, C.; Sarangapani,
M.; Krishna, D. R.; Vidyasagar, J.; Vijay, D.; Sastry, G. N. Bioorg. Med.
Chem. Lett. 2004, 14, 3687-3689. (b) Caggiano, L.; Castoldi, D.; Beumer,
R.; Bayon, P.; Telser, J.; Gennari, C. Tetrahedron Lett. 2003, 44, 7913-
7919. (c) Beumer, R.; Bayon, P.; Bugada, P.; Ducki, S.; Mongelli, N.; Sirtori,
F. R.; Telser, J.; Gennari, C. Tetrahedron Lett. 2003, 44, 681-684.
10.1021/ol050416n CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/18/2005

of this isomeric mixture with DMAD led to [8 + 2] (8) and
isomerized [4 + 2] cycloadducts (7) in a nearly 1:1 ratio.
Since the [8 + 2]-cycloadduct can only arise from the pure
Z isomer of the dienylfuran 6, the process will likely be more
efficient if stereochemically pure Z dienylfurans are em-
ployed. Stereochemically pure dienylfuran derivatives could
be obtained through the coupling of conjugated enyne-
carbonyl systems (10, Table 1) and R,â-unsaturated Fischer
Scheme 1
Table 1. Synthesis of [8 + 2]-Cycloadducts through
Three-Component Coupling of Carbene Complex 3, Enyne 10,
and DMAD
lenedicarboxylate (DMAD)7 provides an incredibly simple
entry into furan-bridged ten-membered rings (e.g., 5). The
benzo fusion required in this transformation is a serious
impediment to use of this reaction for synthesis of eleuthero-
bin derivatives or the related eunicellins; however, benzo
fusion provides tremendous activation for the [8 + 2]-cy-
cloaddition reaction in Scheme 1.8 In this paper, we report
that simple furandienes lacking the isobenzofuran activation
are excellent substrates for this reaction, providing rapid
access to the central ring system of eleutherobin.
entry
R1
R2
R3
R4
furan (%) [8 + 2] (%)
A
B
C
D
E
F
G
n-Bu R2,3 ) Ya
n-Bu R2,3 ) Ya
n-Bu R2,3 ) Ya
n-Bu Ph
n-Bu t-Bu
H
H
H
Me
H
H
64b
78
78c
58b
0c
H
H
H
H
72
74
0c
t-Bu
H
H
62b
60b
The coupling of 2-butadienylfuran (6, Scheme 2) with
DMAD was examined for the preliminary evaluation of
TMS
H
a Y ) -(CCH2)3-. b Yield for a one-pot reaction involving furan
formation and [8 + 2]-cycloaddition. c Yield for [8 + 2]-cycloaddition only.
Scheme 2
carbene complex 3.10,11 The oxygenated dienylfurans (11)
from this reaction were only moderately stable. Treatment
of isolated compound 11 (entry B) with DMAD led to the
[8 + 2]-cycloadduct 12 as the exclusive product of the
reaction. A one-pot procedure involving heating a mixture
of carbene complex and enynecarbonyl compound followed
by addition of DMAD was more efficient for the production
of [8 + 2]-cycloadducts. As noted in Table 1, the process
appears to be quite general. The reaction successfully
afforded [8 + 2] cycloadducts as the exclusive reaction
products in all cases except entries D and E. In these cases,
a steric effect between the bulky R1 and R2 group inhibit
formation of the conformation required for concerted
[8 + 2]-cycloaddition. When the n-butyl group in entry E
was replaced by H (entry F) the reaction was successful.
Additional stereochemically pure Z furan dienes (13, Table
2) were also prepared, and their reaction with electron-
deficient alkynes was examined. As noted in these examples,
dienylfurans as 8π components in cycloaddition reactions.
Compound 6 was easily prepared through the Wittig reaction
as a nearly 1:1 mixture of E and Z isomers.9 Thermal reaction
(6) The [8 + 2]-cycloaddition reaction has been primarily restricted to
substrates where carbons 1 and 8 of the tetraene system are rigidly held in
close proximity (e.g., methylenecycloheptatrienes). For a review, see: Nair,
V.; Anilkumar, G. Synlett 1998, 950-957.
(7) Luo, Y.; Herndon, J. W.; Cervantes-Lee, F. J. Am. Chem. Soc. 2003,
125, 12720-12721.
(8) (a) The greatly enhanced reactivity of isobenzofurans (relative to
furans) in cycloaddition reactions is well documented. Friedrichsen, W. AdV.
Heterocycl. Chem. 1999, 73, 1-96. (b) Ab initio calculations show that
∆E for the [8 + 2]-reaction of butadienylisobenzofuran and acetylene is
-51 kcal/mol, while ∆E for [8 + 2]-reaction of butadienylfuran and
acetylene is -22 kcal/mol.
(9) Ben Attra, T.; Le Bigot, Y.; El Gharbi, R.; Delmas, M.; Gaset, A.
Synth. Commun. 1992, 22, 1421-1425.
(10) Herndon, J. W.; Wang, H. J. Org. Chem. 1998, 63, 4564-4565.
(11) For a discussion of enol ether stereochemistry in chromium carbene-
alkyne couplings, see: McCallum, J. S.; Kunng, F. A.; Gilbertson, S. R.;
Wulff, W. D. Organometallics 1988, 7, 2346-2360.
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Org. Lett., Vol. 7, No. 8, 2005

electrophiles. As expected, the bridgehead enol ether was
the most reactive of the four alkenes in 14a. Treatment of
[8 + 2]-cycloadduct 14a with methanol and acid led to the
ketal 15 (Scheme 3) as a single diastereomer.13 A ring-
Table 2. Coupling of Dienylfurans with Acetylenic Esters
Scheme 3
entry
R1
R2
R3
R4
R5 R6
R7
14 (%)
A
B
C
D
E
F
H
Me
R2,3 ) Za
R2,3 ) Za
H
H
H
H
H
H
H
H
H
H
E
E
E
E
E
E
84
77
79
81c
0
OMe R2,3 ) Za
H
H
H
R2,3 ) Za
R2,3 ) Za
H
E′b COMe
H
E
E
E
H
R4,5 ) Za
56
a Y ) -(CH2)4-. b E′ ) COOEt. c The regioisomer where R6 and R7
are reversed was obtained in 6% yield.
expansion product (16) was obtained through treatment of
[8 + 2]-cycloadduct 14a with dichlorocarbene.14
In summary, the use of simple dienylfurans as 8π-
components in [8 + 2]-cycloadditions has been demonstrated
for a variety of furandienes. The parent ring system of a
variety of biologically active coral-derived natural products
is produced in a single step from readily available compo-
nents. Subsequent reaction of the cycloadducts with elec-
trophilic reagents is highly selective, occurring exclusively
at the bridgehead double bond. Further study of the scope
and limit of this reaction is currently underway in our
laboratory.
the reaction is tolerant of substitution within the furan ring,
and the [8 + 2]-cycloadduct 14 was obtained as the exclusive
product in all of the cases examined. The reaction is
apparently restricted to alkynes that contain two electron-
withdrawing groups. The reaction employing the ester-ketone
substituted alkyne was remarkably regioselective, resulting
in predominantly a single isomer (entry D).12 The reaction
was more efficient in the system where the cyclohexyl fusion
was within the central alkene (entries A-D) than in the one
example employing cyclohexyl fusion at the distal alkene
(entry F). This can likely be attributed to the more exposed
diene-enol ether system of the product, which was unstable
on silica gel and completely decomposed after storage in
the refrigerator for 2 weeks in a frozen benzene matrix. The
relative reactivity of the compounds where R2,3 ) -(CH2)4-,
R1 ) H (13a) or OMe (13c) was also tested. Reaction of an
excess of these compounds with 1 mol of DMAD led to a
2:1 ratio of the [8 + 2]-cycloadducts 14a/14c, indicating that
steric deactivation by the methoxy group is more important
than its electronic activation.
Acknowledgment. This research was supported by the
NIH SCORE Program.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds in Scheme 2
and Tables 1 and 2. Photocopies of spectra for [8 + 2]-
cycloadducts and the products in Scheme 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050416N
The chemistry of the [8 + 2]-cycloadducts was briefly
probed through reaction of cycloadduct 14a with select
(13) The product was assigned as the syn double bond addition product
derived through protonation and addition of methoxy from the convex face.
This isomer is slightly more stable than the anti isomer; ∆E syn to anti is
+0.3 kcal/mol in a simplified analogue of 15 according to ab intio
calculations. Trans-bridged furanophanes were not considered due to
excessive strain in these systems revealed by MM2 calculations.
(14) Parham, W. E.; Soeder, R. W.; Throckmorton, J. R.; Kuncl, K.;
Dodson, R. M. J. Am. Chem. Soc. 1965, 87, 321-328.
(12) A calculation at the 6-31G* level reveals that the regiochemistry
of the [8 + 2]-cycloaddition reaction is consistent with that predicted by
the MO coefficients of the energy-minimized (s-trans) conformation. There
is a higher coefficient at the furan terminus of the tetraene system (0.24)
than at the diene terminus (-0.21). This calculation was very dependent
on the choice of basis set.
Org. Lett., Vol. 7, No. 8, 2005
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