Premium
Evaluation of Protecting Groups for 3‐Hydroxyisoxazoles − Short Access to 3‐Alkoxyisoxazole‐5‐carbaldehydes and 3‐Hydroxyisoxazole‐5‐carbaldehyde, the Putative Toxic Metabolite of Muscimol
Author(s) -
Riess Regine,
Schön Michael,
Laschat Sabine,
Jäger Volker
Publication year - 1998
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/(sici)1099-0690(199803)1998:3<473::aid-ejoc473>3.0.co;2-v
Subject(s) - chemistry , alkylation , metabolite , regioselectivity , diazomethane , hydroxymethyl , bromide , iodide , medicinal chemistry , demethylation , organic chemistry , catalysis , biochemistry , gene expression , dna methylation , gene
The regioselectivity of the 3‐hydroxyisoxazole‐5‐ester 1 is studied with respect to O ‐ versus N ‐alkylation. 3‐ O ‐Alkyl products 2 are highly favoured with benzyl, benzhydryl, and allyl bromide (≥ 91:9), in contrast to known uses of 5‐alkyl‐3‐hydroxyisoxazoles or when methylation with diazomethane (or methyl iodide) is effected. Methoxymethylation leads to the N ‐substituted isoxazolinone 3e only. On reduction with DIBAH, the esters 2 afford 3‐ O ‐protected 3‐hydroxyisoxazole‐5‐carbaldehydes 4 (75−98%). For removal of the benzyl protecting groups, three variations (HBr/HOAc, H 2 ‐Pd/BaSO 4 , NBS/AIBN) were found useful with 5‐ester, 5‐formyl, and 5‐hydroxymethyl derivatives. The free 3‐hydroxy‐5‐carbaldehyde 9 , the putative toxic metabolite of the GABA agonist muscimol, is prepared accordingly. The O ‐protected 3‐hydroxyisoxazole‐5‐carbaldehydes 4 constitute versatile intermediates in various routes to analogues of CNS‐active amino acids and can now be obtained in a highly efficient manner.