If we could render this reaction into a regio- and diaster-
eoselective process, then the employment of enantiopure
starting material in this sequence would furnish enantio-
pure products (see 3f4, Scheme 1). In fact, the related
intramolecular addition of a hydride nucleophile onto an
oxonium ion (itself generated by a 1,2-hydride shift) has
recently proven to be an efficient way of forming trans
substituted tetrahydrofuran rings.8
Scheme 2. Synthesis of Starting Materials
Scheme 1. General Concept
We set out to examine this reaction sequence by starting
from readily available pyridine 5 (Scheme 2).9 Addition of
a nucleophile to the aldehyde was accomplished by the
action of an organometallic reagent, and subsequent qua-
ternerization of the nitrogen with allyl triflate10 activated
the pyridine toward nucleophilic attack. Finally, the nu-
cleophilic hydride species was attached to the C-2 benzylic
alcohol via a temporary silicon linker.
atom to release its hydride nucleophile by the addition of
fluoride (TBAF, 1 equiv) to the heteroatom (Scheme 3).
Using THF as a solvent, this reaction was partially
successful giving 24 but was always in competition with
simple desilylation of the starting material, producing
12. Note that in each case the reaction was quenched
with an acidic workup so that intermediate enol ethers
would be hydrolyzed to the stable, and isolable, dihy-
dropyridones (see A, Scheme 1). A breakthrough came
about when we switched the solvent to toluene, hypothe-
sizing that the loss of an alkoxide from a pentavalent
silicon intermediate might be disfavored in such a non-
polar solvent. Indeed, dihydropyridone 24 was isolated
in improved yield (52%) and with high diastereoselec-
tivity when the reaction was conducted in toluene at
50 °C. While, in each case, the product was isolated as its
silyl ether, we noticed that under the higher temperature
conditions there was a significant amount of desilyation
of the product. Therefore, the decision was made to add
an excess (4 equiv) of TBAF to the reaction mixture
to ensure complete removal of silicon from the product;
in this case product isolation was made significantly
easier by acetylation of the crude alcohol product. Using
this regime, compound 25 was isolated in 85% yield
and with 8:1 diastereoselectivity. The sense of stereo-
selectivity of the hydride transfer reaction was proven to
be as shown by X-ray crystallography on a para-nitro-
benzoate derivative (26) of the major diastereomer of
compound 25.
Taking methyl substituted compound 18 as an example,
we then undertook experiments to encourage the silicon
(6) (a) Wolfe, B. H.; Libby, A. H.; Al-awar, R. S.; Foti, C. J.; Comins,
D. L. J. Org. Chem. 2010, 75, 8564. (b) Barbe, G.; Pelletier, G.; Charette,
A. B. Org. Lett. 2009, 11, 3398. (c) Focken, T.; Charette, A. B. Org. Lett.
2006, 8, 2985. (d) Comins, D. L.; Sahn, J. J. Org. Lett. 2005, 7, 5227.
(e) Legault, C.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 6360.
(f) Yamada, S.; Morita, C. J. Am. Chem. Soc. 2002, 124, 8184. (g) Charette,
A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem.
Soc. 2001, 123, 11829. (h) Comins, D. L.; Joseph, S. P.; Goehring, R. R.
J. Am. Chem. Soc. 1994, 116, 4719.
ꢀ
ꢀ
ꢀ~
ꢀ
(7) (a) Fernandez-Ibanez, M. A.; Macia, B.; Pizzuti, M. G.; Min-
naard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2009, 48, 9339. (b)
Black, D. A.; Beveridge, R. E.; Arndtsen, B. A. J. Org. Chem. 2008, 73,
1906. (c) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc. 2007, 129,
9300. (d) Ichikawa, E.; Suzuki, M.; Yabu, K.; Albert, M.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 11808. (e) Nadeau, C.; Aly,
S.; Belyk, K. J. Am. Chem. Soc. 2011, 133, 2878.
(8) (a) Donohoe, T. J.; Williams, O.; Churchill, G. H. Angew. Chem.,
Int. Ed. 2008, 47, 2869. (b) McCombie, S. W.; Ortiz, C.; Cox, B.;
Ganguly, A. K. Synlett 1993, 541. For a review see: (c) Larson, G. L.;
Fry, J. L. Org. React. 2008, 71, 1.
(9) Compound 5 may be easily prepared by DIBAl-H reduction of
the corresponding methyl ester (85% yield): Sundberg, R. J.; Jiang, S.
Org. Prep. Proced. Int. 1997, 29, 117. Alternatively, 5 is commercially
available, although expensive.
(10) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 5675. The
allyl group is particularly convenient because it is stable to the reaction
conditions and yet can be easily removed afterwards, if so desired;
see ref 4.
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