protection of R-ketoacids via direct annulations with oximes
(eq 1). The resulting 2,5-dihydrooxazole 3-oxides are chemi-
cally and configurationally stable masked R-ketoacids that
can be deprotected under mild reductive conditions.
Scheme 1.
Annulations of Oximes and R-Ketoacidsa
Our studies began by considering strategies to simulta-
neously protect both the acid and ketone functionalities of
the R-ketoacid. Although certain cyclic imines have been
employed as precursors to R-ketoacids, we found such
compounds to be labile to most common purification methods
and chemical transformations.8 The corresponding N-oxides,
that is, cyclic nitrones, were known to be stable compounds,
but the reported methods for their preparation relied on
cycloadditions of nitrosoketenes and ketones, a protocol that
was limited to the preparation of glyoxylic acid derivatives.9
Furthermore, we were primarily interested in identifying a
method for the protection of an existing R-ketoacid rather
than a de novo synthesis of this functionality.
In the course of our investigations of the properties and
reactions of R-ketoacids, we were therefore surprised to find
that R-ketoacids and aliphatic oximes undergo a spontaneous,
chemoselective annulation to afford 2,5-dihydrooxazole
3-oxides in good yields under a variety of conditions.10 The
structure of the annulation product was confirmed by single
crystal X-ray analysis of 8. The reaction of oximes and
R-ketocids under aqueous conditions has been previously
studied as an effective method for oxime hydrolysis, but no
reports of this annulation have appeared.11,12 A screen of
reaction parameters identified nonpolar solvents as preferred,
with reaction temperatures ranging from room temperature
to 40 °C. Oximes derived from either aliphatic aldehydes or
aliphatic ketones were suitable for annulations with a variety
of R-ketoacids (Scheme 1). The reaction usually failed for
oximes adjacent to an sp2 hybridized carbon, such as those
derived from benzaldehyde or cinnamaldehyde (not shown).
Bulky groups on the oxime did not significantly retard the
reaction, while R-ketoacids containing ꢀ-branching coupled
more slowly but were still viable substrates.13
a All reactions were preformed at 0.2 M CH2Cl2 for 12-16 h. Yields refer
to mass yields of isolated, pure products b Reaction performed at 40 °C.
A key feature of the annulation of R-ketoacids and oximes
is the chemoselectivity; selective protection of R-ketoacids
in the presence of unprotected carboxylic acids is possible
(Scheme 2). This enables the transient protection and
Scheme 2
.
Chemoselective Annulation, Elaboration, and
Deprotection of R-Ketoacids
(7) Brady, S. F.; Sisko, J. T.; Stauffer, K. J.; Colton, C. D.; Qiu, H.;
Lewis, S. D.; Ng, A. S.; Shafer, J. A.; Bogusky, M. J.; Veber, D. F.; Nutt,
R. F. Bioorg. Med. Chem. 1995, 3, 1063–1078.
(8) Barnish, I. T.; Cross, P. E.; Danilewicz, J. C.; Dickinson, R. P.;
Stopher, D. A. J. Med. Chem. 1981, 24, 399–404.
(9) (a) Katagiri, N.; Sato, H.; Kurimoto, A.; Okada, M.; Yamada, A.;
Kaneko, C. J. Org. Chem. 1994, 59, 8101–8106. (b) Katagiri, N.; Okada,
M.; Kaneko, C.; Furuya, T. Tetrahedron Lett. 1996, 37, 1801–1804. (c)
Baldwin, S. W.; Long, A. Org. Lett. 2004, 6, 1653–1656.
(10) Afagh, N. A.; Yudin, A. K. Angew. Chem., Int. Ed. 2010, 49, 262–
310.
(11) (a) Hershberg, E. B. J. Org. Chem. 1948, 13, 542–546. (b) Kim,
J. N.; Ryu, E. K. Bull. Korean Chem. Soc. 1992, 13, 184–187
.
(12) We have confirmed that hydrolysis of the oxime occurs upon
treatment with an a-ketoacid under aqueous conditions (tBuOH/H2O, rt).
We do not detect the 2,5-dihydrooxazole 3-oxide as an intermediate.
(13) The use of additives such as Lewis acids or dehydrating reagents
did not significantly improve yield.
elaboration of bifunctional R-ketoacids, a finding that will
extend the utility of the ketoacid-hydroxylamine amide-
forming ligation.
Org. Lett., Vol. 12, No. 9, 2010
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