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 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 (NaBH 4 , 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 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 CO, CS, and CNR O‐, S‐, and N‐atoms in juxtaposition (a feature reminiscent of the side chains in the iron‐binder enterobactin, Fig. 6 ). Imines containing PPh 2 groups are prepared ( 30, 33, 35 ) from the thiotriolides and tested as chiral ligands for Pd II ‐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 NH 2 groups.