Stereospecificity iodolactonization

Iodine is a very good electrophile for effecting intramolecular nucleophilic addition to alkenes, as exemplified by the iodolactonization reaction71 Reaction of iodine with carboxylic acids having carbon-carbon double bonds placed to permit intramolecular reaction results in formation of iodolactones. The reaction shows a preference for formation of five- over six-membered72 rings and is a stereospecific anti addition when carried out under basic conditions. 

The starting acid contains an E-alkene that gives a tram iodonium ion. Inversion occurs in the attack of the carboxylate anion on the iodonium ion and we have shown this by bringing the nucleophile in at 180° to the leaving group with both bonds in the plane of the paper. A single diastereoisomer of the iodolactone results from this stereospecific reaction. 

One of the simplest open-chain examples is 2-methylbut-3-enoic acid, which cyclizes in >95% yield to a single iodolactone with three stereogenic centres. Two come from stereospecific trans addition to the E-alker "ut the third reveals that iodine attacked the face of the alkene opposite the green methyl group in the conformation that can cyclize. 

We have said little in this chapter about the stereospecific transformation of one ring into another but we now have an opportunity to remedy that defect. Iodolactonization of a terminal alkene with a stereogenic centre next to it is as stereoselective as (if not more than) the example we have just seen. The two side chains on the ring end up trans to one another as we should expect. This is a purely stereoselective process as the alkene has no geometry. 

Reaction of the iodolactone product with alkaline methanol transforms it stereospecifically into the methyl ester of an epoxy acid. There is no change in stereochemistry here methoxide opens the lactone and the oxyanion released carries out an internal S>j2 reaction on the primary alkyl iodide. 

A lactone makes a good temporary tether because it can be hydrolysed or reduced to break the ring at the C-0 bond and reveal new stereogenic centres on the old structure. In this sequence a lactone, formed by iodolactonization, controls all the subsequent stereochemistry of the molecule in two ways it fixes the conformation rigidly in one chair form—hence forcing the iodide to be axial— and it blocks one face of the ring. The iodolactonization is very similar to one you saw on p. 872. Next, an alkene is introduced by E2 reaction on the iodide. This stereospecific reaction requires an... 

Use of the enantiomerically pure alcohol 211 revealed a surprising stereospecificity. One enantiomer 215 gave (mostly) the required diastereoisomer 216 and hence the iodolactone 217 having the right stereochemistry at the spiro centre and at the lactone centre in the new ring. Removal of iodine, selective oxidation and addition of a d1 reagent gave (—) -cinatrin B. 

Schemes 10.16 and 10.17 lead to intermediates in which the C-1, C-3, and C-5 substituents are all cis to one another. In Scheme 10.16 the cis relationship between the C-1 and C-3 groups is again established by the Baeyer-Villiger oxidation, which is carried out as the first step in the synthesis. In step C, the cis relationship of the oxygen function at C-5 is established. The iodolactonization is a stereospecific anti addition, and the formation of cis-fused five-membered rings is preferred to the trans ring fusion. The other steps represent reactions that have been discussed previously.

In another approach, Corey, Shibasaki and KnoUe effected a stereospecific Qaisen rearrangement of the unsaturated sugar (107) by reaction with the dimethylaminal of A, A -dimethylacetamide in diglyme, to give the dimethyl-amide (108). The latter then afforded (92b) (a-methoxy epimer) on reaction with iodine and deiodination of the resulting iodolactone with tributyl tin-hydride [92]. 

If in intramolecular versions, comparable to iodolactonization, the nucleophile is represented by a carbon-carbon double bond or triple bond, the stereospecific and stereoselective generation of carbon bonds is at reach (see 171 and 172). 

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