Robinson annulation mechanism

Michael reaction, 894-895 acceptors in, 895 donors in, 895 mechanism of. 894-895 Robinson annulation reactions and, 899-900... 

While this example of the Robinson annulation is clearly not enantioselec-tive, the same antibody converts the mero-ketone [120] into the Wieland-Miescher (WM) decalenedione product kcM = 0.086 min-1 and Km = 2.34 mM at 25°C, parameters that give an impressive ER of 3.6 x 106. Good evidence suggests that the mechanism of the reaction involves the formation of a ketimine with the e-amino group of a buried lysine residue in the antibody, as shown in Fig. 39. Most significantly, the reaction delivers the ( )-(+)-WM product in 96% ee (by polarimetry) and in 95% ee by nmr and hplc analysis for a 100 mg scale reaction. A recent report tells that this antibody is to be made commercially available at a cost of 100 for 10 mg. The realization of that objective would mark the start of a new era of application of abzymes to organic stereoselective synthesis. 

Why does this pathway occur instead of the Robinson annulation when the seemingly trivial change of increasing the concentration of NaOH is made Good question. It is not clear. It seems likely that the Robinson annulation does occur first (because quick quenching helps to increase the quantity of Robinson product), but the Elcb elimination at the end of the annulation mechanism is reversible in the presence of NaOH as base. It seems likely, then, that if NaOEt were used as base instead, only the Robinson product would be observed regardless of the quantity of catalyst. 

This is an example of a Robinson annulation. The mechanism for the Robinson annulation involves a sequence of conjugate addition reactions and aldol condensations. As illustrated, the first step is deprotonation of cyclohexanedione with sodium hydride. The resulting anion then participates in a 1,4-addition to methyl vinyl ketone. The resulting enolate anion then tautomerizes through... 

It is not difficult to predict the products of the Robinson annulation and to draw the mechanisms if you remember that the Michael addition is first, followed by an aldol condensation with dehydration to give a cyclohexenone. 

You can usually spot a product of Robinson annulation because it has a new cyclohexenone ring. The mechanism is not difficult if you remember "Michael goes first," followed by an aldol with dehydration. 

Q Predict the products of conjugate (Michael) additions, and show how to use these reactions in syntheses. Show the general mechanism of the Robinson annulation, and use it to form cyclohexenone ring systems. 

On the basis of distribution of products obtained in these reactions with the change of solvents, temperature and molar ratio of reactants, a mechanism has been suggested for the anomalous annulation which does not involve an initial attack of the tetrasub-stituted isomer of the enamine (equation 16)51. Alkylation of the more stable cis isomer of the enamine (80) with methyl vinyl ketone (MVK) would afford zwitterion 81 (attack by the other side of the enamine leads to strong steric interactions in the transition state). Reaction of the thermodynamically less favorable trans isomer 83 gives rise to zwitterions 84 and 89 (both without axial-axial interactions), and ion 84 is sterically able to undergo intramolecular proton shift to afford enamine 85. Zwitterionic intermediates 81 and 89 can be stabilized by conversion to dihydropyrans 82 and 90, or protonated to immonium ions. The pair 81-82 will lead to enamine 85, while the pair 89-90 will afford enamine 91. Then, cyclization of 85 or 91 will afford the enone expected from the normal enamine version of the Robinson annulation. 

The mechanism of the Robinson annulation consists of two parts a Michael addition to the a,p-unsaturated carbonyl compound to form a 1,5-dicarbonyl compound, followed by an intramolecular aldol reaction to form the six-membered ring. The mechanism is written out in two parts (Mechanisms 24.7 and 24.8) for Reaction [2] between methyl vinyl ketone and 2-methyl-1,3-cyclohexanedione. 

All of the parts of this mechanism have been discussed in previous sections of Chapter 24. However, the end result of the Robinson annulation— the formation of a 2-cyclohexenone ring—is new. 

To draw the product of Robinson annulation without writing out the mechanism each time, place the a carbon of the compound that becomes the enolate next to the p carbon of the oc,P-unsaturated carbonyl compound. Then, join the appropriate carbons together as shown. If you follow this method of drawing the starting materials, the double bond in the product always ends up in the same position in the six-membered ring. 

Draw a stepwise mechanism for the foiiowing Robinson annulation. This reaction was a key step in a synthesis of the steroid cortisone by R. B. Woodward and co-workers at Harvard University in 1951. 

This very useful reaction resulted from a failed attempt to introduce a new protected methyl vinyl ketone equivalent for the all important Robinson annul-lation reaction. This failure turned out to be quite rewarding, for it allowed for a fast, simple, mild, and high yielding construction of a-alkylidene ketones, esters, and nitriles, as well as /3-methylenebutyrolactones, a family of compounds with several representatives among the tumor growth inhibitors. The method, unfortunately, has its own limitations, which will be discussed after exposing probable mechanisms. 

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. ... 

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 enolatcs to enoncs orenals. The combination Michael addition-aldol condensation provides a powerful means of kynihesis of six-membered rings, the Robinson annulation. Don t worry about all these people s names learn the relrosynthetic analysis for compounds containing six-membered rings. 

Displayed here is the mechanism of the Robinson annulation between cyclohexanone and vinyl methyl ketone in the presence of KOH. 

The following reaction illustrates the Robinson annulation reaction (Section 19.7A). Provide a mechanism. 

A useful synthesis of sesquiterpene ketones, called cyperones, was accomplished through a modification of the following Robinson annulation procedure (Section 19.7B). Write a mechanism that accounts for each step of this synthesis. 

The mechanism involves a Michael reaction followed by a Dieckmann reaction (intramolecular Claisen), all base promoted. Loss of the ester group begins with an add-catalyzed hydrolysis, followed by decarboxylation of the resulting carboxylic acid. Finally, a Robinson annulation with methyl vinyl ketone affords the final product. 

The mechanism of the Robinson annulation is explained in three distinct steps. Initially a vinyl ketone undergoes a Michael addition to a cyclic ketone or P-keto ester to give the 3 -oxybutyl adduct 1, which in turn is rearranged to give the 1,5-diketo adduct 2. " This step is then followed by... 

The Robinson annulation is the reaction of alkali metal derivatives of cyclohexanones with a-,p>unsaturated methyl ketones to produce cycloketones and polycycloketones. The standard method for Robinson annulation is exemplified in the mechanism shown above. For the synthesis of the 1,5-diketone side chain, the enolate nucleophile reacts with a Michael acceptor this Michael acceptor is usually a substituted vinyl ketone or the parent methyl vinyl ketone (MVK), although the latter gives low yield due to its propensity to polymerize under the standard reaction conditions. To overcome the drawbacks for using MVK, Robinson, McQuillin and Du Feu introduced the Robinson-Mannich variation of the annulation reaction. This modification uses a quatemized Mannich base formed from the vinyl entity the Maimich base is made in situ and acts as a methyl vinyl ketone precursor after it is converted to its methiodides. The formed methiodides of the Mannich adduct 4-(trimethylamino-2-butanone) is condensed with sodioderivatives of ketones or with the parent ketone in the presence of sodium ethoxide. 

PROBLEM 19.37 Although the mechanism shown in Figure 19.113 is the way the Robinson annulation is always described, there is another (harder) way to write the reaction. Write a mechanism for the general reaction in Figure 19.113 that involves doing the aldol condensation first. 

Mechanism 24.7 The Robinson Annulation—Part [A] Michael Addition to Form a 1,5-Dicarbonyl Compound... 

Mechanism 24.8 The Robinson Annulation—Part [B] Intramolecular Aldol Reaction to Form a 2-Cyclohexenone... 

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