Exploring the Chemistry of Bicyclic Isoxazolidines for the Multicomponent Synthesis of Glycomimetic Building Blocks

Abstract

Starting from a chiral furanone, the nitrone-olefin [3 + 2] cycloaddition can be used to obtain bicyclic isoxazolidines for which we report a set of reactions to selectively modify each functional position. These synthetically versatile bicyclic isoxazolidines allowed us to obtain complex glycomimetic building blocks, like iminosugars, via multicomponent chemistry. For example, a library of 20 pipecolic acid derivatives, a recurring motif in various prescription drugs, could be obtained via a one-pot Staudinger/aza-Wittig/Ugi three-component reaction of a bicyclic isoxazolidine-derived azido-hemiacetal. Notably, specific pipecolic acids in this library were obtained via hydrolysis of an unique tricyclic imidate side product of the Ugi reaction. The azido-hemiacetal was also converted into an aza-C-glycoside iminosugar via an unprecendented one-pot Staudinger/aza-Wittig/Mannich reaction.

Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

“…The glycosidase inhibitory and chaperoning abilities of sp 2 -iminosugars have been found to be strongly dependent on the mono- [ 32 , 33 , 34 , 35 , 36 ] or bicyclic structure of the sugar glycone-like skeleton [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], the configurational pattern [ 45 , 46 , 47 , 48 ], and the nature of nonglycone-type substituents [ 49 , 50 , 51 ]. Differently from classical iminosugars, for which the lability of aminal functionalities prevents the installation of anomeric substituents (except in the case of pseudo- C -glycosides) [ 52 , 53 , 54 , 55 ], sp 2 -iminosugars can bear O -, S -, N -, or C -anomeric aglycone groups while keeping full chemical and configurational stability [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ], even when multivalently presented [ 66 , 67 , 68 , 69 ]. The possibility of accessing reducing analogues with a precise α-like axial orientation of the anomeric hydroxyl is quite unique [ 70 , 71 , 72 ].…”

Sequential Multicomponent Strategy for the Diastereoselective Synthesis of Densely Functionalized Spirooxindole-Fused Thiazolidines

“…Switching to more acidic trifluoroethanol (TFE) increased the reaction rate and yield (entry 4). It also favored a more diastereoselective process, leading to trans-isomer 4 { 1 , 1 , 1 } as the major product (dr 75:25). The dr was further improved by increasing the concentration (0.5 M, entry 5), while either lowering the concentration (entry 6) or running the reaction at 0 °C (entry 7) reduced the conversion without improving the dr.…”

(S)-γ-Hydroxymethyl-α,β-butenolide, a Valuable Chiral Synthon: Syntheses, Reactivity, and Applications

“…More recently, Hoogenboom et al synthesized a library of glycomimetic compounds to offer a wide range of structures for comprehensive studies of the interactions between enzymes (e.g., intestinal glucosidases or glycosyl transferases) and these substrates. 94 They added nitrones on HBO as the first step. Subsequently, the hydroxyl group was substituted with an azide 48 with the goal to inhibit 5-lipoxygenase, an enzyme at the origin of a cascade reaction involved in inflammatory and allergic diseases.…”

“…Unfortunately, they did not highlight any inhibition activity. More recently, Hoogenboom et al synthesized a library of glycomimetic compounds to offer a wide range of structures for comprehensive studies of the interactions between enzymes (e.g., intestinal glucosidases or glycosyl transferases) and these substrates . They added nitrones on HBO as the first step.…”