Asymmetric Robinson

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... 

Agami C (1988) Mechanism of the proline-catalyzed enantioselective aldol reaction. Recent advances. Bull Soc Chim Fr 3 499-507 Agami C, Meynier F, Puchot C, Guilhem J, Pascard C (1984) New insights into the mechanism of the proline-catalyzed asymmetric Robinson cycliza-tion structure of two intermediates. Asymmetric dehydration. Tetrahedron 40 1031-1038... 

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. 

Kondo, K., Yamano, T., Takemoto, K. Functional monomers and polymers, 129. Asymmetric Robinson cyclization reaction catalyzed by polymer-bound L-proline. Makromol. Chem. 1985,186,1781-1785. 

Okano, T., Tamura, M., Kiji, J. Asymmetric Robinson annelation catalyzed by lanthanoid alkoxides. Kldorul 997, 30, 300-301. 

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... 

Pride of place here must go to the asymmetric Robinson annelation, discovered as long ago as 1974, but not appreciated at the time for the landmark that it undoubtedly was.17 The normal Robinson annelation (text chapter 36) is first a Michael addition to produce an achiral triketone 82 which cyclises when the enol of the methyl ketone adds, aldol fashion, to the syn face of either of the other ketones to give 83, and hence the enone 84, the north east corner of a steroid. 

This was an extraordinary result when it was published in 1974 as it was well ahead of its time. It is still one of the best asymmetric reactions with catalytic amounts of a chiral reagent. An example of an asymmetric Robinson annelation using stoichiometric catalyst is in the workbook. 

The asymmetric Robinson annelation relies on an intramolecular aldol reaction to create the new chiral centre. More recently List19 and MacMillan20 have used proline 58 to catalyse intermolecular aldol reactions with nearly as good results. Acetone and isobutyraldehyde 89 can be condensed to give a single enantiomer of the aldol 90 in excellent yield and ee providing 30% proline is used as catalyst. 

What is new here is that attack of the nucleophile on the complex 233 can lead to asymmetric induction in a number of ways. For example either enantiomer 234 or 235 could be formed from the symmetrical complex 233. This involves attack at one enantiotopic end of the allylic system rather than one enantiotopic face and in this sense rather resembles the ring closing step (82 — 83) in the asymmetric Robinson annelation. Though essential early work53 was done on the symmetrical complex 233 R = Ph, we shall concentrate on more recent results. 

In 1969 Yamada and Otani reported an stereoselective stoichiometric synthesis of 4,4-disubstituted 2-cyclohexenones through an asymmetric Robinson annula-tion between preformed chiral aldehyde L-proline-derived enamines 20 and methyl vinyl ketone (Scheme 2.12) [33]. Surprisingly, only few examples of organocatalyzed Michael additions of aldehydes to enones have been reported since then. 

Hong B-C, Wu M-F, Tseng H-C, Huang G-F, Su C-F, Liao J-H (2007) Organocatalytic Asymmetric Robinson Armulation of a,P-Unsaturated Aldehydes Applicatirms to the Total Synthesis of (-H)-Palitantin. J Org Chem 72 8459... 

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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