Single enantiomer synthesis of α-(trifluoromethyl)-β-lactam

Abstract

SummaryThe first synthesis of α-(trifluoromethyl)-β-lactam ((S)-1) is reported. The route starts from α-(trifluoromethyl)acrylic acid (2). Conjugate addition of α-(p-methoxyphenyl)ethylamine ((S)-3b), generated an addition adduct 4b which was cyclised to β-lactam 5b. Separation of the diastereoisomers by chromatography gave ((αS,3S)-5b). N-Debenzylation afforded the desired α-(trifluoromethyl)-β-lactam ((S)-1). The absolute stereochemistry of diastereoisomers 5 was determined by X-ray crystallographic determination of a close structural analogue, (αS,3S)-5c, and then 1H and 19F NMR correlation to the individual diastereoisomers of 5a and 5b.

Short and efficient synthesis of fluorinated δ-lactams

“…The protecting group of choice was the p-methoxybenzyl group due to its electron donating properties, and the ease of removal via oxidative cleavage. 9 Thus, reaction of p-methoxybenzylamine with benzaldehyde yielded the corresponding imine which upon allyl Grignard addition produced the secondary amine 7a in near quantitative yield. HBTU promoted coupling between the amine 7a and 2-fluoroacrylic acid 4 and then proceeded to generate the desired amide 8a in good yield.…”

A general strategy for the synthesis of α-trifluoromethyl- and α-perfluoroalkyl-β-lactams via palladium-catalyzed carbonylation

“… 13–15 Despite the synthesis of many structural variants, relatively few examples of α-fluoroalkyl-substituted derivatives are known. So far, such products and especially α-(trifluoromethyl)-β-lactams are based on multistep syntheses, 21,22 or special methods such as hydrogenolysis of N–O bonds, 16 1,3-dipolar cycloadditions of nitrones to fluoroalkenes, 17 and metal-catalyzed intramolecular C–H amidations ( Scheme 1 ). 18–20 Unfortunately, all these methods have certain shortcomings, which limit their applications to small scale.…”

“… 18–20 Unfortunately, all these methods have certain shortcomings, which limit their applications to small scale. 21 …”