Enantiocontrolled construction of tricyclic furan derivatives via an asymmetric Diels-Alder reaction

Article abstract of DOI:10.1021/ol015622j

(equation presented) The two enantiomers of trycyclic furan derivatives were prepared respectively from Diels-Alder reactions of oxycyclic dienes 3a and 3b, followed by degradation of the 2-(benzyloxy)ethyl group. Compounds 3a and 3b can be selectively synthesized by [3+2]-cycloaddition of vinylpropargyltungsten complex with (2S)-(benzyloxy)-propanal.

Full text of DOI:10.1021/ol015622j

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1295-1298
Enantiocontrolled Construction of
Tricyclic Furan Derivatives via an
Asymmetric Diels−Alder Reaction
Chung-Cheng Pai and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity,
Hsinchu, Taiwan, 30043, ROC
rsliu@mx.nthu.edu.tw
Received January 29, 2001
ABSTRACT
The two enantiomers of trycyclic furan derivatives were prepared respectively from Diels−Alder reactions of oxycyclic dienes 3a and 3b,
followed by degradation of the 2-(benzyloxy)ethyl group. Compounds 3a and 3b can be selectively synthesized by [3+2]-cycloaddition of
vinylpropargyltungsten complex with (2S)-(benzyloxy)-propanal.
Tricyclic furan derivatives are often found in naturally
occurring compounds.1,2 Shown in Scheme 1 are compounds
tions4 of chiral oxacyclic dienes 3a and 3b which are useful
building blocks for enantiopure tricyclic furans. The 2-(ben-
zyloxy)ethyl group remaining after the cycloaddition can be
transformed into an acetate group efficiently (vide infra).
Scheme 1
We previously reported a facile [3+2]-cycloaddition of
propargyltungsten compounds with aldehydes to yield tung-
(1) (a) Appel, H. H.; Bond, R. P. M.; Overton, K. H. Tetrahedon. 1963,
19. 635. (b) Okuda, R. K.; Scheuer P. J. J. Org. Chem. 1983, 48, 1866. (c)
Butler, M. S.; Capon, R. J. Aust. J. Chem. 1993, 46, 1255.
(2) (a) Jansen, B. J. M.; Groot, Ae. De Nat. Prod. Rep. 1991, 8. 309. (b)
Pascual, T. J.; Urones, J. G.; Marcos, I. S.; Diez, D.; Monje, V. A.
Phytochemistry 1986, 25, 711.
(3) (a) Urones, J. G.; Marcos, I. S.; Belen, G.-P.; Lithgow, A. M.; Diez,
D.; Basabe, P.; Gomez, P. M. Tetrahedron Lett. 1994, 35, 3781. (b)
Kanematsu, K.; Soejima, S. Heterocycles 1991, 32, 1483. (c) Ley, S. V.;
Mahon, M. Tetrahedron Lett. 1981, 22, 4747. (d) Baba, Y.; Sakamoto, T.;
Soijima, S.; Kanematsu, K. Tetrahedron 1994, 50, 5645. (e) Nakano, T.;
Maillo, M. A. J. Chem. Soc., Perkin Trans. 1 1987, 2137. (f) Howell, S.
C.; Ley, S. V.; Mahon, M. J. Chem. Soc., Chem. Commun. 1981, 507. (g)
Barrero, A. F.; Alvarez-Manzanefa, E.; Altarejos, J.; Salido, S.; Ramos, J.
M. Tetrahedron Lett. 1994, 35, 2945. (h) Hueso-Rodriguez, J. A.; Rodriguez,
B. Tetrahedron Lett. 1989, 30, 859. (I) Jalani-Naini, M.; Guillerm, D.;
Lallemand, J.-Y. Tetrahedron 1983, 39, 749.
A-D, which represent families of drimane sesquiterpenes
isolated from different marine sources.1,2 These natural
oxygen heterocycles have attracted considerable synthetic
attention; many of them involve semi- or racemic syntheses.3
In this study we report the syntheses and Diels-Alder reac-
(4) Janey, J. M.; Iwama, T.; Kozmin, S. A.; Rawal, V. H. J. Org. Chem.
2000, 65, 9059.
10.1021/ol015622j CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/04/2001

sten-2,5-dihydrofur-3-yl complexes.5 The reaction is pro-
posed to involve a zwitterionic intermediate. To highlight
the utility of this cyclization, we prepared (2S)-2-(benzy-
loxy)propanal (ee ) 98%) according to literature reports.6
Cycloaddition of this chiral aldehyde with vinylpropargyl-
tungsten complex 1 proceeded smoothly in the presence of
Lewis acid to give a mixture of two diastereomeric products
2-syn/2-anti. These two products were separable by column
chromatography and the isolated yields are summarized in
Scheme 2. TiCl4 and SnCl4 lead to syn-selectivity via metal
Table 1. Asymmetric Diels-Alder Reaction of 3a and 3b with
Dienophilesa
Scheme 2
chelation7 of the aldehyde and benzyloxy group whereas BF3‚
Et2O results in the anti-selectivity following a Felkin-Ann
model. The configurations of 2-anti and 2-syn were con-
firmed by X-ray diffraction studies of their Diels-Alder
cycloadducts. Vigorous efforts were made for hydrodemeta-
lation of 2a-syn and 2-anti to obtain the desired oxacyclic
dienes 3a and 3b. We found that m-CPBA oxidation of 2a-
anti and 2a-syn in CH2Cl2 effected hydrodemetalation to
afford 3a and 3b in 83% and 85% yields, respectively. No
1
other byproducts were found according to the H NMR
spectra of the crude products. In our synthetic protocol, the
2-(benzyloxy)ethyl substituent of 3a and 3b is the degradable
group for subsequent Diels-Alder reaction.
a Condition A: BF3‚Et2O (1.0 equiv), 23 °C, CH2Cl2 -78 °C to 23 °C.
Condition B: toluene, 80 °C.
We first examined the cycloaddition of oxacyclic diene
3a with cyclohexenone in hot toluene (Table 1, entry 1).
Three stereoisomers ca. 10:3:1 were obtained in a combined
yield of 86%. Fractional crystallization of this mixture gave
the major diastereomer 4a in only 23% yield. This problem
can be circumvented with the use of BF3‚Et2O which effected
the cycloaddition at 23 °C, yielding a single diastereomer
4a in 63% yield after recrystallization. The configuration of
(5) (a) Wang, S.-H.; Shiu, L.-H.; Liao, Y.-L.; Wang, S.-L.; Lee, G.-H.;
Peng, S. M.; Liu R.-S. J. Am. Chem. Soc. 1996, 118, 530. (b) Shieh, S.-J.;
Tang, T.-C.: Lee, J.-S., Lee, G.-H., Peng, S.-M.; Liu, R.-S. J. Org. Chem.
1996, 61, 3245.
(6) Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50, 3247.
(7) (a) Burke, S. D.; Deaton, D. N.; Olsen, R. J.; Armistead, D. M.;
Blough B. E. Tetrahedron Lett. 1987, 28, 3905. (b) Comins, D. L.; Herrick,
J. J. Tetrahedron Lett. 1983, 48, 2775.
1
4a was determined by H NOE spectroscopy summarized
in Scheme 3. The regiochemistry is inferred from the H3
proton (δ 3.12), which shows a quartet (dd, J ) 10.0, 8.2
Hz), whereas the H4 proton (δ 1.84) shows a complex
multiplet. The structure of 4a indicates that cyclohexenone
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Org. Lett., Vol. 3, No. 9, 2001

Scheme 3
Scheme 4
approaches the diene 3a in an endo fashion but opposite to
the (benzyloxy)ethyl substituent. This stereoselectivity is
remarkable since eight isomers are likely to occur. BF3‚Et2O
also effected asymmetric cycloaddition of 3a with benzo-
quinone and cyclopentenone (CH2Cl2, 23 °C) to afford
compounds 5a and 6a in 72% and 67% yields, respectively,
after a single crystallization (entries 2-3). The reaction of
3a with N-phenylmaleimide and maleic anhydride proceeded
smoothly in hot toluene (80 °C, 3 h), yielding 7a and 8a
exclusively. In entry 5, the products consist of a 6:1
diastereomeric mixture, finally affording pure 8a in 67%
yield after crystallization.
Shown in Table 1 are the results of asymmetric Diels-
Alder reactions of the oxacyclic diene 3b with the same
olefins. Using the same approach, the cycloadducts 4b-8b
were obtained as one diastereomer (64-93% yields) after
purification by recrystallization. These results indicate that
the (benzyloxy)ethyl substituent of 3b is equally effective
as that of 3a in the asymmetric cycloadditions. In entry 10,
the maleic adduct is a 13:1 diastereomeric mixture (96%
combined yields). Crystallization of this mixture gave pure
anhydride 8b in 86% yield. Determination of the stereo-
chemistry relies on 1H NOE effect as well as X-ray
diffraction studies of 5b and 8b.8,9 Again, the observed
stereoselectivities were attributed to the endo-facial cycload-
dition and the steric effect of the 2-(benzyloxy)ethyl sub-
stituent.
afforded the ketone 9 in 82% overall yield. The molecular
structure of 910 was determined by an X-ray diffraction study
which reveals that 9 has two cis-configurations in the three
fused rings. Degradation of the acetyl group follows recent
work by Kusumoto11 who reported the alkoxyalkyl group is
more prone to migration than an alkyl group in Baeyer-
Villager oxidations. m-CPBA oxidation of compound 9 gave
the tricyclic lactol 10 in 94% yield. This transformation was
shown to proceed exclusively via retention of stereochem-
istry. Similarly, we also used compound 7b to obtain the
enantiomers of compounds 9 and 10 in good yields.
following the same protocol. The [R] values of the resulting
products ent-9 ([R] ) +19.2, c 4.22, CHCl3) and ent-10 ([R]
) -71.3, c 1.68, CHCl3) match well with those of 9 ([R] )
+19.1, c 1.64, CHCl3) and 10 ([R] ) +71.3, c 1.02, CHCl3),
respectively. HPLC analyses show that ee values of 9 and
ent-9 were 98% and 97%, respectively. The structure of ent-9
was also confirmed by an X-ray study.12
In summary, we used tungsten-mediated [3+2]-cycload-
dition for selective syntheses of enantiopure oxacyclic dienes
3a and 3b. The 2-(benzyloxy)ethyl substituent of 3a and 3b
effected asymmetric Diels-Alder reaction; the cycloadducts
derived from benzoquinone, cyclohexenone, cyclopentenone,
N-phenylmaleimide, and maleic anhydride were obtained as
a single diastereomers in 63-93% yields. We have also
developed an efficient method for transformation of the
2-(benzyloxy)ethyl substituent into an acetate group. Using
this method, the two enantiomers of tricyclic furan deriva-
tives 10 and ent-10 were obtained separately with high
Notably, compounds 4a-8a are envisaged to be the
enantiomers of 4b-8b if the 2-(benzyloxy)ethyl substituent
is ignored. It is imperative to remove this substituent with
cleavage of the tethered C-C bond to yield a simple furan
derivative. An efficient and stereospecific method has been
developed and the protocol is illustrated in Scheme 4.
The benzyl group of compound 7a was removed by Pd/
H2 which also resulted in the stereoselective hydrogenation
of the internal olefin to give the alcohol (Scheme 4).
Subsequent oxidation of this crude alcohol with PCC
(10) Crystal data for 9: orthorhombic space group, P212121, a ) 9.2239-
(19) Å, b ) 26.248(6) Å, c ) 6.4941(13) Å, z ) 4, V ) 1572.3(6) Å3, R1
) 0.0441 and wR2 ) 0.1064 for 3506 unique reflections > 2 σ(I).
(11) Matsutani, H.; Ichikawa, S.; Yaruva, J.; Kusumoto, T.; Hiyama, T.
J. Am. Chem. Soc. 1997, 119. 4541.
(12) Crystal data for ent-9: orthorhombic space group, P212121, a )
6.4935 (11) Å b ) 9.2208 (19) Å, b ) 26.244(4) Å, z ) 4, V ) 1571.4 (6)
Å3, R1 ) 0.0447 and wR2 ) 0.1019 for 3551 unique reflections > 2 σ(I).
(8) Crystal data for 5b: monoclinic space group, P2(1), a ) 11.3392
(18) Å, b ) 6.4915(11) Å, c ) 12.206 Å, V ) 897.4(3) Å3, Z ) 2, R1 )
0.0607 and wR2 ) 0.1506 for 3514 unique reflections > 2 σ(I).
(9) Crystal data for 8b: orthorhombic space group, P212121, a ) 6.8329
(2) Å, b ) 8.1545(2) Å, c ) 29.8514 Å, V ) 1663.29 Å3, Z ) 4, R1 )
0.0749 and wR2 ) 0.1057 for 3320 unique reflections > 2 σ(I).
Org. Lett., Vol. 3, No. 9, 2001
1297

enantiopurity. The success of this example highlights the use
of oxacyclic dienes 3a and 3b for facile syntheses of
enantiopure forms of tricyclic furan frameworks.
Supporting Information Available: Experimental pro-
cedures and spectral data of new compounds. Crystal data
of compounds 5b, 8b, 9, and ent-9. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Science Coun-
cil, Taiwan, for financial Support of this work.
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