Annulation, Robinson,

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.  

In the laboratory of J.D. White, the asymmetric total synthesis of (+)-codeine was accomplished. The Robinson annulation was the method of choice to build a phenanthrenone precursor starting from a substituted tetralone derivative. As it is usuaiiy the case, the isolation of the Michael adduct allowed the intramolecular aldol reaction to proceed cleanly and to afford a higher yield of the annulated product. 

The Hajos-Parrish reaction can be regarded as the enantioselective version of the Robinson annulation. In the early stages of the synthetic effort targeting the mixed polyketide-terpenoid metabolite (-)-austalide B, L.A. Paquette and co-workers used this transformation to prepare the key bicyclic precursor in enantiopure form. Ethyl vinyl ketone was reacted with 2-methyl-1,3-cyclopentanedione in the presence of catalytic amounts of L-valine to afford the bicyclic diketone with a 75% ee. 

A novel variant of the Stork-Jung modified Robinson annulation was developed and applied to the formal total synthesis of (+)-guanacastepene A by the research group of B.B. Snider. Instead of using MVK directly, they prepared the necessary 1,5-diketone by alkylating the ketone with an allylsilane and generating the ketone functionality via a Fleming-Tamao oxidation. 

Another example of a very common ring-forming sequence is the Robinson annu-lation. This sequence allows a six-membered ring to be appended to an existing carbonyl group. 

The strategy of the sequence is a Michael addition to an a,/3-unsaturated ketone followed by an intramolecular aldol reaction. Treatment of a ketone enolate with a Michael acceptor gives a diketone intermediate which is poised to produce a six-membered ring if an enolate is produced and it intramolecularly adds to the carbonyl group. 

This process nicely accounts for formation of product, but if we consider intermediate I, we see that there are several different a protons that could be removed by base, 1I , Hfe, and Hc. Furthermore the acidities of these various a protons should be comparable so all should be removed to similar extents under the reaction conditions. If we sequentially remove each proton and write the product from an intramolecular carbonyl addition, the following products could be produced. The fact is that only P is produced to any extent. This is due to the preference of six-membered ring formation over the formation of the more 

Furthermore, since the aldol reaction is reversible, if any of these higher energy products were formed, they could open back up under the reaction conditions. The exclusive formation of P is an example of kinetic as well as thermodynamic control as the more stable product is formed fastest. 

For the puiposes of retrosynthetic analysis, a six-membered ring in a target can be related to a Robinson annulation of an existing ketone with an a,/3-unsamrated ketone. Normally cc,/3-unsaturated methyl ketones are used to facilitate the ring closure, but this is not an absolute requirement. Thus the target steroid S could potentially be constructed by a series of Robinson annulations as shown. The last retrosynthetic step (the first synthetic step) could be problematic as a mixture of regioisomers would be formed. 

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. 

Show how you would disconnect each of the following molecules using a Robinson annulation  

5-Dioxygenated compounds are generally prepared by the reaction of an enolate or equivalent with an a,p-unsaturated carbonyl compound. The nucleophile used should be either a p-dicarbonyl compound or an enamine. 

When the enone required for such reactions is unstable, it can be produced in situ by amine elimination from a p-amino carbonyl compound, prepared in turn from an enolate and an imine of formaldehyde in the Mannich reaction. 

The Robinson annulation is used to prepare cyclohexenones. The enone is disconnected to a 1,5-dicarbonyl compound, which is synthesized using an enone and an enolate (either of a p-dicarbonyl compound or an enamine). It is a one-pot process. 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a,/6-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3  

The next step is an intramolecular aldol reaction leading to closure of a six-membered ring. Subsequent dehydration yields the bicyclic enone 4  

Methyl vinyl ketone 2 tends to polymerize, especially in the presence of a strong base the yield of annulation product is therefore often low. A methyl vinyl ketone precursor, e.g. 6, is often employed, from which the Michael acceptor 2 is generated in situ, upon treatment with a base. The quaternary ammonium salt 6 can be obtained by reaction of the tertiary amine 5, which in turn is prepared from acetone, formaldehyde and diethylamine in a Mannich reaction. 

Besides a polymerization of the Michael acceptor, a double alkylation of the starting ketone, by reaction with a second Michael acceptor molecule, may take place as a side reaction, and thus further reduce the yield. The polymerization of the enone 2 as well as the double alkylation of the starting ketone can be avoided by application of a modern procedure for the Robinson annulation that uses an organotin triflate as catalyst.  

When 3-butyne-2-one 7 is used as a Michael acceptor component, a 2,5-cyclohexadienone, e.g. 8, is obtained as the annulation product  

Michael addition of cyclohexanones to methyl vinyl ketone followed by intramolecular aldol condensation to afford six-membered a,p-unsaturated ketones. 

The alkylation of a cyclic enolate by a Michael acceptor proceeds via antiparallel addition. 

One of the most important reactions for the construction of six-member rings (the Diels-Alder reaction is another) is based on a tandem reaction sequence a Michael addition reaction followed by an intramolecular aldol-dehydration reaction. This sequence is called the Robinson annulation (Sir Robert Robinson, Nobel Prize, 1947).  

Note that under basic conditions, dehydration of the bridged aldol product would place a double bond at the bridgehead, forming a highly strained enone. 

Regiochemical Course of the in the classical Robinson annulation, the Michael addition occurs at the more substi-Robinson Annulation tuted carbon via the thermodynamic enolate, except when the normal product experiences severe nonbonded interactions. 

Enolate formation at positions a and b will result in the formation of higher substituted adducts or bridged aldols. 

A major synthetic challenge in the 1930s through the 1950s was construction of various steroid molecules. One important route which emerged from this effort was the use of a Michael addition protocol to produce ti 

One problem with the Robinson annulation is the reversible nature of the initial Michael addition. One solution is to use a conjugated system that is particularly prone to Michael addition and forms the product, essentially irreversibly. a-Silyl vinyl ketones have been shown to be powerful Michael acceptors.The lithium enolate of cyclohexanone reacted with conjugated ketone 559 to produce the Michael product. 560.304b jn this case, the initially formed Michael adduct was stabilized by the presence of the silyl group at the a-position, driving the reaction toward the product. Hydrolysis produced 561, which was converted to the Robinson product (562) in 80% overall yield by treatment with NaOMe/MeOH under the requisite thermodynamic conditions.304b Pq,. this sequential process is justified when compared with normal treatment 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 219, Springer-Verlag Berlin Heidelberg 2009 

Example 3, Double Robinson-type cyclopentene annulation 

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Tran orm-based or long-range strategies The retrosynthetic analysis is directed toward the application of powerful synthesis transforms. Functional groups are introduced into the target compound in order to establish the retion of a certain goal transform (e.g., the transform for the Diels-Alder reaction, Robinson annulation, Birch reduction, halolactonization, etc.). 

Robinson Annulation Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-l-one... 

The 5-oxohexanal 27 is prepared by the following three-step procedure (1) 1,2-addition of allylmagnesium bromide to an a, / -unsaturated aldehyde to give the 3-hydroxy-1,5-diene 25, (2) oxy-Cope rearrangement of 25 to give 26, and (3) palladium catalyzed oxidation to afford 27. The method was applied to the synthesis of A -2-octalone (28), which is difficult to prepare by the Robinson annulation[25]. 

The synthesis of cyclohexenone derivatives by Michael addition followed by intramolec ular aldol condensation is called the Robinson annulation, after Sir Robert Robinson who popularized its use By annulatwn we mean the building of a ring onto some start mg molecule (The alternative spelling annelation is also often used)... 

FUJIMOTO - BELLEAU Cyclohexenone Synthesis Synthesis of fused cyclohexenones from lactones (an alternative to the Robinson annulation). 

Me02C xb Robinson Annulation (Aldol + Michael) MeOjC O Me ... 

Robinson annulation (Section 18.13) A combination of conjugate addition of an enolate anion to an a,p-unsaturated ketone with subsequent intramolecular aldol condensation. 

Robinson annulation (Section 18.13) The combination of a Michael addition and an intramolecular aldol condensation used as a synthetic method for ring formation. 

Comparison witli tlie Hajos-Parrisb asymmetric version of tlie Robinson annulation [81] iSdieme 7.25iaj) shows tlie following distinct differences between tlie two metliods. Firstly, tlie cydoalkenone in tlie CuiOTf)2/ligand 18-catalyzed procedure is tlie Midiael acceptor, whereas tlie cydoalkanone is tlie Midiad donor in tlie proline-mediated annulation. Secondly, tlie asymmetric induction occurs in tlie 1,4-addition step in tlie new metliod, in contrast to tlie asymmetric aldol-cydization in tlie Hajos-Parrisb procedure. 

From a stereochemical point of view the Robinson annulation can be a highly complex reaction, since the configuration at five stereogenic sp -carbon centers... 

Since an annulated six-membered carbocycle is a common structural element of natural products, the Robinson annulation is an important reaction in organic synthesis. 

Davis and co-workers have carried out the first examples of the Knoevenagel condensation and Robinson annulation reactions [61] in the ionic liquid [HMIM][PFg] (HMIM = l-hexyl-3-methylimidazolium) (Scheme 5.1-33). The Knoevenagel condensation involved the treatment of propane-1,3-dinitrile with a base (glycine) to generate an anion. This anion added to benzaldehyde and, after loss of a water molecule, gave l,l-dicyano-2-phenylethene. The product was separated from the ionic liquid by extraction with toluene. 

Scheme 5.1-33 The Knoevenagel condensation and the Robinson annulation in [HMIM][PFg],...

The Robinson annulation of ethyl acetoacetate and trans-chalcone proceeded smoothly to give 6-ethoxycarbonyl-3,5-diphenyl-2-cyclohexenone in 48 % yield. The product was separated from the ionic liquid by solvent extraction with toluene. In both these reactions, the ionic liquid [HMIM][PF6] was recycled and reused with no reduction in the product yield. 

Carbonyl condensation reactions are perhaps the most versatile methods available for synthesizing complex molecules. By putting a few fundamental reactions together in the proper sequence, some remarkably useful transformations can be carried out. One such example is the Robinson annulation reaction for tire synthesis of polycyclic molecules. The word annulation comes from the Latin annulus, meaning "ring," so an annulation reaction builds a new ring onto a molecule. 

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 first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

Figure 23.9 This Robinson annulation reaction is used in the commercial synthesis of the steroid hormone estrone. The nucleophilic donor is a /3-diketone.

Problem 23.21 What product would you expect from a Robinson annulation reaction of 2-methyl-1,3-cyclopentanedioiie with 3-buten-2-one ... 

Problem 23.22 How would you prepare the following compound using a Robinson annulation reaction between a jS-diketone and an, /3-unsaturated ketone Draw the structures of both reactants and the intermediate Michael addition product. 

The following molecule was formed by a Robinson annulation reaction. What reactants were used ... 

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

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