TBD-Catalyzed Direct 5- and 6-enolexo Aldolization of Ketoaldehydes
ety, leading to the more thermodynamically stable enolate. cal outcome of the reaction. The development of a catalytic
This intermediate would then condense onto the aldehyde asymmetric version of this aldol condensation is also un-
affording addition product 4a. However, MTBD and TMG derway.
were found to be less reactive than TBD under the same
conditions, despite their similar basicities (pKa values of
conjugate acids are 25.5, 23.7 and 26.1, respectively),[15]
suggesting another mechanistic pathway. This possible
mechanism is based on the bifunctional reactivity of TBD,
nucleophilic and basic (Scheme 2), by analogy with the re-
ports of Waymouth and Mioskowski, who studied the
TBD-catalyzed polymerization of cyclic esters[13a] and the
aminolysis of esters,[13c] respectively.
Experimental Section
Representative Procedure for the TBD-Catalyzed Intramolecular Al-
dolization: To a solution of ketoaldehyde 3 (250 mg, 1.95 mmol) in
anhydrous THF (0.3 , 6.5 mL) was added TBD (8 mol-%) at room
temperature. The reaction mixture was stirred for 30 min and then
quenched with saturated ammonium chloride solution (10 mL).
The organic layer was separated. The aqueous layer was extracted
with diethyl ether (3ϫ10 mL). The organic layer was dried with
magnesium sulfate, filtered and concentrated in vacuo to afford a
crude product that was purified by flash chromatography to give
desired aldol products 4 as a mixture of two diastereoisomers. The
relative stereochemistry of the diastereoisomers was assigned by
analogy to our results and to reported data (see Supporting Infor-
mation).
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and spectroscopic data for
new compounds.
Acknowledgments
This work was supported by the Ministère Délégué à l’Enseigne-
ment Supérieur et à la Recherche (grant to C. G). We thank Dr. A.
Wagner for scientific discussions.
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Weinheim, 2004, vol. 1, pp. 25–65.
Scheme 2. Possible dual activation mechanism proposed for the
TBD-catalyzed 5-enolexo aldolization.
Inspired by these studies, the first step of the possible
mechanism would be a selective nucleophilic addition of
TBD on the more electrophilic aldehyde of 3a, generating
tetrahedral intermediate I. After proton transfer on the
alcohol functionality, the sp2 nitrogen of TBD would then
allow the intramolecular enolization of the ketone, leading
to intermediate II. This labile species would then release
the guanidinium cation, which will activate the aldehyde of
intermediate III. The subsequent intramolecular addition
of the ketone enolate to this intermediate affords aldol ad-
dition product 4a and regenerates the TBD catalyst.
The rationalization of the diastereoselectivity of addition
product 4a is still unclear on the basis of this proposed
mechanism.
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Conclusions
We described efficient guanidine-catalyzed 5-enolexo and
6-enolexo aldolizations of acyclic ketoaldehydes that lead to
2-ketocyclopentanols and 2-ketocyclohexanols in high
yields. This transformation is organocatalyzed by TBD, an
inexpensive and commercially available guanidine reagent.
This practical reaction enables the straightforward prepara-
tion of important building blocks for further elaboration. In
conjunction with these achievements, studies are currently
underway in our laboratory to rationalize the stereochemi-
[7] N. Itagaki, M. Kimura, T. Sugahara, Y. Iwabuchi, Org. Lett.
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Eur. J. Org. Chem. 2008, 4104–4108
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