Asymmetric synthesis of O-alkylated tetronic acid derivatives via an organocatalytic Mannich reaction and subsequent intramolecular cyclization

The organocatalytic asymmetric Mannich reaction of ethyl 4-chloro-3-oxobutanoate with N-Boc-imines has been studied and Cinchona alkaloids and chiral thiourea-tertiary amines were evaluated as catalysts. A pyrrolidine-based thiourea-tertiary amine was identified as the best catalyst for the transformation. The Mannich adducts readily underwent a one-pot intramolecular cyclization in the presence of triethylamine. A number of O-ethyl tetronic acid derivatives were obtained in good yields and enantioselectivities (up to 91% ee). The products could be further converted to the heteroatomic mimics of prostaglandins via reaction with primary amines.

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(S)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl) (phenyl) methylcarbamateC18H23NO584% ee[α]D20=+17.4 (c 0.50, CH2Cl2)Source of chirality: Asymmetric synthesis

(R)-tert-Butyl (2-chlorophenyl) (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl) methylcarbamateC18H22ClNO591% ee[α]D20=-13.3 (c 0.48, CH2Cl2)Source of chirality: Asymmetric synthesis

(S)-tert-Butyl (3-chlorophenyl) (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl) methylcarbamateC18H22ClNO589% ee[α]D20=+23.6 (c 0.14, CH2Cl2)Source of chirality: Asymmetric synthesis

(S)-tert-Butyl (4-chlorophenyl) (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl) methylcarbamateC18H22ClNO582% ee[α]D20=+29.0 (c 0.10, CH2Cl2)Source of chirality: Asymmetric synthesis

(S)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl) (4-fluorophenyl) methylcarbamateC18H22FNO581% ee[α]D20=+58.0 (c 0.10, CH2Cl2)Source of chirality: Asymmetric synthesis

(S)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl) (2-methoxyphenyl) methylcarbamateC19H25NO683% ee[α]D20=+27.5 (c 0.04, CH2Cl2)Source of chirality: Asymmetric synthesis

(S)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl) (4-methoxyphenyl) methylcarbamateC19H25NO663% ee[α]D20=+34.9 (c 0.32, CH2Cl2)Source of chirality: Asymmetric synthesis

(S)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl) (4-(trifluoromethyl) phenyl) methylcarbamateC19H22F3NO576% ee[α]D20=+3.8 (c 0.34, CH2Cl2)Source of chirality: Asymmetric synthesis

(R)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl) (thiophen-2-yl) methylcarbamateC16H21NO5S86% ee[α]D20=+19.2 (c 0.18, CH2Cl2)Source of chirality: Asymmetric synthesis

(R)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl) (furan-2-yl) methylcarbamateC16H21NO660% ee[α]D20=+15.0 (c 0.22, CH2Cl2)Source of chirality: Asymmetric synthesis

(S)-tert-Butyl (2-(butylamino)-4-oxo-4,5-dihydrofuran-3-yl) (phenyl)methylcarbamateC20H28N2O487% ee[α]D20=+24.1 (c 0.60, CH2Cl2)Source of chirality: Asymmetric synthesis