Hajos-Parrish-Eder-Sauer-Wiechert cyclization

The first example of an organocatalytic enantio-group-differentiating intramolecular G-endo aldol reaction catalyzed by (S)-proline was the Hajos-Parrish-Eder-Sauer-Wiechert cyclization [24]. Although impressive, the synthetic scope of the... 

It has an odd name too the cyclization is sometimes called the Hajos-Parrish-Eder-Sauer-Wiechert reaction, after its discoverers, but only by those who want to impress their friends. 

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]. 

The Hajos-Parrish-Eder-Sauer-Wiechert synthesis (Scheme 5) was the first example of an intramolecular proline-catalyzed asymmetric aldol reaction. Systematically, this reaction can be described as a 6-enolendo cyclization. In 2003, List et al. described the first example of an intramolecular enolexo aldolization 85). This approach was then used by Pearson and Mans for the synthesis of (-i-)-cocaine 92, starting from the weso-dialdehyde 90 on treatment with (S)-12 86). This desymmetrization process gave 91 as a mixture of epimers with good enantio-selectivity. The tropane skeleton 91 could be further transformed into +)-92 by conventional means (Scheme 21). 

Experiments conducted in the mid-1980s by Agami indicated a small nonlinear effect in the asymmetric catalysis in the Hajos-Parrish-Wiechert-Eder-Sauer reaction (Scheme 6.7). Agami proposed that two proline molecules were involved in the catalysis the first proline forms an enamine with the side chain ketone and the second proline molecule facilitates a proton transfer. Hajos and Parrish reported that the proline-catalyzed cyclization shown in Scheme 6.7 did not incorporate when run in the presence of labeled water. While both of these results have since been discredited—the catalysis is first order in catalyst and is incorporated into... 

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)). 

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