Lodolactonization

Conversion of lodolactones into the corresponding epoxy esters- is often one of the major steps in their utilization for the purposes of stereo-control. Methanolysis of the cis isomer of 4,5-dihydro-5-iodomethyl-4-phenyl-2(3H)-furanone to methyl (3RS,4RS)-4,5-epoxy-3-phenylpentanoate is a representative procedure for this transformation. 

Imidate salts hydrolysis, 118-144 syn and anti, 120 isomerization, 142 B-lactam, 142 Iminium salts, 211-221 Imino-ethers, 147 lodolactonization, 169 Ionic state of tetrahedral intermediates, 65, 105-106, 119 Ionophore A-23187, 13 Isochromane-3-one, 70 Isocyanate, 300 Isonitrile, 296... 

Bromolactonization. A key step in a synthesis of ramulosin (4) requires halolac-tonization of the yi.b-unsaturated acid 1, which can result in a "y- or a 8-lactone. Bromolactonization results mainly in the desired 8-lactone (2), which is converted in two steps into 4. lodolactonization of 1 results mainly in the undesired y-lactone and a mixture of isomeric 8-lactones. 

Resolution (21) with 2S,3R-ephedrine provided add [19] of the correct absolute configuration. lodolactonization gave the lactone [20] which vras readily transformed to the Corey lactone. 

D-Glucose ([52], Fig. 9) has served as an intriguing educt for preparation (31) of the Corey lactone equivalent [59] (32). The iodo compound [53] was readily available from glucose in four steps. Reductive fragmentation, induced by zinc in ethanol, gave the unsaturated aldehyde [54]. Reaction with N-methylhydroxylamine was followed by a spontaneous nitrone cycloaddition to provide the oxazolidine [55]. Catalytic reduction of the N-O bond was accompanied by the unexpected loss of tosylate and aziridine formation. Olefin formation from [56] via the N-oxide and chain extension gave acid [57]. lodolactonization and tri-n-butyltin hydride reduction in the standard fashion led to lactone [58]. After saponification of the benzoates, stereoselective epoxide formation gave epoxy lactone [59]. 

Every example of electrophilic addition of a halogen to an alkene that we have shown you so far has been with bromine. This is quite representative bromine is the most widely used halogen for electrophilic addition, since its reactivity is second only to iodine, yet the products are more stable. However, in these lactonization reactions, iodine is the more commonly used reagent, and the products of iodolactonizations are important intermediates (you will meet them again in Chapter 33). In the next example, the lodolactonization product is treated with sodium methoxide, which appears (a) to hydrolyse the lactone, and (b) to substitute the iodide for OMe. In fact, there is a little more to this than meets the eye. 

Cycloalkenes tethered with a y,5- or 5,8-unsaturated acid side chains react with Brj or I2 to furnish the corresponding halolactones. lodolactonization is more commonly used than bromolactonization since iodine is easier to handle (solid) and is more chemoselective (less reactive) than bromine. Halolactonization with aqueous base is kinetically controlled and proceeds via addition of a Br or B atom to the double bond to form a transient halonium ion. In the absence of strong directing steric effects, formation of the halonium ion may occur at either diastereoface of the double bond. However, only the halonium ion intermediate which allows trans-diaxial Sj. 2 opening by the neighboring carboxylate nucleophile leads, if the intramolecular reaction is sterically favorable, to the lactone. 

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