aldehyde isomer. As a result of the prevalence of the
spiroketal moiety in natural products,4 it is surprising that a
tandem hydride transfer/cyclization mechanism has not been
explored as a potential general method for the preparation
of spiroketals. Additionally, since Woodward’s account in
1958, only a few reports have appeared in the literature that
utilize an internal redox mechanism for direct C-H to C-Y
(Y ) O, NR) transformations,5,6 and no general catalytic
method has been established. Herein, we report the scope
and limitations of a Lewis acid catalyzed intramolecular
hydro-O-alkylation of aldehyde substrates leading to spiroket-
al and bicyclic acetal products.
Table 1. Lewis Acid Catalyzed Hydride Transfer/Cyclization
of Aldehyde Substrates
We initiated our studies by subjecting tetrahydropyran
substrate 1 to 30 mol % BF3‚Et2O in methylene chloride. In
less than 3 h, aldehyde 1 was cleanly converted to the
spiroketal 2 at ambient temperature in 91% isolated yield,
1
with 2 being the only identifiable product via H NMR
analysis of the crude reaction mixture (Table 1). Clean
transformation of 1 to 2 could also be accomplished with
Lewis acids such as Sc(OTf)3, GaCl3, and TiF4; Sn(OTf)2
and Zn(OTf)2 proved less effective, and B(C6F5)3 and
trifluoroacetic acid were incompetent. Because of its ease
of handling and its low cost, we proceeded to examine the
scope of this transformation with BF3‚Et2O (Table 1). Both
diastereomeric substrates 3 and 5 produced the same
spiroketal diastereomer 4 in good yield. The trisubstituted
tetrahydropyran substrate 6, containing a chloride substituent,
was smoothly converted to the spiroketal 7 in 90% yield.
Geminal substitution along the aldehyde tether was not
required for efficient cyclization (entries 5 and 7, Table 1).
In addition to 6,6 scaffolds, 5,6 spiroketals could also be
obtained in excellent yields (Table 1, entries 6 and 7), and
notably in the case of substrate 10, as little as 5 mol %
BF3‚Et2O could be used. This transformation was not limited
to spiroketalization, as demonstrated by the conversion of
14 into the cis-fused bicyclic acetal 15 as a single diastere-
omer (Table 1). In this case BF3‚Et2O was unreactive, and
only the strong Lewis acid TiF4 catalyzed the transformation.
Similarly, TiF4 converted the N-protected pyrrolidine sub-
strate 16 into the cis-fused bicyclic aminal 17 as a single
diastereomer; however, 1.3 equiv of TiF4 and elevated
temperature were required (Table 1). In addition to aldehyde
substrates, methyl ketone 18 was converted into the spiroketal
19 under the action of TiF4 in 30% yield (Table 1, entry
10). BF3‚Et2O was unable to promote hydroalkylation of the
less electrophilic ketone, and stronger Lewis acids were
required for the transformation.7 The production of 19 was
accompanied by the formation of unidentified byproducts,
and thus more selective catalysts will have to be discovered
for ketone substrates.
a All reactions were preformed on a 0.5 or 0.25 mmol scale in CH2Cl2
(0.025 M substrate) at room temperature with 30 mol % BF3‚Et2O. Isolated
yields after flash chromatography. b 5 mol % BF3.Et2O used. c 20 mol %
TiF4 used. d 1.3 equiv of TiF4, 50 °C. e 100 mol % TiF4 used.
Convincing evidence for the postulated intramolecular
hydride transfer mechanism was obtained by the subjection
of the deuterated substrate 6-D to the standard conditions to
form 7-D (Scheme 1). 1H NMR analysis of the product 7-D
showed that no loss of deuterium occurred during the course
of the hydride transfer, with approximately 60% and 40%
of the deuterium residing on the axial and equatorial
positions, respectively.8 Additionally, subjection of a 1:1
mixture of 1 and 6-D to 30 mol % BF3‚Et2O resulted only
in the production of 2 and 7-D with no crossover of
deuterium.
(4) For reviews on the synthesis of spiroketals including spirioketal
natural products, see: (a) Mead, K. T.; Brewer, B. N. Curr. Org. Chem.
2003, 7, 227-256. (b) Perron, F.; Albizati, K. F. Chem. ReV. 1989, 89,
1617-1661. (c) Boivin, T. L. B. Tetrahedron 1987, 43, 3309-3362.
(5) C-H to C-O: Schulz, J. G. D.; Onopchenko, A. J. Org. Chem.
1978, 43, 339-340. Only two examples are provided in this report.
(6) C-H to C-N: (a) Wo¨lfling, J.; Frank, EÄ .; Schneider, G.; Tietze, L.
F. Angew. Chem., Int. Ed. 1998, 38, 200-201. (b) Wo¨lfling, J.; Frank, EÄ .;
Schneider, G.; Tietze, L. F. Eur. J. Org. Chem. 2004, 90-100.
(7) GaCl3 performed similarly to TiF4.
(8) For deuterium studies regarding the epimerization of spirostanols,
see: Seo, S.; Uomori, A.; Takeda, K. J. Org. Chem. 1986, 51, 3823-3827.
5430
Org. Lett., Vol. 7, No. 24, 2005
Pastine, Stefan J.
