3-acyl tetronic acids

Tetronic acids (4-hydroxy-2(5//)-furanones) are also an example of 5-membered rings, and they are compounds of potential activity as antibiotics, antiviral and neoplastic agents. The base-promoted Dieckmann condensation is one of the desired methods to produce 3-acyl-tetronic acids. An example is the intramolecular tetrabutylammonium fluoride-promoted Dieckmann cyclization of 53 to give tetronasin (54) in 72% yield. 

A number of fungal 5-substituted 3-acyl tetronic acid metabolites, as shown in Scheme 1.19, have attracted significant attention during the development of new synthetic protocols in the field of tetronic acids. 

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. 

The ionophore antibiotic Ml 39603, unusual in that the acid group is an acyl tetronic acid, has been isolated from Streptomvces lonqisporoflavus and... 

The au rie2Si group is used to protect in the synthesis of morphine, methynoLide from D-glucose, C+)-Aplasmomycin, thromboxane B and lOa-homothrom-boxane A, prostaglandin t d in carbapenein synthesis.3u Ph,Si protects OH in the preparation of the optically pure TriF fragment of acyl tetronic acid... 

The Reforrnatsku reaction of a-halogenated carboxylic esters with silylated cyanohydrins combined with an intramolecular acylation reaction gives fluorinated derivatives of tetronic acid [28] (equation 17) It is noteworthy to mention that this particular reaction sequence only proceeds with ultrasonic irradiation A very... 

As has already been pointed out for 3-acyl-tetronic and -thiotetronic acids, the corresponding 3-acyl-tetramic acid can exist as internal tautomers (136 137,138 139) as a result of prototropy between the two oxygen atoms and as external tautomers (136,137 138,139) as a result of rotation of the side-chain acyl group. 

Effenberger and coworkers have utilized the tolerance of methyl ketones by the recombinant enzyme to develop an alternative synthesis of tetronic acids and their amino derivatives, as shown in Figure 5.18. Treatment of O-acyl cyanohydrins with lithium disilazide resulted in base-induced ring closure to amino tetronic acid derivatives. Alternatively, the cyanohydrins could be converted to a-hydroxy esters prior to acylation, and the same base-induced cyclization then led to tetronic acid derivatives [89]. 

Wadsworth-Emmons olefination with a variety of aldehydes to afford (E)-a,B-unsaturated and diene acyl tetramic and tetronic acids in good to excellent yields upon treatment with potassium tert-butoxide (2 equiv) in tetrahydrofuran. For readily enolizable substrates use of the N-protected systems is generally required. The following compounds have been prepared, in the indicated yields, in this manner ... 

The simple furan-3(2/f)-ones exist in the keto form but may be O-acylated with acetic anhydride and sodium acetate however, they undergo C-alkylation. They are usually stable to acid, merely being protonated. 4-Alkoxyfuran-3(2//)-ones are readily hydrolyzed to tetronic acids. Furan-3(2//)-ones are degraded by aqueous base which attacks in a conjugate fashion so that 2,5-dimethylfuran-3(2iT)-one, readily available from biacetyl, furnishes acetate and acetoin, but compounds with an ester group at the 4-position furnish tetronic acids (Scheme 109). 

The O-antigens of Brucella species are homopolymers of a-l,2-linked 4,6-dideoxy-4-formamido-D-mannopyranose residues in which there may bea-1,3 linkages [102,103], The Yersinia 0 9 antigen is a similar 1,2-linked homopolymer but contains no 1,3 linkages. A related structure Y-acylated by 3-deoxy-L-glycero-tetronic acid in place of the formate group is produced by Vibrio cholerae Inaba and Ogawa strains [104], These structures have been the subject of synthetic work [105-107],... 

Tautomerism in the tetronic acid nucleus concerns only the vinylogous acid and never includes the methylene group [but note obtusifolin (127)]. Two isomers have been detected in 2-acylated tetronic acids15 0a (63) that are... 

Table 28.4.2 SAR of different acylated compounds 7b-7h of tetronic acid 7a against TETRUR and PANOUL...

The combination of these two building blocks leads in a convergent way to the diester 11, which is treated with a base, e.g., potassium-tert-butylate (KOtBu), to form the tetronic acid 6. The final acylation with 2,2-dimethyl-butyryl chloride leads to spirodiclofen 7f (Scheme 28.4.1). 

The further route to spiromesifen 8a is similar to the above shown spirodiclo-fen 7f synthesis (Scheme 28.4.3). Acylation of the cyclopentyl hydroxyester 17 (synthesized from cyclopentanone via the classical cyanohydrin route in three steps) with mesitylacetyl chloride 18 leads to the intermediate 19, which is cyclized to the tetronic acid 20 using, e.g., potassium tert-butylate in N,N-dimethylformamide (DMF). 

Useful methods for specific 2-0 or 4-0 methylations (or ethylations) of tetronic acids have been published (Scheme 20). °" The more reactive -oxygen can be alkylated by treatment with dialkyl sulphates under a variety of conditions whereas preparation of the 2-O-alkyl derivative requires prior acylation of the 4-oxygen, followed by alkylation using trialkyloxonium salts (see ref. 148). Some very interesting chemistry has been evolved during efforts towards a total... 

Agglomerins constitute a group of 3-acyl-5-methyhdene tetronic acids with antibiotic activity [16]. Synthetic efforts toward agglomerins started by bey and coworkers... 

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. 

The title phosphonate and related substances undergo thermal decomposition to B-acyl ketenes at temperatures in excess of 50°C. Thus thermolysis in the presence of alcohols, amines, a-hydroxy esters, and a-amino esters affords the corresponding g-keto esters and amides the latter two classes can be cyclized upon subsequent base treatment to unsaturated tetronic and tetramic acids and the related phosphonate reagents. ... 

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