Asymmetric and diastereoselective Mannich reactions using hydantoin as a chiral auxiliary

The Mannich reaction of titanium enolates of a chiral hydantoin with various aldimines smoothly occurred in good yields and with high anti-diastereoselectivity. The Mannich adducts can be readily cleaved by alcoholysis to afford several β-amino ester derivatives in good yields and in almost enantiomerically pure form.

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(S)-5-Isopropyl-3-phenyl-1-propionylhydantoinC15H18N2O3[α]D20=+10.4 (c 6.33, CH2Cl2)Absolute configuration: (S)Source of chirality: (S)-5-Isopropyl-3-phenylhydantoin

(5S,2′R,3′S)-5-Isopropyl-3-phenyl-1-[2′-methyl-3′-(p-methoxyphenylamino)-3′-phenyl-propionyl]hydantoinC29H31N3O4[α]D20=-21.3 (c 1.04, CH2Cl2)Absolute configuration: (5S,2′R,3′S)Source of chirality: hydantoin induced Mannich reaction

(5S,2′R,3′S)-5-Isopropyl-3-phenyl-1-[2′-methyl-3′-(p-methoxyphenylamino)-3′-(p-chloro-phenyl)-propionyl]hydantoinC29H30ClN3O4[α]D20=-24.2 (c 1.11, CH2Cl2)Absolute configuration: (5S,2′R,3′S)Source of chirality: hydantoin induced Mannich reaction

(5S,2′R,3′S)-5-Isopropyl-3-phenyl-1-[2′-methyl-3′-(p-methoxyphenylamino)-3′-(m-nitro-phenyl)-propionyl]hydantoinC29H30N4O6[α]D20=-23.5 (c 0.92, CH2Cl2)Absolute configuration: (5S,2′R,3′S)Source of chirality: hydantoin induced Mannich reaction

(5S,2′R,3′S)-5-Isopropyl-3-phenyl-1-[2′-methyl-3′-(p-methoxyphenylamino)-3′-(2″,3″-dimethoxyphenyl)-propionyl]hydantoinC31H35N3O6[α]D20=-30.6 (c 1.85, CH2Cl2)Absolute configuration: (5S,2′R,3′S)Source of chirality: hydantoin induced Mannich reaction

(5S,2′R,3′S)-5-Isopropyl-3-phenyl-1-[2′-methyl-3′-(p-methoxyphenylamino)-3′-(2″-furyl)-propionyl]hydantoinC27H29N3O5[α]D20=-28.4 (c 0.83, CH2Cl2)Absolute configuration: (5S,2′R,3′S)Source of chirality: hydantoin induced Mannich reaction

(5S,2′R,3′S)-5-Isopropyl-3-phenyl-1-[2′-methyl-3′-(p-methoxyphenylamino)-3′-(2″-thienyl)-propionyl]hydantoinC27H29N3O4S[α]D20=-25.9 (c 1.45, CH2Cl2)Absolute configuration: (5S,2′R,3′S)Source of chirality: hydantoin induced Mannich reaction

(2R,3S)-Methyl 2-methyl-3-(p-methoxyphenylamino)-3-phenylpropanoateC18H21NO3[α]D20=-50.8 (c 1.02, CH2Cl2)Absolute configuration: (2R,3S)Source of chirality: hydantoin induced Mannich reaction

(2R,3S)-Methyl 2-methyl-3-(p-methoxyphenylamino)-3-(p–chloro-phenyl)propanoateC18H20ClNO3[α]D20=-43.1 (c 0.57, CH2Cl2)Absolute configuration: (2R,3S)Source of chirality: hydantoin induced Mannich reaction

(2R,3S)-Methyl 2-methyl-3-(p-methoxyphenylamino)-3-(m-nitro-phenyl)propanoateC18H20N2O5[α]D20=-48.2 (c 1.16, CH2Cl2);Absolute configuration: (2R,3S)Source of chirality: hydantoin induced Mannich reaction

(2R,3S)-Methyl 2-methyl-3-(p-methoxyphenylamino)-3-(2′,3′-dimethoxyphenyl)propanoateC20H25NO5[α]D20=-53.7 (c 2.20, CH2Cl2)Absolute configuration: (2R,3S)Source of chirality: hydantoin induced Mannich reaction

(2R,3S)-Methyl 2-methyl-3-(p-methoxyphenylamino)-3-(2′-furyl)-propanoateC16H19NO4[α]D20=-47.6 (c 1.05, CH2Cl2)Absolute configuration: (2R,3S)Source of chirality: hydantoin induced Mannich reaction

(2R,3S)-Methyl 2-methyl-3-(p-methoxyphenylamino)-3-(2′-thienyl)-propanoateC16H19NO3S[α]D20=-45.8 (c 1.10, CH2Cl2)Absolute configuration: (2R,3S)Source of chirality: hydantoin induced Mannich reaction

(3R,4S)-1-(4-Methoxyphenyl)-3-methyl-4-phenylazetidin-2-oneC17H17NO2[α]D20=-46.1 (c 0.89, CHCl3)Absolute configuration: (3R,4S)Source of chirality: hydantoin induced Mannich reaction