Retrosynthetic analysis condensations

Mannich condensations permit one-step reactions to form the following substances from substantially less complex starting materials. By retrosynthetic analysis, identify a potential starting material which could give rise to the product shown in a single step under Mannich reaction conditions. 

Borrelidin 1 has attracted attention because it inhibits angiogenesis, and so potentially blocks tumor growth, with an IC of 0.8 nM. Retrosynthetic 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 retrosynthetic analysis of a,/J-unsaturated ketones leading to various methods of synthesis is outlined in Section 5.18.2, p. 798. These methods are equally applicable to aromatic aldehydes. Aromatic aldehydes condense with aliphatic or mixed alkyl aryl ketones in the presence of aqueous alkali to form a,[i-unsaturated ketones (the Claisen-Schmidt reaction). 

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. 

In a reaction which is mechanistically related to the Skraup reaction an a,/ -unsaturated carbonyl compound, generated by way of an acid-catalysed aldol condensation, reacts with a primary aromatic amine in the presence of acid to yield a quinoline derivative (Doebner-Miller reaction). For example, when aniline is heated with paraldehyde (which depolymerises to acetaldehyde during the reaction) in the presence of hydrochloric acid the final product is 2-methyl-quinoline (101) (quinaldine, Expt 8.40). Retrosynthetic analysis for the 1,2-dihydroquinoline reveals crotonaldedhyde as the unsaturated carbonyl component which is in turn formed from acetaldehyde (see Section 5.18.2, p. 799). 

Retrosynthetic analysis suggests a double condensation between diketone 1.26 and ammonia. Pyrrole 2.16 can actually be prepared if this way - see Chapter 2.2. 

Our retrosynthetic analysis of generalised pyridine 5.4 commences with an adjustment of the oxidation level to produce dihydropyridine 5.5. This molecule can now be disconnected very readily. Cleavage of the carbon-heteroatom bonds in the usual way leaves dienol 5.6 which exists as diketone 5.7. The 1,5-dicarbonyl relationship can be derived from a Michael reaction of ketone 5.8 and enone 5.9, which in turn can arise from condensation of aldehyde 5.10 and ketone 5.11. 

Let s try a synthesis. Suppose the target is ethyl 2-methyl-3-oxo-2-propylpentanoate. The presence of the /3-ketoester functionality suggests employing an alkylation reaction and/or an ester condensation. In one potential pathway, the propyl group can be attached by alkylation of a simpler /3-ketoester. Further retrosynthetic analysis suggests that the new target (ethyl 2-methyl-3-oxopentanoate) can be prepared from ethyl propanoate by a Claisen ester condensation. 

Thanks to the reliability of these conversions, compounds like 70-73 can all be regarded as products of a condensation between carbonyl components described in terms of an interaction between an electrophile and a nucleophile. Hence, an important recommendation in retrosynthetic analysis is to identify the presence of fragments identical to 70-73 (or easily derivable from them). Retrosynthetic cleavage of the respective C-C bond will then reveal the structures of possible carbonyl precursors. The retrosynthetic analysis of 74, a basic fragment of the complex macrolide antibiotic 6-deoxyerythronolide B, provides a good example of how workable this principle might be (Scheme 2.27). ... 

Once you understand the mechanisms, concentrate on the synthetic applications of the process. Focus on the carbon-carbon bond-forming examples, with particular emphasis on the Michael addition, the 1,4-addition of enolates to enones or enals. The combination Michael addition-aldol condensation provides a powerful means of synthesis of six-membered rings, the Robinson annulation. Don t worry about all these people s names learn the retrosynthetic analysis for compounds containing six-membered rings. 

This scheme comprises many important organic reactions additions and eliminations, substitution reactions or certain pericyclic reactions. In fact, it is estimated that about 50 percent of all organic reactions can be represented by this reaction scheme. Application of such a reaction scheme onto bonds of a target molecule directly leads to precursors in the synthesis. Figure 5 illustrates how an aldol condensation can be found in a retrosynthetic analysis. 

Each of the following can be prepared by an intramolecular aldol condensation of a diketone. Deduce the structure of the diketone in each case. Hint Apply retrosynthetic analysis, starting with disconnection of C=C.)... 

All P"hydroxy carbonyl compounds are potential products of an aldol reaction. Whenever you see one, your thoughts about synthesis must turn first to the aldol reaction. The same is true for the dehydration products, the a,P-unsaturat-ed carbonyl compounds. It is important to be able to go quickly to the new bond, to find the one formed during the aldol condensation, and to be able to dissect the molecule into its two halves. In doing this operation, you are merely carrying out a retrosynthetic analysis and following the mechanism backward (Fig. 19.76). 

ANSWER (b) In any aldol, or aldol-like condensation, the carbon-carbon n bond is formed through an elimination reaction (Rg. 19.73). So, the first part of our retrosynthetic analysis recognizes that the precursor to the final product is... 

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