Enantiopure α-imino glyoxylate: a versatile substrate for the spontaneous asymmetric synthesis of unnatural hydroxyaryl glycinates

A novel synthesis of useful enantiomerically pure arylglycinates via spontaneous reaction between phenol or naphthol derivatives and enantiopure α-imino glyoxylate in the absence of an acid catalyst is reported. A library of enantiopure substituted phenol or naphthol glycinates was obtained in good yields and high diastereoselectivities. Diastereoisomerically pure aryl glycinates were obtained by direct flash chromatography separation of the crude reaction mixture. The free OH moiety of the phenols or naphthols contributed to the activation of the imino group to form an intermolecular hydrogen bond and promoted the reaction in the absence of an acid catalyst, as shown in the transition state reported. The diastereoselectivity is due to thermodynamic control in the addition step.

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(S)-Ethyl 2-((R)-1-phenylethylamino)-2-(2-hydroxynaphthalen-1-yl)acetateC22H23NO3Ee = 98%[α]D20=+144.4 (c 2.3, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (S,R)

(R)-Ethyl 2-((R)-1-phenylethylamino)-2-(2-hydroxynaphthalen-1-yl)acetateC22H23NO3Ee = 98%[α]D20=-69.2 (c 1.5, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (R,R)

(S)-Ethyl 2-((R)-1-phenylethylamino)-2-(2-mercaptonaphthalen-1-yl)acetateC22H23NO2SEe = 98%[α]D20=+213.2 (c 2.1, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (S,R)

(S)-Ethyl 2-((R)-1-phenylethylamino)-2-(1-hydroxynaphthalen-2-yl)acetateC22H23NO3Ee = 98%[α]D20=+87.9 (c 1.3, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (S,R)

(S)-Ethyl 2-((R)-1-phenylethylamino)-2-(1-hydroxy-4-methoxynaphthalen-2-yl)acetateC23H25NO4Ee = 98%[α]D20=+83.1 (c 2.7, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (S,R)

(S)-Ethyl 2-((R)-1-phenylethylamino)-2-(2-hydroxy-4,6-dimethoxyphenyl)acetateC20H25NO5Ee = 98%[α]D20=+70.6 (c 2.1, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (S,R)

(S)-Ethyl 2-((R)-1-phenylethylamino)-2-(1,3-dihydro-5-hydroxyisobenzofuran-6-yl)acetateC20H23NO4Ee = 98%[α]D20=+133.3 (c 2.7, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (S,R)

(R)-Ethyl 2-((R)-1-phenylethylamino)-2-(1,3-dihydro-5-hydroxyisobenzofuran-6-yl)acetateC20H23NO4Ee = 98%[α]D20=+14.4 (c 1.9, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (R,R)

(S)-Ethyl 2-((R)-1-phenylethylamino)-2-(4-amino-2-hydroxyphenyl)acetateC18H22N2O3Ee = 98%[α]D20=+132.7 (c 3.0, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (S,R)