THE STRATEGIC BOND APPROACH

It is important to emphasize that the following rules are only guidelines. There are many examples of excellent syntheses that have violated one or more of them. They are presented as being a reasonable place to begin planning a synthesis, but by no means are they intended to discourage ideas that do not formally follow these rules. If a disconnection is reasonable and there is either known chemistry or planned chemistry to reconstitute that bond in a synthesis, proceed. 

Corey s analysis begins with an inspection that will determine if there are methods by which the molecule can be simplified. Such simplification will shorten the synthesis and the retrosynthetic analysis will be biased to follow that route. There are three criteria. - 

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However, as we will see below, twistane has been used as a model for testing the validity of the retrosynthetic analysis approach [2], as well as the soundness and/or limitations of the "strategic bond" concept. 

An important feature of the philosophy of retrosynthetic analysis is clearly exposed in the described approaches to the syntheses of quadrone. In general, there are only a few bonds in the target molecule that can be reasonably considered as breakable and even fewer of them as strategic . The selection of the strategic bond will dictate the flavor of the rest of the dismantling down to suitable precursors and hence lead to synthetic plans as varied as those utilized for the the quadrone syntheses. 

Select the strategic bond. This recommendation is especially important in those numerous cases in which the initial analysis does not identify an efficient strategic reaction and, hence, a sequential bond-by-bond dismantling of the structure becomes obligatory. The first bond in this sequence (the strategic bond) defines all subsequent steps in the retrosynthetic analysis. This approach was illustrated in the syntheses of quadrone (Section 3.2.5). 

To build intelligence into the reaction prediction programs, the strategic bonds which are cleaved or formed during a reaction are identified. A disconnection approach is used to reveal the synthon and retron for a reaction which helps the user in designing synthetic routes for a molecule of interest. 

Another alternative approach to the Corey s rules for the selection of "strategic bonds" are the "complexity indices" based on the mathematical model proposed by Bertz [23] which allow the "quantification" of the molecular complexity and to determine whether a given disconnection is indeed simplifying and how much so. The indices predict "strategic bonds" quite well, with the exception of those which are "core bonds" since the limitations imposed by Corey s rule number 4 do not apply here. 

Smith and co-workers reported their second-generation approach to discodermolide in 1999, which was now performed in the correct enantiomeric series [46—48]. By carefully redesigning the route, the overall number of steps was significantly reduced and, importantly, it enabled a gram-scale synthesis. As outlined in Scheme 7, the key bond constructions at C8-C9 and C14-05 were retained, while strategic modifications involved the earlier introduction of the terminal (Z)-diene unit in 44 and a revised C1-C8 subunit 45. 

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