Organic Process Research & Development 2006, 10, 1076−1079
Reductive Cleavage of Acetals and Ketals with 9-Borabicyclo[3.3.1]nonane†
John A. Soderquist,* Iveliz Kock, and Maria E. Estrella
UniVersity of Puerto Rico, Department of Chemistry, Rio Piedras, Puerto Rico 00931-3346
Abstract:
4,6-O-benzylidene acetals of hexapyranosides to the corre-
sponding 4-O-benzyl ethers.4i,j Moreover, these reductive
processes have found applications in the synthesis of
pharmaceuticals and other natural products.4k,l
The reductive cleavage of benzaldehyde acetals and acetophe-
none ketals with the air-stable crystalline 9-borabicyclo[3.3.1]-
nonane dimer provides monobenzylated ether derivatives of
diols and 1,2-oxygen-transposed â-phenethyl alcohols, respec-
tively. The boron moiety is effectively recovered through simple
procedures which involve convenient air-stable reagents and
boron byproducts. The process is particularly selective for 1,3-
diols giving the more substituted monobenzyl ether derivatives
exclusively. With acetophenone ketals both reduction and
elimination occur, permitting 9-BBN-H to hydroborate the
resulting styrene to produce 1,2-oxygen-transposed â-phenethyl
alcohols cleanly. Potential applications of this new process were
illustrated with the synthesis of the hallucinogen, mescaline, and
the analgesic, ibufenac.
The reduction of benzylidine acetals to ethers can also
be viewed as a useful approach to the monobenzylation of
diols.5 Diisobutylaluminum hydride (DIBAL-H) has proven
useful for cyclic benzylidene acetals,5c and with the benzyl
group providing highly versatile alcohol protection, this
methodology has been used in total synthesis.6 This approach
to the selective monoprotection of chemically similar diols
is an important process. While the direct process commonly
gives mixtures, several very creative methods have been
developed for the selective benzylation of of 1,n-diols.5c,7
However, the reductive cleavage of cyclic benzylidene acetals
represents perhaps the most useful protective strategy for
the synthesis of monobenzylated diols.5c,6,8
One other interesting feature of the selective monopro-
tection vs acetal reduction strategies for monoalkylated diols,
is the selectivity of the process. The monoprotection of
unsymmetrical diols favors the less hindered alcohol site.9
On the other hand, the selective synthesis of the more
Introduction
Acetals and ketals have an extensive history as protecting
groups for carbonyls and diols in organic synthesis.1 This
protection is commonly employed in the total synthesis of
multifunctional compounds.2 Normally stable to neutral and
strongly basic conditions, it exhibits the lack of reactivity
associated with ethers. In the absence of Lewis acids, acetals
are insensitive to nucleophiles, making them excellent
carbonyl protecting groups. However, if desired, Lewis acid-
mediated additions to acetals can be highly useful synthetic
processes.3 For example, their reductive cleavage can be
effected through many Lewis acid/hydride combinations such
as LiAlH4/AlCl3, LiAlH4/BCl3 (including BHCl2 or BBr3),
Me3SiH/Me3SiOTf, Et3SiH/Nafion-H, ZrCl4/NaBH4, NaBH3-
CN/(HCl or BF3), Zn(BH4)2/Me3SiCl, BH3‚SMe2/TMSOTf
and BH3‚THF/ Bu2BOTf.4 This last combination provided
the best results for the selective reductive ring opening of
(4) (a) Eliel, E. L.; Badding, V. G.; Rerick, M. N. J. Am. Chem Soc. 1962, 80,
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† This work is dedicated to my mentor, the late, great Professor Herbert C.
Brown whose love of chemistry, standards of excellence, and levels of
accomplishment have been profoundly influential and inspirational to me and
many others. His passing marks the end of an era.
(6) (a) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J.
A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540. (b) Marshall, J. A.;
Fitzgerald, R. N. J. Org. Chem. 1999, 64, 4477.
* To whom all correspondence should be addressed: E-mail: jas@janice.uprr.pr.
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Vol. 10, No. 5, 2006 / Organic Process Research & Development
10.1021/op0601262 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/04/2006