A Facile Method for the Side-Chain Protection of α-Methyl-β-3, 4-dihydroxyphenyl-L-alanine (αMeDopa) for Solid-Phase Peptide Synthesis

Kun-hwa Hsieh; Margaret M. deMaine

doi:10.1055/s-1991-26380

Synthesis 1991; 1991(1): 59-62
DOI: 10.1055/s-1991-26380

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A Facile Method for the Side-Chain Protection of α-Methyl-β-3, 4-dihydroxyphenyl-L-alanine (αMeDopa) for Solid-Phase Peptide Synthesis

Kun-hwa Hsieh^* , Margaret M. deMaine

^*Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, WA 99164, USA

Abstract

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Two approaches have been used to prepare N ^α-tert-butoxycarbonyl-α-methyl-β-3,4-dimethoxy-, or dibenzyloxyphenyl-L-alanine, N ^α-Boc-α-MeDopa(R)₂, where R is the methyl or benzyl ether. In the first approach, α-methyl-β-3,4-dihydroxyphenyl-L-alanine (αMeDopa) is reacted with di-tert-butyl dicarbonate (Boc₂O) in the presence of sodium bicarbonate under anhydrous conditions. The resultant N-protected derivative (Boc-αMeDopa) is methylated with methyl iodide/sodium carbonate, followed by reaction with methyl iodide/tetramethylammonium hydroxide, and saponification with potassium hydroxide in aqueous dioxane to give N ^α-tert-butoxycarbonyl-α-methyl-β-3,4-dimethoxyphenyl-L-alanine, Boc-αMeDopa(Me)₂, in 30% overall yield. In the second approach, methyl ester of α-methyl-β-3,4-dihydroxyphenyl-L-alanine is prepared by the thionyl chloride/methanol procedure, followed by N-protection with di-tert-butyl dicarbonate/sodium bicarbonate, sidechain protection with benzyl chloride/tetramethylammonium hydroxide, and saponification with sodium hydroxide in aqueous dioxane to give N ^α-tert-butoxycarbonyl-α-methyl-β-3,4-dibenzyloxyphenyl-L-alanine, Boc-αMeDopa(CH₂Ph)₂, in 46% overall yield. The latter derivative has been incorporated into angiotensin II under stepwise solid-phase peptide synthesis and solution coupling conditions.

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