A novel approach to the synthesis of bicyclic lactones via an interrupted nazarov reaction of gem-divinyl dihydrofurans

Article abstract of DOI:10.1021/ol026010h

(figure presented) A facile Lewis acid induced interrupted Nazarov reaction of gem-divinyl dihydrofurans to bicyclic lactones is described.

Full text of DOI:10.1021/ol026010h

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2821-2823
A Novel Approach to the Synthesis of
Bicyclic Lactones via an Interrupted
Nazarov Reaction of gem-Divinyl
Dihydrofurans†
,‡
Vijay Nair,* S. Bindu,‡ V. Sreekumar,‡ and Angele Chiaroni§
Organic Chemistry DiVision, Regional Research Laboratory (CSIR),
TriVandrum, India, and Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette, France
gVn@csrrltrd.ren.nic.in
Received April 12, 2002
ABSTRACT
A facile Lewis acid induced interrupted Nazarov reaction of gem-divinyl dihydrofurans to bicyclic lactones is described.
The Nazarov reaction in its original form involves the
cyclization of divinyl ketones to cyclopentenones under the
influence of very strong acids. The recognition that it belongs
to a general class of cationic electrocyclic reactions and that
even mild Lewis acids can promote the cyclization has
contributed significantly to the development of the reaction.1
The scope and synthetic utility of the reaction was further
broadened by the demonstration of Denmark that the strategic
placement of a silyl group can direct the cyclization.2 It may
be noted that the crucial conrotatory electrocyclization of
the pentadienylic cation that defines the Nazarov reaction
creates a carbon-carbon bond and two stereocenters. Some
or all stereochemical information is lost in the subsequent
deprotonation or desilylation step. In the “interrupted Na-
zarov reaction”, a variant of Nazarov cyclization investigated
in detail by West, the stereochemical integrity is retained
by trapping the oxyallyl zwitterion with pendant nucleophiles,
and this has been efficiently applied for the diastereoselective
synthesis of complex ring systems.3 The participation of
dihydrofuran derivatives in such interrupted Nazarov reac-
tions, however, has not been reported so far. Herein we report
the preliminary results of the interrupted Nazarov reaction
of dihydrofurans substituted with a cross conjugated diene
moiety.
The dihydrofurans that served as starting materials for our
investigations were synthesized by a multicomponent reaction
(MCR) between a dienone, acetylenic compound, and
† This paper is dedicated with best wishes to Professor Ian Fleming.
‡ Regional Research Laboratory (CSIR).
§ Institut de Chimie des Substances Naturelles
(3) (a) Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese, S.; West, F.
G. J. Org. Chem. 1998, 63, 2430. (b) Giese, S.; West, F. G. Tetrahedron
Lett. 1998, 39, 8393. (c) Wang, Y.; Arif, A. M.; West, F. G. J. Am. Chem.
Soc. 1999, 121, 876. (d) Browder, C. C.; West, F. G. Synlett 1999, 1363.
(e) Bender, J. A.; Arif, A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121,
7443. (f) Giese, S.; Kastrup, L.; Steins, D.; West, F. G. Angew. Chem., Int.
Ed. 2000, 39, 1970. (g) Browder, C. C.; Marmsa˜ter, F. P.; West, F. G.
Org. Lett. 2001, 3, 3033.
(1) Reviews: (a) Denmark, S. E. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 751.
(b) Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994, 45,
1.
(2) (a) Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc. 1982, 104, 2642.
(b) Denmark, S. E.; Wallace, M. A.; Walker, C. B., Jr. J. Org. Chem. 1990,
55, 5543 and references therein.
10.1021/ol026010h CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/20/2002

dimethoxy carbene.4 When 1,5-bis(3-chloro-phenyl)-penta-
1,4-dien-3-one is treated with dimethyl acetylene dicarboxy-
late (DMAD) and dimethoxycarbene, the latter being gen-
erated in situ by the thermolysis of 2,2-dimethoxy ∆3-1,3,4-
oxadiazoline in refluxing toluene following the Warkentin
protocol,5 a facile reaction leading to the dihydrofuran
derivative in 70% yield occurred (Scheme 1). The product
was characterized by spectroscopic analysis.
The reaction was found to be general with other distyrenyl
dihydrofurans and the cyclopentene derivatives were obtained
in good yields (Scheme 1). Similar reaction occurred when
SnCl4 was employed as the Lewis acid.
A mechanistic rationale for this reaction is given in
Scheme 3. Initial coordination of the Lewis acid to the
Scheme 3
Scheme 1
dihydrofuran derivative 1a yields the diallyl cation, which
undergoes a facile 4π electrocyclic ring closure resulting in
a new C-C bond, two new stereocenters, and an allyl cation.
This allyl cation is trapped by the pendant ortho ester borate,
establishing a new C-O bond and elimination of methanol,
ultimately leading to the bicyclic lactone 2a.
Our studies were set in motion by exposing the dihydro-
furan derivative 1a to a stoichiometric amount of BF3‚Et2O
in dichloromethane. The reaction yielded a single bicyclic
lactone derivative 2a presumably resulting from an inter-
rupted Nazarov reaction (Scheme 2). The product was
The rearrangement reaction of distyrenyl dihydrofurans
with unsymmetrical substitution on the aromatic ring afforded
an inseparable mixture of regioisomers (Scheme 4). Dihy-
Scheme 2
Scheme 4
characterized by spectroscopic analysis.6 Final proof of the
structure assignment was derived from single-crystal X-ray
analysis of 2a.
drofurans with a nonstyrenyl substituent (Scheme 4, 2j and
2k) also gave the corresponding bicyclic lactone albeit in
very low yields. This may be due to the relative instability
of the cation formed in the reaction.
(4) Nair, V.; Bindu, S.; Balagopal, L. Tetrahedron Lett. 2001, 2043.
(5) Warkentin, J. J. Chem. Soc., Perkin Trans. 1 2000, 2161 and
references therein.
(6) Typical Experimental Procedure. To 0.192 mmol of the dihydro-
furan derivative dissolved in 15 mL of dry CH2Cl2 was added 0.22 mmol
of BF3. OEt2 at 0 °C. The mixture was stirred for 3 h. When the reaction
was completed, the reaction mixture was passed through a short pad of
silica, the solvent was removed, and the residue was subjected to column
chromatography on silica column using 70:30 hexanes-ethyl acetate solvent
mixture to afford the bicyclic lactone. Data for compound 2a: colorless
solid; mp 189-190 °C; IR (KBr) νmax 3015, 2955, 2850, 1745, 1738, 1728,
1630, 1594, 1479, 1437, 1393, 1277, 1098, 1052, 993, 758, 703 cm-1; 1H
NMR (300 MHz, CDCl3-CCl4, v/v, 3:1) δ 3.88 (t, J ) 8.3 Hz, CH), 3.91
(s, 6H, OCH3), 5.02 (dd, J ) 6.4 1H, CH), 5.94 (d, 1H, J ) 7.9 Hz), 6.82
(s, 1H,). 7.19-7.35 (m, 8H, ArH); 13C NMR (75 MHz, CDCl3-CCl4, v/v,
It is interesting to note that the basic cyclopentanolactone
moiety of 2 is a recurring structural motif in a number of
biologically active monoterpenoids such as artemesia lactone
Ia, vulgaris lactone7 Ib, and ilexlactone8 II (Figure 1). An
3:1) δ 52.38, 52.95, 53.12, 59.42, 87.05, 127.06, 125.48, 128.57, 128.69,
128.92, 129.08, 129.54, 130.30, 130.52, 133.71, 134.06, 134.68, 135.34,
138.11, 141.63, 160.34, 162.75, 163.85. Anal. Calcd for C24H18Cl2O6: C,
60.90; H, 3.83. Found: C, 61.26; H, 3.93.
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Org. Lett., Vol. 4, No. 17, 2002

been shown that the latter undergo an interrupted Nazarov
reaction to give cyclopentanolactones, which resemble the
structural framework of several monoterpenoid natural
products.
Acknowledgment. S.B. thanks Council of Scientific and
Industrial Research, New Delhi, for a research fellowship,
Ms. Soumini Mathew for recording high resolution NMR
spectra, and Mrs. S. Viji for elemental analysis.
Figure 1.
Supporting Information Available: General experimen-
tal procedures; IR, 1H NMR, and 13C NMR data for
compounds 1a-h, 2a-h, 2i, and 2k; and single-crystal X-ray
structure for 2a. This material is available free of charge
via the Internet at http://pubs.acs.org.
RCM approach to the synthesis of related core of R,â-
unsaturated lactones has been described by Grubbs.9
In conclusion, we have uncovered a facile method for the
synthesis of substituted dihydrofuran derivatives and it has
(7) Ravi, S.; Laxman, A. J. Indian J. Chem., Sect. B 2001, 40, 443.
(8) Hartmut, T.; Herbert, B. Phytochemistry 1980, 19, 1866.
(9) Grubbs, R. H.; Choi, T. L. Chem. Commun. 2001, 2648.
OL026010H
Org. Lett., Vol. 4, No. 17, 2002
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