Synthetic tree

Bertz [5] has drawn the attention to the relationship existing between the concept of potential symmetry and the symmetry present in the corresponding "synthesis tree" (or "synthesis graph") [18]. In the abovementioned synthesis of usnic acid both branches of the synthesis tree are identical, and collapse into a single path, a fact that is most easily visualised by comparing synthetic trees for labelled (a) and unlabelled (b) usnic acid (see Diagram 4.1). 

In the direct-associative approach the chemist has available a number of subunits which he can bring together using standard laboratory reactions with which he is already familiar. This empirical approach is obviously limited to known reactions and subunits. The logic-centered approach on the other hand consists of the generation of sets of intermediates which form a synthetic tree which is used to lead to the target molecule. The different branches of this tree are the alternative routes one would choose or reject. In practice, most chemists use an approach which is a mixture of both. 

The user-friendly main menu driver, which allows the graphic input of educt and/or product structures, management of the (retro)synthetic tree (traversal through and display of nodes), display of structures generated by the SPS generator, selection of acceptable reactions and reaction paths, and similar interactive tasks. 

The input/output driver is also used for the (retro)synthetic tree inspection. The user can walk through the tree generated, inspect the selected nodes, edit them, and submit them for further processing by the SPS generator, thus creating new branches and levels of the (retro)synthetic tree. Each node of the (retrosynthetic trees stores not only the two-dimensional structure of the chemical compound, but also the distance from its father (i.e starting structure) measured by the reaction as well as chemical distances, and also its fragmentation level, measured by its order. 

The construction of a synthetic tree by working backward from the target molecule (TM) is called retro synthetic analysis or antithesis. The symbol ==> signifies a reverse synthetic step and is called a transform. The main transforms are disconnections, or cleavage of C-C bonds, md functional group interconversions (FGI). 

With the present design, a data base of fifty selected starting materials, and two hundred selected reaction rules SYNLMA is currently able to generate synthetic trees, often in a very naive or inefficient manner, for molecules of the size and complexity of Darvon, Ibuprofen,... 

If one of these bonds is to be disconnected, a reaction (or sequence of reactions) must be available that will chemically form that bond in the synthesis. Subsequent simplifications (disconnections) lead ultimately to a molecule that can be recognized as commercially available, available by simple chemical techniques, or already prepared by others. This process of structural simplification via disconnection leads to a series of molecular fragments that serve as key intermediates, and each is a synthetic target. Such intermediates allow the synthetic chemist to mentally bridge the starting material with the final target in a logical and sequential manner. This process therefore constitutes a synthetic tree for which chemical reactions must be provided to accomplish the planned transformations. 

A synthetic tree similar to that presented by Hendrickson is shown in Figure 10.1.40 59 target (Tq) is disconnected to "a logically restricted set of structures which may be converted in a single synthetic operation (a chemical step) to the synthetic target." - This gives the disconnection product in the first retro-reaction. The subtree represents further disconnection of one branch of the synthetic tree. After several retro-reactions, the synthetic tree will yield several starting materials from one or more of the first branches, which can then be used to construct the molecule. 

The second key step is lactone formation from the carboethoxy substituted cyclohexanone unit in 44. The third key step is construction of the tricyclic ring system by asymmetric radical cyclization of 43, and construction of 43 from 2-isopropylphenol (42) using alcohol chiral auxiliaries (R OH) was designated as the fourth key step. This disconnection scheme represents Yang s specific approach using key chemical transformations such as radical cyclization (see sec. 13.7). Clearly, other disconnections are possible, and at each stage other disconnections could lead to alternate synthetic trees. 

Each chemical fragment generated by the synthetic tree must possess chemical properties that are predictable and allow selective combination in only one of many possible modes. 

Transform based strategies. Identify a powerful transform for a specific target that produces a rea.sonable line in the synthetic tree. Two or three powerful simplifying transforms can be applied successively to the target structure. Alternatively, the same simplifying transforms can be repeatedly applied.- ... 

The reactions in Table 10.1 were classified as powerful due to the variety of transformations (formation of rings, molecular reorganization, generation of reactive functional groups from relatively unreactive functionality, or for functional group insertion) that were achieved all in essentially one synthetic step. Other reactions could easily be termed powerful, but these are sufficient to illustrate that if a reaction induces extensive and useful structural modifications, the synthetic tree should be biased to take advantage of that powerful chemistry. 

The synthetic examples in this section show that a biosynthetic pathway can be u.sed to generate a synthetic tree, which can be of great utility and simplifies the task of growing the synthesis tree. If the biosynthesis is unknown one can turn to other processes for guidance. 

In a complex synthetic tree (see Figure 10.18), 46 which pathway is the best As stated by Hendrickson, "selection, not generation, is the central problem."l47 xhe tree must be first simplified and then subdivided. 

A simple analysis of 242 shows a three-level synthetic tree. The first disconnection (I = 1) to 243 (t] = number of carbons = 11) and 244 (r = 5) requires a Diels-Alder disconnection (sec. 11.4.A). The level 2 disconnection to 245 (q = 7) and 246 (q = 4) is also a Diels-Alder disconnection. The final disconnection (level 3) generates cyclopentanone (247, q = 5) suggesting a condensation reaction with an organometallic. For this example, the weighted average (W) is given by the following calculation ... 

These concepts were developed into the computer program SYNGEN147 (SYNthesis GENeration). As with Corey s LHASA program, inspection of the main principles of the program can offer useful information for a synthesis. It is emphasized that this section has only touched the surface of Hendrickson s detailed and comprehensive analysis. Once understood, any target can be analyzed in detail to provide a synthetic tree. 

Structural information about complex molecules is often obtained by degrading a target into simple and identifiable pieces. Hydrolysis, thermolysis, photolysis, and treatment with chemical reagents are common methods for degrading a molecule. The points at which the molecule breaks apart are correlated with the known reactions by which these bonds can be re-formed. Analysis of all degradation products can then be used to construct a complete or partial synthetic tree or it can point to a key reaction that a synthesis can be built around. 

Hecht s synthetic approach was to first synthesize each of the individual pieces. The total synthesis required connection of the nine molecules to give bleomycin. The disconnected pieces are shown in Scheme 10.2li O and the plan to synthesize bleomycin from these pieces constitutes an outline of the synthetic tree. Hecht s synthesis of bleomycin A2 is also an excellent example of a convergent synthesis (sec. 10.3.C). Boger synthesized bleomycin using a different strategy. 

A target may resist hydrolysis or chemical degradation, or the degradation products may not yield useful information. It is also common that insufficient material exists for proper analysis. In these cases, an alternative degradation technique is available that uses the ionizing electron beam of a mass spectrometer. The ionization pathways available from electron impact in the mass spectmm are bond fission processes that occur by known and predictable pathways. Indeed, each pathway usually follows analogous chemical reaction pathways in a retro-synthetic manner. It therefore follows that an examination of mass spectral ionization patterns can give clues for suitable disconnections and a synthetic tree. 

This basic premise was outlined by Kametani and Fukumoto and used for the synthesis of a number of important alkaloids. As mentioned, the key feature of the analysis is the fact that many chemical reactions appear as their retro analog in the mass spectrum. These retro reactions are disconnections that can be translated directly to a synthetic tree. Some examples of retroreactions that have been identified in the mass... 

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