Thermodynamically driven, syn-selective vinylogous aldol reaction of tetronamides

Karak, Milandip; Barbosa, Luiz C. A.; Acosta, Jaime A. M.; Sarotti, Ariel M.; Boukouvalas, John

doi:10.1039/c6ob00895j

Cited by 14 publications

(18 citation statements)

References 81 publications

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“…Detailed discussion and the synthetic procedure to prepare such tetronamide aldolates have already been reported, along with the initial structural characterizations of compounds 1−4, 6, and 8−10 by IR and NMR spectroscopy. 41 The structural formulas of the new compounds 5, 7, and 11d are also supported by the spectroscopic data reported in Figures S17−S22 in the Supporting Information.…”

Section: Methodssupporting

confidence: 63%

“…Crystal and theoretical data for 8 and 9 were briefly presented in our recent paper. 41 Except for compound 3, these theoretical molecular geometries featured the intramolecular N1−H1•••O3 hydrogen bond found experimentally only in compound 7. Indeed, tetronamide 3 is the only one that has the same lowest-energy conformation in solution and the crystal structure.…”

Section: Methodsmentioning

confidence: 69%

“…The configurations of C11 and C12 were established as R for compound 5 on the basis of the reliable Flack parameter of 0.013 (12). However, since the synthetic methodology employed is not enantioselective, 41 we believe that there was chiral resolution upon crystallization and therefore that compound 5 is a conglomerate in the form of a mixture of crystals, of which half have only one enantiomer and the other half are composed solely by the other enantiomer. Occasionally we selected out one crystal of the (11R,12R) enantiomer, but the (11S,12S) enantiomer is expected to be found in the crystal collection with the same molecular geometry and crystal packing despite its opposite chirality.…”

Section: Methodsmentioning

confidence: 99%

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Substituent-Modulated Conformation and Supramolecular Assembly of Tetronamides

Karak

Acosta

Barbosa

et al. 2016

Crystal Growth & Design

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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.

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Section: Methodssupporting

confidence: 63%

Section: Methodsmentioning

confidence: 69%

Section: Methodsmentioning

confidence: 99%

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Substituent-Modulated Conformation and Supramolecular Assembly of Tetronamides

Karak

Acosta

Barbosa

et al. 2016

Crystal Growth & Design

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“…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 .…”

Section: Resultsmentioning

confidence: 99%

“…In particular, Dechoux and co‐workers described a decarboxylative Knoevenagel‐type aldol condensation of N ‐substituted γ‐acyltetronamides with aldehydes to afford ( Z )‐ γ‐alkylidenetetronamides in moderate to good yields (Scheme (A)) . Our group recently reported the vinylogous aldol reaction (VAR) of unactivated tetronamides with aldehydes, giving adducts 9 in high yields and usually excellent syn‐ diastereoselectivity (Scheme (B)) . The ready availability of these adducts prompted us to explore their dehydration for acquiring the desired γ‐alkylidenetetronamides ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

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

Acosta

Karak

Barbosa

et al. 2019

Pest Management Science

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BACKGROUND: The increasing frequency and intensity of cyanobacterial blooms pose a serious threat to aquatic ecosystems. These blooms produce potent toxins that can contaminate drinking water and endanger the life of wild and domestic animals as well as humans. Consequently, the development of effective methods for their control is a matter of high priority. We have previously shown that some -benzylidenebutenolides, related to the rubrolide family of natural products, are capable of inhibiting the photosynthetic electron transport chain (Hill reaction), a target of commercial herbicides. Here we report the synthesis and biological properties of a new class of rubrolide-inspired molecules featuring a tetronamide motif.RESULTS: A total of 47 N-aryl tetronamides, including 38 aldol adducts, were prepared bearing phenyl, biphenyl, naphthyl, aliphatic and heteroaromatic groups. Some of the aldol adducts were dehydrated to the corresponding -benzylidenetetronamides, although satisfactory yields were obtained in only three cases (52-97%). None of the synthesized compounds were capable of blocking the Hill reaction. This notwithstanding, several aldol adducts equipped with a biphenyl substituent displayed excellent inhibitory activity against Synechococcus elongatus and other cyanobacterial strains (IC 50 = 1-5 M). Further, these tetronamides were found to be essentially inactive against eukaryotic microorganisms. CONCLUSION: Several newly synthesized biphenyl-containing tetronamides were shown to display potent and selective inhibitory activity against cyanobacteria. These compounds appear to exert their biological effects without interfering with the Hill reaction. As such, they represent novel leads in the search of environmentally benign agents for controlling cyanobacterial blooms.

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