TMEDA (5.8 g, 7.55 mL, 0.5 mol) was added. The solution was chilled in an ice bath and n-butyllithium (31.4 mL of a 1.6 M solution in hexane, 0.05 mol) was added dropwise. The turbid solution was allowed to warm up to room temperature and then heated under reflux overnight (20 h). During this lithiation period a tannish-yellow precipitate formed. The mixture was again cooled in an ice bath and quenched by dropwise addition of a solution of dimethyl sulfate (6.94 g, 5.2 mL, 0.55 mL) in 50 mL of ether. The precipitate became more dense and turned white. After being stirred for 3 h, the mixture was poured over ice-water, the ether layer was separated, and the aqueous layer was extracted with ether. The combined ether extracts were washed with 2 N NH4OH, 2 N HC1, water, and brine and then dried (MgSQ4) and concentrated. The yellow residue was recrystallized from pentane: mp 168-169 °C;

The application of a binding force (the chelation of a metal by a 2,2,-bipyridyl) to enhance reaction rates is examined with three systems. Metals are shown to increase the rate of cyclization of certain 3,3'-disubstituted, 2,2'-bipyridyl derivatives. Similar effects are seen in the elimination reaction of an appropriate halide and the racemization of asymmetric bipyridyl crown ethers. The last case involves catalysis according to the Pauling principle of maximum binding to the transition state. The relevance of these findings to biochemical processes is discussed.

A convergent, large-scale, chiral synthesis of isoxazoline 1 has been achieved in 37% overall yield and >99.6% optical purity, starting from L-asparagine and 4-cyanobenzaldehyde. Hofmann reaction of N(alpha)-n-Boc-L-asparagine with iodosobenzene diacetate provides optically pure N(alpha)-n-Boc-L-alpha,beta-diaminopropionic acid (8) in 75% yield. A process of lipase resolution-base catalyzed epimerization gives the single enantiomer 5. Reaction of acid 5 with amine 9 in the presence of thionyl chloride forms the framework of 1. A Pinner reaction of intermediate 4 in methyl acetate or anisole, followed by an amidination with ammonium acetate, gives optically pure product 1.

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