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Reported herein is a safe and economical synthesis of methyl 6-chloro-5-(trifluoromethyl)nicotinate, an intermediate in the synthesis of novel anti-infective agents. The key to this process is the trifluoromethylation of an aryl iodide using an inexpensive methyl chlorodifluoroacetate (MCDFA)/KF/CuI system, with an emphasis on the development work which led to this effective process.

The synthesis of LFA-1 inhibitor BIRT2584 on metric-ton scale was accomplished by means of a safe and robust process. Highlights of the process include the asymmetric synthesis of the key advanced intermediate by implementation of Seebach’s self-regeneration of stereocenters principle, and a Ph3PCl2-induced dehydration of a critical urea followed by a regioselective bromination to give the elaborated 1H-imidazo[1,2-a]imidazol-2-one. A sulfonyl chloride intermediate was produced through Br/Mg exchange of iodoimidazole followed by addition to SO2 in THF and subsequent oxidation. In a one-pot operation, the sulfonyl chloride was directly reacted with l-alaninamide using NaOH as base in aqueous DMF/THF to give BIRT2584.

The synthesis of chiral, nonracemic, fully protected α,α-disubstituted α-amino acids via the Beckmann rearrangement of tosylated oximes 1 is described. The desired amino acids were obtained in good yields with excellent enantioselectivities in relatively few steps.

The Lewis acid-promoted intramolecular formal [3+2]-atom «cycloaddition» of alkenes with benzylic cations derived from benzylic alcohols and quinone methides affords products in good yield and with remarkable stereoselectivity. Benzylic alcohol 20 affords hexahydrofluorene 36 with three new stereogenic centers in 73% yield as a 10:1 mixture of diastereomers. The scope and limitations of these reactions were explored by varying the substitution pattern on the benzylic cation, the cyclization initiators, and the alkene terminators

The Lewis acid-promoted intramolecular formal [3+2]-atom «cycloaddition» of alkenes with benzylic cations derived from benzylic alcohols and quinone methides affords products in good yield and with remarkable stereoselectivity. Benzylic alcohol 20 affords hexahydrofluorene 36 with three new stereogenic centers in 73% yield as a 10:1 mixture of diastereomers. The scope and limitations of these reactions were explored by varying the substitution pattern on the benzylic cation, the cyclization initiators, and the alkene terminators

The synthesis of chiral, nonracemic, fully protected α,α-disubstituted α-amino acids via the Beckmann rearrangement of tosylated oximes 1 is described. The desired amino acids were obtained in good yields with excellent enantioselectivities in relatively few steps.

A study to reach the diterpenoid (+)-triptoquinone A (3) or its analog (+)-triptinin A (4) via an asymmetric tandem addition to naphthyloxazolines is described. The tandem addition to the chiral dihydronophthalene 6 resulted in a 70% yield of single diastereomer 10. Further manipulation gave the natural products' tricyclic ring system, compounds 20 and 29 via ring-closing metathesis in 90% yield, using the Schrock catalyst. Final assault to the target compounds 3 or 4 fell short due to the failure to either reduce a neopentyl hydroxymethyl group to a methyl or to install the conjugated carboxylic acid present in 3 or 4.