An improved synthesis of deuterated Schöllkopf’s bis-lactim ether and its use for the asymmetric synthesis of (R)-[α-2H]-phenylalanine methyl esters

Treatment of (S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine with trifluoroacetic acid in MeOD results in regioselective deuteration at its C6-position affording its corresponding (S)-[6-2H2]-isotopomer in excellent yield with no loss of stereochemical integrity at its C3-stereocentre. The lithium aza-enolate of this deuterated chiral template has been alkylated with a range of substituted benzyl bromides to afford (3S,6R)-[6-2H]-3-isopropyl-6-benzyl-bis-lactim ethers that were hydrolysed to afford their corresponding (R)-[α-2H]-phenylalanine methyl esters as hydrochloride salts in good yield.

Figure optionsDownload as PowerPoint slide

(3S)-[6-2H2]-3-Isopropyl-2,5-dimethoxy-3,6-dihydropyrazineC9H14D2N2O2[α]D23=+72.0 (c 1.0, EtOH)Source of chirality: l-valine

(3S,6R)-[6-2H]-3-Isopropyl-6-benzyl-2,5-dimethoxy-3,6-dihydropyrazineC16H21DN2O2[α]D25=-41.2 (c 1.3, CH2Cl2)Source of chirality: l-valine

(3S,6R)-[6-2H]-3-Isopropyl,6-(2-bromobenzyl)-2,5-dimethoxy-3,6-dihydropyrazineC16H20DBrN2O2[α]D25=-7.5 (c 1.0, EtOAc)Source of chirality: l-valine

(3S,6R)-[6-2H]-3-Isopropyl,6-(2-iodobenzyl)-2,5-dimethoxy-3,6-dihydropyrazineC16H20DIN2O2[α]D25=-15.5 (c 1.0, EtOAc)Source of chirality: l-valine

(3S,6R)-[6-2H]-3-Isopropyl,6-(4-fluorobenzyl)-2,5-dimethoxy-3,6-dihydropyrazineC16H20DFN2O2[α]D27=-62.4 (c 1.0, EtOAc)Source of chirality: l-valine

(3S,6R)-[6-2H]-3-Isopropyl,6-(4-bromobenzyl)-2,5-dimethoxy-3,6-dihydropyrazineC16H20DBrN2O2[α]D25=-5.2 (c 1.0, EtOAc)Source of chirality: l-valine

(3S,6R)-[6-2H]-3-Isopropyl,6-(4-trifluoromethylbenzyl)-2,5-dimethoxy-3,6-dihydropyrazineC17H20DF3N2O2[α]D25=-20.7 (c 1.0, EtOAc)Source of chirality: l-valine

(R)-α-[2H]-Phenylalanine methyl ester hydrochlorideC10H13DClNO2[α]D25=-28.3 (c 1.0, EtOH)Source of chirality: l-valine

(R)-α-[2H]-2-Bromophenylalanine methyl ester hydrochlorideC10H12DBrClNO2[α]D25=-20.1 (c 1.0, EtOH)Source of chirality: l-valine

(R)-α-[2H]-2-Iodophenylalanine methyl ester hydrochlorideC10H12DClINO2[α]D25=-13.3 (c 1.0, EtOH)Source of chirality: l-valine

(R)-α-[2H]-4-Fluorophenylalanine methyl ester hydrochlorideC10H12DClFNO2[α]D25=-34.3 (c 1.0, EtOH)Source of chirality: l-valine

(R)-α-[2H]-4-Bromophenylalanine methyl ester hydrochlorideC10H12DBrClNO2[α]D25=-18.5 (c 1.0, EtOH)Source of chirality: l-valine

(R)-α-[2H]-4-Trifluoromethylphenylalanine methyl ester hydrochlorideC11H12DClF3NO2[α]D25=-24.8 (c 1.0, EtOH)Source of chirality: l-valine