N‐(4‐Nitrophenylsulfonyl)‐ and N‐(Fluorenylmethoxycarbonyl)‐N‐ethyl Amino Acid Methyl Esters – A Practical Approach

Abstract

An efficient one-pot preparation of N-ethyl-N-4-nitrophenylsulfonyl (nosyl) amino acid methyl esters was accomplished by a simple N-ethylation reaction by using triethyloxonium tetrafluoroborate in the presence of N,N-diisopropylethylamine. The N-ethylated amino acid methyl esters are obtained with total retention of stereochemistry at the original chiral centers. To further broaden the scope of this methodology, the N-ethylated nosyl-protected compounds are easily con-

Synthesis of N-alkyl-Cα,α-dimethylglycine derivatives

“…Again, in all cases, the N-methyl C α,α -dimethylglycine derivatives were obtained in yields ranging from 75% to 97% (compounds 3a-e, Scheme 1, Table 1) By removal of the Nosyl protecting group from N-Nosyl, N-ethyl amino acid methyl esters and reprotection of the amino function with the 9-fluorenylmethoxycarbonyl group (Fmoc), Liguori demonstrated the compatibility of this N-ethylation procedure with standard Fmoc chemistry. 7 Conversion of the methyl esters of N-ethyl dehydroamino acids to the corresponding acids by treatment with a mixture of an aqueous solution of NaOH and dioxane and coupling with an amino acid was previously carried out by us. 13 To test if this cleavage method could be extended to the methyl esters of N-alkyl, C α,α -dimethylglycine derivatives, compounds 2a and 2c were treated with a mixture of an aqueous solution of NaOH and dioxane, giving the corresponding N-protected, N-ethyl C α,α -dimethylglycine in 54% and 76% respectively (compounds 4a and 4c).…”

Synthesis of Novel Nonproteinogenic Amino Acids: N‐Ethyl‐α,β‐dehydroamino Acid Methyl Esters

“…The methodology proposed by Liguori et al for N ‐ethylation of N ‐nosyl‐protected amino acid derivatives using 2.5 equiv. of the alkylating agent triethyloxonium tetrafluoroborate, requires the use of side‐chain protection in the case of side‐chain‐functionalized amino acids 9b. To avoid the need for side‐chain protection and subsequent deprotection, our initial approach for the synthesis of N ‐ethyl‐α,β‐dehydroamino acid derivatives was a two‐step procedure in which the first step was dehydration followed by the alkylation reaction (Route A, Scheme ).…”

“…The introduction of the tert ‐butoxycarbonyl group makes necessary a deprotection step prior to alkylation; thus, compounds 2b and 2c were treated with a 4 % solution of trifluoroacetic acid (TFA) in dichloromethane to give compounds 3b and 3c in high yields. These N ‐nosyl‐α,β‐dehydroamino acid derivatives were subjected to ethylation by using the conditions proposed by Liguori et al9b [2.5 equiv. of triethyloxonium tetrafluoroborate, 3.5 equiv.…”

“…N ‐(Nitrophenylsulfonyl)amino acid chlorides have also been used to couple to extremely hindered amines on a solid support giving better results than analogous Fmoc‐amino acid chlorides 8. Recently, Liguori et al proposed the ethylation of several 4‐nitrophenylsulfonyl (nosyl) protected amino acids using triethyloxonium tetrafluoroborate (Et 3 OBF 4 ) as alkylating agent to give N ‐ethylamino acid derivatives in high yields 9b. These authors demonstrated the compatibility of the procedure with standard Fmoc chemistry 9.…”

“…In this paper we report the use of a combination of the alkylation procedure reported by Liguori et al9b and our dehydration methodologies12,13 to obtain new nonproteinogenic amino acids, namely, N ‐ethyl‐α,β‐dehydroamino acids.…”