We review the original rationale for the development and the chemistry of a series of new synthetic oleanane triterpenoids (SO), based on oleanolic acid (1) as a starting material. Many of the new compounds that have been made, such as 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (“CDDO”, 8), are highly potent (activities found at levels below 1 nM) anti-inflammatory agents, as measured by their ability to block the cellular synthesis of the enzyme inducible nitric oxide synthase (iNOS) in activated macrophages. Details of the organic synthesis of new SO and their chemical mechanisms of biological activity are reviewed, as is formation of biotin conjugates for investigation of protein targets. Finally, we give a brief summary of important biological activities of SO in many organ systems in numerous animal models. Clinical investigation of a new SO (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, “CDDO-Me”, bardoxolone methyl, 13) is currently in progress.

Bardoxolone methyl (2-cyano-3,12-dioxooleane-1,9(11)-dien-28-oic acid methyl ester; CDDO-Me) (1), a synthetic oleanane triterpenoid with highly potent anti-inflammatory activity (levels below 1 nM), has completed a successful phase I clinical trial for the treatment of cancer and a successful phase II trial for the treatment of chronic kidney disease in type 2 diabetes patients. Our synthesis of bardoxolone methyl (1) proceeds in ∼50% overall yield in five steps from oleanolic acid (2), requires only one to two chromatographic purifications, and can provide gram quantities of 1.

Deprotonation of 2-(phenylsulfonyl)-1,3-oxazole (1) readily provides a useful C-5 carbanion which is reactive with a variety of electrophiles. Aldehydes and ketones are useful substrates, and the formation of 5-iodo- and 5-tri-n-butylstannyl oxazoles affords access to cross-coupling reactions. Subsequent nucleophilic displacement of the 2-phenylsulfonyl group provides a general route for the synthesis of 2,5-disubstituted-1,3-oxazoles.

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Total syntheses of several complex indole alkaloids having potent biological activities are discussed in detail.

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The halogen dance isomerization is a facile and preparatively effective pathway for the synthesis of 2,4,5-trisubstituted-1,3-oxazoles. Keywords oxazoles; halogen dance rearrangement; alkylationIn recent years, structural elucidation studies of biologically significant natural products have frequently incorporated novel 1,3-oxazole ring systems within complex molecular architectures. Numerous examples include hennoxazole A, 1 phorboxazoles A and B, 2 diazonamides A and B, 3 rhizopodin, 4 telomestatin, 5 and the ulapualides. 6 In addition, 1,3-oxazole moieties are commonly displayed within depsipeptides as a result of oxidative cyclodehydrations of serine and threonine residues. 7 These structural features have inspired wide-spread inclusion of substituted 1,3-oxazoles in medicinal chemistry, and particularly in the design of peptidomimetics. The proliferation of complex structures for challenging syntheses has ignited renewed interests in the development of effective methodologies toward substituted oxazoles. We have previously described an oxidative cyclodehydration route as a general strategy for the de novo preparation of 2,4-disubstituted 1,3-oxazoles. 8 Studies toward the elaboration of the oxazole nucleus have reported cross-coupling reactions of alkenylation and arylation at C-2 9 as well as Stille reactions of 2-phenyl-1,3-oxazoles. 10 Efforts for elaboration of the oxazole nucleus can be greatly facilitated by site-selective formation of a reactive carbanion. Kinetic deprotonation of the C-2 hydrogen of the parent oxazole provides access to a ring-closed carbanion as well as the ring-opened isonitrile enolate.11 C-Acylations of the enolate produce 4,5-disubstituted oxazoles via the Cornforth rearrangement.12 Examples of site-selective ring metalations via complex-induced proximity-effects 13 (CIPE) have been recorded in [2,4]-bisoxazoles 14 and for 2-methyl-1,3-oxazole-4-carboxylic acid.15 Furthermore, Stambuli and coworkers have recently described the selective C-5 deprotonation of 2-methylthio-1,3-oxazole leading to the production of 2,5-disubstituted oxazoles.16In this letter, we describe the kinetic C-4 deprotonation of 5-bromo-2-phenylthio-1,3-oxazole (1a) which initially leads to the lithium species 1b. Upon warming to 0 °C, anion 1b undergoes efficient isomerization to afford the reactive 5-lithio-4-bromo-2-phenylthio-1,3-oxazole (2a). Reactions of 2a with a variety of electrophiles yield the trisubstituted oxazoles 3. Transmetalation of the lithium species 2a provides the zinc reagent 2b for effective NIH-PA Author ManuscriptNegishi cross-coupling processes to give products of alkenylation and arylation at the C-5 position (Scheme 1).The nature of the isomerization which leads from the 5-bromo heterocycle 1a to yield the 4-bromo derivative 2a is described as the halogen dance (HD) reaction. This base-induced migration has been studied in aromatic and heteroaromatic systems. 17, 18 Strangeland and Sammakia first demonstrated an example of the halogen dance in a 1,3-thiazole system,19 ...

An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester) from commercially available ursolic acid, which features an oxidative ozonolysis-mediated C-ring enone formation, and provides the first access to ursolic acid-derived cyano enone analogues with C-ring activation. These new ursolic acid analogues show potent biological activities, with potency of approximately five-fold less than the corresponding oleanolic acid derivatives.