Diketone retrosynthetic analysis

The first successful synthesis of longifolene was described in detail by E. J. Corey and co-workers in 1964. Scheme 13.19 presents a retrosynthetic analysis corresponding to this route. A key disconnection is made on going from I => II. This transformation simplifies the tricyclic skeleton to a bicyclic one. For this disconnection to correspond to a reasonable synthetic step, the functionality in the intermediate to be cyclized must engender mutual reactivity between C-7 and C-10. This is achieved in diketone II, because an enolate generated by deprotonation at C-10 can undergo an intramolecular Michael addition to C-... 

Systematic bond disconnection of porantherine [151] with recognition of the double bond-carbonyl equivalence for synthesis generated a synthetic pathway which is based on two intramolecular Mannich reactions. The symmetrical nature of the amino diketone precursor identified by the retrosynthetic analysis facilitates its preparation and subsequent transformations. Moreover, all the hetero atoms (donors) are separated by odd-numbered carbon chains and such arrangements are most amenable to normal modes of assembly. 

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. 

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. 

If the azine structure is considered by itself, then the retrosynthetic analysis can start at the imine structural element (H2O addition O -> C-2, retrosynthetic path a). Suggestions for the cyclocondensation of various intermediates arise based on the 5-aminopentadienal or -one system 145, and further (path g, NH3 loss) on pent-2-endial (glutaconic dialdehyde) or its corresponding diketone 146. Consideration of a retro-cycloaddition (operation c) leads to the conclusion that a synthesis of pyridines by a cocyclooligomerization of alkynes with nitriles is possible. 

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.)... 

For the retrosynthesis of the isoxazole system (see Fig. 5.12), it is essential that the heterocycle possesses the functionality of an oxime and of an enol ether, and that C-3/C-5 are at the oxidation level of a carbonyl function. Therefore, a logical retrosynthetic route (a - c) leads by way of the monoxime 2 to the 1,3-diketone and hydroxylamine. If the retrosynthetic operation a to d is generalized, one arrives at the 4,5-dihydroisoxazole 1. Its analysis, according to a retroanalytically permitted cycloreversion, leads to an alkene unsubstituted by a leaving group and to a nitrile oxide 3. These fragments represent the two components of a 1,3-dipolar cycloaddition. 

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