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

Abstract

A seven-step ex-chiral-pool synthesis of optically active 4-alkylidene-tetrahydroisoquinolines 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. 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 (E)-ethyl 4-(N-6-bromopiperonyl) substituted pentenoates with high yields. Intramolecular Heck cyclization employing the Herrmann-Beller catalyst enabled generation of enantiopure 4-(2-ethoxycarbonylmethylidene)-tetrahydroisoquinoline building blocks with high (Z) selectivity. Subsequent selected functional group transformations gave carbinols and lactones, which will be used as key intermediates in crinane alkaloid total syntheses.