Asymmetric synthesis of cyclic α-amino acid derivatives by the intramolecular reaction of magnesium carbenoid with an N-magnesio arylamine

The synthesis of pipecolic acid and homopipecolic acid derivatives was developed from ω-(2-aminophenyl)-1-chloroalkyl p-tolyl sulfoxides by treatment with i-PrMgCl. An intramolecular nucleophilic substitution reaction of a magnesium carbenoid with an N-magnesio arylamine is the key step of this reaction. Proline and pipecolic acid derivatives were also synthesized from ω-(arylamino)-1-chloroalkyl p-tolyl sulfoxides by the same chemistry. Starting from enantiomerically pure (1S,RS)-1-chloro-3-[2-(N-methylamino)phenyl]propyl p-tolyl sulfoxide, enantiomerically pure (R)-pipecolic acid derivative was obtained. The intramolecular nucleophilic substitution reaction of the magnesium carbenoid with N-magnesio arylamine was proven to take place with inversion of the carbenoid carbon. The stereochemistry of these reactions is also discussed.

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(S,RS)-N-{2-[3-Chloro-3-(toluene-4-sulfinyl)propyl]phenyl}-N-methylamineC17H20ClNOS[α]D29=-158 (c 1.35, CHCl3)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (S,RS)

(R,RS)-N-{2-[3-Chloro-3-(toluene-4-sulfinyl)propyl]phenyl}-N-methylamineC17H20ClNOS[α]D25=-80.8 (c 0.45, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R,RS)

(R)-1-Methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl esterC13H17NO2[α]D26=-32.1 (c 0.5, EtOH)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)