Ex-Chiral-Pool Synthesis of Optically Active 4-Alkylidene-Tetrahydro­isoquinolines – Key Intermediates for Crinane Alkaloid Total Syntheses

A seven-step ex-chiral-pool synthesis of optically active 4-alkylidenetetrahydroisoquinolines was developed. Starting from 6-bromopiperonal and (S)-serine esters, N-benzylation via reductive amination gave enantiopure N-piperonyl serine esters. Subsequent NH and OH protection delivered defined (S)-serine building blocks. The best results to achieve the conversion into the corresponding serinal were obtained via a two-step sequence of NaBH4/LiCl reduction and subsequent TEMPO oxidation. Then, chain elongation using the Masamune–Roush variant of the Horner olefination afforded ethyl (E)-4-(N-6-bromopiperonyl)-substituted pentenoates in high yields. Intramolecular Heck cyclization employing the Herrmann–Beller catalyst enabled generation of enantiopure 4-(2-ethoxycarbonylmethylidene)tetrahydroisoquinoline building blocks in high Z-selectivity. Subsequent selected functional group transformations gave carbinols and lactones, which can be used as key intermediates in crinane alkaloid total syntheses.