Total synthesis of purealin and its analogues synthesis of lagunapyrone B and its isomers with fluorous mixture synthesis

Purealin, a natural product isolated from the sea sponge Psammaplysilla purea is known to inhibit axonemal dynein. A total synthesis of purealin and a small library of purealin analogues are reported herein. These syntheses allowed initial examination of biological properties of purealin and its analogues. The results indicate purealin and some of the analogues inhibited the ATPase activity of isolated cytoplasmic dynein heavy chain. The inhibitory effect of purealin was concentration-dependent. The library of purealidin A showed effective antiproliferative activity against a mouse leukemia cell line, but selective activities against human carcinoma cell lines. These data illustrate small molecule inhibitors of cytoplasmic dynein that could prove to be useful tools for investigation of the cellular function.; Lagunapyrone B, a marine bacteria isolated by Fenical in 1996, possesses an unusual alpha-pyrone functionalized with a highly methyl-branched side chain; a conjugated diene and two skipped dienes. The carbon skeleton of lagunapyrones has not been previously observed. Because of the long distance between the two groups of stereocenters, the absolute configuration of these compounds is difficult to assign using spectroscopic methods. Using fluorous mixture synthesis (FMS), four diastereomers were synthesized in order to determine the absolute configuration of the natural product. Beyond FMS, The approach included Paterson auxiliary anti-aldol, Zirconium-catalyzed and Stille coupling reactions. The longest linear sequence is 23 steps in the synthesis. By comparing the [alpha]D25 data of final four isomers, compound 2.1c was determined to be the natural product, whose configuration is 6R, 7S, 19S, 20S, 21R.