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

Dedicated to Prof. Dr. Johann Mulzer on the occasion of his 80^th birthday

Abstract

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.

Key words

l-serine ester - 6-bromopiperonal - reductive amination - Horner olefination - intramolecular Heck reaction - 4-alkylidene-substituted tetrahydroisoquinolines - ex-chiral-pool synthesis

Publication History

Received: 20 March 2024

Accepted after revision: 15 May 2024

Accepted Manuscript online:
15 May 2024

Article published online:
06 June 2024

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The 1,2-dihydroisoquinoline could be described as a side product involving two successive 1,5-H shifts: a C1→exo alkylidene H shift might have formed an o-quinodimethide intermediate, which immediately undergoes re-aromatization via a C3→C1 H shift delivering the product. Alternatively, C3→ester C=O 1,5-H shift for a dienol intermediate and a subsequent enol/C=O tautomerization (1,3-H shift). For data, see the SI. See also:
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• 53 Still, removal of the dihydroquinoline lactone (double-bond-positional isomer) side product remained problematic (laborious HPLC). In contrast to the major isomer 16, dehydrogenation of the dihydroquinoline forming the isoquinoline enabled a more facile separation. If necessary, remaining dihydroquinoline side products (traces) definitely were removed upon generating the quaternary stereocenters. Here, the dihydroisoquinolines remained as reactants.

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