Application of Stereocontrolled Stepwise [3+2] Cycloadditions to the Preparation of Inhibitors of α₄β₁‐Integrin‐Mediated Hepatic Melanoma Metastasis

Abstract

Inhibitors of the interaction between protein VLA‐4 and its natural ligand VCAM‐1 have been designed, even though the structure of the protein remains unresolved. The rational design relied on the simulation of the steric and electronic properties of the active loop of VCAM‐1, whose structure is known (see picture), and the inhibitors were readily prepared by stereoselective stepwise [3+2] cycloadditions.

Stereoselective Synthesis of Quaternary Proline Analogues

“…[64] Also, the [3+2] cycloaddition between the chiral E-nitroalkene 94 and the imine 93 provided 95 with complete stereocontrol (Scheme 24). [65] This polysubstituted proline belongs to a new family of inhibitors of α4β1-integrin-mediated hepatic melanoma metastasis.…”

Asymmetric 1,3-Dipolar Cycloadditons of Stabilized Azomethine Ylides with Nitroalkenes

“…Such as it was detailed in the previous section, enantiomerically enriched polysubstituted pyrrolydines 1, with a potent antimetastatic activity, were prepared in twelve preparative steps, the formal [3+2] cycloaddition between imines 6 and nitroalkenes7 being the key step (Scheme 2) [4,5]. The reaction of the silver metallodipole -generated from 6, AgOAc (10 mol%) and triethylamine-was completely diastereoselective in most of the examples reported (up to >99:1 dr) including aliphatic aldimines (R 3 = alkyl).…”

“…1), which have a common structural proline derivative core. Molecules 1 are important inhibitors of 4 1 -integrin-mediated hepatic melanoma and in a murine model of colon carcinoma metastasis, as well as potent antiadhesive properties in several cancer cell lines [4,5]. Bicyclic heterocycles 2, containing atropane scaffold have been found as novel inhibitors of hedgehog signaling.…”

Coinage metal complexes as chiral catalysts for 1,3-dipolar cycloadditions

“…Substituted prolinates 45 (Figure 10), obtained from the corresponding 1,3-DC between glycine imino esters and nitroalkenes, are important inhibitors of α 4 β 1 -integrin-mediated hepatic melanoma metastasis [78]. The most simple prolinesexo-46 have been recently used as chiral organocatalysts in aldol reactions [ 79 ].…”