Ring Construction

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Chapter: Organic Chemistry : Planning Organic Syntheses

The use of carbonyl groups to set the polarity of bond disconnections in retrosynthetic analysis is useful for the construction of rings as well.


The use of carbonyl groups to set the polarity of bond disconnections in retrosynthetic analysis is useful for the construction of rings as well. If a carbon electrophile and a carbon nucleophile are connected by a carbon chain, they can react with each other to form a carbon–carbon bond. This is an absolutely nor-mal type of carbon–carbon bond-forming process, but the fact that the carbon nucleophile and carbon electrophile are connected by a chain means that the new carbon–carbon bond closes up the ends of the chain, forming a ring.

For example, the Claisen reaction is a reaction of an ester enolate with an ester to produce a β ketoester. We learned this reaction earlier.

If both ester groups are in the same molecule and are connected by a chain, then a Claisen-type reaction between the α position of one ester and the carbonyl group of the other gives a new carbon–carbon bond and closes up the ring. (This reaction is actually called the Dieckmann condensation, but it is nothing more than an intramolecular Claisen reaction.)

Ring-forming reactions are very important in retrosynthetic analysis because many interesting targets are cyclic compounds and often rings must be installed rather than being present in the starting materials. From a retrosynthetic point of view, there is really no difference between ring-forming reactions and other carbon–carbon bond-forming reactions. One looks for the same polarities and functional group features as in acyclic systems.

The only thing that is different is that some rings are more easily formed than others. The rule of thumb is that rings of three, five, and six members are routinely formed, while rings of four or more than six members are formed with greater difficulty. For example, reaction of diethyl malonate with 1,2-dibromoethane and two equivalents of base gives diethyl cyclopropane-1,1-dicarboxylate in high yield. Ring formation occurs by a double-displacement sequence.

Likewise reactions with 1,3-dibromopropane, 1,4-dibromobutane, or 1,5-dibromopentane give the corresponding cyclobutyl-, cyclopentyl-, and cyclo-hexyl-1,1-dicarboxylates.

The yields of these reactions are not the same, however, and reactions which produce three-, five-, and six-membered rings are generally more effective. Use of 1,6-dibromohexane fails to give the cycloheptyl product.

Ring closure requires that a reactive center at one end of the chain encoun-ters a reactive center at the other end of the same chain in the bond-forming process. The alternative is for the reactive center on one chain to react with a reactive center of a different chain. The first case produces a ring, the second case a polymer. An analogy is a chain with complementary hooks at each end representing electrophilic and nucleophilic carbons at the ends of the chain. If two hooks on the same chain link up, a ring is formed, whereas if hooks from different chains link up, a larger molecule is formed with hooks remaining on each end. These can link up further to form progressively larger molecules.

For short chains which would give three- to six-membered rings upon ring closure, there is a higher probability that one end of the chain will encounter the other end of the same chain and react intramolecularly before it will encounter the end of another chain and react intermolecularly. Thus ring closure is normally favored over oligomerization for smaller rings of three to six members. On the other hand, as the chains become longer, it becomes less likely that the end of a chain will encounter the other end of the same chain before it encounters and reacts with the end of another chain. The break point is between six-membered rings, which are formed readily, and seven-membered rings, which are not easily formed. While this reasoning is a great simplification, it suffices to provide a good working model to predict the success for ring-forming reactions.

We can use this model in retrosynthetic analysis quite successfully. Suppose one were asked to produce cyclohexanone C from acyclic starting materials.

In this monofunctional compound, the ketone could serve as an electrophilic center in a cyclization step. Disconnection at the indicated bond leads to the polarity shown; however, it is immediately obvious that the carbon nucleophile occurs at an unactivated position, and there is no good way to produce it there without a control element at that position.

However, use of an ester group could activate this position toward anion formation and thus we could write instead

Now all is well in terms of polarity and we recognize this as a Dieckmann reaction followed by hydrolysis and decarboxylation of the β-ketoester product. Proceeding backward we write

Alkylation of diethyl suberate with benzyl iodide would produce the α-benzylated product which would cyclize in the presence of base. This particular target does not present a regiochemical difficulty. Base could pull off either α proton and two different enolates would be produced; however, both enolates cyclize to give the same product after decarboxylation.

If molecular symmetry were included in the cyclization precursor, then we would not have to worry about regiochemistry in the ring closure. Noting that the product of ring formation is a β ketoester, which itself is a good carbon nucleophile, an alternate retrosynthesis (which actually is much better) is the following in which the benzyl group is added after the ring is formed (in the forward synthesis):

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