Iodolactonisation reactions

Figure 2. Diels-Alder reaction of acrylic acid with cyclopentadiene and dicyclopentadiene respectively, and removal of 2-norbomene-5-endo-carboxylic acid by the iodolactonisation reaction.

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),... 

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... 

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. 

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. 

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... 

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... 

Often there are stereochemical alternatives, for instance in several Diels-Alder reactions both endo and exo (or syn and anti) adducts can be expected. Quantitative differentiation of such configurational isomers has been made possible by various methods specific chemical treatment (iodolactonisation, to which only do-acids respond) and gravimetry ir or nmr spectroscopic analysis , gas chromatography . Kinetic control was checked in these cases, i.e. it has been experimentally verified that under the reaction conditions there is no isomerisation of the products, as could happen if conditions were severe enough to allow reversion to reactants or intramolecular rearrangement. 

Boeynaems et at studied the iodolactonisation of arachidonic acid and docosahexaenoic acid by iodine and hydrogen peroxide in the presence of lactoperoxidase from the thyroid. The major product is an iodo y- or 6-lactone but minor products obtained with arachidonic acid are the 14- and 15-olide resulting from reaction at the A14 double bond (Scheme 21). 

A unified discussion of supported asymmetric reactions is difficult because many different types of reaction have been investigated. Hodge has already produced a useful review recently [88] and this up-dates previous summaries [39, 89]. Asymmetric modification of alkenes is an important area, and although polymer-supported alkaloids, such as quinine, have been quite widely used in potentially asymmetric synthetic processes, the recent application to dihydroxylation of alkenes is an important step forward [90]. Here the polymer-bound chiral alkaloid has been used with OSO4 to achieve asymmetric dihydroxylation of trans-stil-bene and styrene. Chemical yields of 85% and enantiomeric excesses (ee) of up to 87% have been achieved. The chiral support was re-used once without addition of more OSO4 and with only a small drop in yield. Another new development involves iodolactonisation of pentenamide moieties bound to a chiral auxiliary consisting of (5)-2-pyrrolidine attached to... 

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