Theoretical Study of Asymmetric Transfer Hydrogenation of Ketones Catalyzed by Amino Acid-Derived Rhodium Complexes

Density functional theory calculations are employed to study the asymmetric transfer hydrogenation of ketones catalyzed by rhodium–arene complexes containing hydroxamic acid-functionalized amino acid ligands. Firstly, the ligand–metal binding is investigated and it is shown that both the N,N and O,O binding modes Are viable. For each of these, the full free energy profile for the transfer hydrogenation is calculated according to the outer-sphere reaction mechanism. Three factors are demonstrated to influence the stereoselectivity of the process, namely the energy difference between the metal–ligand binding modes, the energy difference between the intermediate hydrogenated catalyst, and the existence of a stabilizing CH–π interaction between the Cp* ligand of the catalyst and the phenyl moiety of the substrate. Theoretical reproduction of the selectivity of a slightly modified ligand that is shown experimentally to yield the opposite enantioselectivity corroborates these results. Finally, a technical observation made is that inclusion of dispersion interactions (using the B3LYP-D2 correction or the M06 functional) proved to be very important for reproducing the enantioselectivity

Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations

Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case–control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.Funding Agencies|Knut and Alice Wallenberg Foundation|2011.0073|Swedish Research Council for Medicine and Health|A0280001A0258801A80741201|Swedish Research Council for Science and Technology|90559401|Swedish Rheumatism Association||Ragnar Soderbergs Foundation||King Gustaf V 80-year Foundation||COMBINE, the Swedish Heart-Lung Foundation||Stockholm County Council||Karolinska Institutet (ALF)||Foundation in memory of Clas Groschinsky||Swedish Society of Medicine||Alliance for Lupus Research||Kirkland Scholar Award||NIH|AR044804AR02175AR052300M01 RR-000079|Uppsala University, Uppsala University Hospital||Swedish Council for Research Infrastructures|8057680170374401|</p