Cyclohexenones aldol reaction

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

The Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexenones. For example, reaction of the pyrrolidine enamine of cyclohexanone with 3-buten-2-one. followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each. 

Robinson annulation reaction (Section 23.12) A synthesis of cyclohexenones by sequential Michael reaction and intramolecular aldol reaction. 

A titanium(iv) chloride mediated Baylis-Hillman-type or aldol reaction between a-ketoesters and cyclohex-2-enones has been studied (Equation (13)).77 The steric effect of the R2 substituent is crucial for the reaction pathway since the aldol reaction only proceeds with the unsubstituted cyclohexenone (aldol adduct 71 with R2 = H to a small extent the Baylis-Hillman reaction occurs), whereas with the substituted substrate (R2 = Me) gives exclusively the Baylis-Hillman adduct 72. 

In the majority of dehydration reactions, heterocyclic compounds are formed, rather than carbocyclic compounds. Many possibilities for formation of carbocyclic compounds exist, but these are important only if (a) the heterocyclic or acyclic tautomers cannot undergo further elimination reactions, or (b) the conditions of reaction greatly favor the formation of an acyclic tautomer capable of affording only the carbocyclic compound. Both five- and six-membered carbocyclic compounds have been isolated, with reductic acid being the compound most frequently reported. Ring closure occurs by an inter-molecular, aldol reaction that involves the carbonyl group and an enolic structure. Many examples of these aldol reactions that lead to formation of carbocyclic rings have been studied.47 As both elimination and addition of a proton are involved, the reaction occurs in both acidic and basic solutions. As examples of the facility of this reaction, pyruvic acid condenses spontaneously to a dibasic acid at room temperature in dilute solution, and such 8-diketones as 29 readily cyclize to form cyclohexenones, presumably by way of 30, either in acid or base. 

Enolate D of Figure 13.71 can undergo an aldol reaction with the C=0 double bond of the ketone. The bicyclic compound A is formed as the condensation product. It is often possible to combine the formation and the consecutive reaction of a Michael adduct in a one-pot reaction. The overall reaction then is an annulation of a cyclohexenone to an enolizable ketone. The reaction sequence of Figure 13.71 is the Robinson annulation, an extraordinarily important synthesis of six-membered rings. 

Epothilone A (2) is a natural product that exhibits taxoterelike anticancer activity. A new synthesis of the ketoacid 6, a common C1-C6 fragment used in the total synthesis of epothilone A, was accomplished by directed aldol reaction of acetone with the aldehyde 34 (Scheme 2.3c). The aldol reaction of acetone with the aldehyde 3 in the presence of D-proline proceeded smoothly to furnish the expected aldol product (4) in 75% yield and with greater than 99% ee. Intramolecular aldol reaction of the hydroxy ketone 4 in the presence of pyrrolidine gave the cyclohexenone 5 in good yield. Protection of the alcohol as a TBS ether followed by oxidation of the alkene then produced the desired ketoacid (6). 

Tetrahydroxanthen-l-ones have been obtained through enantioselective domino oxa-Michael - aldol reactions between salicylaldehydes and cyclohexenones using a chiral pyrrolidine catalyst in the presence of 2-nitrobenzoic acid <07TL2181>. A similar approach using chiral 4-hydroxycyclohexenones and V-methylimidazole as catalyst leads to a diastereomeric mixture of the reduced xanthones (Scheme 40) <07S2175>. Dimeric... 

The Robinson Annulation—Part [2] Intramolecular Aldol Reaction to Form a 2-Cyclohexenone ... 

Robinson annulation (Section 24.9) A ring-forming reaction that combines a Michael reaction with an intramolecular aldol reaction to form a 2-cyclohexenone. 

Jht last conjugate addition in the synthesis of the first compound is fairly obvious as the jBET.bination of ester and ketone provides a good enolate. Then we have a cyclohexenone rather like at compound in Problem 6. The compound needed for the intramolecular aldol reaction can be faiace by a second conjugate addition using a stable enolate. 

The selectivity observed in the intramolecular aldol reaction of 2,5-h anedione is due to the fact that all steps in the mechanism are rever and an equilibrium is reached. Thus, the relatively strain-free cyclopentenoi product is considerably more stable than the highly strained cycloprop alternative. For similar reasons, intramolecular aldol reactions of 1,5 ketones lead only to cyclohexenone products rather than to cydobutenea. ... 

The aWol reactions we ve seen up to this point have all been intermSSm.-lar, That is, they have taken place between two different molecules. Wher certain dicarbonyl compounds are treated with base, however, an inframo lecuiar aldol reaction can occur, leading to the formation of a cyclic produc. For example, base treatment of a 1,4-diketone such as 2,5-hexanedioii yields a cyclopentenone product, and base treatment of a 1,6-diketone sue as 2,6-heptanedione yields a cyclohexenone. 

The Robinson annulation has three distinct steps the Michael addition of the enol or enolate across the double bond of the a,(3-unsaturated ketone to produce a 1,5-diketone (Michael adduct), followed by an intramolecular aldol reaction, which affords a cyclic (3-hydroxy ketone (keto alcohol), and finally a base-catalyzed dehydration which gives rise to the substituted cyclohexenone. An alternative mechanism via disrotatory electrocyclic ring closure is possible. ... 

Additions to Cyclohexenones. Intramolecular additions in cyclohexene systems also provide access to natural products. Thus the photocyclization of enone (27) affords the adduct (28) which is suggested as a route to the nortaxane or taxane skeleton. Intramolecular reaction of the enone (29) affords two products (30, 70%) and (31, 14%). The identity of the major products was determined by X-ray crystallography and is the result of hemiacetalisation of the original (2-f-2)-adduct (32). The minor product (31) is formed from the major by a yie TTo-Aldol reaction. ... 

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