合成路线1

The first total synthesis of hyperzine A as racemic is carried out as follows: The reaction of pyrrolidine (I) with cyclohexane-1,4-dione monoethyleneketal (II) by means of p-toluenesulfonic acid in refluxing benzene gives the enamine (III), which is cyclized with acrylamide (IV) in refluxing dioxane affording the bicyclic pyridone (V). The benzylation of (V) with benzyl chloride and KH in THF yields the N-benzyl derivative (VI), which is dehydrogenated by means of phenylselenium chloride in THF, followed by a treatment with NaIO4 in refluxing methanol to give the protected pyridone (VII). The debenzylation of (VII) with Pd(OH)2 in acetic acid yields the free pyridone (VIII), which is aromatized with methyl iodide and silver carbonate to the 2-methoxypyridine (IX). Elimination of the ketal group of (IX) with HCl in refluxing acetone affords the tetrahydroquinolone (X), which is carboxylated by means of dimethyl carbonate and KH to give 2-methoxy-6-oxo-5,6,7,8-tetrahydroquinoline-5-carboxylic acid methyl ester (XI). The cyclization of (XI) with 2-methylacrolein (XII) by means of sodium methoxide in methanol or tetramethylguanidine in dichloromethane yields the tricyclic compound (XIII), which is mesylated with mesyl chloride to the mesylate (XIV). Elimination of the mesyl group of (XIV) with refluxing acetic acid - sodium acetate affords the olefinic compound (XV), which is submitted to a Wittig condensation with ethylidenetriphenylphosphorane in ether giving the diolefinic compound (XVI) as a mixture of the E- and Z-isomers. Selective hydrolysis of (XVI) with NaOH in THF - methanol yields acid (XVII) as the E-isomer, which is treated with SOCl2 and sodium azide in a modified Curtius reaction to obtain the urethane (XVIII). Lastly trimethylsilyl iodide is used to effect both N- and O-deprotection.