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An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.

The traditional Ullman reaction is the homocoupling of aromatic halides mediated by copper at elevated temperatures. Ullman first reported this reaction in 1901. Although the coupling conditions first reported are still widely used, a host of modifications have been made to these reactions. Some of these modifications include the use of activated and alternative metals, often resulting in much lower coupling temperatures. Nickel and palladium are the most utilized source of alternative metals, Periodic reviews have been published. This chapter covers the literature on copper, nickel, and palladium mediated homocoupling reactions in biaryl synthesis from 1901 to 2000. The focus of this chapter is the scope and limitation of these processes, preparation of the activated metal, and mechanism of the homocoupling process

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