Enantioselectivity Robinson annulation

In summary, we have demonstrated the first efficient enantio-selective alkylation via phase transfer catalysis. This alkylation was expanded to include an enantioselective Robinson annulation. The methodology was developed for the preparation of either enantiomer. Finally, our kinetic studies have provided additional mechanistic insight into the chiral PT alkylation. 

Formation of the Wieland-Miescher ketone via an enantioselective Robinson annulation represents but one interesting example.91... 

Zhong, G., Hoffmann, T., Lerner, R. A., Danishefsky, S., Barbas, C. F., III. Antibody-Catalyzed Enantioselective Robinson Annulation. J. 

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... 

More importantly from a preparative viewpoint, pericyclic reactions, such as the Claisen rearrangement [569,570] or the Diels-Alder reaction [571,572], have been catalyzed by antibodies, which were raised against bicyclic and tricyclic transition-state mimics (Scheme 3.44). The latter reactions normally cannot be catalyzed by enzymes. Also cationic cyclization reactions [573, 574] and an enantioselective Robinson annulation were achieved [575]. 

In 1997 Barbas, Danishefsky, Zolrng, and co-workers reported an antibody-catalyzed enantioselective Robinson annulation. The antibody used (Ab38C2) catalyzes the cyclodehydration step of the Robinson process for the prochiral starting triketone 60 to give (5)-44 in > 95% ee and with 96% optical purity. The reaction is carried out at room temperature for 10 days to give the product in a 94% yield. ... 

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 most important news from this synthesis is the vahdation in a second research group of the enantioselective Robinson annulation previously described by Professor loigensen. In the assembly of polycarhocycles, the central challenge is the enantioselective construction of the first ring. The lorgensen annulation is a powerful solution to that problem. 

Very recently, Kotsuki and coworkers reported an enantioselective Robinson annulation reaction for the synthesis of cyclohexenone derivatives bearing a quaternary center. Chiral vicinal diamine-chiral Bronsted acid conjugate 168 was found to be the optimal catalyst. The reactions afforded chiral cyclohexenone with moderate yields and good enantioselectivity [75], It was proposed that simultaneous enamine activation of donor and iminium activation of acceptor were involved in the catalytic cycle (Scheme 5.47). 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

Scheme 7.25. Annulation methodology a) Hajosh-Parrish version of the Robinson annulation, b) catalytic enantioselective annulation with functionalised organozinc reagents.

The product in entry 1 of Scheme 2.10 is commonly known as the Wieland-Miescher ketone and is a useful starting material for the preparation of steroids and terpenes. The Robinson annulation to prepare this ketone can be carried out enantioselectively by using the amino acid L-proline to form an enamine intermediate. The 5-enantiomer of the product is obtained in high enantiomeric excess.89 This compound and the corresponding product obtained from cyclopentane-1,3-dione90 are key intermediates in the enantiose-lective synthesis of steroids.91... 

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... 

The Hajos-Parrish reaction can be regarded as the enantioselective version of the Robinson annulation. In the early stages of the synthetic effort targeting the mixed polyketide-terpenoid metabolite (-)-austalide B, L.A. Paquette and co-workers used this transformation to prepare the key bicyclic precursor in enantiopure form. Ethyl vinyl ketone was reacted with 2-methyl-1,3-cyclopentanedione in the presence of catalytic amounts of L-valine to afford the bicyclic diketone with a 75% ee. 

Rajagopal, D., Narayanan, R., Swaminathan, S. Enantioselective solvent-free Robinson annulation reactions. Proc. - Indian Acad. Sci., Chem. Scl. 2001, 113, 197-213. 

In 2000, Barbas carried out the Robinson annulation between 2-methyl-1,3-cyclohexanedione and methyl vinyl ketone catalyzed by several chiral amines, reporting that the process stopped in many cases after the conjugate addition step. However, neither yields nor enantioselectivities were given for those cases. T. Bui and C. F. Barbas III, Tetrahedron Lett., 2000, 41, 6951. 

The next breakthrough was made by Pracejus in 1960 who also used alkaloids as catalysts, namely 0-acetlyquinine in the addition of methanol to phenylmethylke-tene in an impressive ee of 74 % [20]. Then in 1973 the (5)-proUne (27) catalysed Robinson annulation was discovered by Hajos and Parrish and independently by Wiechert and co-workers [21, 22]. High levels of enantioselectivity of up to 93 % were observed using 3 mol% of catalyst in the transformation which later became known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction (Scheme 4.9). 

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. 

A more efficient approach to control the stereochemical outcome for the Robinson annulation can be through the use of chiral catalysts such as in the case of the enantioselective Hajos-Wiechert variation introduced earlier. There are other chiral agents other than the popular (S)-proline-mediated annulation reaction that are used for these transformations—for example the use of (Bronsted acid such as trifluoroacetic (TFA). This new catalyst for the Robinson annulation was reported in 2007 by Endo et. al., where the Bronsted acid, contrary to Hajos-Wiechert reaction, gives the (i )-isomer of the Wieland-Miescher ketone 44 in a moderate yield of 47% and 75% ee. 

In 2009 Miro et al. reported the use of phosphoric acids as a chiral catalyst for enantioselective transformation of the Robinson annulation. Chrial phosphoric acids 61 and 62 are used in sequence first for the Michael reaction step and are then followed by the cyclization step. Synthesis of the aimulation adduct 64 is shown as an example in the group s report. The cyclized adduct is formed from the reaction of the P-keto ester 63 in the presence of the phosphoric acid 61 at 40 °C for 24 h and is followed by... 

Figure 3.3 The 3D structures of TS3 and TS4. (From Yamanaka, M. et al. Kinetic Resolution in Chiral Phosphoric Acid Catalyzed Aldol Reactions Enantioselective Robinson-Type Annulation Reactions. Eur. J. Org. Ghent. 2012. 24, 4508-4514. Copyright Wiley-VCH Verlag GmbH Co. KGaA. Adapted with permission.)...

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