Synthesis of γ-cyclobutane amino acids via visible light

In the present thesis an intramolecular visible light mediated [2+2] photocycloaddition of amide-linked dienes was developed to build up azabicycloheptanones which were transformed into γ-cyclobutane amino acids. Furthermore, these cyclobutane-containing amino acids were generated enantioselective and incorporated in shortened NPY-analogues to find new selective ligands for Y4R. The investigations revealed that the suitable reaction mode for the [2+2] photocycloaddition of amide-linked dienes is an energy transfer mechanism using the Iridium-based photocatalyst [Ir(dtb-bpy)(dF(CF3)ppy)2]PF6 as sensitizer. The substituent on the nitrogen atom is crucial for the diene to adopt the necessary conformation for a successful cycloaddition. N-tert-butyl, N benzyl and N-Boc amide derivatives cyclized to the corresponding bicyclic compounds in moderate to good yields with an excellent diastereoselectivity. In cooperation with the work group of Prof. J. Rehbein DFT-calculations were performed investigating the influence of the N-substituent of the amide-linked dienes on the [2+2] photocycloaddition. All investigated features as stationary points, energy barriers and the nature of transition states prefer the [2+2] photocycloaddition of substrates with a large substituent. The following part is devoted to the upscaling of the photoreaction. Therefore, a reactor with 30 LEDs (λ = 455 nm) was developed in which photoreactions with either 200 mL or 600 mL reaction volumina could be performed. Up to 110 mmol, 26 g, amide-linked diene was converted to the target bicyclic compounds, whereby the catalyst loading was reduced to 0.1 mol%. Another important issue of this thesis constitutes the transformation of the obtained bicyclic compounds into the desired γ-cyclobutane amino acids (Scheme 66). The tert-butyl derivatives A were firstly transformed into the chloride salts of the free amino acids by refluxing in 25% aqueous solution of HCl. The subsequent Boc-protection gave rise to N-Boc-cis-γ-cyclobutane amino acids. Starting from the already Boc-protected bicyclic compounds B, target molecules were easily accessible in a single step by treatment with lithium hydroxide in a THF/H2O mixture at ambient temperature. Applying Birch conditions enabled the removal of the benzyl group in compounds C and the synthesis of the unprotected amide derivatives. In two subsequent steps, Boc-protection and basic hydrolysis, derivatives were converted to racemic γ-cyclobutane amino acids. Three different N-protected products of the photocatalytic [2+2] cycloaddition were successfully transformed into the racemic N-Boc-protected γ-cyclobutane amino acid, which served as starting material for the chiral resolution using (4S,5R)-4-methyl-5-phenyloxazolidin-2-one as chiral auxiliary giving rise to both enantiomers. Another part of this thesis represents the investigation of the Birch reduction of the N-benzyl substituted bicyclic compounds, especially of the enantiomerically pure derivatives. In the case of 6-substituted derivatives a simple deprotection took place, whereas an analog transformation of 7-substituted derivatives provided product which is itself a GABA analogue and also a key intermediate in the synthesis of 3-(aminomethyl)-5-phenylpentanoic acid, an anticonvulsant. By applying this reaction mode, on the one hand a second enantioselective synthetic route towards γ-cyclobutane amino acids and on the other hand a methodology towards both enantiomers was developed. The last chapter describes the incorporation of N-Fmoc-cis-γ-cyclobutane amino acids in shortened NPY-analogues to develop new selective ligands for Y4R in cooperation with the work group of Prof. C. Cabrele. The biological evaluation is currently ongoing in cooperation with the work group of the late Prof. A. Buschauer