Disconnections in retrosynthetic analysis

While the carbonyl group is a very common starting point for bond disconnections in retrosynthetic analysis, an olefinic or acetylenic unit is also a useful reference point in many instances. This is because a terminal acetylene can be used as an... 

This chapter has reviewed the most fundamental concepts of stereochemistry and conformational analysis, with some applications to more complex problems. For students who have had a good undergraduate organic chemistry course, it is intended as a review, since these concepts are integral to the understanding of organic reactions. The concept of disconnection and retrosynthetic analysis is a prelude to a discussion of synthetic strategies in Chapter 10. The disconnection method and pertinent transforms will, however, be presented in virtually every chapter as new reactions are introduced. 

There are three key mles to be followed in retrosynthetic analysis disconnection should follow the correct mechanism, allow maximal simplification of the TM and lead to available starting materials. The fexofenadine molecule can be maximally simplified by discormections made at critical bonds (Scheme 10.3). These are disconnections at the CH2-aryl bond (a) and an alternative disconnection of the CH2-CH2Ar bond (b). In addition, disconnection of the N-CH2 bond, after FGI of the amine to an amide group, represents another possibility (c), which can be completed to create a pathway to the sila-bioisostere of fexofenadine, as described in Sect. 10.4.3. 

Here it is important to note the principle difference between the retrosynthetic steps in Schemes 1.3 and 1.4. In the first one we anticipate interconversion of the functional group (FGI), in the second one the disconnection of the C-C bond (DIS). They reflect the difference between two basic types of reactions in synthetic organic chemistry the transformation of one functional group and formation of a new C-C bond. By far more synthetically important are C-C bond-forming reactions, which enhance the complexity of the carbon skeleton. A rather sharp difference between these two types of reactions in synthetic organic chemistry is reflected in retrosynthetic analysis. Disconnection of the C-C bond in TM la is presented in some detail (Scheme 1.5). 

After appropriate disconnections, the retrosynthetic analysis of GPI-anchored PrP arrived to the simplified building blocks GPI fragments 123-125 and the protein thioester 126 (Scheme 12.17a). The cysteine residue in the GPI was incorporated with the H-phosphonate 125 placing it at the C6 position of Manlll. 

In retrosynthetic analysis, we recognize the need for the Claisen rearrangement when we see a y,6-unsaturated carbonyl compound. Compound 8.19 contains unsaturation y, 6 to the bromo-functional carbon. Consider a carbonyl compound as a likely intermediate and then write a retro-Claisen rearrangement (Scheme 8.19). The ketene acetal could come from ethyl orthoacetate. Continue with a disconnection at the alcohol. The actual synthesis is shown in Equation 8.37 [52]. 

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