A novel stereoselective cyclization to functionalized dihydropyrans

Article abstract of DOI:10.1021/ol990789m

(matrix presented) An indium trichloride-mediated highly diastereoselective tandem carbonyl allylation Prins cyclization chlorination of aldehydes with allylstannane-generated 4-halotetrahydropyrans in high yields. The reaction of 3-trimethylsilylallyltri

Full text of DOI:10.1021/ol990789m

ORGANIC
LETTERS
1999
Vol. 1, No. 7
993-995
A Novel Stereoselective Cyclization to
Functionalized Dihydropyrans
Ganapathy S. Viswanathan, Jun Yang, and Chao-Jun Li*
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118
cjli@mailhost.tcs.tulane.edu
Received July 7, 1999
ABSTRACT
An indium trichloride-mediated highly diastereoselective tandem carbonyl allylation−Prins cyclization−chlorination of aldehydes with allylstannane-
generated 4-halotetrahydropyrans in high yields. The reaction of 3-trimethylsilylallyltributylstannane with aldehydes led to the formation of
2,6-dialkyl-3,4-dihydropyrans with a cis diastereoselectivity.
Tetrahydropyran is the structural core of most carbohydrates
and their polymers. These materials are the most abundant
biological molecules on earth and play several crucial roles
in living organisms. They are found in the cell walls and
the protective coatings of many organisms and also fuel
various metabolic processes. In addition to being the
structural core of carbohydrates, many biologically important
natural products and potential pharmaceutical agents bear
tetrahydropyran structures. Thus, many efforts have been
made toward the synthesis of tetrahydropyran type com-
pounds.1 Examples are via hetero-Diels-Alder reactions,2
oxiranyl anions,3 carbonyl ylides,4 Claisen rearrangements,5
ring opening of epoxides,6 iodocyclizations,7 olefin metath-
esis,8 and others. Among the various methods for tetrahy-
dropyran syntheses, the hetero-Diels-Alder and the olefin-
metathesis approaches provide dihydropyrans in which the
unsaturation provides a handle and versatility for attaching
additional functionalities. Recently, the potential of using the
Prins cyclization9 for synthesizing tetrahydropyran derivatives
has been recognized.10 By using cross-cyclizations between
aldehydes and homoallyl alcohols, tetrahydropyrans were
obtained. We wish to report here a new cyclization that
generates functionalized dihydropyrans stereoselectively
(Scheme 1).
Scheme 1
Because of their effectiveness in controlling reactivity and
selectivity as well as the mildness of the reaction conditions,
allylstannanes have been widely used in synthesis (such as
allylation of aldehydes).11 To start our research, we examined
the formation of tetrahydropyrans via a tandem allylation-
cyclization of aldehydes 1 with allylstannane 2 (Scheme 2).
The milder conditions associated with the tin reaction were
envisioned as advantageous for the formation of dihydro-
pyrans.
(1) For a review, see: Boivin, T. L. B. Tetrahedron 1987, 43, 3309.
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J. D., Ed.; Academic Press: New York, 1984, Vol. 3, Part B, Chapter 6.
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J. S.; Hamelin, O.; Hufton, R. Tetrahedron Lett. 1998, 39, 8321 and
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1998, 54, 4413.
When a mixture of 2 equiv of benzaldehyde and 1 equiv
of allyltributylstannane was stirred with indium chloride in
methylene chloride at room temperature, the disappearance
10.1021/ol990789m CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/13/1999

Table 1. Tetrahydropyran Derivatives via Indium
Trichloride-Mediated Tandem Allylation-Cyclization Reactiona
Table 2. Dihydropyran Derivatives via Indium
Trichloride-Mediated Tandem Allylation-Cyclization Reactiona
a All reactions were carried out in methylene chloride at room temper-
ature. An asterisk indicates that the yields are isolated yields after flash
column chromatography.
of the starting materials was observed by TLC within 5 h.
To ensure that the reaction was complete, the stirring was
continued overnight. After the reaction mixture was con-
a All reactions were carried out in methylene chloride under an
atmosphere of air and at room temperature. Asterisk indicates that the yields
are isolated yields after flash column chromatography. Diastereoselectivities
were determined by GC-MS and 1H NMR. a: no diastereomer was detected
by NMR or GC-MS.
1
centrated in vacuo, the H NMR spectrum of the crude
reaction mixture showed a clean conversion of benzaldehyde
to the cyclization product 3. Subsequently, column chroma-
tography of the crude product on silica gel provided 4-chloro-
2,6-diphenyltetrahydropyran in 72% yield. Due to partial
overlap of the product with a tin derivative, some product
was lost during the isolation. By comparing the spectroscopic
data with our earlier studies as well as literature reported
values, the product was identified as the stereoisomer in
which the two phenyl groups and the chlorine are all
equatorial. The diastereoselectivity for the reaction was
estimated to be greater than 10:1 as the formation of the
other diastereomer (cis-trans-cis) was vaguely observable in
1
the H NMR of the crude material and was not isolated.
When allylsilane was used for the cyclization, under the same
reaction conditions, a low (ca. 20%) conversion was ob-
served. Other compounds including both aromatic and
994
Org. Lett., Vol. 1, No. 7, 1999

corresponding dihydropyrans (Table 2). It should be pointed
out that although the reaction of aromatic aldehydes did not
lead to the cyclization product, aliphatic aldehydes bearing
aromatic substituents did not affect the cyclization (entries,
1, 2, and 5). A halogen (entry 6), a benzyl ether (entry 5),
and an olefin (entry 4) all survive the reaction conditions.
In conclusion, an indium trichloride-mediated tandem
carbonyl allylation-Prins cyclization-chlorination of alde-
hydes with allylstannane generated 4-halotetrahydropyrans
diastereoselectively. The reaction of 3-trimethylsilylallyl-
tributylstannane with aldehydes mediated by indium chloride
led to a diastereoselective formation of 2,6-dialkyl-3,4-
dihydropyrans. Presently, the synthetic potential of this new
dihydropyran formation is under investigation.
Scheme 2
aliphatic aldehydes were similarly converted into 4-chlo-
rotetrahydropyran derivatives (Table 1).
The promising results of the tetrahydropyran study led us
to investigate the formation of dihydropyrans as illustrated
in Scheme 3. When aromatic aldehydes were stirred with
Acknowledgment. We are grateful to the NSF (CA-
REER), an NSF-EPA joint program, and LEQSF for partial
support of our research. We thank Dr. M. Karol for
performing the NOE experiments.
Scheme 3
OL990789M
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tin-silicon reagent 4,12 together with indium chloride in
methylene chloride at room temperature, disappearance of
the starting materials was observed overnight. However, no
distinctive product was obtained with these aldehydes. On
the other hand, when an aliphatic aldehyde was used, the
reaction led to the smooth formation of the desired dihy-
1
dropyran product 5. The H NMR of the crude material
revealed predominantly a single diastereomer (see Table 2
for diastereoselectivities) together with unidentified poly-
meric materials in each case. The stereochemistry of the main
product was assigned by comparing the 1H NMR data with
our tetrahydropyran derivatives as well as by NOE experi-
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similarly reacted with the tin-silicon reagent to generate the
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Org. Lett., Vol. 1, No. 7, 1999
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