On the Macrolactonization of β‐Hydroxy Acids. Crystal structures of the pentolide and the hexolide from (R)‐3‐hydroxybutanoic acid. Molecular modeling studies of the tetrolide

Abstract

Dedicated to Prof. Dr. Wilhelm Simon on the occasion of his 60th birthday (27.VII.89)The temperature and concentration dependence of the previously reported formation of oligolides from (R)-or (S)-3-hydroxybutanoic acid under Yumuguchi's macrolactonization conditions (2,4,6-trichlorobenzoyl chloride/base) was studied. While the content of hexolide 2 in the product mixture is almost invariably cu. 35%, the amounts of pentolide 1 and of the larger rings strongly depend upon the temperature employed (Fig. 1). Cyclic oligomers (5,6) are also obtained from 3-hydroxypentanoic acid. Enantiomerically pure B-butyrolactone can be used for the preparation of pento-, hexo-, and heptolide under Shunzer's macrolactonization conditions (tetraoxadistannacyclodecane 'template'). The X-ray crystal structures of the pentolide 1 and of two modifications (space groups C 2 and P 2,) of the hexolide 2 were detcrmined (Figs. 2 4 and Tables 1 and 5 ) . No close contacts between substituent atoms and atoms in the rings or between ring atoms are observed in these structures. The hexolide C 2 modification is 'just a large ring', while the crystals of the P 2, modification contain folded rings the backbones of which resemble the seam of a tennis ball. A comparison of the torsion angles in the folded hexolide ring of the P 2, modification with those in the helical poly-(R)-3-hydroxybutdnoate (PHB) suggests (Table 2) that the same interactions might be responsible for folding in the first and helix formation in the second case. Molecular modeling with force-field energy minimization of the tetrolide from four homochiral B-hydroxybutanoic acid units was undertaken, in order to find possible reasons for the fact that we failed to detect the tetrolide in the reaction mixtures. The calculated conformational energies (per monomer) for some of the tetrolide models (Figs. 7-9 and Tables 3 and 4 ) are not significantly higher than for the pentolide and hexolide crystal structures. We conclude that thermodynamic instability is an unlikely reason for the lack of tetrolide isolation. This result and failure to observe equilibration of pentolide 1 to a mixture of oligomers under the reaction conditions suggest that product distribution is governed by kinetic control.

On the influence of unsaturation on the macrolactonization of hydroxy fatty acids

“…The regioselectivity of macrolactonization of 1 and 4 is thermodynamically controlled and that is somewhat in contrast with the fact that Yamaguchi lactonization is considered an irreversible, kinetically controlled reaction 13, 14. This anomalous behavior of 1 and 4 can be very probably attributed to the presence of a vicinal dihydroxyl group.…”

Bioactivity Profiling and Untargeted Metabolomics of Microbiota Associated with Mesopelagic Jellyfish Periphylla Periphylla

“…Based on the molecular formula prediction by MassLynx (<10 ppm), some nodes were annotated to the linear analogues as they showed extra 18 Da indicative of hydroxyl groups. Other PHBs putatively annotated include cyclic and linear members containing 6 (hexolide) [ 48 ], 7 (heptolide) [ 49 ], even 8, 9 and 10 monomer units. Many nodes in this cluster remain unannotated.…”