PREPARATION, STRUCTURE, AND REACTIVITY OF THIOXO AND IMINO DERIVATIVES OF THE TRIOLIDE (AND PENTOLIDE) FROM (R)-3-HYDROXYBUTANOIC ACID

Reaction of the triolide 1 from (R)-3-hydroxybutanoic acid with Lawess on's reagent 5 leads to the mono-, di-, and trithio derivatives 6-8 wh ich can be isolated in pure form (20-40% yields), and which have cryst al structures very similar to the parent triolide 1 (Fig. I). Similarl y, pentolide 3 is converted to mixtures of various thio derivatives, t hree of which are separated (10-12) by HPLC and fully characterized. T he X-ray structures of the mono- and of one of the dithiopentolides (1 0, 12) differ remarkably from each other (Fig.3). Reduction of the thi otriolides 6-8 (NaBH4, R(3)SnH, CL(3)SiH, Raney-Ni) gives 12-membered rings containing up to three ether groups (chiral crown ethers, 15, 17 -19) in poor yields. The thiotriolides react spontaneously and in yiel ds of up to 96% with ammonia, certain primary amines, and hydroxylamin e to give imine and oxime derivatives with intact 12-membered-ring bac kbones (20, 22-24, 30, see crystal structures in Figs. 4-7). The rigid structure of all the derivatives of triolide 1 puts the C=O, C=S, and C=NR O-, S-, and N-atoms in juxtaposition (a feature reminiscent of t he side chains in the iron-binder enterobactin, Fig. 6). Imines contai ning PPh(2) groups are prepared (30, 33, 35) from the thiotriolides an d tested as chiral ligands for Pd-II-catalyzed 1,3-diphenylallylations (-->37, enantiomer ratio up to 77:23). The reactions described demons trate that multiple reactions of the triolide 1 from (R)-3-hydroxybuta noic acid which proceed through tetrahedral intermediates are possible without ring opening - the skeleton is remarkably stable, and this mi ght be exploited as a template for bringing up to three pendent substi tuents into close proximity to allow a study of their interactions and cooperative properties. Also, the di- and trithio derivatives 7 and 8 could be used for cross-linking in molecules containing primary NH2 g roups.