Synthetic equivalent groups

The protecting groups discussed in the previous section are essentially passive in nature during a synthetic sequence. They are introduced and removed at appropriate stages, but do not serve to directly influence the reactivity at the points in the molecule where transformations are being carried out. It is often advantageous to 

This nucleophilic species can successfully add to cyclohexenone. Subsequent acidic hydrolysis gives the desired product. 

A number of other systems can be utilized as the synthetic equivalent of a nucleophilic carbonyl group, particularly in Sn2 alkylation reactions. Dithiane derivatives of aldehydes can be converted to nucleophiles by lithiation. The resulting anion is easily alkylated. Hydrolysis leads to a ketone. Lithiated vinyl ethers and 

are nucleophilic species that, after alkylation, can be converted to ketones. For example, a-hydroxyketones are formed when the lithioaldimine adds to a carbonyl group  

It is possible to conceive of a wide variety of synthetic transformations based on the underlying principle associated with the use of synthetic equivalents. Any molecular fragment that has a useful range of synthetic reactivity as well as the ability to be efficiently converted to another functionality after reaction can serve as a synthetic equivalent group. Some examples have already been encountered in the earlier chapters. Diels-Alder adducts of a-chloroacrylonitrile can be converted to 

The care with which a synthesis is analyzed and planned will have a great impact on the likelihood of its success. The investment of material and effort that is made when the synthesis is begun may be lost if the plan is faulty. Even with the best of planning, however, unexpected problems are often encountered. This circumstance again tests the ingenuity of the chemist to devise a modified plan that can overcome the unanticipated obstacle. 

Retrosynthetic analysis may identify a need to use synthetic equivalent groups. These groups are synthons that correspond structurally to a subunit of the target structure, but in which the reactivity of the functionality is masked or modified. As an example, suppose the transformation shown below was to be accomplished. 

3 For a general discussion and many examples of the use of the umpolung concept, see D. Seebach, Angew. Chem. Int. Ed. Engl., 18, 239 (1979). 

These reagents are capable of adding the a-alkoxyvinyl group to electrophilic centers. Subsequent hydrolysis can generate the carbonyl group and complete the desired transformation. 

4 For a review of acyl anion synthons, see T. A. Hase and J. K. Koskimies, Aldrichica Acta, 15, 35 (1982). 

For further discussion of synthetic applications of the carbanions of O-protected cyanohydrins, see J. D. Albright, Tetrahedron 39 3207 (1983). 

Sulfur compounds have also proven to be useful as nucleophilic acyl equivalents. The first reagent of this type to find general use was 1,3-dithiane, which on lithiation provides a nucleophilic acyl equivalent. The lithio derivative is a reactive nucleophile toward alkyl halides, carbonyl compounds and enones.116 117 118 

The electrophilic a,/8-unsaturated ketone is reactive toward nucleophiles, but the nucleophile which is required, 

as in the example above, a synthetic operation may require transfer of an acyl group as if it were a nucleophilic acyl anion. While acyl anions are not commonly 

A third term which has become useful for the discussion of synthetic analysis and planning is synthon. This term refers to a structural unit which has the potential for some specific synthetic operation. Again using the example above, we are searching for a group which would serve as a nucleophilic acyl synthon that is, some structural entity that would correspond to the addition of a nucleophilic acyl equivalent to an electrophilic carbon-carbon double bond. 

The resulting carbanion is an acyl anion equivalent since the carbonyl group can be regenerated by hydrolysis. In fact, this sequence has been used to solve the problem of adding an acetyl group to an a,/3-unsaturated ketone such as cyclo-hexenone. 

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Anions of (3-keto esters are said to be synthetically equivalent to the enolates of ketones. The anion of ethyl acetoacetate is synthetically equivalent to the enolate of acetone, for example. The use of synthetically equivalent groups is a common tactic in synthetic organic chemistry. One of the skills that characterize the most creative practitioners of organic synthesis is an ability to recognize situations in which otherwise difficult transfonnations can be achieved through the use of synthetically equivalent reagents. 

Many other examples of synthetic equivalent groups have been developed. For example, in Chapter 6 we discussed the use of diene and dienophiles with masked functionality in the Diels-Alder reaction. It should be recognized that there is no absolute difference between what is termed a reagent and a synthetic equivalent group. For example, we think of potassium cyanide as a reagent, but the cyanide ion is a nucleophilic equivalent of a carboxy group. This reactivity is evident in the classical preparation of carboxylic acids from alkyl halides via nitrile intermediates. 

Show how synthetic equivalent groups could be used to carry out each of the following transformations ... 

In Sections 10.1 and 10.2, Protective Groups and Synthetic Equivalent Groups, we will consider ways of temporarily modifying functional groups that would interfere with reactions at other points in the molecule. In Section 10.3, Asymmetric Syntheses, we will illustrate how stereochemistry at one point in a molecule can influence the stereochemical outcome of reactions at other points. In Section 10.4, Synthetic Strategy, we will illustrate the planning and execution of multistep syntheses, using examples from the recent literature. 

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