Efficient Synthesis and Subsequent Transformations of Phenylsulfanylbicyclo[2.2.2]octenones and Phenylselenylbicyclo[2.2.2]octenones

Inverse-electron-demand Diels−Alder reactions of masked o-benzoquinones 2 with phenyl vinyl sulfide and phenyl vinyl selenide furnished highly functionalized bicyclo[2.2.2]octenone derivatives 3 and 4, respectively, in excellent regio- and stereoselectivities and yields up to 90%. The bicyclo[2.2.2]octenone derivatives 3 with the sulfur functionality were subjected to an oxidation−elimination process to furnish bicyclo[2.2.2]octadienone systems 7 in good yields. During the reduction process, the Diels−Alder adducts 3e and 4e led to 8, whereas the carbon-centered radicals generated from the other adducts 3a−d and 4a−d provided various rearranged products 9−13 depending on the substitution pattern and reagents utilized (Raney-Ni or n-Bu3SnH). Surprisingly these radicals showed preference for the carbonyl functionality to the olefinic double bond, leading to interesting rearrangement reactions of mechanistic importance and possible synthetic utility. Interestingly the alcohols obtained from the reduction of Diels−Alder adducts 3a−d underwent desulfurization smoothly to give desulfurized products in high yields; thus a detoured method of “reduction−desulfurization−oxidation” provides an entry to desulfurized bicyclo[2.2.2]octenones without rearrangement

Dual Behavior of Masked <i>o</i>-Benzoquinones in Intramolecular Diels−Alder Reactions. Expedient Synthesis of Highly Functionalized <i>cis</i>-Decalins from 2-Methoxyphenols

The potential dual behavior as dienes and dienophiles of the diene moieties of masked o-benzoquinones (MOBs) 10a−e−12a−e, generated upon oxidation of 2-methoxyphenols 1−3 with BTIB in the presence of appropriate dienols, in their intramolecular Diels−Alder (IMDA) reactions has been examined. The IMDA reactions of MOBs 10a−d, 11a,b,d, and 12a,b,d resulted in highly functionalized oxatricyclic compounds 18a−d, 19a,b,d, and 20a,b,d, respectively, with concomitant formation of cis-decalin derivatives 21a−d, 22a,b,d, and 23a,b,d in a highly regio- and stereoselective manner. However, the MOBs 10e−12e provided exclusively oxatricyclic compounds 18e−20e. The formation of cis-decalins in these IMDA reactions illustrates the dienophilic character of MOBs, in addition to their behavior as dienes. The ratio of the two cycloadducts obtained in each reaction as a result of the dual character of MOBs depends on the nature and/or position of the substituents on both the cyclohexadienone moiety and the added 2,4-dienol. The majority of the cycloadducts resulted from the diene property of MOBs in intramolecular Diels−Alder reactions smoothly underwent Cope rearrangement to furnish cis-decalins as sole products in excellent to quantitative yields that provides a short and efficient entry to polyfunctionized cis-decalins from 2-methoxyphenols. Furthermore, the variation of dienophilic and diene characters of MOBs in the IMDA reactions with the electron-donating or electron-withdrawing substituent of both cyclohexadienone moiety and the added conjugated acyclic diene or 2,4-dienol has been studied in detail

Efficient Synthesis and Subsequent Transformations of Phenylsulfanylbicyclo[2.2.2]octenones and Phenylselenylbicyclo[2.2.2]octenones

Inverse-electron-demand Diels−Alder reactions of masked o-benzoquinones 2 with phenyl vinyl sulfide and phenyl vinyl selenide furnished highly functionalized bicyclo[2.2.2]octenone derivatives 3 and 4, respectively, in excellent regio- and stereoselectivities and yields up to 90%. The bicyclo[2.2.2]octenone derivatives 3 with the sulfur functionality were subjected to an oxidation−elimination process to furnish bicyclo[2.2.2]octadienone systems 7 in good yields. During the reduction process, the Diels−Alder adducts 3e and 4e led to 8, whereas the carbon-centered radicals generated from the other adducts 3a−d and 4a−d provided various rearranged products 9−13 depending on the substitution pattern and reagents utilized (Raney-Ni or n-Bu3SnH). Surprisingly these radicals showed preference for the carbonyl functionality to the olefinic double bond, leading to interesting rearrangement reactions of mechanistic importance and possible synthetic utility. Interestingly the alcohols obtained from the reduction of Diels−Alder adducts 3a−d underwent desulfurization smoothly to give desulfurized products in high yields; thus a detoured method of “reduction−desulfurization−oxidation” provides an entry to desulfurized bicyclo[2.2.2]octenones without rearrangement

Facial Selectivity in the Nucleophilic Additions of Vinylmagnesium Bromide to Bicyclo[2.2.2]oct-5-en-2-one Derivatives^†

The levels of diastereoselection attainable by addition of vinylmagnesium bromide to a selection of bicyclo[2.2.2]octenone derivatives 1−6 in the presence of various Lewis acids such as LiBr, CeCl3, TiCl4, ZnBr2, MgBr2, and Et2AlCl have been determined. The 1,2-addition of ketone 1 with vinylmagnesium bromide in THF provided a mixture of anti- and syn-isomers. The reactions of 2 with vinylmagnesium bromide at room temperature afforded anti- and syn-isomers with preference to anti-isomers in most cases. These reactions in the presence of Lewis acids afforded anti-isomers as the major product with an excellent stereoselectivity or as single isomers in some cases. The ketones 3 gave surprisingly different results providing anti-isomers predominantly even in the presence of Lewis acids. The bicyclic ketones 4 and 5 and all-carbon tricyclic ketone 6 furnished the syn-isomer as the main product. There is no significant effect of Lewis acid catalysis in the nucleophilic addition reactions of 1, 4, 5, and 6. The use of a preformed vinylmagnesium bromide−CeCl3 reagent for the addition reactions of 2d−f and 3d−f provided almost exclusively syn-isomers. The substituents and reaction conditions can influence facial selectivity in the nucleophilic additions to the bicyclo[2.2.2]oct-5-en-2-one derivatives

Facial Selectivity in the Nucleophilic Additions of Vinylmagnesium Bromide to Bicyclo[2.2.2]oct-5-en-2-one Derivatives^†

The levels of diastereoselection attainable by addition of vinylmagnesium bromide to a selection of bicyclo[2.2.2]octenone derivatives 1−6 in the presence of various Lewis acids such as LiBr, CeCl3, TiCl4, ZnBr2, MgBr2, and Et2AlCl have been determined. The 1,2-addition of ketone 1 with vinylmagnesium bromide in THF provided a mixture of anti- and syn-isomers. The reactions of 2 with vinylmagnesium bromide at room temperature afforded anti- and syn-isomers with preference to anti-isomers in most cases. These reactions in the presence of Lewis acids afforded anti-isomers as the major product with an excellent stereoselectivity or as single isomers in some cases. The ketones 3 gave surprisingly different results providing anti-isomers predominantly even in the presence of Lewis acids. The bicyclic ketones 4 and 5 and all-carbon tricyclic ketone 6 furnished the syn-isomer as the main product. There is no significant effect of Lewis acid catalysis in the nucleophilic addition reactions of 1, 4, 5, and 6. The use of a preformed vinylmagnesium bromide−CeCl3 reagent for the addition reactions of 2d−f and 3d−f provided almost exclusively syn-isomers. The substituents and reaction conditions can influence facial selectivity in the nucleophilic additions to the bicyclo[2.2.2]oct-5-en-2-one derivatives

Design and Structural Analysis of Novel Pharmacophores for Potent and Selective Peroxisome Proliferator-activated Receptor γ Agonists

Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted PPARα/γ dual agonist 1 to selective PPARγ agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPARγ receptor, with 80- to 100-fold PPARγ selectivity over PPARα receptor. X-ray cocrystal studies in PPARγ and modeling studies in PPARα give molecular insights for the improved PPARγ potency and selectivity for 19 when compared to 1

Fast-Forwarding Hit to Lead: Aurora and Epidermal Growth Factor Receptor Kinase Inhibitor Lead Identification

A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases

Novel Indole-Based Peroxisome Proliferator-Activated Receptor Agonists: Design, SAR, Structural Biology, and Biological Activities

The synthesis and structure−activity relationship studies of novel indole derivatives as peroxisome proliferator-activated receptor (PPAR) agonists are reported. Indole, a druglike scaffold, was studied as a core skeleton for the acidic head part of PPAR agonists. The structural features (acidic head, substitution on indole, and linker) were optimized first, by keeping benzisoxazole as the tail part, based on binding and functional activity at PPARγ protein. The variations in the tail part, by introducing various heteroaromatic ring systems, were then studied. In vitro evaluation led to identification of a novel series of indole compounds with a benzisoxazole tail as potent PPAR agonists with the lead compound 14 (BPR1H036) displaying an excellent pharmacokinetic profile in BALB/c mice and an efficacious glucose lowering activity in KKAy mice. Structural biology studies of 14 showed that the indole ring contributes strong hydrophobic interactions with PPARγ and could be an important moiety for the binding to the protein