Transform, retro-synthetic

TPP = 5,10,15,20-tetraphenylporphine, 252 Tpte protecting group, 216, 217 Trajectories in reactions of nucleophiles, 316 trans-Selectivity. See cis/trans Transcriptase, reverse, 242 Transform, retro-synthetic, 193-196 Triamterene, 308 Trias teranone, 94... 

By applying the principles of retro synthetic analysis, show how each of the indicated target molecules could be prepared from the starting material(s) given. No more than three separate transformations are necessary in any of the syntheses. 

In this section, we will consider several syntheses of five illustrative compounds. We will examine the retro synthetic plans and discuss crucial bond-forming steps and, where appropriate, the means of stereochemical control. In this discussion, we will have the benefit of hindsight in being able to look at successfully completed syntheses. This retrospective analysis can serve to illustrate the issues that arise in planning a synthesis and provide examples of solutions that have been developed. The individual syntheses also provide many examples of the synthetic transformations presented in the earlier chapters and of the use of protective groups in the synthesis of complex molecules. 

Retro-synthetic analyses ( = "antitheses") of relatively simple, but non-commercial target molecules are described. Stepwise disconnections and functional group interconversions are used to transform the desired molecule into inexpensive commercial compounds. 

In a synthesis of tetronomycin (45) published in 1994 [14], Semmelhack et al. probe the scope of intramolecular alkoxypalladations. The retro-synthetic analysis (Scheme 4) shows that the chosen strategy exploits such Pd-catalyzed transformations even twice. The pre-target structure 46 is formally derived from 47 by Pd-mediated cy-clization. Compound 47 can be traced back via 48 to the tetrahydrofuran derivative 49, which in turn should be available by alkoxycarbonyla-tion from a precursor of type 50. 

Organic synthesis has undergone the transformation from a purely heuristic discipline into a solid branch of science with its own logistics and technology based on the principles of retrosynthetic analysis. An essential part of retro-synthetic analysis involves the sequential disconnection of the target molecule... 

Of course, such an effective windfall upon retrosynthetic analysis does not happen very often. Nevertheless, it is generally recommended that the retro-synthetic analysis of polycyclic structures should be directed first to the search of pathways that lead to one stroke framework assemblage. These possibilities can usually be accomplished with the help of cycloaddition reactions. In the course of the initial analysis, special emphasis should be given to identify structural features of the strategic core which might lead to the use of cycloaddition transforms. Let us examine a few more examples that illustrate the fruitfulness of such a retrosynthetic beginning. 

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). 

Reaction Descriptions. Before discussing the work on data base expansion, a short description of the representation used for data storage is in order. The basic unit of information in the data base is the transform 7)which describes, in the retro-synthetic direction, the structural changes caused by a chemical reaction. Each transform consists of three sections ... 

Borrelidin 1 has attracted attention because it inhibits angiogenesis, and so potentially blocks tumor growth, with an IC., of 0.8 nM. Retro.synthetic analysis of 1 led the investigators to the prospective intermediates 2 and 3. To assemble these two fragments, they interatively deployed the elegant enantio- and diastereoselective intermolecular reductive ester aldol condensation that they had recently developed. This transformation is exemplified by the homologation of 4 to 6 catalyzed by the enantiomerically-pure Ir complex 5. 

A synthon may be defined as— a structural unit that becomes an idealized fragment as a result of disconnection of a carbon-carbon or carbon-heteroatom bond in a retro synthetic step (transform) . 

It will be useful to use a few terms coined by Corey and Wipke pS) in the discussion of this work. Since the logic-centred approach of generating a synthetic tree involves analytic processes which depend heavily upon the structural features of reaction products and the consideration of molecular changes in the retro-synthetic sense, the direction of computer analysis is termed antithetic as opposed to the direction of laboratory execution which is termed synthetic . A process in the antithetic direction is called a transform while a process in the synthetic direction is called a reaction . A reac-... 

Taken as a whole, the proposed synthetic route amounts to a retro-synthetic blueprint of extraordinary symmetry and appeal with two different hetero-Diels—Alder reactions comprising the essence of the strategy. Without question, achieving this total synthesis would be predicated on successful execution of each step in a tandem manner, a matter of some consequence as none of the proposed transformations had ever been demonstrated in non-monomeric contexts. For instance, the numerous intermediates of the assumed mechanism for the Komfeld reductive ring contraction conversion (vide infra) could provide ample opportunity for undesired side reactions in the projected isochrysohermidin synthesis. Thus, con-... 

Section 8.12 Retro synthetic analysis can suggest a synthetic transformation by disconnecting a bond to a functional group and considering how that group can be introduced into the carbon chain by nucleophilic substitution. 

A further redox transformation for which enzymes turned out to be suitable is the reduction of an activated C=C bond. Thus, besides reductive transformations of carbonyl moieties, the enzymatic reduction of activated alkenes has also been recently studied very extensively [112,113]. From a retro-synthetic perspective such transformations are of great interest as well, since a broad range of electron-withdrawing groups are conceivable as substituents at the C=C double bond, thus leading to the required activated alkene. In recent years this reaction has attracted a lot of interest due to numerous synthetic applications. 

There are certainly many acceptable methods for achieving the desired transformation. The following retro synthetic analysis represents one such method. An explanation of each of the steps (a-/) follows. 

Now we must replace the nitro group with a bromine atom. One method for accomplishing this transformation involves the use of a Sandmeyer reaction, as seen in the following retro synthetic analysis ... 

Several chemical transformations in the chlorin series were discovered during the course of Woodward s total synthesis of chlorophyll a.3a d An important reaction in the final steps of this total synthesis is the removal of an a-oxo acid ester residue from the 17-position of the chlorin 22, which proceeds very smoothly in the presence of base by a retro-aidol-type fragmentation to yield the chlorin isopurpurin methyl ester (23) which is also available by degradation of chlorophyll a, so that at this point of the synthesis synthetically derived material could be compared with an authentic sample prepared from natural chlorophyll a. 

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

A possible synthetic pathway to seychellene (28) (Scheme 4.9) [23], for example, requires a) the substitution (FGI) of the terminal methylene group by an equivalent synlhon, such as a carbonyl group b) introduction (FGA) of a double bond in one of the cyclohexane rings and c) a retro-Diels-Alder cycloelimination (equivalent to a Diels-Alder transform) (see Heading 6.2) ... 

In conclusion, the longest linear sequence of Yamada s (-)-claenone (42) synthesis consist of 40 steps (6 C/C connecting transformation) with an overall yield of 2.1%. The centrepiece of Yamada s synthetic strategy is the sequence of two Michael additions and a retro-aldol addition to provide a highly substituted cyclopentanone building block (52). 

The structural similarity between claenone (42) and stolonidiol (38) enabled Yamada to exploit an almost identical strategy for the total synthesis of (-)-stolonidiol (38) [40]. A short retrosynthetic analysis is depicted in Fig. 12. An intramolecular HWE reaction of 68 was successfully applied for the macrocyclization. The highly substituted cyclopentanone 69 was made available by a sequence that is highlighted by the sequential Michael-Mi-chael addition between the enolate 53 and the a, -unsaturated ester 70 followed by a retro-aldol addition. However, as is the case for the claenone (42) synthesis, the synthesis of stolonidiol (38) is characterized by numerous functional and protecting group transformations that are a consequence of Yamada s synthetic strategy. 

---