Thiotetronic acids

Unsubstituted 2,3-dihydroxythiophene 86 (71T3839) prefers the mono-keto-mono-enol form 87 both for solid and liquid state and for EtOH and CDCI3 solution (76AHCS1, p. 237). As has been pointed out previously (76AHCS1, p. 238), many 2,4-dihydroxythiophenes 88 were shown to exist as thiotetronic acids 89 (13CB2103 71T3839). 

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. 

Additional studies featuring reactions of thiophene derivatives detail biohydrolysis of (S)-3-(thiophen-2-ylthio)butanenitrile <06TL8119>, lipase catalyzed resolution of thiotetronic acids <06TL7163>, enzymatic kinetic resolution of l,l-dioxo-2,3-dihydrothiophen-3-ol <06TL5273>, and efficient synthesis of 6-methyl-2,3-dihydrothieno[2,3-c]furan 55, a coffee... 

The racemic synthesis of such compounds has been reported.70 Chambers and colleagues have developed an asymmetric synthesis of 5,5-disubstituted thiotetronic acids and the production of an asymmetric synthesis of (5.S )-thiolactomycin ent-69, the enantiomer of the natural product.71 The key step in this synthetic pathway is the ozonolysis of a thioether 73 to the aldehyde 74 (Scheme 11.20). 

A crucial step in the synthesis of thiotetronic acids involves a fully stereoselective allylic xanthate to dithiocarbonate rearrangement45. Rearrangement of ethyl ( )-(4S)-2-methyl-4-[methylthio-(thiocarbonyl)thio]-2-pentenoate (7) gives ethyl (/f)-(2.S)-2-methyl-2-[methylthio(curbonyl)thio]-3-pentenoate (8) as a single diastereomer with an -configurated double bond and at least 98% ee. This value was determined by Mosher derivatization of the alcohol prepared from the dithiocarbonate in three steps. The remainder of the (5S)-thiotetronic acid synthesis is shown in the scheme. 

The use of the (R)-dithiocarbonate allows the preparation of the enantiomeric (5/ )-thiotetronic acids. The (.S )-dithiocarbonate 8 has also been used as the key substrate in a multistep total synthesis of (5S)-thiolactomycin46. 

The utility of the [3,3]-sigmatropic rearrangement of eight-membered thionocarbon-ates for the highly stereo-controlled synthesis of Z- or -double bonds in 10-membered thiolcarbonates has been reviewed.5,5-Disubstituted thiotetronic acids (139) have been synthesized using an allylic xanthate (137) to dithiocarbonate (138) rearrangement which has permitted the introduction of a sulfur at a tertiary centre with concomitant deconjugation of the double bond (see Scheme 39). 

Reaction of hydrogen sulfide with the acyl chloride (337), obtainable by treatment of diketene with chlorine, alfords thiotetronic acid (338) (Scheme 70) <85EUP189097>. 

Treatment of the lactone (440) with hydrogen sulfide in the presence of EtsN affords thiotetronic acid (338), which is treated with ketene to give the thiophene (441) <86EUP189096, 86EUP203495>. 

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. 

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