Retrosynthesis approach

Among the oxazole syntheses not simply deducible from classical retrosynthesis approaches applying isocyanides as starting materials are of considerable interest [263]. (a) In the van Leusm synthesis, TosMIC reacts with aldehydes under base catalysis (e.g., K2CO3) to give 5-substituted oxazoles 41 ... 

Among the several strategies developed for carbazole syntheses, organometallic approaches to carbazoles have received special attention, since they have led, in many cases, to highly convergent total syntheses of carbazole alkaloids (8,10, 570-572). The iron-mediated retrosynthesis of 1-oxygenated carbazoles 7-11 leads to cyclohexadiene (597) and the corresponding arylamines 598-600 as synthetic precursors (Scheme 5.32). 

The retrosynthesis of this compound by Batey and co-workers [96] recognized that the unprecedented hexahydropyrrolo[3,2-c]quinoline core could be synthesized using a three-component Pavarov hetero-Diels-Alder reaction [97]. For this synthetic strategy to be successful, however, reaction conditions that favor the exo approach of the dienophile over the endo approach had to be found. For this purpose, a variety of protic acids were tested, and it was found that the reaction was best carried out in the presence of camphorsulfonic acid (CSA). Indeed, a mixture of 4-aminobenzoate 200 and N-Cbz 2-pyrroline 201 were stirred at room temperature in the presence of catalytic CSA to afford exo cyclo-adduct 203 as the major product (Scheme 12.28). The N-Cbz 2-pyrroline served as both an aldehyde equivalent and a dienophile in this context. The Diels-Alder adduct 203 already bore all the requisite functionalities for the successful completion of the synthesis, which was achieved in six additional steps. 

The disconnection approach to synthesis essentially involves working backwards from a target compound in a logical manner (so-called retrosynthesis), so that a number of possible routes and starting materials are suggested. This approach has been applied mainly to alicyclic, carbocyclic, and saturated heterocyclic systems. Retrosynthetic analyses are presented in this text not as an all-embracing answer to synthetic problems, but rather as an aid to understanding the actual construction of unsaturated heterocycles. 

For the synthesis of a heptanal derivative 30 (D in the retrosynthesis) from 19, we investigated two different approaches. The first approach relied on the Wittig olefination of aldehyde 25 (Scheme 3). The second was based on the attack of 2-lithio-2-methylpropionitrile (a-lithiated isobutyronitrile) [56-60] on the Payne rearrangement product 20 (Scheme 4). Our original attempt at the preparation of heptanal 30 from... 

In the retrosynthesis of 227, the authors identified three types of elements depending on the number of sugar units attached to them. Two components carried sugars at 03 and 06, four held substituents at 02, and the last three had no monosaccharides attached. According to that, the nonasaccharide target could be correlated with only two mannopyranose precursors 228 and 229, since synthon 228 could be used to access the last two kinds of sugars. The approach featured the final link of a pentasaccharide donor with a tetrasaccharide acceptor, as outlined in Scheme 32. 

Retrosynthesis is a synthesis approach that starts at the product level and breaks it into simpler molecules until cheap and commercially available starting materials... 

For the retrosynthesis of the imidazole system (see Fig. 5.15), it is essential that the heterocycle possesses the functionality of an amidine on C-2 and that of a 1,2-enediamine on C-4/C-5. Ret-roanalysis should, therefore, consider two approaches ... 

Figure 7.9 A bimacrocyclic pyridine can be constructed following three different approaches (a) a non-macrocyclic precursor is doubly cyclized to give the bimacrocycle, shown in the middle, or (b) it can be built up stepwise. The left retrosynthesis represents the bridging of a X and Y containing macrocycle by a pyridine bridge while the right retro-synthesis starts from a pyridine-containing macrocycle...

Integerrinecic acid (Scheme 3.25), despite its small size, has branches and functional groups enough to practise meaningful retrosynthesis. The construction plan of three very similar syntheses [40, 41, 42] (sequence of bond formation (1), (2), (3)) shows that all cuts are made to create branches with the aid of the existent functionality. Work backwards (3) —> (2) — (1) to recognize by which reactions a synthesis can be reahzed. For a completely different approach, see reference [43]. 

The discussion in this text has presented rules by which it becomes possible to plan syntheses in a reasonable manner. This textbook approach to retrosynthesis stands in contrast to many surprising artistic solutions to synthesis problems. Such solutions may arise by imaginative incorporation of skeletal rearrangements into the plaiming of syntheses [167]. This holds particularly for the synthesis of bridged polycyclic structures. Scheme 6.48 illustrates some examples relating to the synthesis of the quadrone skeleton. 

The first problem will prepare 4-bromoaniline (168) from benzene. Syntheses that transform one aromatic compound into another aromatic compound, such as this one, do not lend themselves to the retrosynthetic analysis approach presented in Chapter 25. Most of these syntheses involve functional group transformations. For the sake of continuity, a retrosynthesis is shown in which the amino group is removed to generate bromobenzene, which is obtained directly from benzene. The NH2 unit probably comes from reduction of a nitro group (Section 21.6.2), so the first precursor is 4-bromonitrobenzene (59) and disconnection of the C-N bond leads to the preparation of 59 by reaction of bromobenzene (35) with nitric acid/sulfuric acid. Bromobenzene is prepared directly from benzene as shown in the illustration. 

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