Stereoselective synthesis of 3a,7a-dihydro-3H,4H-furo[3,4-c]pyran-1-ones via intramolecular hetero-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2004.04.006

The synthesis of 3a,7a-dihydro-3H,4H-furo[3,4-c]pyran-1-ones via an intramolecular hetero-Diels-Alder reaction of easily accessible α,β-unsaturated γ-ketoesters was investigated. The reaction was found to proceed in a highly stereoselective way leading to

Full text of DOI:10.1016/j.tetlet.2004.04.006

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4297–4300
Stereoselective synthesis of 3a,7a-dihydro-3H,4H-furo[3,4-c]pyran-
1-ones via intramolecular hetero-Diels–Alder reactionq
*
€
Cyril Fuhrer, Roland Messer and Robert Haner
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland
Received 15 March 2004; revised 31 March 2004; accepted 2 April 2004
Abstract—The synthesis of 3a,7a-dihydro-3H,4H-furo[3,4-c]pyran-1-ones via an intramolecular hetero-Diels–Alder reaction of
easily accessible a,b-unsaturated c-ketoesters was investigated. The reaction was found to proceed in a highly stereoselective way
leading to single, cis-configured product isomers. The same diastereomer is formed, independently of the configuration of the enone
double bond of the precursor. The respective E- and Z-isomers react either through an endo-E-syn or an exo-Z-syn transition state.
Ó 2004 Elsevier Ltd. All rights reserved.
The hetero-Diels–Alder reaction is one of the most
important reactions for the construction of heterocyclic
six-membered rings.1–4 Its concerted character allows the
selective formation of up to three stereogenic centers in a
single reaction step. The intramolecular version of the
hetero-Diels–Alder reaction (e.g., of a,b-unsaturated
ketones, such as A in Scheme 1) leads to the formation
of bicyclic dihydropyrane derivatives (B). During the
course of our work aimed at the construction of poly-
cyclic natural product-like scaffolds, we became inter-
ested in the synthesis of furo[3,4-c]pyranones. Dihydro-
and perhydropyranes are common substructures of
many natural products. Among others, they constitute
an essential part of the iridoids, a wide-spread class
of natural compounds.5–7 Starting from an ester
(cf. Scheme 1, X, Y ¼ O), furo[3,4-c]pyranones should
become accessible through an intramolecular hetero-
Diels–Alder reaction. This type of cyclization has been
observed as a side reaction during the investigation of
intramolecular ene-reactions of a,b-unsaturated esters of
allylic alcohols by Snider et al.8 The intramolecular
hetero-Diels–Alder reaction has been used in the syn-
thesis of the monoterpen glycoside secologanin, a key
intermediate in the biosynthesis of many iridoid-derived
alkaloids.5;9 More recently, Murray and coworkers have
reported on the synthesis of pyranopyrrolidinones using
an intramolecular hetero-Diels–Alder reaction.10;11
Furthermore, Aungst and Funk used an intramolecular
hetero-Diels–Alder reaction in the total synthesis of ( )-
euplotin A.12 To our knowledge, however, no general
method leading to furo[3,4-c]pyranone derivatives has
been reported thus far. We therefore investigated this
potential route with regard to the chemistry as well as
the stereochemical course of the reaction.
R
R
R'
R'''
R''
O
R'''
R''
O
R'
X
X
Y
Y
The synthesis of the required building blocks was
straightforward. The diethyl phosphonate esters 1a–c
were prepared through an Arbuzov reaction of the cor-
responding a-bromoacetates13–15 with triethyl phos-
phite.15;16 The phosphonates were converted into the
a,b-unsaturated c-ketoesters 2a–g via the Horner–
Wadsworth–Emmons reaction using commercially
available a-diketones (see Table 1). Products 2a–g were
obtained as isomeric mixtures (E:Z-ratio approximately
1:2). In the cases where separation of the E- and Z-
isomers (i.e., for 2a, b and e) was possible, the pure
A
B
Scheme 1. Intramolecular hetero-Diels–Alder reaction.
Keywords: Hetero-Diels–Alder reaction; Dihydropyrane; c-lactone;
Diastereoselective; Intramolecular.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.04.006
* Corresponding author. Tel.: +41-31-631-4382; fax: +41-31-631-8057;
e-mail: robert.haener@ioc.unibe.ch
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.006

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C. Fuhrer et al. / Tetrahedron Letters 45 (2004) 4297–4300
Table 1. Preparation of furo[3,4-c]pyranones ( )-3a–g via intramolecular hetero-Diels–Alder reaction of a,b-unsaturated c-ketoesters 2
R1
R2
R3
Compound [yield (%); E:Z]b
Product
Yieldc (%)
H
CH3
H
CH3
CH3
CH3
2a (62; 1:2)
2b (73; 1:2)
3a
3b
(traces)
37 from E-2b
46 from Z-2b
58
CH3
CH3
H
CH3
CH3
Phenyl
4-Fluorophenyl
CH3
2c (58; 1:2.3)
2d (42; 1:2.6)
2e (67; 1:2)
3c
3d
3e
64
21 from E-2e
69 from Z-2e
Phenyl
H
H
Phenyl
Phenyl
Phenyl
4-Fluorophenyl
2f (38; 1:2.4)
2g (43; 1:2)
3f
3g
72
56
aLiHMDS (1.1 equiv), THF, )78 °C, 2.5 h.
b E- and Z-isomers could be separated in the case of 2a,b and e; all other compounds 2 were isolated as E/Z-mixtures.
c Isolated yields of 3 starting either from the pure E- or Z-isomers of 2b and e or, alternatively, from the E/Z-mixture.
isomers were used in the following cyclization step. In all
other cases, the obtained mixture of E- and Z-isomers
was used.
depend on the geometry of the diene moiety. The same
isomer was formed from either the E- or the Z-precur-
sor. The relative configurations of the products 3c and 3f
were established by X-ray crystallography. The structure
of 3f is shown in Figure 1.
We then investigated the thermal cyclization of a,b-
unsaturated c-ketoesters 2a–g. Generally, the reaction
was carried out in an autoclave at a temperature of
200 °C using toluene as the solvent. As can be seen from
Table 1, the yield of the reaction increased with the
number of substituents of the ene-moiety (R1 and R2).
Only traces of product (<10%) were observed in the case
of the allylesters E- and Z–2a. With the dimethyl and
phenyl substituted derivatives, the reaction proceeded
considerably better and, with one exception (E–2e), the
expected products could be isolated in yields between
40% and 70%. The finding that alkyl or aryl substituents
at the ene-part have a positive effect on this inverse
electron demand hetero-Diels–Alder reaction is well in
agreement with the theory.4 Some decomposition (ester
cleavage) of the starting material at the relatively high
reaction temperature was observed, which partly
explains the moderate yields in some cases. Attempts to
facilitate the reaction with various Lewis acids (e.g.,
Cu(II), Zn(II), Al(III), BF3) were not successful and led
to complex reaction mixtures at temperatures above
110 °C. Furthermore, we could not observe any product
arising from an ene-reaction,17 which is theoretically
possible with compounds 2b, c and d. An intramolecular
ene-reaction was observed by Snider et al. in a related
system.8
Based on the structural information, the stereochemical
course of the hetero-Diels–Alder reaction must proceed
as illustrated in Scheme 2. Since both geometrical iso-
mers afford the same product, the E-isomer reacts via
the endo-syn and the Z-isomer via the exo-syn transition
state.18;19 The formation of trans-fused products would
require reaction through the exo-E-anti transition state.
This has been observed in an intramolecular hetero-
Diels–Alder reaction of a more flexible system leading to
two annulated six-membered rings.18 In the present case,
however, the sterically less flexible five-membered linker
seems to disfavor this transition state. The final fourth
theoretical possibility (i.e., the endo-Z-anti transition
state) is not possible for geometrical reasons (cf. Tietze
et al.18).
In conclusion, cis-fused furo[3,4-c]pyranones have been
synthesized from easily accessible a,b-unsaturated c-
ketoesters via an intramolecular hetero-Diels-Alder
reaction. The reaction proceeds in a highly stereo-
selective way. Independently of the enone double
bond configuration, a single product diastereomer is
formed.
Generalprocedure for preparation of a,b-unsaturated c-
ketoesters 2a–g: To a stirred solution of n-butyllithium
(1.1 equiv) in absolute THF at 0 °C under a nitrogen
atmosphere, HMDS (1.2 equiv) was added. After
30 min, a solution of the corresponding diethylphos-
phorylacetic acid ester (1a–c, 1 equiv) in THF was added
dropwise. The mixture was cooled to )78 °C and a
solution of the corresponding a-dione (1.1 equiv) in
As expected, the cyclization reaction turned out to be
highly stereoselective. In all cases, formation of a single
product was observed. Structural elucidation revealed a
cis-configuration of the two rings. Furthermore, in the
cases in which R1 and R2 were different (i.e., products
2e–g) again a single diastereomer was formed. Most
importantly, the formation of the product did not

C. Fuhrer et al. / Tetrahedron Letters 45 (2004) 4297–4300
4299
Figure 1. Relative configuration of hetero-Diels–Alder product ( )-3f as determined by X-ray crystallography. (Note that the crystallographic
numbering, which has been kept for reasons of simplicity, is different from the systematic numbering.)
R2
H
O
R3
R3
R1
H
R3
R3
O
O
R3
R3
O
H
H
O
O
R2
H
R1
H
O
O
R2
R1
O
endo - E - syn
(+/-)-3a-g
exo - Z - syn
O
H
R2
R3
R3
R 1
H
O
R3
R3
O
O
H
H
R2
O
O
R 1
exo - E - anti
Scheme 2. Stereochemical course of intramolecular hetero-Diels–Alder reaction leading to cis-fused furo[3,4-c]pyranones.
THF was added. After stirring for 2.5 h, the solution
was quenched with sat. aq. NH4Cl. The mixture was
extracted twice with CH2Cl2. The combined organic
phases were dried (Na2SO4) and concentrated. The
obtained crude material was purified by column chro-
matography (silica gel, EtOAc–hexane).
Acknowledgements
We thank Prof. H. Stoeckli-Evans, University of
^
Neuchatel, for determination of molecular structures of
compounds 3c and f by X-ray diffraction.
General procedure for intramolecular hetero-Diels–Alder
reactions (furo[3,4-c]pyranones 3a–g): Asolution of a,b-
unsaturated c-ketoesters 2a–g in toluene (10 mL per
100 mg of 2) was placed in a Teflonâ reaction chamber
inside a sealed steel autoclave. After heating at 200 °C
for 1–3 days the solvent was removed in vacuo and the
product was purified by column chromatography
(EtOAc–hexane).
References and notes
1. Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10–
23.
2. Desimoni, G.; Tacconi, G. Chem. Rev. 1975, 75, 651–
692.
3. Waldmann, H. Synthesis 1994, 535–551.
4. Jorgensen, K. A. Angew. Chem., Int. Ed. Engl. 2000, 39,
3558–3588.
5. Tietze, L. F. Angew. Chem., Int. Ed. Engl. 1983, 22, 828–
841.
6. Dewick, P. M. MedicinalNaturalProducts––A Biosyn-
thetic Approach; John Wiley & Sons Ltd: Chichester,
2003.
Crystallographic data (excluding structure factors) for
the structures 3c and 3f have been deposited with the
Cambridge Crystallographic Data Centre as Supple-
mentary publications numbers CCDC 233713 and
CCDC 233714, respectively.

4300
C. Fuhrer et al. / Tetrahedron Letters 45 (2004) 4297–4300
7. Kingston, D. G. I.; Gunatilaka, A. A. L.; Zhou, B.-N.;
13. Bongars, C.; Bougeard, P.; Bury, A.; Cooksey, C. J.;
Johnson, M. D.; Mitchell, S.; Owens, P. A.; Rajah, F.
J. Organomet. Chem. 1985, 289, 163–171.
14. Melnick, M. J.; Weinreb, S. M. J. Org. Chem. 1988, 53,
850–854.
15. Toke, L.; Jaszay, Z. M.; Petnehazy, I.; Clementis, G.;
Vereczkey, G. D.; Kovesdi, I.; Rockenbauer, A.; Kovats,
K. Tetrahedron 1995, 51, 9167–9178.
16. Blades, K.; Butt, A. H.; Cockerill, G. S.; Easterfield, H. J.;
Lequeux, T. P.; Percy, J. M. J. Chem. Soc., Perkin Trans. 1
1999, 3609–3614.
17. Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed. Engl.
1978, 17, 476–486.
Abdel-Kader, M.; Berger, J.; Van der Werff, H.; Evans,
R.; Famolare, L.; Mittermeier, R.; Malone, S.; Wisse, J.
H. In Chemistry, Biological and Pharmacological Proper-
ties of MedicinalPal nts from the Americas ; Hostettmann,
K., Gupta, M. P., Marston, A., Eds.; Harwood Academic
Publishers: Amsterdam, 1999; pp 111–124.
8. Snider, B. B.; Roush, D. M.; Killinger, T. A. J. Am. Chem.
Soc 1979, 101, 6023–6027.
9. Tietze, L. F.; Denzer, H.; Holdgrun, X.; Neumann, M.
Angew. Chem., Int. Ed. Engl. 1987, 26, 1295–1297.
10. Murray, W. V.; Mishra, P. K.; Sun, S. G.; Maden, A.
Tetrahedron Lett. 2002, 43, 7389–7392.
11. Murray, W. V.; Mishra, P. K.; Turchi, I. J.; Sawicka, D.;
Maden, A.; Sun, S. Tetrahedron 2003, 59, 8955–8961.
12. Aungst, R. A.; Funk, R. L. J. Am. Chem. Soc. 2001, 123,
9455–9456.
18. Tietze, L. F.; Brumby, T.; Pretor, M.; Remberg, G. J. Org.
Chem. 1988, 53, 810–820.
19. Tietze, L. F.; Brumby, T.; Pretor, M. Synthesis 1987, 700–
703.