Lactone formation with iodine

Cyclopentene derivatives with carboxylic acid side-chains can be stereoselectively hydroxy-lated by the iodolactonization procedure (E.J. Corey, 1969, 1970). To the trisubstituted cyclopentene described on p. 210 a large iodine cation is added stereoselectively to the less hindered -side of the 9,10 double bond. Lactone formation occurs on the intermediate iod-onium ion specifically at C-9ot. Later the iodine is reductively removed with tri-n-butyltin hydride. The cyclopentane ring now bears all oxygen and carbon substituents in the right stereochemistry, and the carbon chains can be built starting from the C-8 and C-12 substit""" ... 

A closely related procedure results in formation of y-lactones. Amides are converted to AHodoamidcs by reaction with iodine and /-butyl hypochlorite. Photolysis of the AHodoamides gives lactones via iminolactone intermediates.372... 

It will be seen that the enediolic system can theoretically be written in the isomeric 2-keto (II) or 3-keto (III) forms and these in turn are seen to be derived from the 2-keto and the 3-keto acids IV and V, respectively (compare with benzoin which reacts with iodine in an analogous fashion to L-ascorbic acid). Consequently the synthesis of L-ascorbic acid and of its analogs has consisted in devising methods for the formation of 2-keto or 3-keto hydroxy acids followed by their enolization and lactonization. Four main methods are available for the synthesis of analogs of L-ascorbic acid containing the characteristic five-membered unsaturated enediolic ring. 

Cyclizations of (3,7-un saturated acids form -lactones (4-exo cyclization) when the reactions are conducted under conditions of kinetic control.1 - The most common procedure for (3-lactone formation, developed by Barnett, involves halolactonization in a two-phase system using an aqueous solution of the carboxylate salt of the substrate with the halogen (Br2 or I2) added in an organic solvent.18 Cyclization with bis(, ym-collidine)iodine(I) perchlorate provides a higher yield than the Barnett procedure in cases where cyclization is not favored by geminal a-substitution (Table 2, entries 1 and 2).14 Iodo- and bromo-... 

The carbanion is trapped with iodine to give 42. which makes a further functionali/aiion possible. Conversion of vinylic iodide 42 into a lactone is accomplished by palladium-cataly/ed carbonyla-tion under Stille conditions.13 This process ean be broken down into the following elementary reactions a) Oxidative addition of Pd° to vinylic iodide 42 with formation of 43 b) An insertion reaction of carbon monoxide with creation of the pallada-acyl species 44 c) Reaction of acid-chloride equivalent 44 with the alcohol to give lactone 13. 

Formation of a highly electrophilic iodonium species, transiently formed by treatment of an alkene with iodine, followed by intramolecular quenching with a nucleophile leads to iodocyclization. The use of iodine to form lactones has been elegantly developed. Bartlett and co-workers216 reported on what they described as thermodynamic versus kinetic control in the formation of lactones. Treatment of the alkenoic acid 158 (Scheme 46) with iodine in the presence of base afforded a preponderance of the kinetic product 159, whereas the same reaction in the absence of base afforded the thermodynamic product 160. This approach was used in the synthesis of serricorin. The idea of kinetic versus thermodynamic control of the reaction was first discussed in a paper by Bartlett and Myerson217 from 1978. It was reasoned that in the absence of base, thermodynamic control could be achieved in that a proton was available to allow equilibration to the most stable ester. In the absence of such a proton, for example by addition of base, this equilibration is not possible, and the kinetic product is favored. 

The iodocyclization of 4-methyl-5-hexenoic acid performed under conditions of thermodynamic control (iodine in acetonitrile in the absence of a base) leads to the preferential formation of the /raw.v-diequatorial 5-lactones (94 6) in 77% yield1. Similar results were observed starting from (S)-4-methyl-5-hexenoic acid (1), obtained from citronellol, with iodine in acetonitrile, followed by tributyltin hydride reduction. The 5,6-dimethylvalerolactone 2 was obtained in 40%) yield and 93.5 6.5 (irans/cis) diastereoselcctivity 2. 

Earlier methods of converting /3y-unsaturated carboxylic acid salts into y-lactones by treatment with iodine have now been shown to involve initial formation of /S-iodo-lactones (41), and a modified procedure has... 

The ascorbic acids are weak acids as a result of the presence of the enolic groups rather than of the lactone ring 1S8, H5). They reduce Fehling solution, and the double bond is oxidized by acidic iodine solution. The reaction with iodine is used as a quantitative method to distinguish them from 2-keto acids. The action of boiling 12 % HCl causes the formation of furfural in very high yields, above 80% (see above). 

T. Dohi, N. Takenaga, A. Goto, A. Maruyama, Y. Kita, Direct lactone formation by using hypervalent iodine(III) reagents with KBr via selective C-H abstraction protocol, Org. Lett. 9 (2007) 3129-3132. 

As inert as the C-25 lactone carbonyl has been during the course of this synthesis, it can serve the role of electrophile in a reaction with a nucleophile. For example, addition of benzyloxymethyl-lithium29 to a cold (-78 °C) solution of 41 in THF, followed by treatment of the intermediate hemiketal with methyl orthoformate under acidic conditions, provides intermediate 42 in 80% overall yield. Reduction of the carbon-bromine bond in 42 with concomitant -elimination of the C-9 ether oxygen is achieved with Zn-Cu couple and sodium iodide at 60 °C in DMF. Under these reaction conditions, it is conceivable that the bromine substituent in 42 is replaced by iodine, after which event reductive elimination occurs. Silylation of the newly formed tertiary hydroxyl group at C-12 with triethylsilyl perchlorate, followed by oxidative cleavage of the olefin with ozone, results in the formation of key intermediate 3 in 85 % yield from 42. 

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