Synthesis and structure of novel (S)-1,6-dialkylpiperazine-2,5-diones and (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones

Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-α-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while the synthesis of (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in the presence of a carbonyl compound proved to be a simple, efficient and general method for the preparation of stable (storable) α-alkylamino acid ester hydrochlorides. The structures of the novel compounds were determined by NMR and X-ray diffraction.

Figure optionsDownload as PowerPoint slide

Methyl (S)-2-(cyclohexylamino)propanoate hydrochlorideC10H20ClNO2Ee = 100%[α]D22=+1.5 (c 1, MeOH)Source of chirality: methyl (S)-alaninateAbsolute configuration: (S)

Methyl (S)-2-(2,3-dihydro-1H-inden-2-yl)propanoate hydrochlorideC13H18ClNO2Ee = 100%[α]D23=+2.1 (c 1, MeOH)Source of chirality: methyl (S)-alaninateAbsolute configuration: (S)

Methyl (S)-2-(isopropylamino)propanoate hydrochlorideC7H16ClNO2Ee = 100%[α]D23=+8.6 (c 1, MeOH)Source of chirality: methyl (S)-alaninateAbsolute configuration: (S)

Methyl (S)-2-(isopropylamino)-3-methylbutanoate hydrochlorideC9H20ClNO2Ee = 100%[α]D22=+28.9 (c 1, MeOH)Source of chirality: methyl (S)-valinateAbsolute configuration: (S)

Methyl (S)-2-(isopropylamino)-3,3-dimethylbutanoate hydrochlorideC10H22ClNO2Ee = 100%[α]D25=+29.7 (c 1, MeOH)Source of chirality: methyl (S)-tert-leucinateAbsolute configuration: (S)

Methyl (S)-2-(isopropylamino)-4-methylpentanoate hydrochlorideC10H22ClNO2Ee = 100%[α]D22=+26.0 (c 1, MeOH)Source of chirality: methyl (S)-leucinateAbsolute configuration: (S)

Methyl (S)-2-(isopropylamino)-3-(4-nitrophenyl)propanoate hydrochlorideC13H19ClN2O4Ee = 100%[α]D22=+52.2 (c 1, MeOH)Source of chirality: (S)-4’-NO2-Phe-OMeAbsolute configuration: (S)

Methyl (S)-3-(4-tert-butoxyphenyl)-2-(isopropylamino)propanoate hydrochlorideC17H28ClNO3Ee = 100%[α]D27=+50.8 (c 1, MeOH)Source of chirality: (S)-O-t-Bu-Tyr-OMeAbsolute configuration: (S)

Methyl (S)-2-(propylamino)propanoate hydrochlorideC7H16ClNO2Ee = 100%[α]D22=+1.8 (c 1, MeOH)Source of chirality: methyl (S)-alaninateAbsolute configuration: (S)

Methyl (S)-3-methyl-2-(propylamino)butanoate hydrochlorideC9H20ClNO2Ee = 100%[α]D27=+27.4 (c 1, MeOH)Source of chirality: methyl (S)-valinateAbsolute configuration: (S)

Methyl (S)-4-methyl-2-(propylamino)pentanoate hydrochlorideC10H22ClNO2Ee = 100%[α]D25=+26.5 (c 1, MeOH)Source of chirality: methyl (S)-leucinateAbsolute configuration: (S)

(S)-1-Cyclohexyl-6-methylpiperazine-2,5-dioneC11H18N2O2Ee = 100%[α]D24=+137.4 (c 0.5, CH2Cl2)Source of chirality: methyl (S)-alaninateAbsolute configuration: (S)

(S)-1-(2,3-Dihydro-1H-inden-2-yl)-6-methylpiperazine-2,5-dioneC14H16N2O2Ee = 100%[α]D24=+123.4 (c 0.5, CH2Cl2)Source of chirality: methyl (S)-alaninateAbsolute configuration: (S)

(S)-1-Benzhydryl-6-methylpiperazine-2,5-dioneC18H18N2O2Ee = 100%[α]D25=+224.6 (c 0.5, CH2Cl2)Source of chirality: methyl (S)-alaninateAbsolute configuration: (S)

(S)-1-Isopropyl-6-methylpiperazine-2,5-dioneC8H14N2O2Ee = 100%[α]D25=+169.8 (c 0.5, CH2Cl2)Source of chirality: methyl (S)-alaninateAbsolute configuration: (S)

(S)-1,6-Diisopropylpiperazine-2,5-dioneC10H18N2O2Ee = 100%[α]D25=+113.6 (c 0.5, CH2Cl2)Source of chirality: methyl (S)-valinateAbsolute configuration: (S)

(S)-1-tert-Butyl-6-isopropylpiperazine-2,5-dioneC11H20N2O2Ee = 100%[α]D22=+80.8 (c 0.5, CH2Cl2)Source of chirality: methyl (S)-tert-leucinateAbsolute configuration: (S)

(S)-6-Isobutyl-1-isopropylpiperazine-2,5-dioneC11H20N2O2Ee = 100%[α]D19=+177.2 (c 0.5, CH2Cl2)Source of chirality: methyl (S)-leucinateAbsolute configuration: (S)

(S)-6-Benzyl-1-isopropylpiperazine-2,5-dioneC14H18N2O2Ee = 100%[α]D24=+170.8 (c 0.5, CH2Cl2)Source of chirality: methyl (S)-phenylalaninateAbsolute configuration: (S)

(S)-1-Isopropyl-6-(4-nitrobenzyl)piperazine-2,5-dioneC14H17N3O4Ee = 100%[α]D24=+157.9 (c 0.5, CH2Cl2)Source of chirality: (S)-4’-NO2-Phe-OMeAbsolute configuration: (S)

(S)-6-(4-tert-Butoxybenzyl)-1-isopropylpiperazine-2,5-dioneC18H26N2O3Ee = 100%[α]D22=+137.3 (c 0.5, CH2Cl2)Source of chirality: (S)-O-t-Bu-Tyr-OMeAbsolute configuration: (S)

Methyl (S)-3-(1-isopropyl-2,5-dioxopiperazin-6-yl)propanoateC11H18N2O4Ee = 100%[α]D24=+137.6 (c 0.5, CH2Cl2)Source of chirality: dimethyl (S)-glutamateAbsolute configuration: (S)

(3S,6S)-3-Benzyl-6-methyl-1-propylpiperazine-2,5-dioneC15H20N2O2Ee = 100%[α]D25=-54.6 (c 0.5, CH2Cl2)Sources of chirality: (S)-AlaOMe and (S)-Z-PheOHAbsolute configuration: (3S,6S)

(3S,6S)-6-Isopropyl-3-methyl-1-propylpiperazine-2,5-dioneC11H20N2O2Ee = 100%[α]D24=+39.8 (c 0.5, CH2Cl2)Sources of chirality: (S)-ValOMe and (S)-Z-AlaOHAbsolute configuration: (3S,6S)

(3S,6S)-6-Isobutyl-3-methyl-1-propylpiperazine-2,5-dioneC12H22N2O2Ee = 100%[α]D25=+80.1 (c 0.5, CH2Cl2)Sources of chirality: (S)-LeuOMe and (S)-Z-AlaOHAbsolute configuration: (3S,6S)

(3S,6S)-6-Benzyl-3-methyl-1-propylpiperazine-2,5-dioneC15H20N2O2Ee = 100%[α]D24=+52.6 (c 0.5, CH2Cl2)Sources of chirality: (S)-PheOMe and (S)-Z-AlaOHAbsolute configuration: (3S,6S)

Methyl 3-[(3S,6S)-3-methyl-2,5-dioxo-1-propylpiperazin-6-yl]propanoateC12H20N2O4Ee = 100%[α]D26=+47.1 (c 0.5, CH2Cl2)Sources of chirality: (S)-Gla(OMe)2 and (S)-Z-AlaAbsolute configuration: (2’S,5’S)