Preparation, Structure, and Reactivity of Thioxo and Imino Derivatives of the Triolide (and Pentolide) from (R)‐3‐Hydroxybutanoic Acid

Abstract

AbstractReaction of the triolide 1 from (R)‐3‐hydroxybutanoic acid with Lawesson's reagent 5 leads to the mono‐, di‐, and trithio derivatives 6–8 which can be isolated in pure form (20–40% yields), and which have crystal structures very similar to the parent triolide 1 (Fig. 1). Similarly, pentolide 3 is converted to mixtures of various thio derivatives, three of which are separated (10–12) by HPLC and fully characterized. The X‐ray structures of the mono‐ and of one of the dithiopentolides (10, 12) differ remarkably from each other (Fig. 3). Reduction of the thiotriolides 6–8 (NaBH4, R3SnH, Cl3SiH, 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 yields of up to 96% with ammonia, certain primary amines, and hydroxylamine to give imine and oxime derivatives with intact 12‐membered‐ring backbones (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 the side chains in the iron‐binder enterobactin, Fig. 6). Imines containing PPh2 groups are prepared (30, 33, 35) from the thiotriolides and tested as chiral ligands for PdII‐catalyzed 1,3‐diphenyallylations (→ 37, enantiomer ratio up to 77:23). The reactions described demonstrate that multiple reactions of the triolide 1 from (R)‐3‐hydroxybutanoic acid which proceed through tetrahedral intermediates are possible without ring opening – the skeleton is remarkably stable, and this might be exploited as a template for bringing up to three pendent substituents 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 groups.