Stereoselective synthesis of a new chiral synthon: a cyclic pseudodipeptide containing an aspartic acid derivative and l-valine

A simple stereoselective synthesis of cyclic synthons 4a,b and 10a,b, derived from an l-valine unit and an unnatural derivative of the aspartic acid, has been accomplished starting from the chiral synthon 1 and following the procedure already reported by us for the synthesis of similar compounds. These cyclic synthons are interesting substrates because they can behave as both electrophiles and nucleophiles and could be useful starting materials for the preparation of higher peptides such as, for instance, the unnatural tetrapeptides 15 and 18, through the condensation of 4a with 6a or 13 with 17, respectively.

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(2R,5S)-(4-Benzyl-6-ethoxy-5-isopropyl-2-methyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acid benzylesterC26H32N2O4[α]D = −6.8 (c 1.4, CHCl3)Source of chirality: l-valineAbsolute configuration: 2R,5S

(2R,5S)-(6-Ethoxy-5-isopropyl-2-methyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acidC12H20N2O4[α]D = −9.2 (c 0.6, CHCl3)Source of chirality: l-valineAbsolute configuration: 2R,5S

(2R,5S)-(6-Ethoxy-5-isopropyl-2-methyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acid benzyl esterC19H26N2O4[α]D = −12.8 (c 0.6, CHCl3)Source of chirality: l-valineAbsolute configuration: 2R,5S

Dipeptide [(EtO)Val-(2R)-methyl-Asp(OBn)]·HClC19H29ClN2O5[α]D = −9.6 (c 0.7, CHCl3)Source of chirality: l-valineAbsolute configuration: S,R

(2R,5S)-(4-Benzyl-6-ethoxy-5-isopropyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acid ethyl esterC20H28N2O4[α]D = +31.2 (c 0.6, CHCl3)Source of chirality: l-valineAbsolute configuration: 2R,5S

(2S,5S)-(4-Benzyl-6-ethoxy-5-isopropyl-2-methyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acid ethyl esterC21H30N2O4[α]D = −3.6 (c 0.5, CHCl3)Source of chirality: l-valineAbsolute configuration: 2S,5S

(2S,5S)-(4-Benzyl-6-ethoxy-5-isopropyl-2-methyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acidC19H26N2O4[α]D = −1.0 (c 0.8, CHCl3)Source of chirality: l-valineAbsolute configuration: 2S,5S

(2S,5S)-(6-Ethoxy-5-isopropyl-2-methyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acidC12H20N2O4[α]D = −4.3 (c 0.3, CHCl3)Source of chirality: l-valineAbsolute configuration: 2S,5S

(2R,5S)-(6-Ethoxy-5-isopropyl-2-methyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acid pentafluorophenyl esterC18H19F5N2O4[α]D = −0.2 (c 0.6, CHCl3)Source of chirality: l-valineAbsolute configuration: 2R,5S

(2R,5S,2′S,5′R)-(6-Ethoxy-5-isopropyl-2-methyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-8′-[3′,6′-diaza-4′,7′-dioxo-2′-isopropyl-5′-methyl-5′-(acetic acid benzylester)]-ethyl octanoateC31H46N4O8[α]D = −4.3 (c 0.8, CHCl3)Source of chirality: l-valineAbsolute configuration: 2R,5S,2′S,5′R

(2R,5S)-(2,4-Dibenzyl-6-ethoxy-5-isopropyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acid benzylesterC32H36N2O4[α]D = −26.3 (c 1, CHCl3)Source of chirality: l-valineAbsolute configuration: 2R,5S

(2S,5S)-(6-Ethoxy-5-isopropyl-2-methyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acid benzyl esterC19H26N2O4[α]D = −5.2 (c 0.6, CHCl3)Source of chirality: l-valineAbsolute configuration: 2S,5S

Dipeptide [(EtO)Val-(2S)-methyl-Asp(OBn)]·HClC19H29ClN2O5[α]D = −4.5 (c 0.4, CH3OH)Source of chirality: l-valineAbsolute configuration: S,S

(2R,5R,2′S,5′R)-(6-Ethoxy-5-isopropyl-2-methyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-8′-[3′,6′-diaza-4′,7′-dioxo-2-isopropyl-5′-methyl-ethyloctanoateC22H38N4O6[α]D = +32.2 (c 0.9, CHCl3)Source of chirality: l-valineAbsolute configuration: 2S,5R,2′S,5′R

Dipeptide [(EtO)Val-(2R)-Ala]·HClC10H21ClN2O3[α]D = −9.4 (c 1.5, CHCl3)Source of chirality: l-valineAbsolute configuration: S,R

(2R,5S)-(2-Benzyl-6-ethoxy-5-isopropyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acidC18H24N2O4[α]D = +3.2 (c 1.4, CHCl3)Source of chirality: l-valineAbsolute configuration: 2R,5S

(2R,5S)-(2-Benzyl-6-ethoxy-5-isopropyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acid benzyl esterC25H30N2O4[α]D = +2.7 (c 0.7, CHCl3)Source of chirality: l-valineAbsolute configuration: 2R,5S

(2S,5S)-(2-Benzyl-6-ethoxy-5-isopropyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acidC18H24N2O4[α]D = −69 (c 0.2, CHCl3)Source of chirality: l-valineAbsolute configuration: 2S,5S

(2S,5S)-(2,4-Dibenzyl-6-ethoxy-5-isopropyl-3-oxo-2,3,4,5-tetrahydro-pyrazin-2-yl)-acetic acidC25H30N2O4[α]D = −52.6 (c 0.4, CHCl3)Source of chirality: l-valineAbsolute configuration: 2S,5S

(2R,5S)-(6-Ethoxy-5-isopropyl-2-methyl-3-oxo)-2,3,4,5-tetrahydropyrazineC10H18N2O2[α]D = +101.2 (c 0.8, CHCl3)Source of chirality: l-valineAbsolute configuration: 2R,5S