Synthesis, structure and antiproliferative activity of chiral polyamines based on a 2-azanorbornane skeleton

A series of enantiopure 2-azanorbornane-based amines were prepared via a stereoselective aza-Diels–Alder reaction and further modifications of the obtained cycloadduct. In particular, derivatives containing two bicyclic moieties linked by NCCN fragments were synthesized. Two dimeric derivatives exhibited a significant antiproliferative activity against selected cell lines, comparable to cisplatin in certain cases.

Figure optionsDownload as PowerPoint slide

N,N′-Bis{[(1S,3R,4R)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptan-3-yl]methyl}ethan-1,2-diamineC32H46N4[α]D20 = +41.1 (c 0.32, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: bis (1S,3R,4R,1′S) (by chemical correlation)

(E)-1,1-Diphenyl-N-{[(1S,3R,4R)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptan-3-yl]methylene}methanamineC28H30N2[α]D20 = −24.9 (c 0.42, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (1S,3R,4R,1′S) (by chemical correlation)

(E)-(1S,3R,4R)-2-[(S)-1-Phenylethyl]-2-azabicyclo[2.2.1]heptan-3-al oximeC15H20N2O[α]D20 = +16.9 (c 0.26, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (1S,3R,4R,1′S) (by chemical correlation)

(1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-aminemethyl-2-azabicyclo[2.2.1]heptaneC15H22N2[α]D20 = −26.1 (c 0.23, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (1S,3R,4R,1′S) (by chemical correlation)

N-Benzyl-bis-{[(1S,3R,4R)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptan-3-yl]methyl}amineC37H47N3[α]D20 = +65.8 (c 0.38, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: bis (1S,3R,4R,1′S) (by chemical correlation)

N-1,1,1-Triphenylmethyl-bis-{[(1S,3R,4R)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptan-3-yl]methyl}amineC49H55N3[α]D20 = +57.2 (c 0.6, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: bis (1S,3R,4R,1′S) (by chemical correlation)

N-Benzoyl-bis-{[(1S,3R,4R)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptan-3-yl]methyl}amineC37H45N3[α]D20 = +69.6 (c 0.66, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: bis (1S,3R,4R,1′S) (by chemical correlation)

Bis-{[(1S,3R,4R)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptan-3-yl]methyl}amineC30H41N3[α]D20 = −13.9 (c 0.5, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: bis (1S,3R,4R,1′S) (by chemical correlation)