Ketones annulation

Conjugate addition of vinylcyclopropylcuprate reagents to j8-iodo enones, e.g. to 42 and 46, provides a convenient means of synthesis of cyclic ketones annulated with the cyclohepta-1,4-diene moiety. Where permitted, the initially formed product, e.g. 44, isomerizes into conjugation under the reaction conditions. Thus, enone 45 (n = 1,2) is the only product from the isomerization of fran.9-vinylcyclopropyl enones 43 (R = H). 

We have seen that Michael reactions and aldol additions both form new carbon-carbon bonds. The Robinson annulation is a reaction that puts these two carbon-carbon bond-forming reactions together in order to form an a,j8-unsaturated cychc ketone. Annulation comes from annulus, Latin for ring, so an annulation reaction is a ring-forming reaction. The Robinson annulation makes it possible to synthesize many complicated organic molecules. 

K. Kong, D. Romo, Diastereoselective, vinylogous Mukaiyama aldol additions of silyloxy furans to cyclic Ketones annulation of buteno-lides and y-lactones, Org. Lett. 8 (2006) 2909-2912. 

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... 

Several 1,4-dicarbonyl compounds are prepared based on this oxidation. Typically, the 1,4-diketone 10 or the 1,4-keto aldehyde 12 can be prepared by the allylation of a ketone[24] or aldehyde[61,62], followed by oxidation. The reaction is a good annulation method for cyclopentenones (11 and 13). Syntheses of pentalenene[78], laurenene[67], descarboxyquadrone[79], muscone (14 R = Me)[80]) and the coriolin intermediate 15[71] have been carried out by using allyl group as the masked methyl ketone (facing page). 

Allyllic ether 53 is oxidized regioselectively to the /3-alkoxy ketone 54, which is converted into the a,/i-unsaturated ketone 55 and used for annulation[99]. The ester of homoallylic alcohol 56 is oxidized mainlv to the 7-acetoxy ketone 57[99]. 

A convenient annulation procedure based on cycHc hydroboration—carbonylation of 1-vinyl- and l-aHylcycloalkenes with thexylborane provides trans-fused bicychc ketones (312). 

Methyl ketones are important intermediates for the synthesis of methyl alkyl carbinols, annulation reagents, and cyclic compounds. A common synthetic method for the preparation of methyl ketones is the alkylation of acetone derivatives, but the method suffers limitations such as low yields and lack of regioselectivity. Preparation of methyl ketones from olefins and acetylenes using mercury compounds is a better method. For example, hydration of terminal acetylenes using HgSO gives methyl ketones cleanly. Oxymercuration of 1-olefins and subsequent oxidation with chromic oxide is... 

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. 

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 ,/3-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 ... 

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." ... 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

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. 

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. 

To set the stage for the crucial aza-Robinson annulation, a reaction in which the nucleophilic character of the newly introduced thiolactam function is expected to play an important role, it is necessary to manipulate the methyl propionate side chain in 19. To this end, alkaline hydrolysis of the methyl ester in 19, followed by treatment of the resulting carboxylic acid with isobutyl chlorofor-mate, provides a mixed anhydride. The latter substance is a reactive acylating agent that combines smoothly with diazomethane to give diazo ketone 12 (77 % overall yield from 19). 

The reaction processes shown in Scheme 8 not only accomplish the construction of an oxepane system but also furnish a valuable keto function. The realization that this function could, in an appropriate setting, be used to achieve the annulation of the second oxepane ring led to the development of a new strategy for the synthesis of cyclic ethers the reductive cyclization of hydroxy ketones (see Schemes 9 and 10).23 The development of this strategy was inspired by the elegant work of Olah 24 the scenario depicted in Scheme 9 captures its key features. It was anticipated that activation of the Lewis-basic keto function in 43 with a Lewis acid, perhaps trimethylsilyl triflate, would induce nucleophilic attack by the proximal hydroxyl group to give an intermediate of the type 44. 

Benzo-annulated dihydrooxepinones are readily accessible (see Houben-Weyl, Vol. 6/4, pp453) and can be converted to the corresponding hydroxy derivatives by reduction of the ketone function. The elimination of water from 10,ll-dihydrodibenz[fc,/]oxepin-10-ol to give 1 was accomplished with /t-toluenesulfonic acid.165-167... 

The asymmetric Michael addition of chiral nonracemic ketone enolates has most frequently been used as part of the Robinson annulation methodology in the synthesis of natural products171-172. The enolates are then derived from carbocyclic chiral ketones such as (+)-nopinone, (-)-dihydrocarvone, or (-)-3-methylsabinaketone. 

The condensation of an ester enolate and a ketone can be used as part of a Robinson annulation-like sequence (see 16-38). 

This section contains alkylations of ketones and protected ketones, ketone transpositions and annulations, ring expansions and ring openings and dimerizations. Conjugate reductions and Michael alkylations of enone are listed in Section 74 (Alkyls from Alkenes). 

A particularly important example of the intramolecular aldol reaction is the Robinson annulation, a procedure that constructs a new six-membered ring from a ketone.171 The reaction sequence starts with conjugate addition of the enolate to methyl... 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

The role of the trimethylsilyl group is to stabilize the enolate formed in the conjugate addition. The silyl group is then removed during the dehydration step. Methyl 1-trimethylsilylvinyl ketone can be used under aprotic conditions that are compatible with regiospecific methods for enolate generation. The direction of annulation of unsymmetrical ketones can therefore be controlled by the method of enolate formation. 

Methyl 1-phenylthiovinyl ketones can also be used as enones in kinetically controlled Robinson annulation reactions, as illustrated by Entry 6. Entry 7 shows a annulation using silyl enol ether as the enolate equivalent. These reactions are called Mukaiyama-Michael reactions (see Section 2.6.3). 

The Robinson annulation is a valuable method for preparing bicyclic and tricyclic structures that can serve as starting materials for the preparation of steroids and terpenes.175 Reaction with 2-methylcyclohexan-l,3-dione gives a compound called the Wieland-Miescher ketone. 

These ,(i-unsaLurated ketones and aldehydes are used as reactants in conjugate additions (Section 2.6), Robinson annulations (Section 2.1.4), and in a number of other reactions that we will encounter later. Entries 8 and 9 in Scheme 2.12 illustrate... 

Compound 23-V is known as the Wieland-Miescher ketone and can be obtained by Robinson annulation of 2-methylcyclohexane-l,3-dione. 

The 1,5- and 1,6-dialdehydes 22 and 24 undergo the annulative pinacol coupling to give the cyclic vzc-diols 23 and 25, respectively (Scheme 13) [29]. The vanadium-catalyzed intramolecular coupling reaction of 1,5-diketone 26 also proceeds with excellent selectivity (Scheme 14) although the intermolecular coupling of ketones such as acetophenone results in low diastereoselectivity under these conditions [21]. 

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