Nitroalkene (4+2) cycloadditions of achiral and chiral vinyl ethers. The stereochemical consequence of the Lewis acid promoter and studies toward the total synthesis of (+)-pretazettine

Chiral enol ether dienophiles derived from (1R,2S)-($-$)-2-phenylcyclohexanol and (R)-($-$)-2,2-diphenylcyclopentanol (($-$)-6 have been found to provide high levels of asymmetric induction in tandem inter (4+2) /intra (3+2) nitroalkene cycloadditions. Either enantiomeric series of tandem cycloaddition/hydrogenolysis product is available from the chiral auxiliary of a single absolute configuration by judicious selection of the Lewis acid promoter, Ti(Oi-Pr)\sb{2}Cl\sb{2} (98% ee, ($-$)) or methylaluminum bis-(2,6-diphenylphenoxide) (MAPh) (93% ee, (+)). Propenyl ethers derived from ($-$)-6 undergo endo-selective (4+2) cycloadditions (2.3/1-8.2/1) in the presence Ti(Oi-Pr)\sb2Cl\sb2, however, exoselective (4+2) cycloadditions (10.2/l-54.8/l) are observed in the presence of MAPh.2-(Acyloxy)vinyl ethers undergo regioselective (4+2) cycloadditions with nitroalkenes (promoted by SnCl\sb4) to afford substituted 5-acetoxy nitronates in good yields (68%-91%). The endo/exo selectivity in the cycloadditions has been found to be dependent on the nitroalkene substitution; 2-aryl-1-nitroalkenes provided exclusively exo cycloadducts while 2-cyclohexyl-1-nitroethene afforded predominately endo cycloadducts (12/1). The resulting nitronates can be elaborated to N-tosyl-4-substituted-3-hydroxypyrrolidines by hydrogenolysis (160 psi of H\sb2/PtO\sb2) or to bicyclic $\alpha$-hydroxy lactams by (3+2) cycloaddition followed by hydrogenation (14.7 psi of H\sb2/Raney nickel). A chiral 2-acetoxyvinyl ether derived from ($-$)-6 has been employed in the cycloaddition-hydrogenation sequence to prepare an optically active N-tosyl-3-hydroxypyrrolidine in high enantiomeric excess (96% ee). The strategy of nitroalkene (4+2) cycloadditions employing 2-acetoxyvinyl ethers as dienophiles has been explored toward the total synthesis of the Amaryllidaceae alkaloid (+)-pretazettine.U of I OnlyETDs are only available to UIUC Users without author permissio

Discovery of a Potent and Selective Sphingosine Kinase 1 Inhibitor through the Molecular Combination of Chemotype-Distinct Screening Hits

Sphingosine kinase (SphK) is the major source of the lipid mediator and G protein-coupled receptor agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival, and migration and is a key regulator of lymphocyte trafficking. Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme-based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to compound <b>22a</b> (PF-543) with 2 orders of magnitude improved potency. Compound <b>22a</b> inhibited SphK1 with an IC₅₀ of 2 nM and was more than 100-fold selective for SphK1 over the SphK2 isoform. Through the modification of tail-region substituents, the specificity of inhibition for SphK1 and SphK2 could be modulated, yielding SphK1-selective, potent SphK1/2 dual, or SphK2-preferential inhibitors

Discovery of <i>N</i>‑(4-Fluoro-3-methoxybenzyl)-6-(2-(((2<i>S</i>,5<i>R</i>)‑5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)‑2<i>H</i>‑tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis

Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound <b>43a</b> lacking the previously observed preclinical toxicology at comparable exposures