alpha-Acyloxynitroso dienophiles in [4+2] hetero Diels-Alder cycloadditions:mechanistic insights

alpha-Acyloxynitroso derivatives are a class of heterodienophiles leading to valuable 3,6-dihydro-1,2-oxazines or the corresponding aminoalcohols in good yields. The discovery that a beta-oxygenated moiety led to a domino [4+2] cycloaddition/sigma(N-O) bond cleavage in the presence of a catalytic amount of Lewis acid was investigated in detail, through kinetic profiling of the reaction both in the absence and presence of a promoter. These studies showed that the role of the Lewis acid was to accelerate the sigma(N-O) bond cleavage thereby promoting a highly reproducible sequence. In addition, our preliminary results on an asymmetric version of this domino sequence are reported. (C) 2010 Elsevier Ltd. All rights reserved

Using the noncanonical metallo-amino Acid [Cu(II)(2,2′-Bipyridin-5-yl)]-alanine to study the structures of proteins

International audienceGenetic code expansion allows modification of the physical and chemical properties of proteins by the site-directed insertion of noncanonical amino acids. Here we exploit this technology for measuring nanometer-scale distances in proteins. (2,2′-Bipyridin-5-yl)alanine was incorporated into the green fluorescent protein (GFP) and used as an anchoring point for Cu(II) to create a spin-label. The incorporation of (2,2′-bipyridin-5-yl)alanine directly into the protein resulted in a high-affinity binding site for Cu(II) capable of outcompeting other binding positions in the protein. The resulting Cu(II)-spin label is very compact and not larger than a conventional amino acid. By using 94 GHz electron paramagnetic resonance (EPR) pulse dipolar spectroscopy we have been able to determine accurately the distance between two such spin-labels. Our measurements revealed that GFP dimers can adopt different quaternary conformations. The combination of spin-labeling using a paramagnetic nonconventional amino acid with high-frequency EPR techniques resulted in a sensitive method for studying the structures of proteins

Total synthesis of rapamycin.

For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product