The condensation of 5-methoxy-3-nitro-3,4-dihydro-2H-1-benzopyran (I) with methyl acrylate (II) by means of benzyltrimethylammonium methoxide in methanol gives the propionic ester (III), which is submitted to a reductive cyclization with H2 over RaNi in methanol yielding the racemic spiro compound (IV). Optical resolution of (IV) by means of (+)-1,1'-dinaphthyl-2,2'-diyl hydrogen phosphate [(+)-BNP] in methanol/dichloromethane affords (+)(R)-(V), which is finally condensed with 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione (VI) by means of triethylamine (TEA) in hot DMF.
The chiral intermediate (V) can also be obtained as follows: The cyclization of L-proline (VII) with pivalaldehyde (VIII) by means of LDA gives the pyrrolooxazolidinone (IX), which is condensed with the benzaldehyde (X) by means of LDA in THF yielding the alcohol (XI). The reaction of (XI) with I2, PPh3 and imidazole affords the corresponding iodide (XII), which is deiodinated with SmI2 to the intermediate (XIII). The hydrolysis of the oxazolidinone ring of (XIII) with refluxing methanol/water gives the pyrrolidine-carboxylic acid (XIV), which is reduced with BH3 in THF yielding the carbinol (XV). The protection of the NH group of (XV) with Boc2O in THF affords the carbamate (XVI), which is treated with trimethylsilyl bromide in dichloromethane to provide he diol (XVII). The cyclization of (XVII) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in ether gives the chiral protected spiro-benzopyran (XVIII), which is finally deprotected with TFA in dichloromethane to afford the desired chiral intermediate (V).