Enantioselective reactions Robinson annulation reaction

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. 

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

Zhao and coworkers devised enantioselective syntheses of chiral cyclohexenones using primary-secondary diamine-catalyzed cascade reactions (Scheme 3.17). Diamine 13b promoted a cascade Michael-aldol-dehydration reaction between ketoester 77 and enones 78, affording highly functionalized chiral cyclohexenones 79 in good yields and with high enantioselectivities, although the diastereoselectiv-ity was poor [52]. The same group also applied a similar approach for an enantioselective synthesis of fluorinated cyclohexenones via Robinson annulation reaction [53]. 

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). 

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. 

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. 

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]. 

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 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. ... 

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.)...

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 combinational use of two chiral Bronsted acids was also investigated. In 2009, AMyama and coworkers developed a novel dual catalysis strategy for the enantioselective two-step Robinson-type annulation reaction in the presence of two different chiral Bronsted acid catalysts (Scheme 43.2) [11]. In the first step, a chiral... 

There is also one example in which a chiral phosphoric acid has been employed as catalyst in the reaction. In particular, the addition of several cyclic p-ketoesters to methyl vinyl ketone was found to occur smoothly in the presence of several chiral phosphoric acids (Scheme 4.35). As mentioned earlier, a key feature of the chiral phosphoric acid catalyst is the backbone binaphthyl axial chirality together with the incorporation of bulky substituents at the 2 positions. In this case, 60b was identified as an appropriate promoter of the reaction leading to the corresponding Michael adducts in excellent yields, although with moderate enantioselectivity. In addition, the authors succeeded in applying this reaction to a procedure to carry out a subsequent Robinson-type annulation. 

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