intermediates more closely related to natural or unnatural
targets with macrolactone structure (compounds 1) by
oxidative cleavage of the CdN bond using one of the many
mild methods available for oximes.10 This would lead to
compounds 2 with a ketone carbonyl γ to the lactone oxygen
and a hemiacetal function, which should spontaneously lose
a molecule of hydroxylamine and give an aldehyde group
in the R position (Scheme 1).
Scheme 1. Proposed Connection of Bridged Bicyclic
Macrolactones 3 and Simple Functionalized Macrolactones
Figure 1. Structures of some natural macrolactones and
welwistatin.
bonds by a variety of reactions.4a,c,7 Generally speaking,
routes starting from open-chain precursors have the disad-
vantage of requiring the use of high-dilution conditions to
prevent intermolecular reactions and often lead to inadequate
yields, which has prompted the development of methods
based on ring expansion8 that often allow these shortcomings
to be overcome.
We present here a novel procedure for the one-pot syn-
thesis of functionalized medium-sized lactones or macro-
lactones by reaction of cyclic R-nitroketone anions with
R-substituted R,â-unsaturated aldehydes in aqueous solution,
which was discovered in the course of our studies on an
approach to analogues of the MDR inhibitor welwistatin (N-
methylwelwitindolinone C isothiocyanate)9 based on R-ni-
troketone chemistry. This reaction led to the isolation of
bridged lactones 3, which can be linked to synthetic
R-Nitroketones are important synthetic intermediates,11
which have been employed as starting materials in the
preparation of building blocks such as nitrocyclohexenes,12
ω-nitro alcohols and spiroketals,13 â-nitro alcohols,14 â-amino
alcohols,15 ω-amino acids,16 R-hydroxyketones,17 and ni-
trones,18 among others.19 In this context, we have recently
shown that R-nitroketones 1 react with unsubstituted R,â-
unsaturated aldehydes and ketones in water at room tem-
perature, giving the expected Michael adducts,20 which could
also be obtained using dilute potassium carbonate as the
reaction medium if the reaction times were kept short enough
to prevent opening of the nitroketone moiety by a retro-
Claisen-type mechanism. However, in the case of the more
hindered R,â-unsaturated aldehydes bearing an alkyl group
at their R position, the reaction did not take place in the
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Carreira, E. M. J. Org. Chem. 2003, 68, 9274. (g) Vidya, R.; Eggen, M. J.;
Nair, S. K.; Georg, G. I.; Himes, R. H. J. Org. Chem. 2003, 68, 9687. (h)
Kusaka, S.-i; Dohi, S.; Doi, T.; Takahashi, T. Tetrahedron Lett. 2003, 44,
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Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425. (k) Kobayashi, Y.;
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261. (b) Ballini, R. Synlett 1999, 1009. For more general reviews of the
synthetic applications of nitroalkanes, see: (c) Ono, N. The Nitro Group
in Organic Synthesis; Wiley-VCH: Weinheim, 2001. (d) Ballini, R.; Bosica,
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