Preparation, structure, and reactivity of thioxo and imino derivatives of the triolide (and pentolide) from (R)-3-hydroxybutanoic acid

Article abstract of DOI:10.1002/hlca.19960790202

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. 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. 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). 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). Imines containing PPh₂ groups are prepared (30, 33, 35) from the thiotriolides and tested as chiral ligands for Pd(II)-catalyzed 1,3-diphenylallylations (→ 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.