7-Chloro-3-(4-methyl-benzene-sulfon-yl)pyrrolo[1,2-c]pyrimidine.

In the title compound, C14H11ClN2O2S, the dihedral angle between the pyrrolo-[1,2-c]pyrimidine ring system (r.m.s. deviation = 0.008 Å) and the benzene ring is 80.2 (9)°. In the crystal, inversion dimers linked by pairs of C-H⋯O inter-actions generate R 2 2(16) loops. Several aromatic π-π stacking inter-actions between the pyrrolo-[1,2-c]pyrimidine rings, as well as separately between the pyrrolo and pyrimidine groups [shortest centroid-centroid separation = 3.5758 (14) Å], help to consolidate the packing.

Design, synthesis, and biological activity of second-generation synthetic oleanane triterpenoids.

We report the synthesis and biological activity of C-24 demethyl CDDO-Me 2 and the C-28 amide derivatives 3 and 4, which are analogues of the anti-inflammatory synthetic triterpenoid bardoxolone methyl (CDDO-Me) 1. Demethylation of the C-24 methyl group was accomplished via "abnormal Beckmann" rearrangement and subsequent ring A reformation. Amides 3 and 4 were found to be potent inhibitors of the production of the inflammatory mediator NO in vitro.

An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester): analogues, biological activities, and comparison with oleanolic acid derivatives.

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.

Synthesis and biological evaluation of amino acid methyl ester conjugates of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid against the production of nitric oxide (NO).

2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO, 2) was condensed with various amino acid methyl esters at the C-28 carboxylic acid. The new amide conjugates were evaluated for their inhibition of nitric oxide (NO) production in RAW264.7 cells stimulated with interferon-γ (IFNγ). Of these new compounds, CDDO conjugates with alanine, valine, and serine are nearly equipotent to CDDO-ethyl amide (4), a triterpenoid with promising biological activity in numerous disease models. Some of these conjugates also induce the in vitro expression of heme oxygenase-1, and inhibit the proliferation of Panc-1343 pancreatic cells.

Synthesis of a dicyano abietane, a key intermediate for the anti-inflammatory agent TBE-31.

The synthesis of dicyano abietane 11, a potential precursor to the biologically active tricyclic bis-cyano enone 6 (TBE-31), was accomplished in eight steps from epoxide 13. The synthesis features a Lewis acid promoted stereoselective cyclization of epoxide 13 to generate the tricyclic ring system 12 in one step.

Efficient and scalable synthesis of bardoxolone methyl (cddo-methyl ester).

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.

New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress.

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.

Efficient Suzuki and Stille Reactions for Regioselective Strategies of Incorporation of the 1,3-Oxazole Heterocycle. Mild Desulfonylation for the Synthesis of C-4 and C-5 Monosubstituted Oxazoles.

Suzuki and Stille cross-coupling reactions are surveyed for site-selective C-4 and C-5 elaboration of 2-(phenylsulfonyl)-1,3-oxazole derivatives. Conditions for mild reductive desulfonylations provide for direct incorporation of the intact oxazole heterocycle through bonding at C-4 and C-5.

Enantioseparation and absolute configuration of the atropisomers of a naturally produced hexahalogenated 1,1'-dimethyl-2,2'-bipyrrole.

Hexahalogenated 1,1'-dimethyl-2,2'-bipyrroles (HDBPs) are a group of marine halogenated natural products (HNPs) that have been detected in environmental samples from all over the world. The most frequently described congener is the 5,5'-dichloro-1,1'-dimethyl-3,3',4,4'-tetrabromo-2,2'-bipyrrole (DBP-Br(4)Cl(2), BC-10). This compound is axially chiral, by virtue of hindered rotation about the interannular pyrrole-pyrrole bond forming stable atropisomers. This effect was proven by the separation of synthesized racemic DBP-Br(4)Cl(2) by enantioselective high performance liquid chromatography (HPLC). Pure enantiomers were isolated using enantioselective HPLC. Crystallization led to white crystals studied by X-ray analyses to determine the absolute configuration. Subsequent polarimetric measurements verified the first eluting enantiomer on HPLC as R(a)-(+)-DBP-Br(4)Cl(2) and the second as S(a)-(-)-DBP-Br(4)Cl(2). We also investigated the gas chromatography (GC) enantioseparation of DBP-Br(4)Cl(2). However, too high temperatures in the injector port led to partial racemization at temperatures >150 degrees C. GC coupled to mass spectrometry was used to study DBP-Br(4)Cl(2) in marine mammal samples. All samples contained both atropisomers of the natural product DBP-Br(4)Cl(2) with enrichment of the levo (-) enantiomer. This led to the assumption that both enantiomers of DBP-Br(4)Cl(2) were already produced in the environment.

General methodology for the preparation of 2,5-disubstituted-1,3-oxazoles.

Deprotonation of 2-(phenylsulfonyl)-1,3-oxazole (1) readily provides a useful C-5 carbanion that 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.

Methodology for the Synthesis of Substituted 1,3-Oxazoles.

The halogen dance isomerization is a facile and preparatively effective pathway for the synthesis of 2,4,5-trisubstituted-1,3-oxazoles.