Retrosynthetic approach

Most programs take a retrosynthetic approach. This is a means for systematically working backward from the target compound to available precursors... 

The most important connective transforms in retrosynthetic analysis are the family of C=C cleavage transforms, including one-step (e.g. ozonolytic) or two-step (e.g. OSO4 followed by Pb(OAc)4) (Chart 25). There are many elegant syntheses of challenging molecules which depend on such processes. Two examples will provide an idea of the underlying retrosynthetic approach. 

In order to prepare multi-kilogram quantities of 1 our efforts were strictly focused on the development of an asymmetric route. Our retrosynthetic approach was centered on the preparation of cyclopentenone 27 which, we envisioned, could be elaborated to chiral hydroxy acid 26 through a series of asymmetric transformations (Scheme 7.4). Etherification of the hydroxy group of 26 with benzylic alcohol 25 followed by installation of (P)-nipecotate 23 at the acid position of 24, would furnish the drug candidate 1. This section will address the following ... 

This time-honoured view of ring construction preceded the retrosynthetic approach it is still of value since it provides an indication of which bonds could be selected for disconnection. The more rigorous application of the principles of retrosynthetic analysis leads of course to the formulation of synthons and their reagent equivalents. 

The retrosynthetic approach to welwitindolinone A isonitrile (6) used by the Wood group is shown in Scheme 33. After recognition of the possibility of deriving the vinyl isonitrile fragment from a ketone, the disconnection of 6 to 140 was proposed. A literature report of a samarium (II) iodide-mediated reductive coupling of acrylates with isocyanates to give amides, which could be expected to lead to a new spirooxindole synthesis, prompted the disconnection of 140 to 141. This compound was to be obtained from the readily available cyclohexadiene derivative 143, by way of bicyclic ketone 142. 

As usual, we think backward (the retrosynthetic approach). Each product is made from CH3C=CH, which in turn is synthesized from CH3CH=CH2-... 

Retrosynthetic approach to aminocarbenes from chlorouninium chlorides and caiboxamides. 

Fig. 12. Retrosynthetic approach to target substituted phenyl-dipyridyl libraries.

SYNLMA, an expert system for organic synthesis, with a theorem prover as its inference engine and NCI s XTCHEM as its user interface, uses a retrosynthetic approach to find reaction pathways and generate a problem-solving tree representing the alternative designs it has explored. 

Although the addition of carbene to a double bond to make a cyclopropane is well known, it is not particularly useful synthetically because of the tendency for extensive side reactions and lack of selectivity for thermally or photochemically generated carbenes. Similar processes involving carbenoids (species that are not free carbenes) are much more useful from the preparative standpoint [91,92]. For example, metal catalyzed decomposition of diazoalkanes usually results in addition to double bonds without the interference of side reactions such as C-H insertions. Consider the possible retrosynthetic approaches to a 1,2-disubstituted cyclopropane shown in Figure 6.8. Disconnection a entails the addition of a methylene across a double bond, a conversion that is often stereospecific e.g., the Simmons-Smith reaction [93]). Disconnections b and c are more problematic, since the issue of cis/trans product isomers (simple diastereoselection) arises. 

Scheme 12. Retrosynthetic approach to indole alkaloids through the Fukuyama method...

Smith s retrosynthetic approach, Fig. (11), to enr-calyculin A and to (-)-calyculin B (the C2 geometrical isomer of calyculin A) begins with the disconnection at C(2) via a Peterson olefination which would provide both molecules from a common advanced intermediate. Further... 

With the identification of the hemiatninal moiety at the core diazonamide A in 2001 [97], numerous retrosynthetic approaches to the molecule have taken advantage of the logical disconnection at the anomeric carbon to reveal an oxindole... 

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