Asymmetric reactions Robinson annulation

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. 

Robinson Annulations Asilicagel-absorbedaminoacidsalt(39)-catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 1.12). A tricyclic ring stracture 40 was obtained in 84% yield and up to 97% ee [15]. hitermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]. 

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... 

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. 

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. 

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

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. 

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... 

As shown in the scheme above, cyclohexene scaffolds are easily produced in MBFTs with the aid of the three-component approach. Hong and coworkers, however, managed the generation of the very similar cyclohexadiene scaffold by using only one starting material [15]. The asymmetric dimerization reaction is facilitated by proline in another enamine/iminium approach, but now in repeat (Scheme 14.7). This enantioselective Robinson annulation approach provides the opportunity to explore a new route to (-l-)-palitantin, an antiprotozoal and antifungal agent [16]. 

The large number of research programs aimed at the syntheses of steroids produced a phenomenal wealth of reaction methods for organic synthesis. The development of the asymmetric proline-catalyzed Robinson annulation reaction for the preparation of the Wieland-Miescher ketone (36, Equation 3) in the early 1970s [41] is noteworthy and marks an important milestone for catalysis by small organic molecules. Asymmetric amine-catalyzed aldol reactions represent an additional variant of the stereoselective aldol addition reaction. The mechanism of the proline-catalyzed aldol addition reaction has been the subject of extensive debate, but the general consensus, based on recent mechanistic studies and quantum mechanical calculations, supports the notion of the involvement of a single amino acid molecule in the transition state structure (39, Scheme 4.4) [42]. 

Anilide 2a catalysed asymmetric intramolecular Michael reaction of formyl enones to chiral cyclic keto-aldehydes in excellent yields with good stereoselectivity (eqn. (1) in Scheme 6.3). The intramolecular Michael addition of a ketosulfone to an unsaturated ketone (eqn. (2) in Scheme 6.3) catalysed by 15e has heen used as a key step in the synthesis of the carbon tricyclic framework of Lycopodine. The same sulfonylprolinamide served as catalyst in the construction of all-carhon substituted quaternary stereocentre via Robinson-type annulation process (eqn. (3) in Scheme 6.3). 

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