Aldolases direct catalytic asymmetric aldol

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

Although the development of a range of catalytic asymmetric aldol-type reactions has proven to be a valuable contribution to asymmetric synthesis [35—37], in all of these reactions pre-conversion of the ketone moiety to a more reactive species such as an enol silyl ether, enol methyl ether, or ketene silyl acetal has been an unavoidable necessity. However, quite recently Shibasaki et al. reported that a direct catalytic asymmetric aldol reaction, which is known in enzyme chemistry, is also possible in the presence of heterobimetallic lanthanoid catalysts [38]. Using fR)-LLB (20 mol%), which shows both Lewis acidity and Bron-sted basicity similar to the corresponding aldolases, the desired optically active aldol adducts were obtained with up to 94% ee. A variety of aldehydes and unmodified ketones can be used as starting materials (Scheme 11). 

Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

Class II aldolase mimics (Scheme 10.4) were the first small-molecule catalysts that were reported for the direct intermolecular aldol reaction. These catalysts are characterized as bimetallic complexes that contain both Lewis acidic and Brpnsted basic sites. Shibasaki et al. first reported on the use of such a catalyst in the aldol reaction in 1997, demonstrating its potential with the reaction of various acetophenones 52 and aldehydes 53 (Scheme 10.13). Aldols 55 were obtained in good yields and enantioselectivities. A similar approach was used in the direct catalytic asymmetric aldol-Tishchenko reaction.Nevertheless, for the moment, this method does not provide access to true polypropionate fragments. ... 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

It is worth noting that, in a similar manner to enzymatic conversions with type I or II aldolases, a direct asymmetric aldol reaction was achieved when L-proline was used as catalyst. Accordingly, the use of enol derivatives of the ketone component is not necessary, i.e. ketones (acting as donors) can be used directly without previous modification [72]. So far, most asymmetric catalytic aldol reactions with... 

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