Alkenes retrosynthetic analysis

A retrosynthetic analysis for the alkene R R2C=CH R3 shows two possible carbonyl compounds as starting materials. 

The diol can be prepared from syn hydroxylation of (Z)-2-butene. The c/s-alkene can be prepared by hydrogenation of 2-butyne, and 2-butyne can be prepared by alkylation of propyne. The retrosynthetic analysis is ... 

Applying retrosynthetic analysis, the presence of the alkene group in the target suggests using a Wittig reaction in its preparation. 

Using retrosynthetic analysis, we recognize that the c/.v-epoxide can be prepared from the c/s-alkene. The m-alkene can be prepared by catalytic hydrogenation of an alkyne. Finally, substituted alkynes can be prepared by nucleophilic substitution reactions using acetylide ion nucleophiles (see Section 10.8). On the basis of this analysis, the synthesis reported in the literature was accomplished as shown in Figure 23.3. 

Chapter 8 begins the treatment of organic reactions with a discussion of nucleophilic substitution reactions. Elimination reactions are treated separately in Chapter 9 to make each chapter more manageable. Chapter 10 discusses synthetic uses of substitution and elimination reactions and introduces retrosynthetic analysis. Although this chapter contains many reactions, students have learned to identify the electrophile, leaving group, and nucleophile or base from Chapters 8 and 9. so they do not have to rely as much on memorization. Chapter 11 covers electrophilic additions to alkenes and alkynes. The behavior of carbocations, presented in Chapter 8, is very useful here. An additional section on synthesis has been added to this chapter as well. 

Q Use retrosynthetic analysis to solve multistep synthesis problems with alkenes as reagents, intermediates, or products. 

A systematic retrosynthetic analysis begins with an examination of the structure of the product. We will consider the synthesis of the following compound from alkenes containing up to five carbon atoms. 

A thoughtful reader would have noticed that, while plenty of methods are available for the reductive transformation of functionalized moieties into the parent saturated fragments, we have not referred to the reverse synthetic transformations, namely oxidative transformations of the C-H bond in hydrocarbons. This is not a fortuitous omission. The point is that the introduction of functional substituents in an alkane fragment (in a real sequence, not in the course of retrosynthetic analysis) is a problem of formidable complexity. The nature of the difficulty is not the lack of appropriate reactions - they do exist, like the classical homolytic processes, chlorination, nitration, or oxidation. However, as is typical for organic molecules, there are many C-H bonds capable of participating in these reactions in an indiscriminate fashion and the result is a problem of selective functionalization at a chosen site of the saturated hydrocarbon. At the same time, it is comparatively easy to introduce, selectively, an additional functionality at the saturated center, provided some function is already present in the molecule. Examples of this type of non-isohypsic (oxidative) transformation are given by the allylic oxidation of alkenes by Se02 into respective a,/3-unsaturated aldehydes, or a-bromination of ketones or carboxylic acids, as well as allylic bromination of alkenes with NBS (Scheme 2.64). 

To use the Heck reaction in synthesis, you must determine what alkene and what organic halide are needed to prepare a given compound. To work backwards, locate the double bond with the aryl, COOR, or CN substituent, and break the molecule into two components at the end of the C = C not bonded to one of these substituents. Sample Problem 26.3 illustrates this retrosynthetic analysis. 

The brief report of Jacobsen s total synthesis starts with a detailed retrosynthetic analysis. The compound was broken into four pieces 21a after removal of the phosphate. The unsaturated lactone 24 (M is a metal) could be made by an asymmetric oxo-Diels-Alder reaction from diene 22 and ynal 23. The epoxide 25 provides a second source of asymmetry. One cis alkene comes from an alkyne 26 and the rest from a dienyl tin derivative 27. 

Electrophilic addition to alkenes ch19 Electrophilic attack on benzene Retrosynthetic analysis ch28... 

It s often a good idea to start retrosynthetic analysis of target molecules containing isolated double bonds by considering FGI to the alkyne because C—C disconnections can then become quite easy. The cis-alkene below is an intermediate in the synthesis of a component of violet oil. FGI to the alkyne reveals two further disconnections that make use of alkyne alkylations. The reagent we need for the first of these is, of course, the epoxide as there is a 1,2-relationship between the OH group and the alkyne. 

In this chapter we described methods for the synthesis of alkenes using dehydrohalogenation, dehydration of alcohols, and reduction of alkynes. We also introduced the alkylation of alkynide anions as a method for forming new carbon-carbon bonds, and we introduced retrosynthetic analysis as a means of logically planning an organic synthesis. 

The oxidative cleavage of alkenes has also been used to establish the location of the double bond in an alkene chain or ring. The reasoning process requires us to think backward much as we do with retrosynthetic analysis. Here we are required to work backward from the products to the reactant that might have led to those products. We can see how this might be done with the following example. 

The retrosynthetic analysis is outlined in Scheme 22. The amide was introduced by the Curtius rearrangement, and the macrolide 117 was formed by Horner-Emmons macrocyclization at the C2-C3 bond. The C17-C18 bond was constructed by the ring-opening of epoxide 118. 119 was formed via the Kocienski-Julia olefination at the C8-C9 bond. The cis-2,6-disubstituted tetrahydropyran in 120 was constructed by the Petasis-Ferrier rearrangement. The C4-C5 (Z)-trisubstituted alkene in 121 was formed by carbomet-allation to an alkyne. 

Retrosynthetic analysis of nitrile 164 disconnects the C-CN bond because it is clear that the six carbons of the methylcyclopentene starting material are more or less intact in the remainder of the molecule. This disconnection requires a C-C bond-forming reaction involving cyanide. Because cyanide is associated with a carbon nucleophile, assign Cj to the cyanide and to the cyclopentene carbon. The synthetic equivalent for Cg is an alkyl halide, and 2-bromo-l-methylcyclopentane (168) is the disconnect product. Bromide 168 is obtained directly from the alkene starting material, but it requires the use of a radical process to generate the anti-Markovnikov product (see Chapter 10, Section 10.8.2). 

In order to complete the synthesis, the starting material must be converted into the alkene. At this point, we can think forward, in an attempt to converge with the pathway revealed by the retrosynthetic analysis ... 

Wittig reactions, and reactions related to it, are used for the regiospecific synthesis of alkenes from aldehydes and ketones. Their retrosynthetic analysis begins with disconnecting the double bond as shown and introduces a novel stmctural type called an yiide. 

In the next example disconnection of an alkene reveals some typical pitfalls when proposing a synthetic route based on seemingly acceptable retrosynthetic analysis. 

It is not immediately obvious how to carry out this synthesis, so let s use retrosynthetic analysis to find a way. The only method you know for introducing a C=N group into a molecule is nucleophilic substitution. The alkyl halide for that substitution reaction can be obtained from die addition of HBr to an alkene in the presence of a peroxide. The alkene for that addition reaction can be obtained from an elimination reaction using an alkyl halide obtained by benzylic substitution. 

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