Misc

The highly ligand acceleration effect of spiro bis(isoxazoline) ligand (SPRIX) on the Pd(II)-catalyzed intramolecular aminocarbonylation of alkenyl amine derivatives was realized. Furthermore, the chiral Pd(II)-SPRIX catalyst accomplished the first enantioselective intramolecular aminocarbonylation. The reaction of N-(2,2-dimethyl-pent-4-enyl)-p-toluenesulfonamide in the presence of Pd(II)-SPRIX catalyst and p-benzoquinone in methanol under a carbon monoxide atmosphere afforded [4,4-dimethyl-1-(p-toluene-sulfonyl)-pyrrolidin-2-yl]-acetic acid methyl ester in good yield with moderate enantioselectivity. (C) 2003 Elsevier Science Ltd. All rights reserved.

Systematic and quantitative measurements of the roles of stereochemistry and skeleton-dependent conformational restriction were made using multidimensional screening. We first used diversity-oriented synthesis to synthesize the same number (122) of [10.4.0] bicyclic products (B) and their corresponding monocyclic precursors (M). We measured the ability of these compounds to modulate a broad swath of biology using 40 parallel cell-based assays. We analyzed the results using statistical methods that revealed illuminating relationships between stereochemistry, ring number, and assay outcomes. Conformational restriction by ring-closing metathesis increased the specificity of responses among active compounds and was the dominant factor in global activity patterns. Hierarchical clustering also revealed that stereochemistry was a second dominant factor; whereas the stereochemistry of macrocyclic appendages was a determinant for bicyclic compounds, the stereochemistry of the carbohydrates was a determinant for the monocyclic compounds of global activity patterns. These studies illustrate a quantitative method for measuring stereochemical and skeletal diversity of small molecules and their cellular consequences.

A novel bis(isoxazole) ligand, (M*)-4,4',5,5',6,6',7,7'-octahydro-7,7'-spirobi[benzo[c]isoxazole] (5) bearing a spiro chirality was designed and synthesized. Characterization of the ligand and its application to the enantioselective tandem cyclizaton of alkenyl alcohol via oxy-palladation are described.

Synthesis of two kinds of new bis(isoxazoline) ligand, achiral 2,2'-bis(isoxazolinyl)propane and (R)-2,2'-bis(isoxazolinyl)-1,1'-binaphthyl bearing an axial chirality is described. Both of the bis(isoxazoline) ligands accelerated the Pd(II)-catalyzed Wacker-type cyclization of alkenyl alcohol. The isoxazoline ligands were found to be essential to promote the cyclization.

As a part of a exploring the N-glycan-mediated glycoprotein quality control in endoplasmic reticulum, 2-fluorinated derivative Glcalpha1 --> 3Man(F) 1, Glcalpha1 --> 3Man(F) alpha1 --> 2Man2, and Glcalpha1 --> 3Man(F) alpha1 --> 2Manalpha1 --> 2Man 3 were synthesized in a concise manner. These oligosaccharides were subjected to binding studies with calreticulin by using isothermal titration calorimetry. It was revealed that disaccharide 1 was a poor ligand, while tri-( 2) and tetrasaccharide ( 3) had observable affinity.

New chiral bis(isoxazoline) ligands bearing a spiro[5.5]undecane skeleton were designed and synthesized in five steps from diethyl malonate (3). These ligands showed a coordinating ability to Cu(II) as chiral ligands. A complex of (+)-(M*,S*,R*)-[5.5]-SPRDC 2b and Cu(OTf)(2) catalyzed the conjugate addition of diethylzine to 2-cyclohexenone (8) to give (S)-3-ethyl-cyclohexanone (9) in 93% yield with 54% ee. (C) 2002 Wiley-Liss, Inc.

The first synthesis of spiro bis(pyrazole) ligands, 2,2',4,4'-tetrahydro-6,6'-spirobi[5H-cycopentapyrazole] (l a) and 2,2'-dibenzyl-2,2',4,4'-tetrahydro-6,6'-spirobi[5H-cycopentapyrazole] (1b) was achieved. The application of spiro bis(pyrazole) ligand to asymmetric catalysis was also examined.