1,4-Dioxene in organic synthesis: Rapid access to the oxabicyclo[4.2.1]nonene system

Article abstract of DOI:10.1021/ol005718y

Oxidation of 2,3-disubstituted 1,4-dioxenes 3 with m-chloroperbenzoic acid in methanol followed by nucleophilic addition of allyltrimethylsilane in the presence of TiCl₄ afforded dienes 5, which have been converted to oxabicyclo[4.2.1] nonenes

Full text of DOI:10.1021/ol005718y

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1141-1143
1,4-Dioxene in Organic Synthesis:
Rapid Access to the
Oxabicyclo[4.2.1]nonene System
Issam Hanna* and Vale´rie Michaut
Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique,
F-91128 Palaiseau Cedex, France
hanna@poly.polytechnique.fr
Received February 24, 2000
ABSTRACT
Oxidation of 2,3-disubstituted 1,4-dioxenes 3 with m-chloroperbenzoic acid in methanol followed by nucleophilic addition of allyltrimethylsilane
in the presence of TiCl4 afforded dienes 5, which have been converted to oxabicyclo[4.2.1] nonenes 8 in excellent yield by olefin ring-closing
metathesis reaction.
Oxabicyclic compounds have become increasingly important
in organic synthesis. Not only are they synthetically useful
in their own right, but they might also be used as templates
to control the regio- and stereoselectivity in polyfunction-
alized cycloalkenes.1 While a variety of methods for the
preparation of oxabicyclo[2.2.1] and oxabicyclo[3.2.1] com-
pounds are reported, few reliable methods for the synthesis
of oxobicyclo[4.2.1]nonanes have been published.2 A ring-
opening strategy would result in the conversion of these
substrates into functionalized eight-membered ring found in
many natural products.3 In this communication we describe
a new approach to 9-oxabicyclo[4.2.1]nonenes based on the
chemistry of 1,4-dioxene. Earlier disclosures from this
laboratory have demonstrated the utility of 1,4-dioxene (2,3-
dihydro-1,4-dioxin) in the formation of carbon-carbon bonds
with rapid elaboration of useful functional groups.4 Thus,
addition of dioxenyllithium to ketones and aldehydes leads
to allylic alcohols 15 which may be transformed into variety
of functionalized compounds via, for example, dehydration,
oxidation, or hydrolysis. We recently reported the behavior
of 1 toward nucleophilic displacement reactions in the
presence of a Lewis acid. For instance, 1 reacts with
1-(trimethylsilyloxy)cyclopentene in the presence of a cata-
lytic amount of trimethylsilyl trifluoromethanesulfonate
(TMSOTf) to furnish exclusively 2 as the sole regioisomer
which led, after isomerization of the double bond, to 2,3-
disubstituted 1,4-dioxene 3 in good yield (Scheme 1).6
Scheme 1
(1) For a recent review, see: Chiu, P.; Lautens, M. Top. Curr. Chem.
1997, 190, 1-85.
(2) For recent examples, see: Rainier, J. D.; Xu, Q. Org. Lett. 1999, 1,
1161-1163. Blake, A. J.; Higton, A. J.; Magid, T. N.; Simpkins, N. S.
Org. Lett. 1999, 1, 1787-1789.
(3) For reviews, see: Petasis, N. A.; Patane, M. A. Tetrahedron, 1992,
48, 5757-5821. Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881-930.
10.1021/ol005718y CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/30/2000

On the basis of a preceding work,7 we anticipated that
Lewis acid-mediated addition of allyltrimethylsilane to acetal
4, readily prepared from 3, would release the oxygen
funtionalities present in the dioxene ring with simulaneous
introduction of new carbon-carbon bonds.8,9 Initial experi-
ments were carried out on 2-cyclohexyl-3-(ketocyclopentyl)
dioxene 3a. Oxidation of 3a with m-chloroperbenzoic acid
(m-CPBA) in methanol at 0 °C gave almost exclusively only
(Scheme 2). This result is in agreement with the postulated
structure of 4a.
Under the same conditions, 2.3-disubstituted 1,4-dioxenes
(3b-e) bearing cyclopentyl, cycloheptyl, isopropyl, or
2-phenethyl groups undergo m-CPBA oxidation followed by
allylation to give compounds 5b-e, respectively, in 50-
55% overall yield from 3 (Table 1). However, with 2-(4-
1
one acetal as shown by H and 13C NMR of the crude
product. However, these data did not allow the unambiguous
determination of the regiochemistry of the reaction. Structure
4a was tentatively assigned and was confirmed later in the
synthesis (Scheme 2). Treatment of 4a with excess allyltri-
Table 1. 9-Oxabicyclo[4.2.1] Nonenes 8 from
2,3-Disubstituted-1,4-dioxenes 5 by Ring-Closing Olefin
Metathesis
Scheme 2
methylsilane (5 equiv) in the presence of titanium tetra-
chloride (TiCl4) (2.2 equiv) in dichloromethane at -70 °C
afforded the syn diallyl product 5a as a single diastereo-
isomer in 54% overall yield from 3a. Besides 5a, a minor
product was isolated in 8% yield, and its structure 6a was
assigned on the basis of its spectroscopic data. It is worthy
of note that when the allylation reaction was carried out with
equimolecular amount allyltrimethylsilane and TiCl4, the
monoallyl product 7a was isolated as the major component
(4) For a review of the chemistry of 1,4-dioxene, see: Fe´tizon, M.;
Goulaouic, P.; Hanna, I. Heterocycles 1989, 28, 521-527. For examples
on the use of dioxene in synthesis, see: (a) Hanna, I.; Prange´, T.; Zeghdoudi,
R. Tetrahedron Lett. 1996, 37, 7013-7016 and references cited threin. (b)
Boger, D.; Zhu, Y. J. Org. Chem. 1994, 59, 3453-3458. (c) Horito, S.;
Amano, M.; Hoshimoto, H. J. Carbohydr Chem. 1989, 8, 681-684.
(5) Fe´tizon, M.; Goulaouic, P.; Hanna, I.; Prange´, T. J. Org. Chem. 1988,
53, 5673-5679.
(6) Hanna, I. Tetrahedron Lett. 1999, 40, 863. Hanna, I.; Ricard, L.
Tetrahedron Lett. 1999, 40, 2521.
(7) Hanna, I. Tetrahedron Lett. 1995, 36, 889-892.
(8) For a review on Lewis acid-mediated addition to acetals, see:
Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043-1054.
(9) For addition of allylsilane to R-diketone diketals, see: Pellissier, H.;
Santelli, M. J. Chem. Soc., Chem. Commun. 1995, 607-608.
benzyloxybutyl) as substituent, a complex mixture was
obtained, from which the expected diallyl compound 5f was
isolated only in poor yield (15-20%).
1142
Org. Lett., Vol. 2, No. 8, 2000

A typical procedure is as follows: to a stirred solution of
crude 4 (0.5 mmol) and allyltrimethylsilane (5 mmol) in dry
CH2Cl2 (4 mL) at -70 °C was added a 1.0 M solution of
TiCl4 (1.1 mL). The reaction was monitored by TLC until
complete conversion, and the mixture was then quenched
with water, extracted with ether, and dried over MgSO4. After
evaporation of the solvent, the pure products 5 were isolated
by flash chromatography [AcOEt/petroleum ether (1:9 v/v)].
this stage, in the presence of an excess of reagents, further
allylation may take place to give the final product 5.
Having successfully achieved the TiCl4-mediated domino
allylation annulation of 4, we turned to the carbocyclization
of dienes 5 by ring-closing olefin metathesis. This reaction
was carried out on 5 by the use of 5% Grubbs catalyst
[RuCl2(CHPh)(Pcy3)2]10,11 in CH2Cl2 at room temperature
(Table 1). In all cases, the expected 9-oxabicyclo[4.2.1]-
nonene compounds (8a-f) were obtained in excellent yield
(Table). These reactions also allow the stereochemical
outcome of the allylation to be determined.
The formation of 5 and 7 can be rationalized as indicated
in Scheme 3. We assume that the first allylation of the ketal-
In conclusion, we found that TiCl4-mediated reaction of
allyltrimethylsilane and 4, readily prepared from 2,3-disub-
stituted 1,4-dioxenes, provides stereoselectively the diallyl
derivatives 5. These products readily undergo ring-closing
metathesis, leading to highly functionalized 9-oxabicyclo-
[4.2.1]nonene compounds 8. Cleavage of the oxa bridge of
8 should lead to the 5,8-fused ring system present in many
natural products, in particular the ophiobolin and fusicoccin
families.3 Preliminary investigations have demonstrated the
feasibility of this process using single-electron reducing
reagents. Further studies are in progress and will be reported
in due course.
Scheme 3
Supporting Information Available: Spectroscopic data
for compounds 5a-f, 6a, 7a, and 8a-f. This material is free
of charge via the Internet at http://pubs.acs.org.OL005718Y
OL005718Y
(10) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(11) For recent reviews concerning ring-closure metathesis reactions, see
(a) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388. (b)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
Lewis acid complex A occurs on the carbonyl group and
involves sequential cyclization and dioxane ring-opening
leading to intermediate B, which could give rise to 7. At
Org. Lett., Vol. 2, No. 8, 2000
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