High regiocontrol in the nucleophilic ring opening of 3-aralkyl-7-oxa-3-aza-bicyclo[4.1.0]heptanes with aliphatic and aromatic amines – A new short-step synthesis of FBT (4-fluorobenzyltrozamicol)

The 3,4-disubstituted piperidine framework plays an important role in many fields of pharmaceutical research[1] The ring opening of a conformationally rigid oxirane, annelleted to an N-protected six membered piperidine by an amine nucleophile, is a powerful method for establishing a trans-beta-aminoalcohol at the 3,4-position. Compounds derived from azavesamicol (trozamicol), which have been reported as usefulligands for the vesicular acetylcholine transporter (VAChT),[2] are displaying a 3-amino-piperidin-4-ol as a consistent structural feature. As part of our efforts in the search for new VAChT ligands for F18-PET (positron emission tomography) we have found a regioselective ring opening approach applying 3-(4-fluorobenzyl)-7-oxa-3-azabicyclo[4.1.0]heptane, which was utilized for a new 4-step synthesis of 4-fluorobenzyltrozamicol.
In contrast to former methodology, processing a common acyl[3] or carbamoyl[4] protective group at the piperidine nitrogen, we choose an N-benzyl protection. Starting from pyridine, which was converted to an N-4-fluorobenzylpyridinium salt, we obtained the corresponding N-protected 1,2,3,6-tetrahydropyridine via a standard hydrogenation using NaBH4 in EtOH. It was possible to epoxidize the olefine in high yield without interfering the basic tertiary amine, if applying trifluoroacetic acid in combination with its anhydride and H2O2-urea. As expected, the LiCIO4 assisted reaction of 1-aralkyl-3,4-epoxypiperidines with a series of aliphatic and aromatic amines in acetonitril led to a regioselective attack at position 4 of the piperidine to obtain 1-aralkyl-4-amino-piperidin-3-ol.[5] However, if applying EtOH as a protic solvent, without a coordinating Li-cation as additive, the inverse reg ioselectivity was observed. In this case, 1-aralkyl-3-aminopiperidin-4-oIs were derived as main products from the cleavage of the epoxy C-O bond at position 3. Following these protocols the aminoalcohol products were obtained as pure compounds by simple work-up without the need of chromatographic
separation.
In summary, we present an efficient method for the preparation of 3-amino-4-hydroxypiperidines and its regioisomers in 4-steps. The highly VAChT affine 4-fluorobenzyltrozamicol was obtained in an overall yield of 35%.