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This Review compiles the evolution, mechanistic understanding, and more recent advances in enantioselective Pd-catalyzed allylic substitution and decarboxylative and oxidative allylic substitutions. For each reaction, the catalytic data, as well as examples of their application to the synthesis of more complex molecules, are collected. Sections in which we discuss key mechanistic aspects for high selectivity and a comparison with other metals (with advantages and disadvantages) are also included. For Pd-catalyzed asymmetric allylic substitution, the catalytic data are grouped according to the type of nucleophile employed. Because of the prominent position of the use of stabilized carbon nucleophiles and heteronucleophiles, many chiral ligands have been developed. To better compare the results, they are presented grouped by ligand types. Pd-catalyzed asymmetric decarboxylative reactions are mainly promoted by PHOX or Trost ligands, which justifies organizing this section in chronological order. For asymmetric oxidative allylic substitution the results are grouped according to the type of nucleophile used.

The asymmetric inter- and intramolecular Heck and related reactions are comprehensively reviewed, from their original development to recent advances in terms of substrate scope, reactivity, regio- and enantioselectivity. Their reaction mechanisms/catalytic cycles are discussed in order to understand the concepts underpinning the significant recent developments of these processes. The design and application of new chiral ligands has been pivotal to reaction enhancements and, for each Heck and related process, we classify ligands by the nature of the denticity, chirality and donor atoms involved. In this manner, the continued development of ligand architectural design and application can be more easily monitored for each process. Significant improvements in reaction times, a disadvantage in many Heck reactions, have been addressed through a combination the use of microwave-assisted protocols and ligand design. The asymmetric Fujiwara-Moritani and oxidative boron Heck-type reactions, recent additions to Heck type processes, will also be discussed in this critical review (149 references).

SUMMARY The role of inflammation in obesity-related pathologies is well established. We investigated the therapeutic potential of LipoxinA4 (LXA4:5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E,-eicosatetraenoic acid) and a synthetic 15(R)-Benzo-LXA4-analogue, as interventions in a 3-month high-fat-diet [HFD; 60%fat]-induced obesity model. Obesity caused distinct pathologies, including impaired glucose-tolerance, adipose inflammation, fatty liver and chronic-kidney-disease (CKD). Lipoxins (LXs) attenuated obesity- induced CKD; reducing glomerular expansion, mesangial matrix and urinary H2O2. Furthermore, LXA4 reduced liver weight, serum alanine-aminotransferase and hepatic triglycerides. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-α and CD11c+ M1-macrophages (MΦs), while restoring CD206+ M2-MΦs and increasing Annexin-1. LXs did not affect renal or hepatic MΦs, suggesting protection occurred via attenuation of adipose inflammation. LXs restored adipose expression of autophagy markers LC3-II and p62. LX-mediated protection was demonstrable in adiponectin−/− mice, suggesting that the mechanism was adiponectin independent. In conclusion, LXs protect against obesity- induced systemic disease and these data support a novel therapeutic paradigm for treating obesity and associated pathologies.

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Lipoxins, which are endogenously produced lipid mediators, promote the resolution of inflammation, and may inhibit fibrosis, suggesting a possible role in modulating renal disease. Here, lipoxin A4 (LXA 4 ) attenuated TGF-b1-induced expression of fibronectin, N-cadherin, thrombospondin, and the notch ligand jagged-1 in cultured human proximal tubular epithelial (HK-2) cells through a mechanism involving upregulation of the microRNA let-7c. Conversely, TGF-b1 suppressed expression of let-7c. In cells pretreated with LXA 4 , upregulation of let-7c persisted despite subsequent stimulation with TGF-b1. In the unilateral ureteral obstruction model of renal fibrosis, let-7c upregulation was induced by administering an LXA 4 analog. Bioinformatic analysis suggested that targets of let-7c include several members of the TGF-b1 signaling pathway, including the TGF-b receptor type 1. Consistent with this, LXA 4 -induced upregulation of let-7c inhibited both the expression of TGF-b receptor type 1 and the response to TGF-b1. Overexpression of let-7c mimicked the antifibrotic effects of LXA 4 in renal epithelia; conversely, anti-miR directed against let-7c attenuated the effects of LXA 4 . Finally, we observed that several let-7c target genes were upregulated in fibrotic human renal biopsies compared with controls. In conclusion, these results suggest that LXA 4 -mediated upregulation of let-7c suppresses TGF-b1-induced fibrosis and that expression of let7c targets is dysregulated in human renal fibrosis.