356531-67-4Relevant articles and documents
H2 Activation by Non-Transition-Metal Systems: Hydrogenation of Aldimines and Ketimines with LiN(SiMe3)2
Elliott, Daniel C.,Marti, Alex,Mauleón, Pablo,Pfaltz, Andreas
supporting information, p. 1918 - 1922 (2019/01/16)
In recent years, H2 activation at non-transition-metal centers has met with increasing attention. Here, a system in which H2 is activated and transferred to aldimines and ketimines using substoichiometric amounts of lithium bis(trimethylsilyl)amide is reported. Notably, the reaction tolerates the presence of acidic protons in the α-position. Mechanistic investigations indicated that the reaction proceeds via a lithium hydride intermediate as the actual reductant.
An efficient palladium-catalyzed N-alkylation of amines using primary and secondary alcohols
Dang, Tuan Thanh,Ramalingam, Balamurugan,Shan, Siah Pei,Seayad, Abdul Majeed
, p. 2536 - 2540 (2013/11/19)
PdCl2 in the presence of dppe or Xantphos(t-Bu) as the ligand is found to be an efficient catalyst for the N-alkylation of various primary and cyclic secondary amines using primary alcohols at 90-130 C under neat conditions. Interestingly, good to excellent yields were achieved when more challenging secondary alcohols were used as alkylating agents at 130-150 C. The reaction could be easily scaled up, as demonstrated for a 10 mmol scale achieving yields up to 90% with a TON of 900.
Optimization of Triazine Nitriles as Rhodesain Inhibitors: Structure-Activity Relationships, Bioisosteric Imidazopyridine Nitriles, and X-ray Crystal Structure Analysis with Human CathepsinL
Ehmke, Veronika,Winkler, Edwin,Banner, David W.,Haap, Wolfgang,Schweizer, W. Bernd,Rottmann, Matthias,Kaiser, Marcel,Freymond, Celine,Schirmeister, Tanja,Diederich, Francois
supporting information, p. 967 - 975 (2013/07/27)
The cysteine protease rhodesain of Trypanosoma brucei parasites causing African sleeping sickness has emerged as a target for the development of new drug candidates. Based on a triazine nitrile moiety as electrophilic headgroup, optimization studies on the substituents for the S1, S2, and S3 pockets of the enzyme were performed using structure-based design and resulted in inhibitors with inhibition constants in the single-digit nanomolar range. Comprehensive structure-activity relationships clarified the binding preferences of the individual pockets of the active site. The S1 pocket tolerates various substituents with a preference for flexible and basic side chains. Variation of the S2 substituent led to high-affinity ligands with inhibition constants down to 2nM for compounds bearing cyclohexyl substituents. Systematic investigations on the S3 pocket revealed its potential to achieve high activities with aromatic vectors that undergo stacking interactions with the planar peptide backbone forming part of the pocket. X-ray crystal structure analysis with the structurally related enzyme human cathepsinL confirmed the binding mode of the triazine ligand series as proposed by molecular modeling. Sub-micromolar inhibition of the proliferation of cultured parasites was achieved for ligands decorated with the best substituents identified through the optimization cycles. In cell-based assays, the introduction of a basic side chain on the inhibitors resulted in a 35-fold increase in antitrypanosomal activity. Finally, bioisosteric imidazopyridine nitriles were studied in order to prevent off-target effects with unselective nucleophiles by decreasing the inherent electrophilicity of the triazine nitrile headgroup. Using this ligand, the stabilization by intramolecular hydrogen bonding of the thioimidate intermediate, formed upon attack of the catalytic cysteine residue, compensates for the lower reactivity of the headgroup. The imidazopyridine nitrile ligand showed excellent stability toward the thiol nucleophile glutathione in a quantitative invitro assay and fourfold lower cytotoxicity than the parent triazine nitrile.
