No abstract

Sphingosine kinases (SphKs) are oncogenic enzymes that regulate the critical balance between ceramide and sphingosine-1-phosphate. Much effort has been dedicated to develop inhibitors against these enzymes. Naturally occurring pachastrissamine (jaspine B) and all its stereoisomers were prepared and evaluated for their inhibitory effects against SphKs. All eight stereoisomers exhibited moderate to potent inhibitory activity against SphK1 and SphK2. Inhibitory effects were profiled against protein kinase C (PKC) isoforms by in vitro experiments. Atypical PKCs (PKCζ and PKCι) were inhibited by several pachastrissamine stereoisomers. The improved activity over N,N-dimethylsphingosine suggests that the cyclic scaffold in pachastrissamines facilitates potential favorable interactions with SphKs and PKCs.

A divergent short synthesis of four diastereomers of pachastrissamine was achieved. Natural pachastrissamine was synthesized through bis-tosylation of the common intermediate and cyclization. 2-epi-Pachastrissamine was obtained by monotosylation and spontaneous cyclization of D-ribo-phytosphingosine derivative. By use of regio- and stereospecific ring-opening reaction of the orthoester assisted by a Boc group as a key step, 3-epi- and 2,3-epi-pachastrissamines were synthesized. The three stereogenic centers of all the diastereomers were constructed by using Garner's aldehyde as the sole chiral source.

Palladium(0)-catalyzed cyclization of bromoallenes, propargyl chlorides, and carbonates bearing hydroxy and benzamide groups as internal nucleophiles stereoselectively provides functionalized tetrahydrofuran. Cyclization reactivity is dependent on the relative configuration of the benzamide and leaving groups, and on the nature of the leaving groups. This bis-cyclization was used as the key step in a short total synthesis of pachastrissamine, which is a biologically active marine natural product.

Palladium(0)-catalyzed cyclization of bromoallenes bearing hydroxyl and benzamide groups as internal nucleophiles stereoselectively provides functionalized tetrahydrofuran. With this bis-cyclization as the key step, a short total synthesis of pachastrissamine, a biologically active marine natural product, was achieved.