Forward synthetic analysis

FIGURE 9.2 Forward synthetic analysis in DOS. (Reproduced with permission from American Chemical Society from Lee, D., Sello, J. K., Schreiber, S.L. Pairwise use of complexity-generating reactions in diversity-oriented organic synthesis. Org. Lett. 2000, 2(5), 709-712. Copyright 2000, American Chemical Society.)... 

Diversity being the core criterion, the synthesis is planned generally by forward synthetic analysis. To synthetically access the core structure of validated small molecule, e.g., a natural product scaffold, retrosynthetic analysis is important. However, for adding diversity, forward synthetic analysis is also helpful. 

Figure 4.1. Planning strategies and end goals involved in target-oriented synthesis, focused library synthesis (combinatorial synthesis), and diversity-oriented synthesis. The first two approaches use retrosynthetic analysis to design the synthesis of target compounds. Diversity-oriented synthesis uses forward synthetic analysis to produce libraries that occupy diffuse regions of chemical space.

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. 

Organic Synthesis Organic synthesis is stressed throughout this book, with progressive discussions of the process involved in developing a synthesis. Retro synthetic analysis is emphasized, and the student learns to work backward from the target compound and forward from the starting materials to find a common intermediate. 

In contrast to retrosynthetic analysis used for TOS and combinatorial chemistry, DOS requires forward synthetic planning that enables the conversion of simple starting materials into complex and diverse products. 

Below are summarized some important guidelines for choosing disconnections of bonds. Thus, the initial stage of the retrosynthetic analysis key fragments are recognized, which then can be recombined in the forward synthetic step in an efficient way. ... 

The retrosynthetic analysis of a complex molecule to key intermediates will involve antithetic transforms or bond disconnections. That is, the retrosynthetic analysis consists of the reverse of the synthetic process. These steps must be made in light of the availability of synthetic methods to carry out the desired transformation in the forward synthetic direction. Thus antithetic transforms must consider the functional groups which must be present to permit individual bond formations to take place. 

As the program continued to move forward the team once again faced the need to evaluate the synthetic approach to taranabant, this time with regard to implementation on scales in excess of 100kg and for potential manufacturing purposes. Despite the significant advancements outlined in Section 9.1, a route analysis indicated a number of issues and shortcomings still to be addressed, as outlined below (Table 9.3). 

Pinacol rearrangement of endocyclic diol n-D and hydrolysis of dibromide B would also furnish the target K. Thus each retrosynthetic step in our backward analysis corresponds to a synthetic step to the target in the forward direction. 

So the synthesis could be done in one step by making the anion of methyl acetate and reacting it with bromocyclohexane. The polarities of the reaction partners match nicely, but the problem is that alkylations of secondary bromides with enolates often give poor yields. The enolate is a strong base, which promotes elimination in the secondary bromide rather than giving the substitution product needed in the synthesis. Thus elimination from cyclohexyl bromide to cyclohexene would be a major process if the reaction were attempted. While the retrosynthetic step seems reasonable, the synthetic step has known difficulties. It is important to work backward in the retrosynthetic analysis and then check each forward step for validity. 

This analysis suggests that condensation of 4.10 with hydroxylamine 4.11, hydrazine 4.12, or thiohydroxylamine 4.13 should give the corresponding 1,2-azole..This approach represents an important route to isoxazoles and pyrazoles, but thiohydroxylamine 4.13, although known, is far too unstable for synthetic purposes. The synthesis of isothiazoles will be mentioned later. The mechanism of the forward process is illustrated by the preparation of isoxazole 4.14 and is simply two consecutive condensations. 

Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and functional group interconversions. Structural changes in the retrosynthetic direction should lead to substrates that are more readily available than the TM. Synthons are fragments resulting from disconnection of carbon-carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SE). Also, reagents derived from inverting the polarity (IP) of synthons may serve as SEs. 

Synthetic design involves two distinct steps (1) retrosynthetic analysis and (2) subsequent translation of the analysis into a forward direction synthesis. In the analysis, the chemist recognizes the functional groups in a molecule and disconnects them proximally by methods corresponding to known and reliable reconnection reactions. 

In this chapter we have presented and discussed the use of the basic tools for spectral analysis. However, it should always be remembered that synthetic methods are more powerful, more likely to achieve success and, probably, quicker. Analytical methods should only be used to treat spectra that are either, particularly straightforward, or, paradoxically, particularly difficult. The first category represents simple problems that can be dealt with more efficiently by a rapid analysis than by a drawn-out ab initio calculation. The second category represents a failing synthetic approach and under these circumstances analysis offers, possibly, the only way forward. 

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