Scheme 1. Retrosynthetic Analysis of Catechols 1 and 2
unwanted side reactions. The homoallylic alcohol may be
prepared via a stereoselective addition of the synthon 5 to
the benzaldehyde derivative 4.
Figure 1. Proposed mechanism for the reaction of a benzylic
homoallylic alcohol with RCHO, TMSOAc, AcOH, and BF3‚OEt2.
This approach was validated using racemic alcohol 6,
which was readily prepared in 92% yield from commercially
available piperonal and allylmagnesium chloride. Several
methods have been reported for the introduction of oxygen-
ated substituents at C-4 of tetrahydropyrans in Prins cycliza-
tions with varying success.4 In recent studies into the
stereocontrolled synthesis of 4-hydroxy-2,5-disubstituted
tetrahydropyrans, we have shown that hydrolysis of the esters
formed from reaction of homoallylic acetals with either
trifluoroacetic acid or BF3‚OEt2, in the presence of AcOH
as the nucleophile and TMSOAc to act as a fluoride trap,
gave yields of between 50% and 70%.5
Thus, cyclization of homoallylic alcohol 6 with hexanal
was investigated using BF3‚OEt2 in the presence of AcOH
and TMSOAc at room temperature, giving the required
tetrahydropyran 7 as a single diastereomer but in a disap-
pointing 16% yield (Scheme 2). Another tetrahydropyran,
electron-donating substituents on the aromatic ring, oxycar-
benium ion I may be formed either directly from the
homoallylic alcohol or via the benzylic cation II (which is
the direct precursor of the homoallylic acetate). An oxonia-
Cope rearrangement of I to III is favored, leading to IV via
an allyl transfer, and hence the symmetrical tetrahydropyran
V is formed as the major product. In support of this
mechanism, we have shown that, on reaction of an enan-
tioenriched homoallylic alcohol with propanal in the presence
of BF3‚OEt2, AcOH, and TMSOAc, the resultant tetrahy-
dropyran had low ee (<5%) in the presence of electron-
donating groups on the aromatic ring. In contrast, under the
same conditions, a homoallylic alcohol that possesses an
electron-withdrawing group, which would not favor the
formation of the benzylic cation II or the oxonia-Cope
rearrangement to III, gave the unsymmetrical tetrahydropy-
ran as the sole product, with little loss in enantiopurity.6
To further verify the mechanisms illustrated in Figure 1
we undertook isotopic labeling experiments (Scheme 3). It
would be expected that the percentage incorporation of an
oxygen-18 label in the hydroxyl group of the starting
homoallylic alcohol 11 with an electron-rich aromatic ring
would be significantly reduced in both tetrahydropyrans 12
and 13, if the pathway involving the stabilized benzylic cation
II is favored. In contrast, the label should be retained in the
tetrahydropyran 17, derived from the homoallylic alcohol
16 containing an electron-deficient aromatic ring, where the
benzylic cation is less stabilized. The required substrates 11
and 16 were prepared by labeling the corresponding ben-
Scheme 2. Reaction of Homoallylic Alcohol 6 with Hexanal,
BF3‚OEt2 (2 equiv), AcOH (5 equiv),and TMSOAc (4 equiv) in
C6H12 at Room Temperature
(4) (a) Nishizawa, M.; Shigaraki, T.; Takao, H.; Imagawa, H.; T.
Tetrahedron Lett. 1999, 40, 1153. (b) Zhang, W.-C.; Viswanathan, G. S.;
Li, C.-J. Chem. Commun. 1999, 291. (c) Zhang, W.-C.; Li, C.-J.; Sugihara
Tetrahedron 2000, 56, 2403. (d) Hu, Y.; Skalitzky, D. J.; Rychnovsky, S.
D. Tetrahedron Lett. 1996, 37, 8679. (e) Viswanathan, G. S.; Yang, J.; Li,
C.-J. Org. Lett. 1999, 1, 993. (f) Rychnovsky, S. D.; Yang, G.; Hu, Y.;
Khire, U. R. J. Org. Chem. 1997, 62, 3022.
(5) Al-Mutairi, E. H.; Crosby, S. R.; Darzi, J.; Harding, J. R.; Hughes,
R. A.; King, C. D.; Simpson, T. J.; Smith, R. W.; Willis, C. L. Chem.
Commun. 2001, 835.
8, was isolated as the major heterocycle (24% yield), the
plane of symmetry being clearly revealed in the 13C NMR
spectrum, which contained only 10 signals. In addition, the
acetate 9 (8% yield) and parent aldehyde 10 (34% yield)
were also isolated from the reaction.
A proposed mechanism to account for the formation of
these products is shown in Figure 1.6 In the presence of
(6) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C.
L. Org. Lett. 2002, 4, 577.
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Org. Lett., Vol. 4, No. 20, 2002