Robinson annulation, application

Basis and Example of Use. This reagent acts as the alkyla-tive equivalent of 3-buten-2-one (methyl vinyl ketone), permitting regiospecific enolate alkylation under nonequilibrating conditions. As a vinylsilane it can be converted, via the corresponding a,/3-epoxy silane, into a 3-oxobutyl moiety, and hence used in an alkylative equivalent of Robinson annulation. Application of such methodology can be seen (eq 1) in the preparation of bicyclodecenones via the alkylation of dihydrocarvone with this reagent. Apart from this application, and its use in combination with potassium iodide, it has seen little use so far. 

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.). 

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 ... 

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." ... 

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. 

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. 

A popular and useful application of the conjugate addition reaction is the combined conjugate addition-intramolecular aldol strategy, commonly known as the Robinson annulation. When the Michael donor is a ketone and the Michael acceptor an a,p-unsaturated ketone, the product is a 1,5-diketone which can readily undergo cyclization to a six-membered ring. Typical Michael donor substrates are 2-substituted cyclohexanones, which condense with alkyl vinyl ketones to give the intermediate conjugate addition products 42 (1.52). The subsequent intramolecular... 

Although asymmetric organocatalysis is now considered as a powerful tool for the synthesis of chiral compounds this research held experimented its own revolution. It was restricted after the seventies only to the nse of simple a-amino acids as catalyst for the Robinson annulations and above all with the application of proline to the enantioselective intermolecular aldol reaction. 

Historical perspective C. H. Heathcock, Comp. Org. Syn. 2, 133-179 (1991). General review T. Mukaiyama, Org. React. 28,203-331 (1982). Application of lithium and magnesium enolates C. H. Heathcock, Comp. Org. Syn. 2, 181-238 (1991) of boron enolates B. M. Kim etal, ibid. 239-275 of transition metal enolates I. Paterson, ibid. 301-319. Stereoselective reactions of ester and thioester enolates M. Braun, H. Sacha, J. Prakt. Chem. 335,653-668 (1993). Review of asymmetric methodology A. S. Franklin, I. Paterson, Contemp. Org. Syn. 1,317-338 (1994). Cf. Claisen-Schmidt Condensation Henry Reaction Ivanov Reaction Knoevenagel Condensation Reformatskv Reaction Robinson Annulation. 

The more useful synthetic applications based on chemistry in this chapter are formation of allylic halides from conjugated dienes, Michael addition of organocuprates to conjugated compounds, and the Robinson annulation. The homework has synthetic problems that address these transformations. 

The application of the Robinson annulation to a carbohydrate derivative has been disclosed (Scheme 30). Thus trapping of die enolate derived from ketone (85) with 3-trimethylsilylbut-3-en-2-one gives compound (86) which can be converted to the Robinson product (87) with base. Compound (87) was reduced with a variety of reducing agents to compounds (88). On the other hand trapping of the enolate derived from (85) with deuterated methyl iodide led to axially substituted product (89) instead. 

Hong BC, Wu MF, Tseng HC, Huang GF, Su CF, Liao JH. Organocatalytic asymmetric Robinson annulation of a, 3-unsaturated aldehydes applications to the total synthesis of (-FFpalitantin. J. Org. Chem. 2007 72(22) 8459-8471. 

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