CYCLIC OLIGOMERS OF (R)-3-HYDROXYBUTANOIC ACID - PREPARATION AND STRUCTURAL ASPECTS

The oligolides containing three to ten (R)-3-hydroxybutanoate (3-HB) u nits (12-through 40-membered rings 1-8) are prepared from the hydroxy acid itself, its methyl ester, its lactone ('monolide'), or its polyme r (poly(3-HB), mol. wt. ca. 10(6) Dalton) under three sets of conditio ns: i) treatment of 3-HB (10) with 2,6-dichlorobenzoyl chloride/pyridi ne and macrolactonization under high dilution in toluene with 4-(dimet hylamino)pyridine (Fig. 3); ii) heating a solution (benzene, xylene) o f the beta-lactone 12 or of the methyl ester 13 from 3-HB with the tet raoxadistanna compound 11 as trans-esterification catalyst (Fig. 4); i ii) heating a mixture of poly(3-HB) and toluene-sulfonic acid in tolue ne/ 1,2-dichloroethane for prolonged periods of time at ca. 100-degree s (Fig. 6). In all three cases, mixtures of oligolides are formed with the triolide 1 being the prevailing component (up to 50% yield) at hi gher temperatures and with longer reaction times (thermodynamic contro l, Figs. 3-6). Starting from rac-beta-lac-tone rac-12, a separable 3:1 to 3:2 mixture of the lu- and the l,l-triolide diastereoisomers rac-1 4 and rac-1, respectively, is obtained. An alternative method for the synthesis of the octolide 6 is also described: starting from the appro priate esters 15 and 17 and the benzyl ether 16 of 3-HB, linear dimer, tetramer, and octamer derivatives 18-23 are prepared, and the octamer 23 with free OH and CO2H group is cyclized (-->6) under typical macro lactonization conditions (see Scheme). This 'exponential fragment coup ling protocol' can be used to make higher linear oligomers as well. Th e oligolides 1-8 are isolated in pure form by vacuum distillation, chr omatography, and crystallization, an important analytical tool for det ermining the composition of mixtures being C-13-NMR spectroscopy (each oligolide has a unique and characteristic chemical shift of the carbo nyl C-atom, with the triolide 1 at lowest, the decolide 8 at highest f ield). The previously published X-ray crystal structures of triolide 1 , pentolide 3, and hexolide 4 (two forms), as well as those of the l,u -triolide rac-14, of tetrolide ent-2, of heptolide 5, and of two modi fications of octolide 6 described herein for the first time are compar ed with each other (Figs. 7-10 and 12-15, Tables 2 and 5-7) and with r ecently modelled structures (Tables 3 and 4, Fig. 11). The preferred d ihedral angles tau1 to tau4 found along the backbone of the nine oligo lide structures (the hexamer and the larger ones all have folded rings !) are mapped and statistically evaluated (Fig. 16, Tables 5-7). Due t o the occurrence of two conformational minima of the dihedral angle O- CO-CH2-CH (tau3 = +151 or -43-degrees), it is possible to locate two t ypes of building blocks for helices in the structures at hand: a right -handed 3(1) and a left-handed 2(1) helix; both have a ca. 6 angstrom pitch, but very different shapes and dispositions of the carbonyl grou ps (Fig. 17). The 2(1) helix thus constructed from the oligolide singl e-crystal data is essentially superimposable with the helix derived fo r the crystalline domains of poly(3-HB) from stretched-fiber X-ray dif fraction studies. The absence of the unfavorable (E)-type arrangements around the OC-OR bond ('cis-ester') from all the structures of (3-HB) oligomers known so far suggests that the model proposed for a poly(3- HB)-containing ion channel (Fig. 2) must be modified.