Robinson annulation reaction mechanism

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

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... 

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

Tropinone (Problem 48) was first synthesized by Sir Robert Robinson (famous for the Robinson annulation reaction Section 18-11), in 1917, by the following reaction. Show a mechanism for this transformation. 

The large number of research programs aimed at the syntheses of steroids produced a phenomenal wealth of reaction methods for organic synthesis. The development of the asymmetric proline-catalyzed Robinson annulation reaction for the preparation of the Wieland-Miescher ketone (36, Equation 3) in the early 1970s [41] is noteworthy and marks an important milestone for catalysis by small organic molecules. Asymmetric amine-catalyzed aldol reactions represent an additional variant of the stereoselective aldol addition reaction. The mechanism of the proline-catalyzed aldol addition reaction has been the subject of extensive debate, but the general consensus, based on recent mechanistic studies and quantum mechanical calculations, supports the notion of the involvement of a single amino acid molecule in the transition state structure (39, Scheme 4.4) [42]. 

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. 

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. 

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. ... 

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

In Section 17.5.6, we discussed the Robinson annulation, both with simple enolate nucleophiles and with enamines as the nucleophile. It s a good moment to reread that section and make sure that you are confident with the reaction mechanism, as it is a long and complex one. We will now look at it from the other point of view and see how we can disconnect such six-membered rings. Consider 20.20. We first disconnect the enone to a dicarbonyl compound—a 1,5-dicarbonyl compound. This is then disconnected to a ketone plus an enone. In practice, the forward reaction is a one-pot process, using KOH/EtOH as the base. Where the initial nucleophile is a p-dicarbonyl compound, no activation is necessary in other cases, an enamine is sometimes used. 

This reaction was first reported by Fischer and Jourdan in 1883. It is a synthesis of indole derivatives by the treatment of aryl hydrazones coupled from aromatic hydrazines and ketones or aldehydes with either a mineral or Lewis acid. Therefore, it is generally known as the Fischer indole synthesis. In addition, it is also referred to as Fischer cyclization, Fischer indole cyclization, Fischer indole reaction, Fischer indolization, Fischer reaction, and Fischer indole annulation. Although the mechanism has been extensively studied, the one formulated by Robinson and Robinson is now generally accepted. It involves the following steps (a) initial acid-catalyzed tautomerization of an aromatic hydrazone to an ene-hydrazine, b) a [3,3]-sigmatropic rearrangement of ene-hydrazine to a M-imine intermediate, (c) re-aromatization to aniline, d) intramolecular nucleophilic attack to form aminal, and (e) extrusion of an ammonia to afford the indole. 

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