Synthesis and Structure of Linear and Cyclic Oligomers of 3-Hydroxybutanoic Acid with Specific Sequences of (R)- and (S)-Configurations

To study the stereoselectivity of enzymatic cleavage of poly(3-hydroxybutyrates) (PHB) in a well-defined system (purified depolymerase and monodisperse substrate of specific relative configuration), linear and cyclic oligomers of HB (OHBs) containing (R)- and (S)-3-hydroxybutanoate residues were synthesized. The starting material (R)-HB was prepared from natural sPHB, and (S)-HB by enantioselective reduction of 3-oxobutanoate with yeast or with H₂/Noyori-Taber catalyst (Scheme 2). The HB building blocks were then protected (O-benzyl/tert-butyl ester; Scheme 3) and coupled to give dimers 3 , 4 , tetramers 5 – 9 , and octamers 10 – 18 ; for analytical comparison, a 3mer, 5mer, 6mer, and 7mer ( 19 – 22 ) were also prepared. Two of the tetramers were subjected to macrolactonization conditions (Yamaguchi) to give the cyclic tetramers 23 and 25 and octamers 24 and 26 . All new compounds were fully characterized (m.p., α]_D, CD, IR, ¹H- and ¹³C-NMR, MS, elemental analysis). Single-crystal X-ray structure analyses were performed with oligolides 24 and 25 (Figs. 2 and 4), and the structures, as well as the crystal packing, were compared with those of analogs containing only (R)-HB units or consisting of 3-amino- instead of 3-hydroxybutanoic-acid moieties.