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-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.

Publication History

Received: 20 March 2024

Accepted after revision: 15 May 2024

Accepted Manuscript online:
15 May 2024