Building the Carbon Skeleton

There are still at least five reaction steps, but only three sequential steps and if each of these proceeds in 90% yield, the overall yield would be (0.90)3 X 100 = 73%. The parallel approach is especially important in the synthesis of polymeric substances such as peptides, proteins, and nucleic acids in which many subunits have to be linked. 

Finally, product yields are very dependent on manipulative losses incurred in each step by isolating and purifying the synthetic intermediates. The need to minimize losses of this kind is critically important in very lengthy syntheses. 

Exercise 13-15 Syntheses have been carried out with one hundred or more sequential reactions. If the yield in each step is 99%, what would be the overall yield after one hundred steps Repeat the calculation for a yield of 99.9% in each step. What do you conclude from these calculations about the importance of yield in multistep syntheses (It is interesting to contemplate how even simple organisms can synthesize molecules by what appear to be sequences of 10,000 or more separate steps with very few, if any, errors, and what means the organisms have to check the accuracy of the sequence after each incorporation of a new subunit.) 

According to the suggested approach to planning a synthesis, the primary consideration is how to construct the target carbon skeleton starting with smaller molecules (or, alternatively, to reconstruct an existing skeleton). Construction of a skeleton from smaller molecules almost always will involve formation of carbon-carbon bonds. Up to this point we have discussed only a few reactions in which carbon-carbon bonds are formed and these are summarized in Table 13-4. Other important reactions that can be used to enlarge a carbon framework will be discussed in later chapters. 

The most logical approach to planning the synthesis of a particular carbon framework requires that one work backward by mentally fragmenting the molecule into smaller pieces that can be rejoined by known C-C bondforming reactions. The first set of pieces in turn is broken into smaller pieces, and the mental fragmentation procedure is repeated until the pieces correspond to the carbon skeletons of readily available compounds. There almost always will be several different backward routes, and each is examined for its potential to put the desired functional groups at their proper locations. In almost all cases it is important to use reactions that will lead to pure compounds without having to separate substances with similar physical properties. 

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A three-step synthesis of a mixture of stereoisomers of 5,9 -dimethylpentadecane, the sex pheromone of the coffee leaf miner, Leucoptera coffeella, has been described. The key step being the unsymmetrical Wittig olefination to build the carbon skeleton of the molecule. 

This exhaustive approach is very time-consuming. It works well on a large computer, but most organic chemists solve problems more directly by attacking the crux of the problem steps that build the carbon skeleton. Once the carbon skeleton is assembled (with usable functionality), converting the functional groups to those required in the target molecule is relatively easy. 

The disconnections we have made so far have all been of C—O, C-N, or C-S bonds, but, of course, the most important reactions in organic synthesis are those that build the carbon skeleton by forming C-C bonds. We can analyse C-C disconnections in much the same way as we ve analysed C-X disconnections. Consider, for example, how you might make the simple compound in the margin, which is an intermediate in the synthesis of a carnation perfume. 

Count the carbon atoms of the carbon skeleton of the target molecule. Determining how to build the carbon skeleton from available starting materials is often the most challenging part of a synthesis. If you must add carbons, you need to consider... 

In the 1950s, acetylenic compounds were employed in a variety of ways for building the carbon skeleton of natural retinoids. The reason for this is that acetylenes, after metalation with a Grignard reagent, can be employed for a very large variety of carbon-carbon coupling reactions (see Section V, A) (Isler et al., 1956 Isler and Schudel, 1963). 

Bond-line drawings show the carbon skeleton (the connections of all the carbon atoms that build up the backbone, or skeleton, of the molecule) with any functional groups that are attached, such as - OH or -Br. Lines are drawn in a zigzag format, where each comer or endpoint represents a carbon atom. For example, the following compound has 7 carbon atoms ... 

Methods with Building Up of the Carbon Skeleton of the Allene... 

Level 2 The atoms or groups of atoms of the different control elements, once the control has been exerted, are used in subsequent stages of the synthesis to build up the carbon skeleton of the target molecule, so that they become an integral part of it. This is the case in Woodward s synthesis of strychnine. 

The overall strategy is to build the carbon-nitrogen skeleton of a purine ring system in a 12-step process directly on the sugar-phosphate starting material, a. The first step creates the multi-purpose intermediate 5 -phosphorihosyl-l-... 

A word of warning is also necessary. Some natural products have been produced by processes in which a fundamental rearrangement of the carbon skeleton has occurred. This is especially common with structures derived from isoprene units, and it obviously disguises some of the original building blocks from immediate recognition. The same is true if one or more carbon atoms are removed by oxidation reactions. 

The aim of biosynthetic experiments with fungal metabolites is to establish the structure of the building blocks, the order in which they are assembled, the way in which chains are folded to form the carbon skeleton and the sequence interrelating precursors with the final metabolite. Biosynthesis is concerned with both sequences and reaction mechanisms. The sequence of the biosynthetic events, the role of intermediates and the stereochemistry of enzymatic reactions can be studied with appropriately isotopically-labelled substrates and with structural analogues of the natural intermediates. The chemical enzymology of individual steps and the role of key components and structures of the enzyme may be studied with isolated enzyme systems obtained from fungi. The features that determine the function of the enzyme and which control its activity may be determined by genetic studies in which mutants play an important role. 

By retro synthetic analysis collagenase inhibitor RO0319790 (1) can be assembled from two chiral building blocks, (R) -succinate 2 and (S)-tert-leucine N-methyla-mide 13. As the latter can be prepared from commercially available (S)-tert-leucine 8 our work concentrated in particular on the construction of the first building block 2. In order to assemble the carbon skeleton of 2 in the most efficient way, extremely cheap maleic anhydride 4 was converted in a known ene reaction with isobutylene to provide the cyclic anhydride 6. Hydrogenation of the double bond followed by the addition of EtOH/p-TsOH yielded the racemic diethyl ester substrate 9 for the enzyme reaction. The enzymatic monohydrolysis of 9 afforded the monoacid (R)-2a. (R)-2 a was coupled via its acid chloride with leucine amide 13 to ester 14, which finally was converted into the hydroxamic acid 1. 

For simplicity, the structures in Figure 6.32 do not show the titanium complexes in full, as these would make the crucial changes in the carbon skeleton more difficult to see. Also for the same reason, the cedrane skeleton is drawn in a different way from that used in previous figures. (Any reader who does not see that the drawings of (6.91) in Figures 6.31 and 6.32 represent the same molecule, should build a molecular model to convince him/herself that this is the case.) The first stage involves the addition of an acyl cation equivalent to cedrene to give the... 

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