Current Organic Chemistry - Volume 8, Issue 14, 2004

The simple heterocycle 2-(3H)-oxazolone has long proven itself a versatile tool in the hands of the synthetic organic chemist. Its numerous derivatives have served in many roles - from activating groups in coupling reactions, to efficient and reliable chiral auxiliaries, as focal points for asymmetric catalysis, or more recently as a versatile synthon in target-oriented synthesis. Although several obvious comparisons are prone to arise, in particular with the structurally related yet more celebrated oxazolidinones, the extensive use of the latter are beyond the scope of this work. Instead, the purpose of this review is to highlight some of the broader capabilities of oxazolone itself, indeed many of which we feel are underutilized as of yet. Wherever relevant, comparison with analogous heterocyclic species will be presented. Specific areas under consideration will include: synthesis and simple derivatization, including N- and O- alkylations and acylations; reactivity of the parent heterocycle in processes involving the pi-system, such as electrophilic addition, radical reactions, cycloadditions and so on, in both inter- and intramolecular fashion; operation of the oxazolone framework in development and utilization of novel asymmetric processes In addition, the direct incorporation and manipulation of the oxazolone framework as a valuable synthon in target-oriented synthesis, in particular toward a variety of alkaloid systems, will be covered as appropriate.

Chiral auxiliary-based reactions constitute one the most intense research areas in organic chemistry. During the last three decades (R)-pantolactone and to a minor extent its (S)-enantiomer have been used as very efficient chiral auxiliaries, thus contributing to the development of chiral auxiliary-based asymmetric synthesis as a common approach for the preparation of enantiomerically pure compounds. This review covers the syntheses of both (R)- and (S)-pantolactone, as well as their applications not only as chiral auxiliaries in asymmetric synthesis, but also in racemate resolutions and as chiral templates. The development and applications of several analogs of pantolactone with improved profile is also discussed.

The medical application of cardenolides and bufadienolides is associated with a high risk, due to their toxicity and the small difference between the therapeutic and toxic doses. In the past few years, increasing attention has been paid to the mechanism of cardiotonic action and the synthesis of cardenolide and bufadienolide analogs which are expected to have better therapeutic indices. A cardenolide analog in which the lactone ring is replaced by a nitrogen-containing unsaturated heterocycle was found to be almost as active as the parent compound. A knowledge of the activity of such compounds would contribute to the question of the structural requirements for a heterocyclic substitutent. Pharmacological examinations have shown that the cardiotonic activity of the 17β-exoheterocyclic steroids is weaker than that of the parent compound, although the ratio of the therapeutic effect to the toxic effect is favorable. Besides cardiotonic activity, a large number of exo-heterocyclic steroids display a potential as inhibitors of human cytochrome P450 17α, the enzyme responsible for the conversion of C21 steroids to the related C19 steroids (androgens). This is a potential approach for the therapeutic treatment of this disease, which frequently exhibits an androgen dependence. This review deals with recent studies of the synthesis of modified cardenolides which are expected to have better cardiotonic activities, and with the synthesis of steroids with a variety of heterocycles at C-17 which have been tested against P45017α.

Substituted tricarballylic acid has found many technical and biological applications and this reflected a number of such compounds synthesized to date. In this review an attempt has been made to be the only review appeared in the literature up to date. Presenting only a selection of synthetic interest and stereochemistry of tricarballylic acid moieties of some natural products. The important issues for the existing of the tricarballylic acid in some natural products and the chemistry studies are recapitulated.