合成路线1

Cycloaddition of norbornene (I) with chlorosulfonyl isocyanate (II) in EtOAc or Et2O followed by treatment with aqueous Na2SO3 affords (±)-exo-3-azatricyclo[4.2.1.O2,5]nonan-4-one (III), which by hydrolysis with HCl gives 3-aminonorbornane-2-carboxylic acid hydrochloride (IV). Treatment of amino acid (IV) with EtOH or MeOH by means of SOCl2 at reflux provides the hydrochloride salts of the corresponding ethyl (Va) or methyl (Vb) esters, respectively, which are neutralized with NaHCO3 to yield the free amines (VIa) and (VIb). Resolution of the racemic amino esters (VIa) or (VIb) with (S)-(+)-CSA in EtOAc/EtOH followed by neutralization of the obtained CSA salts (VIIa) or (VIIb) with Na2CO3 or K2CO3 in EtOAc leads to ethyl (VIIIa) or methyl (VIIIb) (1S,2R,3S,4R)-3-aminonorbornane-2-carboxylate, respectively. Alternatively, amino ester (VIIa) can be obtained by ring opening of racemic lactam (III) with EtOH in the presence of (S)-(+)-CSA in EtOAc at 50-75 °C. Reductive alkylation of amines (VIIIa) and (VIIIb) with 4-fluorobenzaldehyde (IX) by means of NaBH3CN and AcOH or NaOAc in EtOH gives the secondary amines (XIa) or (XIb) , which can also be prepared by alkylation of amines (VIII) with 4-fluorobenzyl bromide (Xa) or iodide (XIb) in the presence of Et3N in DMF at 70 °C . N-Acylation of amino esters (XIa) or (XIb) with the carboxylic acid (XII) using as coupling reagents EDC in the presence of DMAP , or NMM in DMF, or DCC in CH2Cl2/DMF, or HATU and NMM in DMF , yields amides (XIIIa) and (XIIIb) . Finally, amide esters (XIII) are submitted to intramolecular Claisen condensation by means of NaOEt in EtOH at 60 °C or Et3N at 60 °C . Alternatively, methyl ester (XIb) can be condensed with the carboxylic acid (XII) in the presence of DCC, NMM and Et3N in DMF at 50 °C , or in acetonitrile .