New efficient enantioselective synthesis of 2-oxopiperazines: a practical access to chiral 3-substituted 2-oxopiperazines

The development of efficient and stereoselective methods to produce 1,4-disubstituted-2-oxopiperazine in enantiomerically pure form, from a readily available starting material is crucial. Herein, we report a reduction modification to our previously described synthesis of 1,4-disubstituted-2-oxopiperazine and also two original shortly accessed pathways. These new pathways can be routinely performed on a multigram scale and should rapidly find a place in the preparation of the 3-substituted-2-oxopiperazine diastereomers. Stereoselective alkylation of 1,4-disubstituted-2-oxopiperazine led to the corresponding (3S)-diastereomer or (3R)-diastereomer from the corresponding 2-oxopiperazine enantiomer with the chiral inductor substituted at the N1 (1∗) position, respectively, in good yield.

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Methyl (2S)-6-tert-butoxycarbonyl-2-benzyloxymethyl-3,6-diaza-4-thioxohexanoateC18H26N2O5S[α]D28=+32 (c 0.3, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (S)

(2R)-6-tert-Butoxycarbonyl-2-benzyloxymethyl-1-hydroxy-3,6-diazahexane-4-thioneC18H26N2O4S[α]D28=+27 (c 0.4, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (R)

(2R)-6-tert-Butoxycarbonyl-2-benzyloxymethyl-1-hydroxy-3,6-diazahexaneC17H28N2O4[α]D28=+5 (c 0.4, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (R)

Methyl (2S)-6-(4-nitrobenzenesulfonyl)-2-(benzyloxymethyl)-3,6-diaza-4-oxohexanoateC19H21N3O8S[α]D24=+7 (c 0.1, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (S)

Methyl (2S)-3-benzyloxy-2-[4′-(4-nitrobenzenesulfonyl)-2′-oxopiperazin-1′-yl]propanoateC21H23N3O8S[α]D28=-4 (c 0.4, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (S)

(1′R)-4-(4-Nitrobenzenesulfonyl)-1-[1′-benzyloxymethyl-2′-hydroxyethyl]-2-oxopiperazineC20H23N3O7S[α]D28=+6 (c 0.1, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (R)

(1’R)-1-[1′-Benzyloxymethyl-2′-hydroxyethyl]-2-oxopiperazineC14H20N2O3[α]D20=+25 (c 0.05, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (R)

(1′R)-4-(tert-Butoxycarbonyl)-1-[1′-benzyloxymethyl-2′-hydroxyethyl]-2-oxopiperazineC19H28N2O5[α]D24=+7 (c 0.1, EtOH)Source of chirality: O-benzyl-l-serine or O-benzyl-d-serineAbsolute configuration: (R)

(1′R)-4-(4-Thiophenylbenzenesulfonyl)-1-[1′-benzyloxymethyl-2′-hydroxyethyl]-2-oxopiperazineC20H28N2O5S2[α]D23=-26 (c 0.01, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (R)

(2R)-3-Benzyloxy-2-hydroxypropanoic acidC10H11O4[α]D22=-2 (c 0.5, EtOH)Source of chirality: O-benzyl-d-serineAbsolute configuration: (R)

Methyl (3R)-3-benzyloxy-2-hydroxypropanoateC11H14O4[α]D23=-6 (c 0.5, EtOH)Source of chirality: O-benzyl-d-serineAbsolute configuration: (R)

Methyl (2S)-3-benzyloxy-2-[4′-(tert-butoxycarbonyl)-1′-piperazinyl]propanoateC20H30N2O5[α]D23=-16 (c 0.5, EtOH)Source of chirality: O-benzyl-d-serineAbsolute configuration: (S)

(2S)-3-Benzyloxy-2-[4′-(tert-butoxycarbonyl)-2′-oxopiperazin-1′-yl] propanoateC20H28N2O6[α]D23=-12 (c 0.3, EtOH)Source of chirality: O-benzyl-d-serineAbsolute configuration: (S)

(2S)-3-Benzyloxy-2-hydroxypropanoic acidC10H11O4[α]D22=+2 (c 0.5, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (S)

Methyl (3S)-3-benzyloxy-2-hydroxypropanateC11H14O4[α]D22=+6 (c 0.5, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (S)

Methyl (2R)-3-benzyloxy-2-[4′-(tert-butoxycarbonyl)-1′-piperazinyl]propanoateC20H30N2O5[α]D23=+16 (c 0.5, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (R)

Methyl (2R)-3-benzyloxy-2-[4′-(tert-butoxycarbonyl)-2′-oxopiperazin-1′-yl]propanoateC20H28N2O6[α]D23=+12 (c 0.3, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (R)

(1′S)-4-(tert-Butoxycarbonyl)-1-[1′-benzyloxymethyl-2′-hydroxyethyl]-2-oxopiperazineC19H28N2O5[α]D24=-7 (c 0.1, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (S)

(1R,3S)-4-(tert-Butoxycarbonyl)-1-[1′-hydroxymethyl-2′-hydroxyethyl]-3-benzyl-2-oxopiperazineC26H34N2O5[α]D18=+16 (c 0.1, EtOH)Source of chirality: O-benzyl-d-serineAbsolute configuration: (1R,3S)

(1S,3R)-4-(tert-Butoxycarbonyl)-1-[1′-hydroxymethyl-2′-hydroxyethyl]-3-benzyl-2-oxopiperazineC26H34N2O5[α]D18=-16 (c 0.1, EtOH)Source of chirality: O-benzyl-l-serineAbsolute configuration: (1S,3R)