Synthesis of diaminomethylidene derivatives of tetronic acid

Methyl 4-chloro-3-oxobutanoate reacts with benzoylcyanamide in the presence of catalytic amounts of Ni(acac)₂ to give the corresponding ketene N-benzoylaminal, which is transformed in boiling AcOH into 3-[(amino)(benzoylamino)methylidene]tetrahydrofuran-2,4-dione. Debenzoylation of the latter in the presence of EtONa in EtOH yields a N,N-unsubstituted diaminomethylidene derivative of tetronic acid. Cyclization of the adduct of methyl 4-chloro-3-oxobutanoate with benzoylcyanamide in the presence of triethylamine follows a different pathway leading to methyl 2-amino-1-benzoyl-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylate.     

Flexible synthesis of vulpinic acids from tetronic acid

Several vulpinic acids were synthesized in a few steps from a single precursor, the tetronic acid. This commercial compound was converted in a few steps to an iodide. Suzuki-Miyaura cross-couplings involving this common intermediate and various arylboronates allowed to gain access to several vulpinic acids (or methyl pulvinates). Among them, two natural products, vulpinic acid and pinastric acid, were prepared.     

Synthesis of novel furoquinolines and furobenzodiazepines from tetronic acid

Condensation of tetronic acid with 2-cyano-, 2-ethoxycarbonyl-, 2-carboxy-, and 2-aminoanilines gave novel furoquinolines and furobenzodiazepines. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2220–2226, November, 2007.     

Synthesis of vulpinic and pulvinic acids from tetronic acid

A common precursor, tetronic acid, was used in the synthesis of several vulpinic acids and pulvinic acids, which are pigments found in several lichens and mushrooms. The key features of this method are a two-step alkylidenation of benzyl tetronate and a Suzuki-Miyaura cross-coupling. The synthesis of several natural products, vulpinic acid, pinastric acid, xerocomic acid is described.     

The constitution of vertinolide,a new derivative of tetronic acid,produced by Verticillium intertextum

From the culture of Verticillium intertextrum a new tetronic acid derivative, vertinolide, has been isolated as the main constituent of the chloroform extract. Structure 1a was established for vertinolide by X-ray diffraction analysis. Vertinolide (1a) was also transformed to an O-methyl-(1b), an O-acetyl-(1c), a tetrahydro- (1d) and a tetrahydro-O-methyl-derivative (4). The spectroscopic properties of 1a, of its derivatives 1a, 1c, 1d and 4 as well as of three model compounds are compared and discussed.     

Unexpected Knoevenagel self-condensation reaction of tetronic acid: synthesis of a new class of organic heterocyclic salts

A new class of pyridinium, quinolinium, isoquinolinum, and N-methylimidazolium-3-(2,5-dihydro-5-oxofuran-3-yl)-4-hydroxyfuran-2(5H)-one salts have been prepared in high yields by reacting pyridine, quinoline, isoquinoline, N-methylimidazole, 1,4-diazabicyclo[2.2.2]octane, and their derivatives with tetronic acid in CH₂Cl₂.     

An unusual rearrangement during pyridine synthesis. Anomalous condensation of a β-keto enamine with a tetronic acid.

The condensation of β-keto enamine 1 with 5-methyltetronic acid takes an anomalous course. Single crystal X-ray analysis and chemical evidence establish the rearranged pyridine structure 15 for this condensation product.     

Advancements in tetronic acid chemistry. Part 1: Synthesis and reactions

The preparation and the properties of the elusive tetronic acid are reviewed, including its synthesis, chemical reactivity and reactions.     

Tautomerism in acyl tetronic acids

The tautomeric structures of some acetyl tetronic acids are studied by NMR analysis.     

Palladium catalyzed allylic C-alkylation of highly acidic and enolic heterocyclic substrates: tetronic acid and triacetic acid lactone

Tetronic acid (pK_a 3.76) and triacetic acid lactone (pK_a 4.94) have been alkylated at their active carbon atoms by means of thermodinamically controlled palladium catalyzed allylic alkylations.     

Conformationally constrained beta-amino acid derivatives by intramolecular [2 + 2]-photocycloaddition of a tetronic acid amide and subsequent lactone ring opening

[reaction: see text] The N-Boc-protected N-3-alkenyltetronic acid amides 9 and 12 were prepared from tetronic acid bromide (7) and the corresponding amines 6 and 10 by nucleophilic substitution and subsequent acylation in 71% and 39% overall yield. They underwent an intramolecular [2 + 2]-photocycloaddition upon direct irradiation (lambda = 254 nm) to yield diastereoselectively the strained lactones 15 (76%) and 16 (91%) with a 2-azabicyclo[3.2.0]heptane core. In attempts to defunctionalize the 1-hydroxymethyl substituent of the 2-azabicyclo[3.2.0]heptane skeleton, lactone 15 was converted into mesylate 18 (74% overall yield). Intermolecular substitution reactions on this mesylate, however, proceeded sluggishly or failed completely. Lactone 15 could be opened reductively (Dibal-H) or by substitution with benzylamine to the N-Boc-protected 2-azabicyclo[3.2.0]heptanes 21 (71%) and 22 (81%). Conformationally constrained beta-amino acid derivatives were obtained by quantitative N-Boc deprotection of photocycloaddition product 15, followed by N-functionalization and subsequent lactone ring opening. The N-functionalization was conducted by acylation (to 24-26), alkylation (to 27), tosylation (to 28), and isocyanate addition (to 30). The reactions proceeded in yields of 70-84%. Lactone ring opening reactions were conducted with amines to establish the suitability of this process for library synthesis. As an example, the tripeptide 38 was obtained from photocycloaddition product 15 in an overall yield of 51%.     

Stereoselective synthesis of biologically active tetronic acids

(4R)-3-Amino-4-trimethylsilyloxy-2-alkenoates (R)-3, obtained from O-trimethylsilyl protected optically active cyanohydrins (R)-1 via the Blaise reaction, are hydrolyzed under mildly acidic conditions to give optically active tetronic acids (R)-4 without racemization. From the follow-up reactions of (R)-4 investigated, only methylation with diazomethane afforded the biologically active tetronic acid derivative (R)-5a without racemization whereas acylation and reductive alkylation, respectively, resulted in partial racemization or failed on the whole.     

Synthesis of tetronic acid enamine. Dienamine derivatives from 3-(2H)furanones

The synthesis of 5-aryl (or alkyl) aminomethylene-3-(1-amino or 1-alkylaminoethylidene)-2,4-dioxo-(3H,5H)furans and 5-arylaminomethylene-3-(1-hydroxyethylidene)-2,4-dioxo-(3H,5H)furans (new 3-acetyltetronic acid derivatives) are described. The stereochemistry of these compounds from the ¹H nmr data is discussed.     

Asymmetric synthesis of O-alkylated tetronic acid derivatives via an organocatalytic Mannich reaction and subsequent intramolecular cyclization

The organocatalytic asymmetric Mannich reaction of ethyl 4-chloro-3-oxobutanoate with N-Boc-imines has been studied and Cinchona alkaloids and chiral thiourea-tertiary amines were evaluated as catalysts. A pyrrolidine-based thiourea-tertiary amine was identified as the best catalyst for the transformation. The Mannich adducts readily underwent a one-pot intramolecular cyclization in the presence of triethylamine. A number of O-ethyl tetronic acid derivatives were obtained in good yields and enantioselectivities (up to 91% ee). The products could be further converted to the heteroatomic mimics of prostaglandins via reaction with primary amines.     

Calorimetric approach to tetronic/water interactions

Tetronic^®comprises X-shaped copolymers formed by four poly(propylene oxide) (PPO) andpoly(ethylene oxide) (PEO) block chains bonded to an ethylene diamine centralgroup. Micellization behaviour of three representative Tetronics (T304, T904and T1307) was characterized to gain an insight into the interactions betweenthe copolymer unimers and the state of water in their solutions. The enthalpyof demicellization, recorded at 37°C in an isoperibol microcalorimeter,indicated that the process was in all cases exothermic and the enthalpy rankedin the order T1307≥T904>>T304. Micellization is entropy-driven owing tohydrophobic interactions between the PPO chains.DSC analysisshowed that the crystallization and melting peaks of the free water remainingin T304 and T904 solutions were progressively shifted toward lower temperaturesas the surfactant proportion increased, owing to a colligative effect. Boundwater corresponded to 3 water molecules per EO repeating unit. In the caseof T1307, which has longer PEO chains, a splitting of the melting peak wasobserved, one peak appearing around 0°C due to free water and anotherat –15°C due to interfacial water. As T1307 proportion raised, theenthalpy of the former decreased, whilst the enthalpy of the latter increased.In 40% T1307 solutions, interfacial water overcame the proportion of freewater; there being 1 interfacial and 3 bound water molecules per EO repeatingunit. Gaussian deconvolution of FTIR spectra also enabled to characterizethe evolution of free water as a function of Tetronic proportion. The dependenceof micellization and water interaction behaviour on Tetronics structure shouldbe taken into account to use these copolymers as drug solubilizers and micellarcarriers.     

Investigation in tetronic acid ketoxime derivatives. Structure and beckmann rearrangement. Synthesis of 3-acetamidotetronic acids

The structure and tautomeric equilibria of 3-(1-hydroxyiminoethylidene)tetronic acids have been investigated by ¹H and ¹³C nmr spectroscopy. These oximes are convertible into 3-acetamidotetronic acids.     

Lipase-catalyzed kinetic resolution of tetronic acid derivatives bearing a chiral quaternary carbon: total synthesis of (S)-(−)-vertinolide

We have developed a chemoenzymatic synthesis of (S)-vertinolide 1 with a chiral quaternary carbon atom at C5. In the kinetic resolution of tetronic acid precursor 6, lipase PS-D furnished the recovered alcohol 6 with an (R)-stereochemistry in a ratio of 95% ee, whereas lipase AY gave (S)-alcohol 6 with 93% ee. Chemical transformations of (S)-alcohol 6 provided (S)-vertinolide 1 in 33% yield in five steps with no loss of enantiomeric excess.