P-Tetronic acids

The synthesis of medicinally relevant 4-substituted 2(5//)-furanones has been achieved by a coupling reaction of the triflate derived from p-tetronic acid with alkyl-and cyclopropylboronic acids (Scheme 10.8).22 This reaction was mediated by bis(acetonitrile)dichloropalladium and silver oxide. Interestingly, optically active cyclopropyl boronic acids were not racemized during this coupling reaction. 

Basler, B., Schuster, O., and Bach, T. (2005) Conformationally constrained p-amino acid derivatives by intramolecular [2 + 2]-photocycloaddition of a tetronic acid amide and subsequent lactone ring opening. Journal of Organic Chemistry, 70, 9798-9808. 

The enolic thiofuranone derivatives 35 (e.g. R = n-propyl and R = n-decyl) and 36 are also inhibitors of fatty acid synthase and have served as drug leads against Plasmodium falciparum (malaria) and Trypanosoma (sleeping sickness) . Several tetronic acid derivatives exhibit significant inhibition toward bacterial peptidoglycan synthesis (K = 0.19 p.M for the derivative R = 2-naphthalene and (R, R ) = vinyl-1-naphthalene in equation 8 analogous to 39) . ... 

Tetronic acids and P-keto-y-butyrolactones are easily prepared by reaction of an 0-trimethylsilylated cyanohydrin with a-bromo esters in the presence of a Zn- u couple in a Reformatsky-type reaction (Scheme 12). ... 

Keto-y-butyrolactones teironic acids Zinc, activated with Cu(OAc)2, promotes a Reformatsky-type reaction of a-bromo esters with O-silylated cyanohydrins to provide p-keto-y-butyrolactones or tetronic acids. 

A number of substituted benzenesulfonic acid esters and p-chlorophenoxy-isobutyric acid esters produced hypolipidemic activity.35 Among a series of p-alkoxybenzoic acids, enhanced hypotriglyceridemic and hypocholesterol-emic activity was observed with oximino- (14) and chloro- (15) substituents.98 Hypocholesterolemia was observed after the administration of 16 to rats.97 Tetronic 701, a polymeric surfactant, also lowered serum cholesterol the tetrabenzoate of Tetronic 701 is of particular interest, since it produced comparatively less growth depression.98 Two linoleamide derivatives, (-)N-fa-phenyl-B-(p-tolyl)ethylllinoleamide (PTLA) and N-(a-methyl-benzoyl)linoleamide, suppressed serum and liver cholesterol levels in rats and inhibited cholesterol absorption b interfering with the hydrolysis of cholesteryl esters in the intestine.99 101... 

The Claisen ester enolate reaction has proven extremely useful in the synthesis of a large number of natural products [3], In addition, the rearrangement has been extended to allow the preparation of a number of useful intermediates such as, a-alkoxy esters [79,313,315.320-327], a-phenylthio esters [323,328, 329], a- and p-amino acids [324,330-334], a-fluoro esters [335], cycloalkenes [336,337], tetronic acids [338], and dihydropyrans [339-341],... 

Before its true nature as a vitamin deficiency disease was firmly established, a connection was made between the incidence of pehagra and the consumption of mouldy maize. Several Penicillium species were isolated from this source. Examination of one of these, P. charlesii, by Raistrick between 1933 and 1935 led to the isolation of a series of acidic metabohtes that were derivatives of tetronic acids and exemplified by L-y-methyltetronic acid (6.11), carolic acid... 

Not all fungal tetronic acids are derived by this pathway. The biosynthesis of multicolic acid (6.17), a metabolite of P. multicolor, has been shown by carbon-13 labelling experiments to follow entirely a polyketide pathway. The proposed biosynthetic pathway (Scheme 6.2) involves the intermediacy of a 6-pentylresorcylic acid (6.16) and the cleavage of an aromatic ring. 

P. Pollet and S. Gelin, Tetronic acids and derivatives. VII. Structure of dehydro-ascorbic acid osazone and related compounds, Tetrahedron, 36 (1980) 2955-2959. 

Hannick and Kishi cyclized an intermediate bromozinc enamino ester (41 Scheme 21) to obtain the heterocycle (42), used for the synthesis of saxitoxins. The Kishi procedure for the Blaise reaction has been applied to a facile synthesis of p-keto-S-butyrolactones (43), or tetronic acids (44 Scheme 22). 

The new antitumour antibiotic pyrrolosporin A (11) is a macrolide with an unusual spiro-a-acyl tetronic acid moiety. It also contains a 4-amino-2,4,6-trideoxy-P-D-aru6mo-hexopyranose unit, a sugar not previously found in nature (see Vol. 24, p. 148-9 for the synthesis of this sugar in studies of antibiotic analogues), and methanolysis of pyrrolosporin A gave the methyl a-pyranoside, with the pyrrole unit still linked to the sugar. 

N. G. Kozlov, S. L. Bondarev, A. P. Kadutskii, L. I. Basalaeva, F. S. Pashkovskii, Russ. J. Org. Chem. 2008, 44, 1031-1037. Tetronic acid in reaction with aromatic aldehydes and 2-naph-thylamine. Investigation of fluorescent and nonlinear-optical characteristics of compounds obtained. 

Five-membered cyclic p-ketoesters (p-ketolactones 1) and cyclic p-ketothioesters (p-ketothiolactones 2) differ from their acyclic counterparts in at least two regards (1) by being mostly enolized and (2) by being so acidic that they are called tetronic acids (1) and thiotetronic acids (2), respectively (Fig. 1). Even 5-membered cyclic p-ketoamides, i.e., p-ketolactams 3, are sufficiently acidic to be known as tetramic acids. The parent compound 3 (Fig. 1 R t = H), for instance, exhibits a pKa of 6.4." Standard tetramic acids prefer the keto (keto-3) over the enol tautomer enol-3). 

FIG. 1 5-Membered rings composed of P-ketocaiboxylic esters ( tetronic acids, 1), P-ketocarboxylic thioesters ( thiotetronic acids, 2) or P-ketocarboxylic amides ( tetramic acids, 3), and their respective tautomers. 

The fungal metabolites patulin (10) and multicolic acid (79) are derived in nature via oxidative cleavages of polyketide derived aromatic intermediates a similar pathway has been established for the tetronic acid penicillic acid (185). By contrast, the biosynthesis of carolic acid (76a) which is found with dehydrocarolic acid (75) in P. charlesii, has been shown to occur from Krebs cycle intermediates. 

Synthesis of Tetronic Acids. —Lithiation of methyl p-methoxyacrylate and reaction with the dienone (198) leads to the tetronate (199), in one step. Further lithiation of (199), followed by acylation, is then shown to produce the enol ether isomer (200) of natural aspertetronin A (Scheme 108). In similar studies. 

Regio-directed metallations have been used this year to good effect in the synthesis of tetronic acids. Two papers have appeared on the lithiation of the acrylates (8) at the p-position to yield tetronic acids (9 X = H) after reaction with aldehydes, ketones, and esters. " The tetronic acids (9 X = H) can then be lithiated to give (9 X = Li) and further reacted to provide the substituted tetronic acids (9 X = E). " " In this way isomers of the naturally occurring gregatins and aspertetronins have been synthesized. "... 

Lactones General Synthesis Synthesis of P-Lactones Synthesis of Butyrolactones Synthesis of Butenolides Synthesis of Phthalides Synthesis of Tetronic Acids Synthesis of a-Methylenebutyrolactones Synthesis of Valerolactones... 

An elegant, general method for the synthesis of 2-alkyl tetronic acids has been reported. Producing 66—87% overall yields, (he sequence employs the useful one carbon nucleophile tris(thiomethyl)methyl lithium (Scheme 13). Acetylacetone derivatives (73) are smoothly converted into 2-alkoxybutenolides (74) on treatment with toluene-p-sulphonic acid. ... 

Duffy, R.J., Morris, K.A., Vallakati, R., Zhang, W., and Romo, D. (2009) Asymmetric synthesis, structure, and reactivity of unexpectedly stable spiroepoxy-P-lactones including facile conversion to tetronic acids Application to (+)-maculalactone A. J. Org. Chem., 74, 4772 781. 

In a heteroannulation reaction, optically active y-hydroxy-a,p -acetylenic esters undergo regiospecific hydration in the presence of Zeise s dimer, [PtCl2(C2H4)]2, to generate, by tandem hydration/annulation reaction, optically active tetronic acids in 74-92% yields [131] (Scheme 72). 

Amaresh R, Rajaram AR, Pu L (2006) Regiospecific hydration of y-hydroxy-ot, P-acetylenic esters a novel asymmetric synthesis of tetronic acids. Org Lett 8 2011-2019... 

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