Synthetic dissonance

Bifunctional systems In the case of bifunctional systems (or molecules) only two alternatives are possible the bifunctional relationships are either "consonant" or "dissonant" (apart from molecules or systems with functional groups of type A to which we have referred to as "assonant"). In the first case, the synthetic problem will have been solved, in principle, in applying the "heuristic principle" HP-2 that is to say, the molecule will be disconnected according to a retro-Claisen, a retro-aldol or a retro-Mannich condensation, or a retro-Michael addition, proceeding if necessary by a prior adjustment of the heteroatom oxidation level (FGI). 

On the contrary, if a "dissonant" bifunctional relationship is present in the system or molecule under consideration, then the synthetic problem may be much more complex and we will have to resort to some of the methods especially designed for such purposes, which will be discussed in the next Chapter. 

The synthetic applications of sigmatropic rearrangements to the synthesis of dissonant molecules (mainly 1,6-D) were extensively studied by Evans [22]. Although such a methodology meets the first two requirements of "logical disconnections", it does not meet the third one since it lacks simplicity. 

Since disconnection of any of the C-C bonds of a dissonant system leads to two fragments of identical reactivity (either nucleophilic or electrophilic), in the synthetic direction the reactivity of one of the two fragments must be inverted (see 5.1, "illogical disconnections"). Another possibility, however, is to oxidise or to reduce the resulting fragments to radical species. 

In contrast, the so-called bis-nor-Wieland-Miescher ketone (2) is a more complex synthetic problem, since the molecule is a multidissonant system with two dissonant bifunctional group relationships (1,4-D and 1,6-D) and two dissonant cyclopentane rings, besides a 1,5-consonant bifunctional group relationship. Its synthesis was only accomplished 30 years after the synthesis of its consonant homologue [5],... 

In the preceding Chapter we have already referred to some classical synthetic methods which proceed via radicals and which are usually used for the synthesis of dissonant molecules, including some cyclic and polycyclic systems. 

As in the heterolytic cleavage of bonds, the resulting synthons must be elaborated to give the reagents or synthetic intermediates that should be used in the laboratory. In our example, the dissonant 1,4-carbonyl system can be synthesised in the laboratory following either route A or B. 

Remember, however that CHAOS does not intend to be a database of "synthetic methods" presently available to organic chemists. CHAOS is aimed at finding the intermediate precursors of the "synthesis tree" by means of selected basic disconnections (either "consonant" or "dissonant"). In the author s view, it is of minor importance, for instance, how a "carbene" -resulting from a -(2 + 1) cycloelimination- is generated, or whether a double bond is the direct result of a Wittig reaction or the dehydration of an alcohol formed in a Grignard reaction. In... 

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