Asymmetrische Synthese von 1,3-Aminoalkoholen und deren Anwendung zur Synthese von Azetidinen und 1-Azabicyclen

The focus of this thesis work is the asymmetric synthesis of N,O-protected 1,3-aminoalcohols using SAMP/RAMP Hydrazones and their application in asymmetric synthesis. Furthermore, the asymmetric synthesis of 2-substituted azetidines was developed. - Asymmetric synthesis of 1,3-aminoalcoholsA flexible diastereo- and enantioselective synthesis of N,O-protected 1,3-aminoalcohols was developed. In a three step synthesis, first the N,O-protected 1,3-aminoalcohols were synthesized using a nucleophilic 1,2-addition to the C=N-double bond of the SAMP/RAMP hydrazones with organolithium- or organocer-reagents. Second, an epimerization-free reductive N,N-bond-claverage with BH3-THF-complex was performed. Lastly, N-protection with chloroformic acid benzyl ester or tosylchloride afforded the benzylcarbamates or tosylamides, respectively, in overall yields of 22 to 69%. Importantly, the products were formed in high enantio- and diastereomeric purities (ee, de >= 89–96%). - Synthesis of 2-substituted azetidines using activated leaving groups Extending the previous work of J.H. Kirchhoff, 2-substituted azetidines were synthesized using activated leaving group. The 1,3-aminoalcohols, whose amine and alcohol groups were benzylcarbamate and silyl protected, respectively, were first de-silylated. Conversion of the free alcohol to iodide or tosylate afforded the azetidine precursors. Cyclization gave the desired 2-substituted azetidines in 38 to 50% yields over three steps in excellent enantiomeric purities (ee >= 96%). - Synthesis of 2-substituted azetidines under Mitsunobu conditions The 1,3-aminoalcohols, whose amine and alcohol groups were p-tosyl and benzyl protected, respectively, were first de-benzylated with palladium on activated charcoal in methanol. Then, cyclization was effected by treatment with triphenylphosphine and DIAD in THF. The desired 2-substituted azetidines were obtained in 73 to 93% yields over two steps and in excellent enantiomeric excesses (ee >= 96%). Notably, a variety of substituents could be incorporated (n-Bu, t-Bu, n Hexyl, Phenyl, TBSOCH2(CH2)nCH2, n = 1, 2, 3).