Thiolactones formation

C. l Equilibrium constants for thiolactone formation from y-thiolacids 252, C.2... 

Few relevant data are available. Both equilibrium and rate constants have been measured for very few reaction series in solution, but comparisons are possible for lactone and thiolactone formation, and for a few anhydrideforming reactions (Tables 4 and 5). For lactone formation (Table 4) the EM for the rate process is of the same order of magnitude as that derived from the equilibrium constant data, and in some cases actually exceeds it (though only in one case by an amount clearly greater than the estimated uncertainty which is nominally a factor of 4 for these ratios). Lactonization generally involves rate-limiting breakdown of the tetrahedral intermediate, and the transition state is expected to be late and thus close in structure to the conjugate acid of the lactone. 

Thiirane 1,1-dioxides extrude sulfur dioxide readily (70S393) at temperatures usually in the range 50-100 °C, although some, such as c/s-2,3-diphenylthiirane 1,1-dioxide or 2-p-nitrophenylthiirane 1,1-dioxide, lose sulfur dioxide at room temperature. The extrusion is usually stereospeciflc (Scheme 10) and a concerted, non-linear chelotropic expulsion of sulfur dioxide or a singlet diradical mechanism in which loss of sulfur dioxide occurs faster than bond rotation may be involved. The latter mechanism is likely for episulfones with substituents which can stabilize the intermediate diradical. The Ramberg-Backlund reaction (B-77MI50600) in which a-halosulfones are converted to alkenes in the presence of base, involves formation of an episulfone from which sulfur dioxide is removed either thermally or by base (Scheme 11). A similar conversion of a,a -dihalosulfones to alkenes is effected by triphenylphosphine. Thermolysis of a-thiolactone (5) results in loss of carbon monoxide rather than sulfur (Scheme 12). 

An interesting C-S bond formation mediated by benzyltriethylammonium tetrathiomolybdate converts -halo acid chlorides into thiolactones [64] (Scheme 4.16). 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Figure 22.7 Homocysteine formation from methionine and formation of thiolactone from homocysteine. The homocysteine concentration depends upon a balance between the activities of homocysteine methyltransferase (methionine synthase) and cystathionine p-synthase. Both these enzymes require vitamin B12, so a deficiency can lead to an increase in the plasma level of homocysteine. (For details of these reactions, see Chapter 15.) Homocysteine oxidises spontaneously to form thiolactone, which can damage cell membrane.

A plausible mechanism for the formation of 4 is rationalized on the basis that photolysis of 3 results in [2-1-2] cyclization to thietane 4 and is subsequently followed by rearrangement to thiolactone 5 (Scheme 6). Ring opening of the initially formed thietane 4 leads to a zwitterion, which is facilitated by lone pair electrons of nitrogen and oxygen atoms, and nucleophilic reaction of the thiolate anion to carbonyl carbon gives 5. For the tricyclic thietane 4a, nucleophilic addition of the thiolate anion is difficult, and results in the formation of stable thietane 4a. 

Thiepane (35) has been synthesized by an intramolecular radical addition of the thiyl radical (equation 59) which was generated by photolysis of a thiol (71TL2025). Similarly, C—S bond formation has been achieved (equation 60) by an intramolecular condensation of 6-mercaptohexanoic acid to give the thiolactone, thiepan-2-one (135) (64MI51700). A Dieckmann-type base-catalyzed cyclization of a diester precursor followed by acid-catalyzed hydrolysis and decarboxylation has been used in the synthesis of thiepan-3-one (41) as indicated in equation (61) (52JA917). 

Silver ion also catalyzes nucleophilic reactions of thiol esters, including reactions of acetylhomocysteine thiolactone (12) and diethylethylphosphonothiolate (52). In the first reaction, an insoluble complex of silver ion and the substrate was first produced at pH 7.5, which then reacted with the nucleophile, in this case an amino group of a protein. In the second reaction silver ion complexes of the substrate were also postulated, on the basis that silver ion complexes with sulfur are much more stable than those with oxygen (I). The complexes postulated were 1 1 and 2 1 silver ion-substrate complexes. These complexes were suggested to react with the nucleophiles, water and fluoride ion, giving as products phos-phonic acid and phosphonyl fluoride, respectively, and silver mercaptide. It is evident that the last reaction at least must involve only the direct interaction of a silver ion with the sulfur atom of the thiol ester without chelate formation. Therefore it appears the metal ion-catalyzed reactions of thiol esters are unique, in that they involve complex formation, but not chelate formation in their catalytic mechanism. 

Hydroxy and 7-thiol acids (32 Z = 0, S) usually cyclize spontaneously to give lactones and thiolactones (33). 7-Amino acids (32 Z=NH) require heating to effect lactam formation (33 Z = NH). 

The cyanobromide (371) was condensed with the bc portion (347) to give the thioether (372) sulfide contraction to give (373) was accomplished using tris(/3-cyanoethyl) phosphine, and with phosphorus pentasulfide the thiolactam-thiolactone (374) was produced. After treatment with Meerwein s salt, reaction with dimethylamine opened the lactone with concomitant formation of an exocyclic methylene group, and subsequent treatment with cobalt chloride or iodide gave the chelate (375) which was reacted with diazabicyclononane to give bisnorcobyrinic add [Pg.435]

Thiones, in general, do not undergo similar photoreactions. An exception to this behavior has been found in the thiolactone (483), which on irradiation in methanol is converted to the ether (484).422 Photocyclization of a different type has been observed in the thione (485), leading to the formation of the thiophen (486).423 Details of the mechanism of this and related photo-cyclizations424 are not completely clear. 

Condensation of 5 with methyl tetrahydro-4-oxothiophene-3-carboxyl-ate (64) led to the formation of the ring-closed enamino thiolactone 65. Chemical transformation of 65 with sodium hydride/methyl iodide gave 67, whereas 4H, 10//-thieno[3,4-c][l,5]benzothiazepin-10-one (66) was obtained upon aromatization of the thiophene ring by the action of sulfuryl chloride (Scheme 18) (80JOC497). 

Similar absolute asymmetric synthesis was demonstrated in the solid-state photoreaction of A-(P,y-unsaturated carbonyl)thiocarbamate 41. [27] Achiral 0-methyl AT-(2.2-dmeth ibut-3-enoyl)-iV-phenylthiocarbarnate 41 crystallized in chiral space group P2i, and irradiation of these crystals gave optically active thiolactone in 10-31% ee. A plausible mechanism for the formation of 42 is rationalized on the basis that photolysis of 41 undergoes [2 + 2] cyclization to thietane and is subsequently followed by rearrangement to thiolactone 42. 

The solid-state photoreaction of O-methyl iV-(/3,7-unsaturated carbonyl)-iV-phenylthiocarbamate resulted in intramolecular [2+2]-thietane 23 formation, followed by rearrangement to 7-thiolactone 24 (Scheme 1) <1998CC2315>. 

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