Umpolung Synthons

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Chapter: Organic Chemistry : Planning Organic Syntheses

Because of the polarities associated with carbonyl groups, some difunctional compounds are much easier to produce than others.


Because of the polarities associated with carbonyl groups, some difunctional compounds are much easier to produce than others. For example, 1,3-dicarbonyl compounds and 1,5-dicarbonyl compounds are easy to produce using standard retrosynthetic steps with normal polarities induced by the carbonyl group.

In contrast, 1,2-dicarbonyl compounds or 1,4-dicarbonyl compounds are more difficult to disconnect by valid retrosynthetic steps. Consider a 1,2-diketone. Disconnection of the bond between the carbonyl groups requires that one of the carbonyl groups has the normal electrophilic character, but the other carbonyl carbon must have nucleophilic character (an acyl anion or its equivalent), which is not the normal polarity of a carbonyl group.

In the same way, disconnection of a 1,4-diketone requires either an acyl anion equivalent reacting with a normal β-carbonyl electrophile or a normal α-carbonyl nucleophile reacting with an abnormal α-carbonyl electrophile. These abnormal or reversed-polarity reagents are said to have umpolung reactivity.

There is consequently a need for synthetic equivalents (synthons) of these reversed-polarity (umpolung) reagents. The development of reagents with umpol-ung reactivity has been an important addition to modern synthetic methodology. Acyl anion equivalents, among the most common umpolung synthons, can be pro-duced by many strategies. For instance, nitroalkanes can be used as nucleophiles and the nitro function can be cleaved to the carbonyl group. Thus nitronates can be thought of as acyl anion equivalents.

Likewise 1,3-dithianes can be deprotonated by alkyl lithium bases and the result-ing anions are strong nucleophiles. The dithiane group can be hydrolyzed back to the carbonyl group. Thus the dithiane serves as a synthon for the acyl anion.

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the α position (pKa 25) and the α proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group.

These are only three of many ways that have been reported for the formation of acyl anion equivalents, which are among the most common umpolung synthons to be found in the literature. All are prepared by a similar strategy in that they contain functional groups which can sustain a negative charge on an adjacent carbon and can be converted back to a carbonyl group.

Another common umpolung synthon is a homoenolate. Normally the β posi-tion of a carbonyl compound is an electrophilic center (by Michael addition to an α,β-unsaturated carbonyl derivative). To make it a nucleophilic center, an organometallic is needed since it is unactivated and nonconjugated. A common way to do this is to use a β-bromo acetal.

The bromine substituent can be metallated to give a carbanion equivalent β to the acetal group. Now since the acetal is easily hydrolyzed to the ketone, it is a synthon for a β-carbonyl anion—an umpolung reagent. So it is important to recognize normal and reversed polarities when doing retrosynthetic analysis of a target in order to use umpolung synthons when they are needed.

For the lactone target L shown below, cleavage of the lactone ring gives a γ-hydroxy acid. This can be disconnected at any one of the three intervening bonds between the hydroxyl group and the carbonyl group (a, b, c).

If each of these is considered independently, it is easily seen that none of the disconnections has normal carbonyl polarities. (The same conclusion could be reached by merely noting that the hydroxy group and the carboxyl group have a 1,4 relationship. It was seen above that normal carbonyl-based polarities are not suited to the formation of 1,4 difunctional systems.) Thus one either has to use an umpolung synthon or go to functional groups other than carbonyl groups to guide the reactivity. For example, one could use an epoxide electrophile rather than a carbonyl electrophile for the bond-forming reaction.

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