Substituent-Modulated Conformation and Supramolecular Assembly of Tetronamides

Abstract

The crystal structures of nine compounds (1−9) bearing the 4-aminofuran-2(5H)-one scaffold (commonly known as tetronamide, C 4 H 5 NO 2) and two decorating aromatic/ heteroaromatic moieties with two stereocenters have been determined. Tetronamides bearing at the 5-position a phenyl moiety (1 and 2, 3-chloro derivatives with either a 4-p-tolylamino or 4-p-bromophenylamino substituent), an o-bromopyridyl moiety (3, a 3-bromo-4-p-tolylamino derivative), or an o-tolyl moiety (4, a 3-bromo-4-p-tolylamino derivative) adopt a U-shaped conformation. This conformation is stabilized by an intramolecular contact involving either the phenyl o-CH moiety (1 and 2) or the substituent at the ortho position (3 and 4) and the π system of the N-phenyl ring. The other five tetronamides (5−9) are not present with such an intramolecular contact. In fact, these last five compounds are not U-shaped and feature the presence at the 5-position of a p-biphenyl moiety (5 and 7, 3-bromo-4-p-tolylamino diastereomers differing as 5R and 5S), a p-methoxyphenyl moiety (6, a 3-chloro-4-pbromophenylamino derivative), or a 5-chlorofuran-2-yl moiety (8 and 9, 3-chloro-4-p-tolylamino diastereomers differing as 5R and 5S). Crystal structures of a 5,5-disubstituted tetronamide bearing m-nitrophenyl moieties (10) and a parent tetronamide without a substituent at the 5-position (11d) reinforce the conformational trend found in 1−9. Furthermore, OH•••O centrosymmetric dimers are formed only in the crystal structures of the U-shaped tetronamides. Chain motifs assembled through OH•••O and NH•••O hydrogen bonds are preferred in the line-shaped tetronamides. Furthermore, the conformer energies were calculated in both the gas and solution phases (B3LYP/6-31G*). The lowest-energy conformations feature an intramolecular N−H•••O hydrogen bond as in the crystal structure of 7. In the U-shaped tetronamides, the crystal structure conformations are similar to the third or fourth energetically ranked stable calculated conformer. Therefore, it is concluded that the substitution pattern in the U-shaped tetronamides allows for accessible secondary minimum-energy conformations that are easily adopted in the crystal structure as a result of their compatibility with the robust centrosymmetric O−H•••O dimer formation.

Synthesis of new tetronamides displaying inhibitory activity against bloom‐forming cyanobacteria

“…The synthesis of new tetronamides ( 9a‐v ) was carried out as previously reported . Conjugate addition of substituted anilines to commercially available α,β‐dichlorobutenolide ( 11a ) or α,β‐dibromobutenolide ( 11b ), followed by in situ β‐elimination, afforded intermediates 8a‐h and 8j in high yields .…”

“…The resulting aldol adducts 9a ‐ v were obtained in yields of 54–99%. In keeping with previous observations, the syn adduct was the major isomer in most cases . Their structures and yields are shown in Table .…”

Effects of Synthetic Tetronamides and Methylated Denigrins on Bacterial Quorum Sensing and Biofilm Formation

“…All compounds were synthesized using previously reported procedures, as summarized in Figure A,B. − In general, the tetronamides were prepared from commercially available 3,4-dihalofuran-2­(5 H )-ones, which were subjected to an aza -Michael addition/elimination reaction to afford tetronamide intermediates 6 – 9 (Figure A, step 1). These intermediates were treated with several substituted aldehydes via a vinylogous aldol reaction (VAR), followed by tosylate-mediated dehydration (Figure A, steps 2 and 3).…”

“…For details on the experimental synthetic procedures and full spectroscopic data for new compounds, see the Supporting Information material. For details on the preparation and spectroscopic data for known compounds, see references in our previously published works. − …”