Synthesis of N-Methyl-N-{(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl}amine

Abstract

N-Methyl-N-[(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl]amine (1)(1) is a key intermediate in the preparation of premafloxacin (2), which was under development as an antibiotic for use against pathogens of veterinary importance. This paper describes the development of a practical, efficient, and stereoselective process for the preparation of 1 from isobutyl (3S)-3-[methyl[(1S)-1-phenylethyl]amino]butanoate (5c). The key steps in the synthetic sequence are an asymmetric Michael addition, which yields 5c, and a stereoselective alkylation, which yields (3S,4S)-3-allyl-1,4-dimethylazetidin-2-one (17).

An Unusual Conformation of α‐Haloamides Due to Cooperative Binding with Zincated Porphyrins

“…The ( R )‐2‐fluorolactam 36 was accessed through Evans auxiliary controlled asymmetric fluorination of compound 33 (Scheme b),51 followed by ozonolysis,52 to afford aldehyde 35 . Reductive amination of 35 with mono‐Boc‐protected 1,4‐phenylenediamine provided the corresponding secondary amine, which cyclizes in situ and upon treatment with TFA yields lactam 36 53. The ( R )‐2‐iodolactam 37 was obtained directly from 36‐Boc by Finkelstein reaction 54…”

1′-Methyl-4′-phenyl-H-fluorene-9-spiro-3′-pyrrolidine-2′-spiro-3′′-1H-indol-2′'(3′′H)-one

“…Spiro compounds are often encountered in many pharmacologically relevant alkaloids (Cravotto et al, 2001). Pyrrolidinecontaining derivatives are used as antibiotics against pathogens of veterinary importance (Fleck et al, 2003). Fluorene derivatives are found to have anticonvulsant activity (Vanvakides et al, 2004).…”

Efficient synthesis of β’-amino-α,β-unsaturated ketones

“…Conjugate addition of ( R )- N -benzyl- N -methylbenzylamide to methyl cinnamate under basic conditions led to β–aminoester 5 with high diastereoselectivity (dr >94%) [11–12]. Subsequent transformation of the ester moiety to a Weinreb amide [18] followed by changing the nitrogen protecting group to a carbamate furnished the key intermediate 6 , which could be further alkylated with Grignard reagents to give β’-amino protected α,β-enone 1 in good overall yield and high enantiomeric excess.…”

“…One of the most powerful approaches is the Mannich reaction, which can be conducted under different protocols in which the stereoselectivity of the reaction can be introduced through the use of a chiral catalyst [9–10] (Lewis acid, Brønsted acids, L-proline, Cinchona alkaloids derivatives, thioureas, etc. ), or by the addition of chiral amines to α,β-unsaturated esters [11–12] or the reaction of chiral imines with enolates derived from Weinreb amides [13–14]. In previous work on the asymmetric synthesis of 2,6-disubstituted piperidines by C–N bond formation, we demonstrated that intramolecular aza-Michael ”type” cyclisation [15] using a β'-carbamate-α,β-unsaturated ketone predominantly induces the formation of a piperidine ring with the 2,6- trans configuration (Scheme 1).…”