Iodolactonisation

Answer> The first reaction is iodolactonisation and is a stereospecific Li ans addition to the double bond. The iodine adds to form intermediate (28) which opens by S, -2 inversion (arrows) to give (25),... 

Dehydrobromination of bromotrifluoropropene affords the more expensive trifluoropropyne [237], which was metallated in situ and trapped with an aldehyde in the TIT group s [238]synthesis of 2,6-dideoxy-6,6,6-trifluorosugars (Eq. 77). Allylic alcohols derived from adducts of this type have been transformed into trifluoromethyl lactones via [3,3] -Claisen rearrangements and subsequent iodolactonisation [239]. Relatively weak bases such as hydroxide anion can be used to perform the dehydrobromination and when the alkyne is generated in the presence of nucleophilic species, addition usually follows. Trifluoromethyl enol ethers were prepared (stereoselectively) in this way (Eq. 78) the key intermediate is presumably a transient vinyl carbanion which protonates before defluorination can occur [240]. Palladium(II)-catalysed alkenylation or aryla-tion then proceeds [241]. 

A detailed study of the iodocyclization of a series of unsaturated hydroxy acids has demonstrated that a ground-state conformational analysis can serve as a reliable indicator of the relative reactivities of various conformations. Thus, while 153 undergoes exclusive iodolactonisation, 154 gives the corresponding iodotetrahydrofuran as the sole product, in full agreement with the MM2 prediction224. 

A recently published full account of another synthesis [69] of the same alkaloid starting from the /rans-cinnamic ester 264 represented a different approach (ACD -> ACDB) to ( )-lycorine (Scheme 42). An intramolecular Diels-Alder reaction of 264 in o-dichlorobenzene furnished the two diastereomeric lactones 265 (86%) and 266 (5%) involving the endo and exo modes of addition respectively. The transposition of the carbonyl group of 265 to 267 was achieved by reduction with lithium aluminium hydride, followed by treatment of the resulting diol with Fetizon s reagent, which selectively oxidised the less substituted alcohol to give isomeric 5-lactone 267. On exposure to iodine in alkaline medium 267 underwent iodolactonisation to afford the iodo-hydroxy y-lactone 268. The derived tetrahydropyranyl ether... 

Smith exploited a Lewis-acid-mediated asymmetric Diels-Alder reaction34 between 1,3-butadiene and the Oppolzer acryloyl camphorsultam 78 to set the remote C(29) stereocentre in phenylsulfone 57 (Scheme 17.17). This tactic procured acid 8 in 93% enantiomeric excess (ee), after base-promoted hydrolysis of the chiral auxiliary. Utilising a procedure published by Martin and co-workers,35 Smith iodolactonised acid 8, and... 

Ring stereochemistry can be efficiently created through multicenter reactions, and in this respect the Diels-Alder reaction is extremely useful. Other tricks are to use intramolecular reactions, e.g. iodolactonisation.[18]... 

The carbon-carbon double bond (olefin or alkene) is a structural feature on the border of framework and functionality. Unlike the carboxylic acid in 1 it is inside the skeleton of the molecule and involves no atoms except carbon and hydrogen. It has no polarity and yet it has the potential of producing highly polar functionality at two carbon atoms in a single reaction, as in the iodolactonisation to give 2 from 1. 

In the same reaction stereochemistry may be generated two stereogenic centres are in fact produced in this reaction and in the epoxidation of 3. The sense of the stereochemistry produced in these reactions depends critically on two factors the inherent stereoselectivity of the reactions (anti in the iodolactonisation and syn in the epoxidation) and the geometry of the alkene. Inside a six-membered ring of 1 the alkene must of course by cis or Z. In the open chain allylic alcohol 3 it can be E or Z depending on the method of synthesis. This chapter explores ways to control the stereochemistry of alkenes as an essential preliminary to the control of three-dimensional stereochemistry in chapter 25 where you will meet a method to make single enantiomers of 4 from the alkenes in E- and Z-3. 

We shall discuss the synthesis of the intermediate 155. The combination of a double bond and a lactone in ring B looks as though it could come from an iodolactonisation and elimination. We can draw the disconnections for these steps to reveal a possible starting material 158. 

Note the chemoselectivity between the two alkenes in the cyclohexadiene 160. This is the expected selectivity as Danishefsky s diene, with two electron-donating substituents is obviously electron rich and prefers to react with the electron-deficient alkene. The next two steps are the planned iodolactonisation and elimination with the usual reagents. There is chemoselectivity here too as iodine will attack the more nucleophilic double bond in 158, regioselectivity in that the carboxylate anion attacks the nearer end of the alkene 163, and stereoselectivity in that the anion can reach only the bottom face of the alkene. 

Halolactonisation works well because bromine and iodine form three-membered ring intermediates when they attack an alkene. Sulfur (II) and selenium (II) electrophiles form even better defined intermediates of this kind and similar cyclisation reactions occur with impressive control over selectivity.27 A simple example would be the formation of the bicyclic lactone 181. As the carboxylic acid is tethered to the five-membered ring, it can cyclise only to the intermediate with S(e) on the other face 180. The mechanism is similar to that of iodolactonisation and the stereochemical points are the same. The products are useful for the generation of radicals as Bu3SnH removes a PhSe group and leaves a radical behind while oxidation and elimination leaves a new alkene (chapter 33). 

Reduction ofenones prepared by the aldol or Wittig reactions Elimination on or reduction of iodolactonisation products Addition of vinyl metals to aldehydes and ketones... 

Slightly more unusual is the elimination and hydrolysis or reduction of iodolactonisation products 20 (chapter 17). Elimination replaces the alkene but in a different position 20 and cleavage of the lactone bridge4 by methanolysis gives 21 or by reduction gives 22. As we get on to the reactions of allyl alcohols you will see how these and other methods are used to make particular compounds. 

Methyl shikimate 116 has been made using a strategy with iodolactonisation at its heart.26 Note that shikimate has three chiral centres. Interestingly, these three centres are controlled in the synthesis by a centre that is finally destroyed. The first steps are iodolactonisation of 103 and subsequent elimination and epoxidation to give 109 as described above. 

There are several reactions that have a similar flavour to iodolactonisation.27 That is, where an intramolecular nucleophile attacks an electrophilic site that is derived from a double bond. The most... 

An interesting version of iodolactonisation is used to remove the chiral auxiliary from 220. Iodine attacks the alkene with participation of the amide oxygen atom 221 to give a salt 222 that hydrolyses to the iodolactone 223 with recovery of the auxiliary 26 if required. 

We pointed out in chapter 27 that Schultz s asymmetric Birch reduction can be developed with iodolactonisation to remove the chiral auxiliary and set up new chiral centres. Now we shall see how he applied that method to alkaloid synthesis.1 The first reaction is the same as in chapter 27 but the alkyl halide is now specified this gave diastereomerically pure acetate in 96% yield and hydrolysis gave the alcohol 4. Mitsunobu conversion of OH to azide and enol ether hydrolysis gave 5, the substrate for the iodolactonisation. Iodolactonisation not only introduces two new chiral centres but cleaves the chiral auxiliary, as described in chapter 27. Reduction of the azide 6 to the amine with Ph3P leads to the imine 7 by spontaneous ring closure. 

Unsaturated chiral cyanohydrins bear another synthetically interesting functionality, the C-C double bond. Among the opportunities of transforming unsaturated cyanohydrins, oxidative cleavage [208, 215], epoxidation [209, 210], iodolactonisation [209], addition reactions [211, 212, 216] and metal assisted... 

Substituted 5-iodo-2-pyrones, obtained by iodolactonisation, react with activated zinc, giving species that can be protonolysed or used to make 5,6-disubstituted 2-pyrones via Pd(0)-catalysed coupling. ... 

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