Synthesis of enantiopure 2,4,8,10-tetrasubstituted Tröger base derivatives

Chiral tetramethyl and dibromo-dimethyl substituted Tröger base derivatives are readily prepared in enantiomerically pure forms using camphor sulfonic acid as a resolving agent. The (S,S)-isomers of these derivatives were obtained with 95–99% ee by precipitation using (1S)-(+)-10-camphor sulfonic acid and the partially resolved samples present in the mother liquor were enriched by treatment with (1R)-(−)-10-camphor sulfonic acid to obtain the (R,R)-isomers of tetrasubstituted Tröger base derivatives with 96–99% ee. In the case of 2,8-dibromo-4,10-dimethyl derivative, the (R,R)-isomer was obtained with 96–97% ee from the filtrate fraction after the (S,S)-enantiomer precipitated out. The dibromo derivative is readily functionalized to access a new chiral amine system containing a chiral phenylethylamine moiety.

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(5R,11R)-2,4,8,10-Tetramethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocineC19H22N2ee = 99%[α]D25 = −28.8 (c 0.50, CHCl3)Source of chirality: resolutionAbsolute configuration: (5R,11R)

(5S,11S)-2,8-Dibromo-4,10-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocineC17H16Br2N2ee = 98%[α]D25 = +160.6 (c 0.60, CHCl3)Source of chirality: resolutionAbsolute configuration: (5S,11S)

(5S,11S)-4,10-Dibromo-2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocineC17H16Br2N2ee = 99%[α]D25 = −180.0 (c 0.32, CHCl3)Source of chirality: resolutionAbsolute configuration: (5S,11S)

(1S,1′S)-N,N′-(((5S,11S)-2,8-Dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-4,10-diyl)bis(methylene))bis(1-phenylethanamine)C35H40N4dr = 99%[α]D25 = −139.2 (c 0.26, CHCl3)Source of chirality: inherentAbsolute configuration: (5S,11S)