Stereoselective preparation of (Z)-2-(trialkylsilyloxy)-2-alkenals by retrocycloaddition reactions of 4H-4-alkyl-5-(trialkylsilyloxy)-1,3-dioxins. Useful reactants for Lewis acid catalyzed [4 + 3] cyclizations

Article abstract of DOI:10.1021/ol016668f

(matrix presented) Retrocycloadditions of 4H-4-alkyl-5-(trialkylsilyloxy)-1,3-dioxins proceed smoothly in refluxing toluene to afford (Z)-2-(trialkylsilyloxy)-2-alkenals with complete stereoselectivity. These enals undergo Sasaki-type [4 + 3] cyclizations

Full text of DOI:10.1021/ol016668f

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3553-3555
Stereoselective Preparation of
(Z)-2-(Trialkylsilyloxy)-2-alkenals by
Retrocycloaddition Reactions of
4H-4-Alkyl-5-(trialkylsilyloxy)-1,3-dioxins.
Useful Reactants for Lewis Acid
Catalyzed [4 + 3] Cyclizations
Ronald A. Aungst, Jr. and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
rlf@chem.psu.edu
Received August 28, 2001
ABSTRACT
Retrocycloadditions of 4H-4-alkyl-5-(trialkylsilyloxy)-1,3-dioxins proceed smoothly in refluxing toluene to afford (Z)-2-(trialkylsilyloxy)-2-alkenals
with complete stereoselectivity. These enals undergo Sasaki-type [4 + 3] cyclizations with dienes in the presence of Lewis acids, in many
instances with excellent regio- and/or stereoselectivity.
The direct construction of seven-membered rings via [4 +
3] cyclization reactions is the most attractive strategy for
preparing this frequently observed natural product substruc-
ture.1 Accordingly, a great amount of effort has been focused
on methods for generating the less accessible three-atom
component of this reaction. One such method reported by
Sasaki2 involves the treatment of 2-(trimethylsilyloxy)-
acrolein (1) with a Lewis acid in the presence of a diene to
afford, after acidic workup, an R-hydroxycycloheptenone,
e.g., 2 (Scheme 1). However, attempts to expand the scope
of this reaction by employing â-substituted enals related to
propenal 1 in both inter- and intramolecular [4 + 3]
cycloaddition reactions was not reported.3 We envisaged a
convenient, stereoselective preparation of (Z)-2-(trialkyl-
silyoxy)-2-alkenals 4 by application of our 1,3-dioxin-based
methodology.4 Thus, based on this previous work it was
anticipated that 4H-4-alkyl-5-(trialkylsilyloxy)-1,3-dioxins 3
would be available by silylation of the corresponding 1,3-
Scheme 1
(1) (a) Noyori, R.; Hayakawa, Y. Org. React. 1983, 29, 163. (b)
Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984, 23, 1. (b) Mann,
J. Tetrahedron 1986, 42, 4611. (c) Hosomi, A.; Tominaga. Y. Compre-
hensiVe Organic Synthesis; Trost, B. M, Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 5, pp 593-615. (d) Rigby, J. Org. React. 1997, 51,
351. (e) Harmata, M. Tetrahedron 1997, 53, 6235.
(2) Sasaki, T.; Ishibashi, Y.; Ohno, M. Tetrahedron Lett. 1982, 23, 1693.
10.1021/ol016668f CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/09/2001

dioxin-5-ones and would undergo facile retrocycloadditions
in refluxing toluene to provide the (Z)-enals 4 (Scheme 1).
A stereoselective preparation of these enals was considered
to be critical for investigating the regio- and stereoselectivity
of the subsequent [4 + 3] cycloaddition reactions, thereby
providing insight into the mechanism of this intriguing
transformation. The recent report by Harmata5 that 2-(tri-
alkylsilyloxy)acroleins 7 also undergo [4 +3] cycloaddition
reactions and can be prepared from dioxinone 6 via a 1,3-
dioxin intermediate (Scheme 2) prompts us to disclose the
results of our investigation at this time.
Table 1. [4 + 3] Cyclization Reactions of
(Z)-2-(Trialkylsilyloxy)-2-enals
Scheme 2
The preparation of the 5-(silyloxy)dioxins 3 was easily
accomplished. Thus, the aza-enolate6 derivative of the imine
8 underwent efficient alkylation and upon hydrolytic workup
afforded the desired butylated dioxinone 9. Kinetic depro-
tonation of ketone 9 with sodium hexamethyldisilyl azide
afforded the less-substituted enolate that could be O-silylated
by several trialkylsilyl halides (Scheme 3). As expected, each
Scheme 3
of the resulting (trialkylsilyloxy)dioxins 10 was smoothly
converted to only the Z-stereoisomer of the (silyloxy)enals
11 in nearly quantitative yields in refluxing toluene. The
stereoselectivity is presumably a consequence of preferential
retrocycloaddition through the boatlike conformer eq-10
rather than boatlike conformer ax-10 that is destabilized by
a flagpole-flagpole interaction between the butyl group and
axial lone pair. Thermodynamically controlled isomerization
to (Z)-enals 11 was ruled out by heating a mixture of 11c
and its E-isomer (83:17), obtained by photoisomerization of
11c (Hanovia 500 W, toluene), and observing no change in
the ratio of isomers. Finally, the (Z)-2-(tert-butyldimethyl-
silyloxy)-2-enals 12 and 13 were also prepared by straight-
forward application of this protocol.
a Isomers separated by column chromatography. b Inseparable mixture
of isomers.
We were pleased to discover that (Z)-2-(trialkylsilyloxy)-
alkenals smoothly participated in Lewis acid catalyzed [4 +
3] cyclization reactions with a variety of dienes (Table 1).
Several observations merit comment. In all cases the silyl
group is cleanly transferred to the aldehyde oxygen. More-
over, all of the cycloadducts possess a cis-stereochemical
relationship7 between the â-alkyl substituent of the enal and
the newly formed silyloxy substituent.8 In addition, endo-
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Org. Lett., Vol. 3, No. 22, 2001

adducts are uniformly preferred over the exo counterparts
and the stereoselectivity is better for smaller silyl substituents
(compare entries 1 vs 2, 3 vs 4, and 10 vs 11). The endo/
exo ratio can also be significantly improved by the choice
of the Lewis acid catalyst (entry 3). Not surprisingly, acyclic
dienes are not as reactive as the cyclic dienes, but acceptable
yields were obtained with butadiene, isoprene, and trans-
piperylene. It is of interest to note that the regioselectivity
of the cyclization with isoprene is also sensitive to the
substituents on the silyl group (entries 7 and 8) and that
piperylene is the only diene which favors the exo-adduct in
a highly regioselective and stereoselective cyclization (entry
9). Finally, the retrocycloaddition of 5-(trialkylsilyloxy)-1,3-
dioxins can be catalyzed by a Lewis acid9 with concomitant
intramolecular [4 + 3] cyclization of the resulting 2-(tri-
alkylsilyloxy)-2-enal to afford fused bicyclic adducts (entries
10 and 11), of potential value in natural product synthesis.
In conclusion, we have demonstrated that 2-(trialkylsily-
loxy)-2-enals constitute another class of useful reactants that
can be generated with high stereoselectivity by retrocycload-
dition reactions of substituted 4H-1,3-dioxins. The [4 + 3]
cyclizations of these enals documented herein substantially
expand the scope and limitations of the original Sasaki
account. Although the precise structure of the allyl cation
intermediate generated in these reactions requires further
clarification, the ability to control the regio- and stereose-
lectivity of these cyclization reactions by choice of the silyl
substituents as well as the Lewis acid makes 2-(trialkylsi-
lyloxy)-2-enals particularly attractive among the various
three-atom components for [4 + 3] cycloadditions. Accord-
ingly, additional studies and application of this methodology
in natural product synthesis are underway in our laboratories.
(3) The methyl ketone analogous to aldehyde 1 was examined and gave
only the Diels-Alder/[4 + 2] adducts (SnCl4, -45 °C, 7 h, 29%). However,
in a subsequent investigation a 1:1.5 mixture of the [4 + 3] and [4 + 2]
adducts, respectively, was isolated using similar reaction conditions (SnCl4,
-78 °C, 6 h), see: Blackburn, C.; Childs, R. F.; Kennedy, R. A. Can. J.
Chem. 1983, 61, 1981.
(4) For the preparation and cycloaddition reactions of (E)-2-alkenals,
see: (a) Funk, R. L.; Bolton, G. L. J. Am. Chem. Soc. 1988, 110, 1290.
2-(Acyloxy)acroleins, see: (b) Funk, R. L.; Yost, K. J., III. J. Org. Chem.
1996, 61, 2598. 2-Acylacroleins, see: (c) Funk, R. L.; Fearnley, S. P.; Gregg,
R. Tetrahedron 2000, 56, 10275. 2-(Amido)acroleins, see: (d) Maeng, J.-
H.; Funk, R. L. Org. Lett. 2001, 3, 1125. (e) Greshock, T. J.; Funk, R. L.
Org. Lett. 2001, 3, 3511. (f) (Z)-2-Acyl-2-enals, see: Aungst, R. A., Jr.;
Funk, R. L. J. Am. Chem. Soc. 2001, 123, 9455.
(5) Harmata, M.; Sharma, U. Org. Lett. 2000, 2, 2703.
(6) We have been unable to efficiently alkylate the enolate derivative of
1,3-dioxin-5-one due to a competing aldol reaction. For similar problems,
see: Majewski, M.; Gleave, D. M.; Nowak, P. Can. J. Chem. 1995, 73,
1616.
(7) Stereochemical assignments for all adducts were made using NOESY
experiments. See the Supporting Information for the diagnostic observations.
The regiochemistry for entries 7 and 9 was determined by 2D COSY NMR
experiments. The methine proton on the silyloxy carbon of the major product
of entry 7 was directly coupled to two allylic protons which were both
coupled to one another as well as the vinylic proton. The methine proton
on the silyloxy carbon of the major product of entry 9 was coupled to only
one other proton which in turn was coupled to the methyl protons as well
as one of the vinylic protons.
(8) A crossover experiment suggests that the silyl group is transferred
both intra- and intermolecularly. Thus, when the cyclization shown in entry
2 was performed in the presence of an equivalent amount of enal 12, the
endo adduct shown in entry 2 was obtained accompanied by the endo adduct
of entry 1 (86:14, respectively). Similarly, the endo cyclization product
derived from enal 12 (TBS ether) was accompanied by the corresponding
endo TES ether adduct (86:14, respectively).
(9) This protocol was necessary since thermolysis of the dioxin of entry
9 in refluxing toluene gave rise to the product derived from an intramolecular
Diels-Alder reaction of the intermediate 2-(tert-butyldimethylsilyloxy)-2-
enal.
Supporting Information Available: We appreciate the
financial support provided by the National Institutes of Health
(GM28553).
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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