Proline enantioselective aldol cyclization

The detailed mechanism of this enantioselective transformation remains under investigation.178 It is known that the acidic carboxylic group is crucial, and the cyclization is believed to occur via the enamine derived from the catalyst and the exocyclic ketone. A computational study suggested that the proton transfer occurs through a TS very similar to that described for the proline-catalyzed aldol reaction (see page 132).179... 

The mechanism of the proline-catalyzed enantioselective aldol reaction has been studied. An extension of the asymmetric aldolization deals with the cyclization of diketones. Also investigated was the dehydration of racemic p-ketols in the presence of (S)-proline and a kinetic resolution was observed. ... 

Enamine-mediated aldolizations offer much better prospects for a stereo-controlled process. The famous enantioselective proline-catalyzed triketone cyclization to the Wieland-Miescher ketone 43 [56], as well as the chemistry of type I aldolase enzymes [57],provide ample precedents for stereo- and enantioselective enamine-mediated reactions. 

Enantioselective aldol condensation (cyclization) using (S)-proline as catalyst, with high optical yield. 

S)-proline-catalyzed reaction is not sufficient therefore, a large number of (S)-proline-derived secondary amine catalysts have been developed. Primary amine catalysts derived from natural amino acids and cinchona alkaloids have also emerged as highly versatile and powerful catalysts [25]. For example, in the intramolecular 6-endo aldol reaction of diketone 43, quinine-derived primary amine 44 in acetic acid affords the cyclic ketone (S)-46 in 94% yield with 90% ee (Scheme 28.3) (S)-proline gives the cyclization product in low yield with moderate ee. In addition, the pseudo-enantiomeric quinidine-derived primary amine 45 delivers the opposite product, the (R)-enantiomer 46, with similar yield and enantioselectivity [26]. 

As to the applications of proline, it can modify the surface of palladium on charcoal to give an enantioselective hydrogenation catalyst (Section D.2.3.1.). Forming amides with aromatic carboxylic acids, proline has served as an auxiliary in the enantioselective Birch reduction of the aromatic system (Section D. 1.1.1.3.1.). An interesting application is the catalysis of the aldol-type cyclization of triketones. Among the amino acids tested, it is often the best choice for high enantiomeric excess3 4. 

After development of the proline-catalyzed intermolecular aldol reaction by List, Lemer and Barbas in 2000 [16], which led to intense world-wide investigation, List himself developed a further intramolecular proline catalyzed cyclization which was enol-exo in nature as opposed to the enol-endo type cyclization of the Hajos-Parrish-Eder-Sauer-Wiechert process (Scheme 1.15). A range of substrates were applied using the methodology and excellent enantioselectivities were obtained [17]. 

Hajos and Parrish at Hoffmann La Roche discovered that proline-catalyzed intramolecular aldol reactions of triketones such as 104 and 107 furnish al-dols 105 and 108 in good yields and vith high enantioselectivity (Scheme 4.17). Acid-catalyzed dehydration of the aldol addition products then gave condensation products 106 and 109 (Eqs. (1) and (2)). Independently, Eder, Sauer, and Wiechert at Schering AG in Germany directly isolated the aldol condensation products vhen the same cyclizations vere conducted in the presence of proline (10-200 mol%) and an acid co-catalyst (Eqs. (3) and (4)). 

In contrast to the early report of intramolecular desymmetrization reactions [6], the intramolecular ring-closing reactions of achiral substrates via enamine catalysis were not disclosed until the beginning of the twenty-first century. In 2003, list reported the first highly stereoselective intramolecular aldol reaction of achiral dicarbonyl compounds. Cyclic aldol products 6a-< were delivered from heptanedials 5 with excellent diastereo- and enantioselectivity by the catalysis of L-proline (Scheme 36.2). The cyclization of ketoaldehyde 7 afforded alcohol 8 as a 2 1 diastereomeric mixture but with 99% ee. This strategy could provide P hydroxyl carbonyl derivatives that are of potential applications in organic synthesis [7aj. 

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