Mini-ISES identifies promising carbafructopyranose-based salens for asymmetric catalysis: Tuning ligand shape via the anomeric effect

This study introduces new methods of screening for and tuning chiral space and in so doing identifies a promising set of chiral ligands for asymmetric synthesis. The carbafructopyranosyl-1,2-diamine(s) and salens constructed therefrom are particularly compelling. It is shown that by removing the native anomeric effect in this ligand family, one can tune chiral ligand shape and improve chiral bias. This concept is demonstrated by a combination of (i) x-ray crystallographic structure determination, (ii) assessment of catalytic performance, and (iii) consideration of the anomeric effect and its underlying dipolar basis. The title ligands were identified by a new mini version of the in situ enzymatic screening (ISES) procedure through which catalyst-ligand combinations are screened in parallel, and information on relative rate and enantioselectivity is obtained in real time, without the need to quench reactions or draw aliquots. Mini-ISES brings the technique into the nanomole regime (200 to 350 nmol catalyst/20 ml organic volume) commensurate with emerging trends in reaction development/process chemistry. The best-performing b-D-carbafructopyranosyl-1,2-diamine–derived salen ligand discovered here outperforms the best known organometallic and enzymatic catalysts for the hydrolytic kinetic resolution of 3-phenylpropylene oxide, one of several substrates examined for which the ligand is “matched.” This ligand scaffold defines a new swath of chiral space, and anomeric effect tunability defines a new concept in shaping that chiral space. Both this ligand set and the anomeric shape-tuning concept are expected to find broad application, given the value of chiral 1,2-diamines and salens constructed from these in asymmetric catalysis

Structure of p300 in complex with acyl-CoA variants

Histone acetylation plays an important role in transcriptional activation. Histones are also modified by chemically diverse acylations that are frequently deposited by p300, a transcriptional coactivator that uses a number of different acyl-CoA cofactors. Here we report that while p300 is a robust acetylase, its activity gets weaker with increasing acyl-CoA chain length. Crystal structures of p300 in complex with propionyl-, crotonyl-, or butyryl-CoA show that the aliphatic portions of these cofactors are bound in the lysine substrate-binding tunnel in a conformation that is incompatible with substrate transfer. Lysine substrate binding is predicted to remodel the acyl-CoA ligands into a conformation compatible with acyl-chain transfer. This remodeling requires that the aliphatic portion of acyl-CoA be accommodated in a hydrophobic pocket in the enzymes active site. The size of the pocket and its aliphatic nature exclude long-chain and charged acyl-CoA variants, presumably explaining the cofactor preference for p300