α-Alkylation versus retro-O-Michael/γ-alkylation of bicyclic N,O-acetals: an entry to α-methylthreonine

The synthesis of a new threonine equivalent based on a bicyclic N,O-acetal substructure incorporating four stereogenic centres is developed from Boc-l-threonine methyl ester in one step. Its use as an excellent chiral building block was demonstrated in a new diastereoselective synthesis of α-methylthreonine by an α-alkylation reaction and in the synthesis of chiral α,β-dehydroamino acid derivatives, using the tandem retro-O-Michael/γ-alkylation reactions as key steps.

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7-Methoxy-2,7,7a-trimethyl-5-oxotetrahydro-2H-oxazolo[4,3-b]oxazole-3-carboxylic acid methyl esterC11H17NO6Ee >93%[α]D25=-122.3 (c 0.95, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S,7R,7aS)

7-Methoxy-2,3,7,7a-tetramethyl-5-oxotetrahydro-2H-oxazolo[4,3-b]oxazole-3-carboxylic acid methyl esterC12H19NO6Ee >93%[α]D25=-118.3 (c 1.08, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S,7R,7aS)

(Z)-Methyl 2-(4′-hydroxy-5′-methoxy-4′,5′-dimethyl-2′-oxooxazolidin-3′-yl)pent-2-enoateC12H19NO6Ee >93%[α]D25=-122.3 (c 1.15, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4′S,5′R)

(Z)-Methyl 2-(4′-hydroxy-5′-methoxy-4′,5′-dimethyl-2′-oxooxazolidin-3′-yl)but-2-enoateC11H17NO6Ee >93%[α]D25=-116.5 (c 1.02, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4′S,5′R)

(Z)-Methyl 2-(4′-hydroxy-5′-methoxy-4′,5′-dimethyl-2′-oxooxazolidin-3′-yl)-4-deuteriumbut-2-enoateC11H16DNO6Ee > 93%[α]D25=-96.8 (c 0.97, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4′S,5′R)