Retro-Synthesis

Throughout this section, and indeed the majority of this article, we have been concerned with developing and using evaluations in order to model reactions in a forward direction, that is, to predict the products from given starting materials. We now briefly consider how the reactivity functions could have application in retro-synthesis studies. 

Dioxalicyclo[3.2.1]octane, or (+)-exo-brevicomin (66), is the aggregating pheromone of the western pine beetle. It has been prepared from glucose using a procedure based on the retro synthesis design shown in Figure 1-2884 ... 

The antibiotic sarkomycin (5), an antitumor agent, is a good target for synthetic efforts based on a Diels-Alder reaction. The retro synthesis of this compound is depicted in Scheme 5-3. 

Taking 1,2-disubstituted cyclopropane as an example, retro synthesis analysis shows that there are three possible ways to disconnect the three-membered ring—a, b, and c as shown in Figure 5-11. Route a involves the addition of methylene across a double bond, and this is often a stereospecific conversion or Simmons-Smith reaction.92 One can clearly see that route b or c will encounter the issue of cis/trans-product formation. 

Mukaiyama s Synthesis. Mukaiyama s synthesis starts with construction of the B-ring moiety, and aldol reactions are used extensively throughout the entire synthesis process.34 The retro synthesis is outlined in Scheme 7-66. 

Many examples of the convergent strategy (b) can be found in contemporary approaches to natural products synthesis. Usually the routes to target molecules (e.g. I) are derived by retro-synthesis from the final product [6]. This involves transformation of the target molecule to lower molecular weight precursors (e.g. A-F). 

Figure 6.1 Alkene complexes in organic (retro)synthesis ( n isomers shown iso or branched alternatives are also accessible)...

A similar disconnection strategy was adopted by Dixon et al. in the United Kingdom in the synthesis of muricatetrocin The retro-synthesis disconnected the... 

In order to confirm the structures of solanapyrones, chemical synthesis of these phytotoxins were attempted based on biogenetic consideration [55], The retro synthesis envisaged intramolecular Diels-Alder reaction of the achiral polyketide triene (a), a key intermediate, which is further divided into a pyrone moiety (b) and a diene moiety (c). The moieties a and b were prepared from dehydroacetic acid and hexadienyl acetate, respectively. Aldol condensation of the aldehyde (72) with the dithioacetal (73) gave a dienol, which was further converted to a triene (74). The intramolecular Diels-Alder reaction of 74 in toluene at 170-190 °C for 1 hr in a sealed tube yielded a mixture of the adducts (75) and (76) in a ratio of 1 2. This product ratio depends on the solvents, i.e. in water (1 7), and should be useful in differentiating between artificial and enzymatic reactions in biosynthetic studies. Removal of the thioacetal groups in 75 and 76 yielded solanapyrone A (67) and D (70) in a ratio of 3 5. Though solanapyrone D (70) had not been isolated from the natural resources at this stage, the structure and stereochemistry were confirmed by H NMR spectrum. 

The first disconnection lib (reductive amination) takes no consideration of the chirality at all - we will worry about this later. We already have a six membered ring and it now contains all the chirality. The introduction of double bonds by FGA is used to considerable effect in this retro-synthesis. The first new alkene allows us to do an aldol disconnection 13 that not only removes a carbon chain but also reveals an electron-withdrawing group on the six-membered ring 14. This is, of course, one vital component of the Diels-Alder reaction. The next FGA puts in the double bond that allows us to do the retrosynthetic Diels-Alder step 15. 

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