3-Triphenylphosphonio-2,5-piperazinediones as new chiral glycine cation equivalents

3-Triphenylphosphonio-2,5-piperazinediones were effectively synthesized from homochiral valine or proline via Boc-Val-Gly-OMe, Boc-Pro-Gly-OMe or Cbz-Pro-Gly-OMe. Retention of configuration of the primary stereogenic center of the valine and proline moieties was observed. Diastereoselective nucleophilic substitution of the triphenylphosphonium group in 2,5-piperazinediones with S-, N-, P- and C-nucleophiles was observed. The configuration of the substitution products was assigned either by their hydrolysis and decarboxylation or based on the analysis of the H–C(3)–N–H coupling constants of 3-substituted-2,5-piperazinediones derived from proline. The trans-stereoselectivity was predominant in reactions of 3-triphenylphosphonio-1,6-trimethylene-2,5-piperazinediones with the nucleophiles investigated. The stereodifferentiating ability of the proline moiety is much stronger than that of the valine unit and allowed nucleophilic α-functionalization of the glycine moiety with good to excellent diastereoselectivity.

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(3R,6S)-3-Triphenylphosphonio-1,6-trimethylene-2,5-piperazinedione tetrafluoroborateC25H24BF4N2O2PDe > 99%[α]D23=-42.0 (c 0.9, CH3CN)Absolute configuration: (3R,6S)Source of chirality: l-proline—chiral substrate

(3R,6S)-3-Benzylthio-1,6-trimethylene-2,5-piperazinedioneC14H16N2O2SDe > 99%[α]D23=-15.8 (c 0.3, CH3CN)Absolute configuration: (3R,6S)Source of chirality: l-proline—chiral substrate

(3RS,6S)-6-Isopropyl-3-triphenylphosphonio-2,5-piperazinedione tetrafluoroborateC25H26BF4N2O2PDe = 28%[α]D23=-29.8 (c 0.7, CH3CN)Absolute configuration: (3RS,6S)Source of chirality: l-valine—chiral substrate

(3R,6S)-3-[Di(methoxycarbonyl)methyl]-6-izopropyl-2,5-piperazinedioneC12H18N2O6De > 99%[α]D23=-4.8 (c 2.1, CHCl3)Absolute configuration: (3R,6S)Source of chirality: l-valine—chiral substrate

(3S,6S)-3-[Di(methoxycarbonyl)methyl]-6-izopropyl-2,5-piperazinedioneC12H18N2O6De > 99%[α]D23=-48.3 (c 1.3, CHCl3)Absolute configuration: (3S,6S)Source of chirality: l-valine—chiral substrate

(3R,6S)-3-Dimethoxyphosphoryl-1,6-trimethylene-2,5-piperazinedioneC9H15N2O5PDe > 99%[α]D23=-31.7 (c 0.5, MeOH)Absolute configuration: (3R,6S)Source of chirality: l-proline—chiral substrate

(3R,6S)-3-Phthalimidoyl-1,6-trimethylene-2,5-piperazinedioneC15H13N3O4De > 99%[α]D23=-65.1 (c 0.6, CH3CN)Absolute configuration: (3R,6S)Source of chirality: l-proline—chiral substrate

(3R,6S)-3-(Diacetylmethyl)-1,6-trimethylene-2,5-piperazinedioneC12H16N2O4De > 99%[α]D23=-54.4 (c 1.0, CH2Cl2)Absolute configuration: (3R,6S)Source of chirality: l-proline—chiral substrate