Reductive amination of the bicyclic ketone 4 led diastereoselectively to endo-configured amines, which were transformed into the amides 7-10. The synthesis of the diastereomers 25 with an exo-configured amino moiety at position 6 was only successful after deactivation of both N-atoms of the 1,4-diazabicyclo[3.3.1]nonane system. The N-1-oxide 19 with an N-4-tosyl moiety was the crucial intermediate, which allows SN2 substitution with NaN3 under inversion of the configuration at position 6. Whereas the endo-configured pyrrolidine 7a (WMS-1302) revealed a kappa receptor affinity of 73 nM, the exo-configured diastereomer 25a was almost inactive at the kappa receptor (Ki > 1 microM). Replacement of the 3,4-dichlorophenylacetyl residue by other acyl and sulfonyl residues showed that it is essential for high kappa affinity. The kappa receptor affinities of the conformationally constrained pyrrolidines 7a and 25a were correlated with the dihedral angle N(pyrrolidine)-C-C-N(acetamide). A systematic conformational analysis of the potent but flexible kappa agonist 2 showed that a dihedral angle of 168 degrees (as in 25a) is energetically more disfavored than a dihedral angle of 58 degrees (7a). However, even the conformation with a dihedral angle of 58 degrees does not represent an energy minimum, which might explain the reduced kappa affinity of 7a.

1,4-Diazabicyclo[3.3.1]nonanes (aza-morphans) represent conformationally constrained piperazine derivatives. Herein, we report a six-step synthesis of the benzyl and allyl substituted bicyclic ketones 3a and 3b, which represent interesting building blocks for the synthesis of conformationally restricted receptor ligands. The key steps of the synthesis are the regioselective addition of ethyl acrylate to the piperazine 8, the sodium hexamethyldisilazide-induced Dieckmann cyclization of the diesters 10, and the decarboxylation of the enol esters 11 with dilute HCl. The complete sequence is only successful when a benzyl (10a) or allyl moiety (10b) is attached to N-1, since the tosyl derivative 10f failed to give a Dieckmann cyclization product, and the decarboxylation failed with the acyl derivatives 11c and 11d.

Synthesis of a Silanol-Substituted Proline Analogue as Organocatalyst. -The synthesis of the title catalyst cat.1 is based on the combination of an acidic and a basic functionality with a silanol moiety within the same molecule. X-ray crystal structure analysis of cat.1 shows a favorable orientation of the crucial functional groups. Both a novel chiral HPLC method and a chiral capillary electrophoresis method are developed to observe the kinetic resolution of racemic alcohols (I) and (IV). However, the reaction rate in the presence of cat.1 is not considerably increased and the enantiomeric excess of the formed acetates (III) and (V) is rather low. A similar result is observed with organocatalyst cat.2 , indicating that the silanol moiety has no influence on the enantioselective acetylation of secondary alcohols. -(KRACHT, D.; SAITO, S.; FROEHLICH, R.; WUENSCH*, B

A proline-derived silanol, was designed as a novel potential organocatalyst, and synthesized starting from the tetrazole 3. The central idea was the combination of an acidic (tetrazole) and a basic functionality (pyrrolidine) with a silanol moiety in the same molecule. The synthesis of 7 was performed in four reaction steps starting with the tetrazole 3. In the solid state (X-ray crystal structure analysis) the crucial functional groups show a favorable orientation. A chiral HPLC method and a chiral capillary electrophoresis method have been established for the investigation of the kinetic resolution of the racemic alcohols 9 and 11. Acetylation reactions of alcohols were not accelerated by the organocatalyst 7, and the produced ee values were rather low.