Retrosynthetic Considerations, Examples

It is interesting that the retrosynthetic approach to heterocycles is not considered in monographs or review articles on the synthesis of individual classes of heterocyclic compounds. The examples that follow illustrate the retrosynthetic approach to the five- and six-membered heterocyclic structures often encountered in natural or synthetic biologically active compounds. Examples 7.2, 7.3, 7.6, 7.11 and 7.12 demonstrate syntheses of biologically active compounds developed to large-scale production by chemists at PLIVA Co. (Croatia). 

Example 7.1 Consider the retrosynthesis and then propose the synthesis of lanicyl TM 7.1, an inhibitor of the S3mthesis of chlorophyll. 

We start the retrosynthetic analysis with the following observations  

Example 7.2 Complete the retrosynthetic analysis and then propose the synthesis of 

This disconnection suggests that in the synthetic direction, the OH group of oxime TM 7.2d approaches the cyano group, completing the cyclization. Presentation of both functional groups as acyclic cyano-oxime suggests interconversion to 3-cyanobutan-2-one and then to 3-chlorobutan-2-one, easily available by chlorination of butan-2-one. Acetanilide is an available commodity used in the production of para-chlorosulfonyl derivative TM 7.2c. 

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A fiiran synthesis which cannot easily be deduced from retrosynthetic considerations is the ring transformation of oxazoles by a Diels-Alder reaction with activated alkynes. For example, 4-methyloxazole 20 reacts with dimethyl acetylenedicarboxylate to provide furan-3,4>dicarboxylic ester 22 [6] via a nonisolable adduct 21 ... 

Now we start with the study of retrosynthesis by the problem-solving approach. This approach has characteristics of seminar work promoting knowledge of organic synthesis by retrosynthetic consideration of selected target molecules. They are either of commercial or scientific interest, and their retrosynthetic analysis has a certain didactic value. In the next few examples we approach the disconnection of compounds with one functional group, represented by carbinols, and tertiary alcohols. 

As in the former example, here we meet a target molecule with conjugated E,Z double bonds. Therefore, a similar retrosynthetic consideration is proposed (Scheme 2.21). 

This example shows how retrosynthetic consideration of the next generation target molecules is sometimes more demanding than the choice in the first step. The logical first retrosynthetic step of TM 2.12 is the disconnection of the C-C bond in the P position to the carbonyl group generating two stable synthons, carbanion on the a-C atom to the carbonyl group and carbocation on the a-C atom to the double bond, known as the allylic cation (Scheme 2.27). 

When as the nucleophilic component a-carbanion stabilized by a carbonyl group or masked as enamine reacts, the reaction products are 1,4- or Y-hydroxycarbonyl compounds. The next example illustrates the utility of such retrosynthetic considerations. 

Another category Ic indole synthesis involves cyclization of ot-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retrosynthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization with ZnCl2 gave indole-3-acetate ester[l]. Additional examples are given in Table 4.3. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

Quite often, rerro-Baeyer-Villiger consideration enables synthetic chemists to propose smprising retrosynthesis of target molecules where this rearrangement is not obvious. Anticipation of Baeyer-Villiger rearrangement of ketone to lactone hidden in the remote retrosynthetic step is elaborate and requires considerable retrosynthetic imagination. The next example serves to support this deliberation. 

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