Stereoselective Synthesis of Enantiopure Cycloalkylglycines by 1,3‐Dipolar Cycloaddition of a Chiral Nitrone to Cycloalkenes

Abstract

The design of cyclic analogues of 4‐hydroxyisoleucine, a natural remedy used by type‐2 diabetic patients, can provide putative hypoglycemic drugs. To this end, the 1,3‐dipolar cycloaddition of a (–)‐menthone‐derived nitrone to cycloalkenes afforded isoxazolidines in high yields and with high stereoselectivity. The cycloadducts led to α‐amino lactones after a one‐pot cleavage of the N–O, amide, and N–C–N bonds. Subsequent base‐catalyzed hydrolysis provided enantiopure cycloalkylglycine derivatives in good overall yields (>40 %) in three simple synthetic steps from the menthone‐based chiral nitrone. The conformational analysis of these analogues by DFT calculations highlight some interesting features of the volume occupied by the cycloalkyl residues in comparison to that occupied by the natural 4‐hydroxyisoleucine.

Crystal structure of 2-isopropyl-5,7′-dimethyl-1′,3′,3a',6′,8a',8b'-hexahydrospiro[cyclohexane-1,6′-furo[3,4-d]imidazo[1,5-b]isoxazol]-8′(7′H)-one

“…1). Each molecule has six stereogenic centres (Abda et al, 2014) although the absolute configuration for the molecule was not determined definitively in this analysis. The isoxazolidine ring (O1/N2/C7-C9) adopts an envelope conformation with atom O1 displaced by 0.617 (1) Å from the mean plane through atoms N2/C7-C9.…”

A Reversible Optical Sensor Film for Mercury Ions Discrimination Based on Isoxazolidine Derivative and Exhibiting pH Sensing

“…Recently, we have described the synthesis of isoxazolidine derivatives which can be used as potential alternatives to modulating T2DM (type 2 diabetes mellitus) [ 28 ]. In addition, isoxazolidine is a precursor of many bioactive molecules such as amino acids [ 29 ], β-lactams [ 30 ], amino lactones [ 31 ], and alkaloids accessible by breaking the N-O bond of the isoxazolidine ring [ 32 ].…”

A stereoselective method for the synthesis of enantiopure 3-substituted 4-hydroxyproline derivatives via 1,3-dipolar cycloadditions

“…Another approach in which the nitrone cycloaddition is followed by a Cu(I)-catalyzed azideealkyne cycloaddition (CuAAC) provides rapid access to enantiopure 1,2,3triazolylisoxazolidine derivatives [8]. A recent strategy towards cycloalkylglycines has been demonstrated [9].…”