Enantioselective catalysts Robinson annulation

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. 

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... 

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). 

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. 

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... 

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