Abstract:The highly enantioselective reduction of imines is achieved by employing chiral Zn/diamine catalysts. This new catalytic protocol offers attractive features such as use of a non-precious metal and an inexpensive silane, easy modification of chiral diamine ligands and provides ready access to chiral amines in good yields and with excellent enantioselectivities. Keywords:enantioselectivity; hydrosilylation; imine; ligands; zinc The catalytic, enantioselective reduction of imines [1] to produce chiral amines is of great importance due to the prevalence of chiral amines in natural products and pharmaceutical targets. Although greater attention has been paid to the asymmetric hydrogenation, [2] asymmetric hydrosilylation employing safe and inexpensive hydrosilanes such as polymethylhydrosiloxane (PMHS) provides an alternative and attractive route to chiral amines. Catalysts derived from transition metals such as Ti, [3] Rh, [4] Ru, [5] Cu, [6] and recently Re [7] were employed for enantioselective hydrosilylation of imines: with regard to Rh and Ru, only limited examples have been reported by rhodium or ruthenium-chiral bisphosphine catalysts, and none of these reactions afforded amines with high enantioselectivity. Highly enantioselective reduction systems were developed with Ti, Cu, and Re, but either synthesis of complex catalysts (ligand-metal) or use of unusually modified substrates was necessary. Therefore, the development of more general and simpler catalyst systems for the reduction is required. Herein, we describe a highly enantioselective hydrosilylation of imines catalyzed by simple Zn-diamine catalysts.Chiral diamine coordinated zinc catalysts for the enantioselective hydrosilylation of aromatic ketones first appeared in the literature in the late 1990s. [8] However, asymmetric hydrosilylation of imines based on zinc remains undeveloped. Recently, Carpentier et al. included a few reduction examples of imines in their report on zinc-catalyzed hydrosilylation of ketones, [9] but their system reduced imine substrates, particularly aromatic imines in very low yields and with poor enantioselectivities (0-4 % ee).The major problem in developing a new reduction methodology of imines based on zinc is that a strong zinc-nitrogen (Zn À N) bond [10] formed by addition of Zn À H to the imine substrate during the catalytic cycle (Scheme 1). For optimal reactivity, this particular bond should be easily cleaved by an incoming hydrosilane without disturbing the interaction between the metal and the diamine ligand. Moreover, when a Scheme 1. Presumed reaction pathway for Zn-catalyzed reduction of imines.

Although several agents have been identified to provide therapeutic benefits in Huntington disease (HD), the number of conventionally used treatments remains limited and only symptomatic. Thus, it is plausible that the need to identify new therapeutic targets for the development of alternative and more effective treatments is becoming increasingly urgent. Recently, the sphingosine-1-phosphate (S1P) axis has been reported to be a valid potential novel molecular target for therapy development in HD. Modulation of aberrant metabolism of S1P in HD has been proved to exert neuroprotective action in vitro settings including human HD iPSC-derived neurons. In this study, we investigated whether promoting S1P production by stimulating Sphingosine Kinase 1 (SPHK1) by the selective activator, K6PC-5, may have therapeutic benefit in vivo in R6/2 HD mouse model. Our findings indicate that chronic administration of 0.05 mg/kg K6PC-5 exerted an overall beneficial effect in R6/2 mice. It significantly slowed down the progressive motor deficit associated with disease progression, modulated S1P metabolism, evoked the activation of pro-survival pathways and markedly reduced the toxic mutant huntingtin (mHtt) aggregation. These results suggest that K6PC-5 may represent a future therapeutic option in HD and may potentially counteract the perturbed brain function induced by deregulated S1P pathways.

Alpha,beta-unsaturated nitriles are chemoselectively reduced to the corresponding saturated nitriles in high yields using a copper-DPEphos or Xantphos complex as catalyst in the presence of polymethylhydrosiloxane (PMHS) as the stoichiometric reducing agent and t-butanol as additive.

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