Synthesis of enantiopure morpholines through the post-Ugi transformations

by Niyaz

ABSTRACT

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The multicomponent reactions (MCRs) are powerful tools for the construction of complex molecules from simple starting materials. Among them, Ugi reaction can be considered as one of the most prominent for diversity-oriented synthesis. The wide range of biologically relevant compounds was synthesized by utilizing the Ugi and post-Ugi transformations, however, the poor stereoselectivity during the Ugi reaction restricts its application. Only recently an efficient enantioselective Ugi reaction was developed using the chiral phosphoric acid as a catalyst. We thought out of alternative approach to resolve this problem by using enantiopure compounds as starting materials to provide stereocontrol in the post-transformation steps. 

Mandelic acid, which is readily available in both R and S forms, can be used for the synthesis of enantiopure morpholinones. In the proposed reaction, 2-oxo aldehyde combines with (R)-mandelic acid, primary amine, and isocyanide to form Ugi adduct, that undergoes one-pot cyclization under acidic conditions. The corresponding product 2,6- substituted- 2H-1,4-oxazin-3(4H)-one, can serve as a building block to provide enantiomerically pure morpholinones. The retention of the chiral center allows further transformations with a high degree of steric control. The amide group and double bond can be selectively reduced providing a wide range of compounds possessing morpholine core. Additionally, the substitution pattern of the resulting morpholine is similar to natural products chelonin C and chelonin A, opening a possibility for their stereoselective total synthesis.