Stereoselective synthesis of β-hydroxy-α-amino acids β-substituted with non-aromatic heterocycles

We have stereoselectively synthesised β-hydroxy-α-amino acids β-substituted with non-aromatic heterocycles by means of a condensation reaction between enantiomerically pure heterocyclic aldehydes and the (R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (Schöllkopf’s reagent) as a chiral auxiliary. The stereocontrolled addition gave mixtures of diastereoisomers whose steric configurations were assigned on the basis of spectroscopic data and X-ray analysis. Upon controlled hydrolysis, the adducts were transformed into the corresponding methyl esters of β-hydroxy-β-heterocyclic substituted α-amino acids.

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(S)-1-Acetyl-pyrrolidine-2-carbaldehydeC7H11NO2Dr = >99% [NMR][α]D20=-37.5 (c 1.07, CHCl3)Absolute configuration: (S)

(R)-4-Formyl-1,3-thiazolidine-3-carboxylic acid, tert-butyl esterC9H15NO3SDr = >99% [NMR][α]D20=-130 (c 0.81, CH3OH)Absolute configuration: (R)

(R)-4-[(N-Methoxy-N-methylamino)carbonyl]-3-thiazolidinecarboxylic acid, 1,1-dimethyl esterC11H20N2O4SDr = >99% [NMR][α]D20=-117 (c 0.91, CH3OH)Absolute configuration: (R)

(S)-2-[(R)-Hydroxy-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl esterC19H33N3O5Dr = >99% [NMR][α]D20=+13.8 (c 0.98, Et2O)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (S,R,S,R)

(R)-((S)-1-Benzyl-pyrrolidin-2-yl)-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-methanolC21H31N3O3Dr = >99% [NMR][α]D20=+8.0 (c 0.65, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (R,S,S,R)

(R)-4-[(S)-Hydroxy-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-methyl]-thiazolidine-3-carboxylic acid tert-butyl esterC16H27N3O4Dr = >99%[NMR][α]D20=+6.9 (c 0.84, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (S,R,S,R)

(S)-2-[(R)-Hydroxy-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-methyl]-piperidine-1-carboxylic acid tert-butyl esterC20H35N3O5Dr = >99% [NMR][α]D20=+23.3 (c 1.72, CH2Cl2)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (S,R,S,R)

(S)-2-[(S)-Hydroxy-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl esterC19H33N3O5Dr = >99% [NMR][α]D20=-6.2 (c 0.84, Et2O)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (S,S,S,R)

1-{(S)-2-[(S)-Hydroxy-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-methyl]-pyrrolidine-1-yl}-ethanoneC16H27N3O4Dr = >99% [NMR][α]D20=+0.3 (c 1.01, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (S,S,S,R)

(S)-2-[(S)-Hydroxy-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-methyl]-piperidine-1-carboxylic acid tert-butyl esterC20H35N3O5Dr = >99% [NMR][α]D20=-3.1 (c 0.62, CH2Cl2)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (S,S,S,R)

(R)-2-[(R)-Hydroxy-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-methyl]-piperidine-1-carboxylic acid tert-butyl esterC20H35N3O5Dr = >99%[NMR][α]D20=-26.95 (c 1.1, CH2Cl2)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (R,R,S,R)

(R)-2-[(S)-Hydroxy-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-methyl]-piperidine-1-carboxylic acid tert-butyl esterC20H35N3O5Dr = >99% [NMR][α]D20=+14.3 (c 1.04, CH2Cl2)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (R,S,S,R)

(S)-2-[(S)-2-Amino-(S)-1-hydroxy-2-methoxycarbonyl-ethyl]-pyrrolidine-1-carboxylic acid tert-butyl esterC13H24N2O5Dr = >99% [NMR][α]D20=-51.1 (c 0.86, CH2Cl2)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (S,S,S)

(S)-2-[(S)-2-Amino-(S)-1-hydroxy-2-methoxycarbonyl-ethyl]-piperidine-1-carboxylic acid tert-butyl esterC14H26N2O5Dr = >99% [NMR][α]D20=-30.0 (c 0.5, CH2Cl2)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (S,S,S)

(S)-2-[(S)-2-Amino-(R)-1-hydroxy-2-methoxycarbonyl-ethyl]- piperidine-1-carboxylic acid tert-butyl esterC14H26N2O5Dr = >99% [NMR][α]D20=-54.25 (c 0.92, CH2Cl2)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (S,S,R)

(R)-2-[(S)-2-Amino-(S)-1-hydroxy-2-methoxycarbonyl-ethyl]-piperidine-1-carboxylic acid tert-butyl esterC14H26N2O5Dr = >99%[NMR][α]D20=+67.95 (c 0.63, CH2Cl2)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (R,S,S)

(R)-2-[(S)-2-Amino-(R)-1-hydroxy-2-methoxycarbonyl-ethyl]-piperidine-1-carboxylic acid tert-butyl esterC14H26N2O5Dr = >99% [NMR][α]D20=21.3 (c 0.5, CH2Cl2)Source of chirality: Schöllkopf’s reagentAbsolute configurations: (R,S,R)