Synthesis of monodisperse linear and cyclic oligo[(R)-3-hydroxybutanoates] containing up to 128 monomeric units

Using benzyl ester/(tert-butyl)diphenylsilyl ether protection, (COCl)(2)/pyridine esterification conditions, and a fragment-coupling strategy (with H-2/Pd-C debenzylation and HF pyridine desilylation), linear oligomers of (R)-3-hydroxybutanoic acid (3-HB) containing up to 125 3-HB building blocks (mel. weight > 11000 Da) are assembled (Schemes 1, 2, 5, and 6). In contrast io the previously employed protecting-group combination, and due to the low-temperature esterifying conditions, this procedure leads to monodisperse oligomers: all steps occur without loss of single 3-HB units. The product oligomers with two, one, and no terminal protecting groups (mostly prepared in multi-gram amounts) are characterized by all standard spectroscopic methods, especially by mass spectroscopy (Figs. 2 and 3), by their optical activity, and by elemental analyses, Cyclization of the oligo[(R)-3-hydroxybutanoic acids] with up to 32 3-HB units, using thiopyridine activation and CuBr2 for the ring closure, produces oligolides consisting of Lip to 125 ring atoms (Scheme 7). Mixed oligolides containing 3-HB and (R)-3-hydroxypentanoic units are prepared from the corresponding linear trimers, using Yamaguchi's method for the ring closure (Scheme 8 and Fig. 4 (X-ray crystal structures of two folded conformers)). Comparisons of melting points (Table 1), of [alpha](20)(365) values (Tables 2 and 3), of H-1-NMR coupling constants (Table 3), and of molecular volume/hydroxyalkanoate unit (Table 4) of linear and cyclic oligomer derivatives and of the high-molecular-weight polymer show that the monodisperse oligomers appear to be surprisingly good models for the polymer. Besides this insight, our synthesis is supplying the samples to further test the role of P(3-HB) (ca. 140 units) as a component of complexes forming channels through cell-wall phospholipid bilayers.