Synthesis of Furanophane Derivatives through [8+2]-Cycloaddition of Dienylisobenzofurans and Alkynes

Article abstract of DOI:10.1021/ja037500n

The coupling of various dienylisobenzofurans with dimethyl acetylenedicarboxylate (DMAD) has been examined. In most cases, this reaction proceeds via [8+2]-cycloaddition to afford furan-bridged decatetraene ring systems. The major competing reaction pathw

Full text of DOI:10.1021/ja037500n

Published on Web 09/26/2003
Synthesis of Furanophane Derivatives through [8+2]-Cycloaddition of
Dienylisobenzofurans and Alkynes
Yumei Luo,† James W. Herndon,*,† and Francisco Cervantes-Lee‡
Department of Chemistry and Biochemistry, New Mexico State UniVersity, MSC 3C,
Las Cruces, New Mexico 88003, and Department of Chemistry, UniVersity of Texas at El Paso,
El Paso, Texas 79968
Received July 23, 2003; E-mail: jherndon@nmsu.edu
The [8+2]-cycloaddition reaction1,2 is a potentially powerful
Table 1. Three-Component Coupling of Alkynylbenzophenones
(1), Carbene Complexes (2), and DMAD
method for the preparation of 10-membered ring systems, although
1
2
3
4
entrya reactants
R
R
R
R
4
5
it has been restricted to examples where carbons 1 and 8 of the
tetraene are rigidly held in close proximity.3 Although these
cycloadditions involve the interaction of 10 π-electrons spread over
10 carbon atoms, the net result in most cases is merely appendage
of a five-membered ring onto a preexisting ring.4 In this manuscript,
the [8+2]-cycloaddition reaction between variously generated
dienylisobenzofurans (e.g., 3, Scheme 1) and dimethyl acetylene-
dicarboxylate (DMAD) leading to the 11-oxabicyclo[6.2.1]undecane
ring system (e.g., 4) is reported. This represents the first generally
successful [8+2]-cycloaddition reaction for conformationally flex-
ible tetraene systems. The 11-oxabicyclo[6.2.1]undecane ring
system is a key structural feature of many compounds collectively
known as 2,11-cyclized cembranoids or cladiellanes.5 Many of these
compounds display potent biological activity, including antiinflam-
matory and antitumor activity. The reaction in Scheme 1 results in
direct synthesis of the complete ring skeleton of the eunicellin
diterpenes in a single step.6
A
B
C
D
E
F
1A + 2A Bu
1B + 2A Me
Ph
Ph
Ph
R3,4 ) -(CH2)3-
R3,4 ) -(CH2)3-
R3,4 ) -(CH2)3-
R3,4 ) -(CH2)3-
76% 3%
61% 0%
72% 9%
5% 62%
45% 30%
56% 19%
1C + 2A
H
1D + 2A TMS Ph
1E + 2A Bu
1A + 2B Bu
1A + 2C Bu
2-benzofuryl R3,4 ) -(CH2)3-
Ph
Ph
Me
H
G
R3,4 ) -O(CH2)3- 39% 0%
a Table entry letters correlate with the substituent letters for compounds
3-5.
Initial studies have focused on generation of dienylisobenzofuran
intermediates through the coupling of R,â-unsaturated Fischer
carbene complexes (2) with 2-alkynylbenzophenone derivatives (1).7
The relatively stable nature of 1-phenyl-3-alkenylisobenzofuran
intermediates and their subsequent trapping through Diels-Alder
reactions had previously been demonstrated. Prior to the initiation
of these studies involving R,â-unsaturated carbene complexes,
anticipated reaction pathways included: (1) the Do¨tz benzannulation
reaction resulting in ketone 6,8 and (2) isobenzofuran formation
followed by Diels-Alder reaction resulting in 5. Surprisingly, the
coupling of alkenylcarbene complex 2A (entry A of Table 1, see
Table 1 for correlation of substituent letters with R1-4) with
benzophenone 1A, followed by addition of DMAD afforded
predominantly the [8+2]-cycloadduct 4A (76%) and only a minor
amount (3%) of the Diels-Alder product 5A. Compound 6A was
not observed in the reaction mixture. The indicated stereochemistry
results from suprafacial addition as is predicted on the basis of
orbital symmetry considerations.2 Crystals suitable for X-ray
analysis could be obtained for closely related structural analogue
4B (Figure 1). The 11-oxabicyclo[6.4.1]-undeca-1,3,6,9-tetraene
ring system has no precedent; however, related examples of
6-carbon-bridged furanophane ring systems have been reported.9
Notable sources of strain in this ring system include: (1) twisting
of the alkene exocyclic to the furan ring by 14°, and (2) deviation
of the endocyclic bond angles at the asterisked carbons by 11°
greater than ideal.
Figure 1. Crystal structure for compound 4B.
of DMAD) were tested (Table 1). The remaining examples were
assigned on the basis of spectral similarity to compound 4B. In all
cases except entry D, the [8+2]-cycloadduct was the major product.
This failure can be attributed to a steric effect. The energy-
minimized (RHF/6-31G) conformation for isobenzofuran intermedi-
ate 3D features orthogonal enol ether and isobenzofuran groups,
versus a more planar orientation in 3C. An orthogonal orientation
between the enol ether and isobenzofuran would prevent [8+2]-
cycloaddition. The selectivity for the [8+2]-cycloadduct was
noticeably lower using the benzofuranyl ketone derivative 1E and
for the example using the 2-propenylcarbene complex 2B in entry
F. The relatively unstable carbene complex 2C afforded a lower
overall yield of adducts (entry G); however, only the [8+2]-
cycloadduct was observed.
Several examples of this reaction using the optimized conditions
(alkyne carbene coupling in dioxane at 85 °C followed by addition
To determine if chromium has a unique role,10 non-chromium-
based methods for the generation of dienyl-isobenzofuran inter-
mediates were tested.11 Keto alcohol 8 (Scheme 2) was prepared
† New Mexico State University.
‡ University of Texas at El Paso.
9
12720
J. AM. CHEM. SOC. 2003, 125, 12720-12721
10.1021/ja037500n CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
Scheme 2
References
(1) First report: Doering, W. v. E.; Wiley, D. W. Tetrahedron 1960, 11, 183-
198.
(2) Mechanistic work: (a) Liu, C. Y.; Ding, S. T. J. Org. Chem. 1992, 57,
4539-4544. (b) Liu, C. Y.; Houk, K. N. Tetrahedron Lett. 1987, 28,
1371-1374. (c) Daub, J.; Hirmer, G.; Kakob, L.; Maas, G.; Pickl, W.;
Pirzer, E.; Rapp, K. M. Chem. Ber. 1985, 118, 1836-1856. (d) Bau¨mler,
A.; Daub, J.; Pickl, W.; Rieger, W. Chem. Ber. 1985, 118, 1857-1867.
(e) Hayakawa, K.; Nishiyama, H.; Kanematsu, K. J. Org. Chem. 1985,
50, 512-517.
(3) Most examples involve alkylidenecycloheptatrienes or indolizines as the
8π-component. (a) For the most recent example using alkylidenecyclo-
heptatrienes, see: Pham, W.; Weissleder, R.; Tung, C. H. Tetrahedron
Lett. 2002, 43, 19-20. (b) For the most recent example using indolizines,
see: Babaev, E. V.; Simonyan, V. V.; Pasichnichenko, K. Y.; Nosova,
V. M.; Kisin, A. V.; Jug, K. J. Org. Chem. 1999, 64, 9057-9062.
(4) We are aware of a single example involving six-membered ring formation.
Farrant, G. C.; Feldmann, R. Tetrahedron Lett. 1970, 11, 4979-4982.
(5) For a review, see: Bernardelli, P.; Paquette, L. A. Heterocycles 1998,
49, 531-556.
in four steps12 from readily available bromo-diene 7.13 Compound
8, which appears to be predominantly hemiketal, converted to
yellow isobenzofuran 9 upon attempted purification on silica gel.14
Treatment of compound 9 with DMAD led to the expected [8+2]-
cycloadduct 10 in 64% yield as the exclusive product.
In summary, a novel method for the synthesis of furanophanes
has been developed, which might be applicable to all dienylisoben-
zofurans, no matter how they are generated. This reaction is
currently under investigation in this laboratory.
(6) Synthetic work since 2002: (a) Corminboeuf, O.; Overman, L. E.;
Pennington, L. D. J. Am. Chem. Soc. 2003, 125, 6650-6652. (b)
Corminboeuf, O.; Overman, L. E.; Pennington, L. D. Org. Lett. 2003, 5,
1543-1546. (c) Chai, Y.; Vicic, D. A.; McIntosh, M. C. Org. Lett. 2003,
5, 1039-1042. (d) Jung, M. E.; Pontillo, J. J. Org. Chem. 2002, 67, 6848-
6851. (e) Molander, G. A.; Jeffrey, S. C. Tetrahedron Lett. 2002, 43,
359-362.
(7) Jiang, D.; Herndon, J. W. Org. Lett. 2000, 2, 1267-1269.
(8) For recent studies of the Do¨tz reaction using ortho-carbonyl containing
phenylacetylenes, see: Anderson, J. C.; Cran, J. W.; King, N. P.
Tetrahedron Lett. 2002, 43, 3849-3852.
(9) Chen, X. T.; Gutteridge, C. E.; Bhattacharya, S. K.; Zhou, B.; Pettus, T.
R. R.; Hascall, T.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37,
185-187.
(10) Numerous examples of higher order cycloadditions have been reported
for chromium systems. Rigby, J. H. Tetrahedron 1999, 55, 4521-4538.
(11) For a review of isobenzofurans, see: Friedrichsen, W. AdV. Heterocycl.
Chem. 1999, 73, 1-96.
Acknowledgment. This work was supported by the National
Institutes of Health. We thank the mass spectral facilities at U.C.-
Riverside and U. Nebraska for acquisition of mass spectral data.
(12) The sequence involves: (i) conversion to the ester with CO, Pd(0), and
MeOH, (ii) ester hydrolysis and conversion to the Weinreb amide, and
(iii) reaction with 2-LiC6H4C(OLi)Ph.
(13) Sharp, J. T.; Wilson, P.; Parsons, S.; Gould, R. O. J. Chem. Soc., Perkin
Trans. 1 2000, 1139-1148.
Supporting Information Available: Experimental details for
reactions in Table 1 and characterization of major products (PDF). X-ray
data for compound 4B. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) For generation of isobenzofurans from similar precursors, see: Smith, J.
G.; Fogg, D. E.; Munday, I. J.; Sandborn, R. E.; Dibble, P. W. J. Org.
Chem. 1988, 53, 2942-2953.
JA037500N
9
J. AM. CHEM. SOC. VOL. 125, NO. 42, 2003 12721