Stereoselectivity in cyclic molecules

We start with stereochemistry in rings. Not only is stereochemistry easier to understand in cyclic compounds, it is also better behaved in cyclic compounds. Suppose you were to reduce this ketone to one of the corresponding alcohols. 

To achieve a stereoselective reaction at the new stereogenic centre (shown in black) the green stereogenic centre would somehow have to influence the direction of attack of the nucleophile on the C=0 group. Separated from it by three bonds, in a molecule with a high degree of flexibility, makes this a very tall order. A more or less 50 50 mixture of the two diastereoisomers would be expected. 

The key to the difference between these two compounds is in their conformations. The six-membered ring of the cyclic ketone has one conformation and the two approaches to the faces of the ketone are very different. In the open-chain compound rotation about all the C-C bonds is possible and very many conformations will be populated. In any one conformation, attack on one face of the ketone or the other may happen to be preferred, but summed over all of them the average selectivity will be close to 1 1. There is all the difference in the world between cyclic and open-chain compounds when it comes to stereoselective reactions. 

In this chapter we shall look at reactions happening to cyclic compounds, reactions with cyclic intermediates, and reactions with cyclic transition states. We shall investigate what happens to stereochemistry when two (or even more) rings are joined together at a bond or at an atom. You have already looked in detail at reactions which close rings (Chapter 31, p. 805), and many of the reactions in this chapter you will have met earlier in the book. Our task is to reveal new features and subtleties, and to show you how to use these reactions to control stereochemistry. 

As you saw in Chapter 16, cyclohexanes benefit from very well defined conformational preferences. Substituents are orientated either axially or equatorially, and usually prefer the equatorial orientation, especially when they are large. The strong preference for substituents to adopt the equatorial position means that when diastereoisomeric cyclohexanes equilibrate by processes such as enolization they may give high selectivity for the all-equatorial compound. For example, this fine perfumery material is made worthless by enolization. 

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Stereoselectivity in cyclic molecules 825 [2,3]-Sigmatropic rearrangements [1,5]-Sigmatropic hydrogen shifts 917 919... 

Control over regioselectivity and stereoselectivity in the formation of new C-C a-bond is required to utilize the Heck reaction in complex molecule synthesis. For the intramolecular Heck reaction, the size of the ring formed in the insertion step controls the regiochemistry, with 5-exo and 6-exo cyclization favoured. A mixture of regioisomers is formed from Heck insertions of acyclic alkenes, whereas cyclic alkenes such as cycloalkenes as a Heck substrate produce a a-arkylpalladium(II) intermediate A, which has only one syn-P-hydrogen. Syn-elimination of the hydrogen provides only product B (Scheme 5.6). 

The electrophile-promoted cyclization in cyclic systems is a highly regio- and stereoselective reaction that can be carried out under various conditions and with a range of electrophiles. The bicyclic lactone products have the cfs-ring fusion, indicating that the electrophile approaches from the face of the molecule anti to the carboxyalkyl side chain. Such halolactonizations constitute a useful approach to bicyclic and polycyclic compounds. 

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