Synthesis of New N‐Ethyl Dehydroamino Acid Derivatives: N‐Ethyl β,β‐Dibromo, N‐Ethyl β‐Bromo β‐Substituted, and N‐Ethyl β,β‐Disubstituted N‐Protected Dehydroamino Acid Methyl Esters

Abstract

Recently, we reported the use of a sequence of alkylation and dehydration methodologies to obtain new non‐proteinogenic amino acids (N‐ethyl α,β‐dehydroamino acids) from the methyl esters of N‐(4‐nitrophenylsulfonyl) β‐hydroxy amino acids. Thus, it was possible to obtain for the first time, non‐natural amino acids that incorporate both N‐ethyl and α,β‐dehydro moieties. Herein, we report the application of this N‐alkylation procedure to several methyl esters of β,β‐dibromo and β‐bromo β‐substituted dehydroamino acids protected with standard amine protecting groups such as tert‐butyloxycarbonyl, benzyloxycarbonyl, and (4‐nitrobenzyl)oxycarbonyl, as well as acyl and sulfonyl groups. The procedure allows the synthesis of the methyl esters of N‐protected N‐ethyl β,β‐dibromo and N‐ethyl β‐bromo β‐substituted dehydroamino acids in fair to high yields. Some of these N‐ethylated dehydroamino acid derivatives were used as substrates in cross‐coupling reactions to give β,β‐disubstituted N‐ethyldehydroalanine derivatives.

High yielding synthesis of N-ethyl dehydroamino acids

“…Synthesis of compounds Z(NO 2 )-L-Ser-OMe (Ferreira et al 1999), Z-L-Ser-OMe (Ferreira et al 1999), Boc-L-Ser-OMe (Ferreira et al 1999), Z(NO 2 )-L-Thr-OMe (Ferreira et al 1999), Z-L-Thr-OMe (Ferreira et al 1999), Boc-L-Thr-OMe (Ferreira et al 1999), Tos-L-Thr-OMe (Ferreira et al 1999), Z(NO 2 )-D,L-Phe(-OH)-OMe (Ferreira et al 1999), Z-D,L-Phe(-OH)-OMe (Monteiro et al 2011), Boc-D,L-Phe(-OH)-OMe (Ferreira et al 2001), Tos-D,L-Phe(-OH)-OMe (Ferreira et al 2007) The synthesis of these compounds was described in the references given above.…”

“…Synthesis of the methyl esters of N-protected -halo dehydroamino acids Synthesis of compounds Boc-Ala(,-Br)-OMe (4c) (Silva et al 2002), Z(NO 2 )-E-Abu(-Br)-OMe (E-5a) (Ferreira et al 2007), Z(NO 2 )-Z-Abu(-Br)-OMe (Z-5a) (Ferreira et al 2007), Z-Z-Abu-(-Br)OMe (Z-5b) (Ferreira et al 2007), Boc-E-Abu(-Br)-OMe (E-5c) (Silva et al 2002), Boc-Z-Abu(-Br)-OMe (Z-5c) (Silva et al 2002), Z(NO 2 )-Z-Phe(-Br)-OMe (Z-6a) (Monteiro et al 2011), Z-Z-Phe(-Br)-OMe (Z-6b) (Monteiro et al 2011), Boc-Z-Phe(-Br)-OMe (Z-6c) (Abreu et al 2004), Boc-Z-Phe(-I)-OMe (Z-7c) (Queiroz et al 2008).…”

“…In the case of N-alkylation of dehydroamino acids, an alternative to the electron withdrawing effect of the amine protecting group could be the presence of electron withdrawing substituents on the -carbon atom. Thus, we tested the triethyloxonium tetrafluoroborate / N,Ndiisopropylethylamine N-alkylation procedure with several methyl esters of -dibromo and -bromo, -substituted dehydroamino acids protected with standard amine protecting groups such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) and 4-nitrobenzyloxycarbonyl [Z(NO 2 )] as well as acyl and sulfonyl amine protecting groups (Monteiro et al 2011). Depending on the nature of the halogenated dehydroamino acid and of the protecting group, variable ratios of product to reactant were obtained.…”

Conformational preferences and synthesis of isomers Z and E of oxazole‐dehydrophenylalanine

“…αβ‐Didehydro‐α‐amino acids, commonly known as dehydroamino acids (ΔXaa), belong to nonstandard amino acids occurring primarily in natural peptides produced by bacteria and fungi . Dehydroamino acids continuously attract attention in various areas, mainly in synthesis, as designed products or suitable substrates, including asymmetric hydrogenation as well as in the conformational studies . Dehydrophenylalanine (ΔPhe), although scarcely presented in natural compounds, is the most often studied dehydroamino acid .…”

Synthesis of Dehydrodipeptide and N-ethyl-dehydrodipeptide Derivatives with an α-Aminoisobutyric Acid Residue

“…[9] The application of this N-alkylation procedure to several methyl esters of -dibromo and -bromo, substituted dehydroamino acids protected with standard amine protecting groups was subsequently reported. [10] By substituting potassium tert-butoxide for N,N-diisopropylethylamine the method was applied to obtain in high yields N-ethyl -halogenated dehydroamino acid derivatives and also non-halogenated N-ethyl dehydroamino acid derivatives. [11] -Dialkylglycines, such as -aminoisobutyric acid (Aib), also known as dimethylglycine or 2-methylalanine, diethylglycine (Deg) and isovaline (Iva) are the main feature of peptaibols.…”