Asymmetric Robinson annulation

In 1986, Puchot et al.104 studied the nonlinear correlation between the enantiomeric excess of a chiral auxiliary and the optical yield in an asymmetric synthesis, either stoichiometric or catalytic. Negative NLEs [(—)-NLEs] were observed in the asymmetric oxidation of sulfide and in [.S ]-proline-mediated asymmetric Robinson annulation reactions, while a positive NLE [(+)-NLEs]... 

Another key event in the history of organocatalytic reaction was the discovery of efficient r-proline-mediated asymmetric Robinson annulation reported during the early 1970s. The so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction (an intramolecular aldol reaction) allowed access to some of the key intermediates for the synthesis of natural products (Scheme 1.4) [37, 38], and offered a practical and enantioselective route to the Wieland-Miescher ketone [39]. It is pertinent to note, that this chemistry is rooted in the early studies of Langenbeck and in the extensive investigations work of Stork and co-workers on enamine chemistry... 

Asymmetric Robinson Annulation. 2-Propyl-1-indanone undergoes Robinson annulation with the catalyst and methyl vinyl ketone (eq 6). Higher ee values were achieved using 1,3-dichloro-2-butene (Wichterle Reagent) as an MVK surrogate for the Michael addition and overall Robinson annulation (eq 9)... 

An asymmetric Robinson annulation is available in which the ketone is reacted with a chiral amine to provide a chiral imine, which is then added to MVK to furnish, after annulation, the chiral product. 

J. Wicha and co-workers reported the enantioseiective synthesis of the CD side-chain portion of enf-vitamine D3. The key step in their approach was the amino acid mediated asymmetric Robinson annulation between 2-methyi-cyciopentane-1,3-dione and 1-phenyisuifanyi-but-3-en-2-one. During their optimization studies they found that the annuiation is most efficient if the reaction is carried out in the presence of (S)-(-)-phenylalanine and D-camphorsuifonic acid, giving the product in 69% yieid and 86.2% ee. The opticai purity of the enone couid be improved to 95.6% by recrystaiiization from methanoi. 

Bui, T., Barbas, C. F. A proline-catalyzed asymmetric Robinson annulation reaction. Tetrahedron Lett. 2000, 41, 6951-6954. 

The continued fascination chemists possess with asymmetric synthesis provides the basis for the next four procedures. The synthesis of (R)-(-)-10-METHYL-l(9)-OCTALONE-2 is a nice demonstration of an asymmetric Michael addition by a chiral imine followed by an aldol—in short an asymmetric Robinson annulation. The asymmetric glycolization to STILBENE DIOL (R,R-l,2-DIPHENYL-I,2-ETHANEDIOL) represents an olefin oxidation using catalytic alkaloids in tandem with osmium tetroxide. As reagents for a variety of asymmetric alkylations, the preparation of 2-CYANO-6-PHENYLOXAZOLOPIPERIDINK is pavscnicd as well as another route to... 

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. 

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. 

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. 

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone with methyl chloride in 50% sodium hydroxide/toluene using M-(p-trifluoro-methylbenzyDcinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2--phenyl-l-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation enqploying 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7 dichloro-5-methoxy 2-propyl-l-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3 dihydroxy-5-methoxy-2-propyl-l-inden-l-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an intermediate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. 

Comparison with the Hajos-Parrish asymmetric version of the Robinson annulation [81] (Scheme 7.25(a)) shows the following distinct differences between the two methods. Firstly, the cycloalkenone in the Cu(OTf)2/ligand 18-catalyzed procedure is the Michael acceptor, whereas the cycloalkanone is the Michael donor in the proline-mediated annulation. Secondly, the asymmetric induction occurs in the 1,4-addition step in the new method, in contrast to the asymmetric aldol-cyclization in the Hajos-Parrish procedure. 

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. 

Rajagopal, D., Narayanan, R., Swaminathan, S. Asymmetric one-pot Robinson annulations. Tetrahedron Lett. 2001,42,4887-4890. 

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. 

The Wichterle reagent has also been employed in enantioselective Robinson annulations involving the use of phase-transfer catalysis (PTC). Bhattacharya and co-workers had previously investigated the asymmetric alkylation of inadanones, such as 59, using substituted N-benzylcinchoninium salts realizing their ability to produce enantio-enriched... 

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. 

Developed in the early 1970s, this reaction, also called the Hajos-Parrish reaction or Hajos-Parrish-Ender-Sauer-Wiechert reaction, is one of the earliest processes for the stereoselective synthesis of Wieland-Miescher ketone, an important building block for steroids and terpenoid synthesis. This reaction is a proline mediated asymmetric variation to the Robinson annulation. Hajos and Parrish of Hoffmann-La Roche Inc. in 1971 and 1974 published an asymmetric aldol cyclization of triketones such as that of structure 39, which affords optically active annulation products in the presence of catalytic amounts of (S)-proline (Z-proline). One of the early examples is the synthesis of 41 from the triketone 39 (a product of the Michael addition of MVK to the corresponding 2-methylcyclopentane-l,3-dione), the reaction is performed in two steps first by ring formation in the presence of 3 mol % of (iS)-proline in DMF to afford the ketol 40 in 100% yield after crystallization with 93% ee and then by reaction with toluenesulfonic acid to give the dehydrated adduct 41. The formation of the Wieland-Miescher Ketone 44 follows the same synthetic route, starting from the tri-ketone 42 to give the end product in 75% optical purity and 99.8% of optical yield. 

In 2007, Ramachary et al. reported an asymmetric Knoevenagel/hydrogenation/Robinson annulation sequence to obtain Wieland-Miescher ketone 189 [88] (Scheme 2.62). The reaction of 5 equiv of aldehyde 9 with the 1,3-dicarbonyl compounds 186 (with CH acid) and Hantzsch ester 187 under proline catalysis furnished the expected cyclo-hexane-1,3-dione B in good yields. Once the solvent was removed by vacuum pump, the crude reaction mixture was diluted with DMF and treated with methyl vinyl ketone 188 in the presence of (S)-proline (1) furnishing the expected... 

D. B. Ramachary, M. Kishor, J. Org. Chem. 2007, 72, 5056-5068. Organocatalytic sequential one-pot double cascade asymmetric synthesis of Wieland-Miescher ketone analogues from a Knoevenagel/hydrogenation/Robinson annulation sequence scope and apphcations of organocatalytic biomi-metic reductions. 

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