Stereoselective access to allenic sphingosine analogues as SphK inhibitors.

Identifier:  imarina:9597620

Handle: https://hdl.handle.net/20.500.11797/imarina9597620

Authors:  Miró E; Jaureguizar J; Ivanova V; Beltrán-Debón R; Benet-Buchholz J; Juárez-Jiménez J; Boutureira O; Díaz Y; Matheu MI

Abstract:
Axially chiral allenes are distinctive structural motifs whose potential in sphingolipid-based inhibitor design remains largely unexplored. Herein, we describe a concise and stereodivergent synthetic strategy to access allenic sphingosine analogues, in which an allene unit is incorporated into the sphingoid backbone as a rigid surrogate of the native trans-olefin. The approach relies on a copper-promoted allenation of terminal alkynes (ATA reaction), enabling efficient access to 1,3-disubstituted allenes from propargylic alcohols and aliphatic aldehydes. Fine tuning of the catalytic system with achiral secondary amines afforded high-yielding allenation reactions that produced nearly equimolar mixtures of allenic diastereomers, while the use of either enantiomer of a chiral prolinol-derived secondary amines under double stereodifferentiating conditions enabled stereodivergent access to each allenic diastereisomer with high selectivity. These chiral allene intermediates constitute versatile platforms for late-stage diversification of the polar head group, affording structurally well-defined sphingosine analogues. Preliminary inhibitory studies revealed that the allene scaffold is well tolerated and leads to low micromolar sphingosine kinase inhibitors, with a preference for SphK2.