Hajos-Parrish-Eder-Sauer-Wiechert synthesis

Scheme 5 Hajos-Parrish-Eder-Sauer-Wiechert synthesis...

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). 

Further breakthroughs in enantioselectivity were achieved in the 1970s and 1980s. For example, 1971 saw the discovery of the Hajos-Parrish-Eder-Sauer-Wiechert reaction, i.e. the proline (l)-catalyzed intramolecular asymmetric aldol cyclodehydration of the achiral trione 11 to the unsaturated Wieland-Miescher ketone 12 (Scheme 1.3) [12, 13]. Ketone 12 is an important intermediate in steroid synthesis. 

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... 

Hoffman-La Roche in the USA [28]. The so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction provided access to key intermediates for the synthesis of natural products and offered a practical route to the Wieland-Miescher ketone (Equation 10.12). 

Scheme 1-13 Collection of formulae relevant to a synthesis of (—)-desogestrel 40 opened by the asymmetric Hajos-Parrish-Eder-Sauer-Wiechert reaction.

Even though the use of (S)-proline (1) for the synthesis of the Wieland-Miescher ketone, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaetion, was reported in the early 1970s, aminocatalysis - namely the catalysis promoted by the use of chiral second-aiy amines - was rediscovered only thirty years later. The renaissance of aminocatalysis was prompted by two independent reports by List et al. on the asymmetric intermolecular aldol addition catalysed by (S)-proline (1) and by MacMillan et al. on the asymmetric Diels-Alder cycloaddition catalj ed by a phenylalanine-derived imidazolidinone 2. These two reactions represented the archetypical examples of asymmetric carbonyl compound activation, via enamine (Figure ll.lA) and iminium-ion (Figure 11.IB), respectively. 

Proline-catalyzed enolendo aldolizations have been applied to a number of substrates, most often in steroid synthesis. Selected products from such Hajos-Parrish-Eder-Sauer-Wiechert reactions are sho vn in Scheme 4.18 [98-104]. 

Even though the use of chiral amines and consequently the stereoselective reaction of enamines and aldehydes or ketones have been applied successfully as the Hajos-Parrish-Eder-Sauer-Wiechert reaction [29], it has been revived and applied to total synthesis starting in 2000 with the publication from Barbas and List (Scheme 2.118) [30]. 

The intramolecular aldol reaction of triketones with asymmetric desymmetrization has been known for a long time. When Eder, Sauer, and Wiechert [97, 98], and in parallel Hajos and Parrish [99-101] reported this reaction in the early 1970s it was the first example of an asymmetric catalytic aldol reaction, and one of the first examples of an organocatalytic asymmetric synthesis [104]. 

The initial spark for proline catalysis was provided independently and simultaneously by two groups in 1971. Hajos and Parrish on the one hand (Scheme 5.1), and Eder, Sauer and Wiechert (Scheme 5.2) on the other developed an asymmetric aldol cyclisation of triketones such as 1 to bicyclic allq l ketones 2. In the former report, (S)-proline was applied at 3 mol%, a low organocatalyst loading, even to date. The quantitative cyclisation reaction was completed in the reasonable time of 20 h, and provided the product in 93.4% ee. Dehydration to enone 3 completed the synthesis of a valuable building block in steroid chemistry. 

In 1971, Eder, Sauer, and Wiechert at Schering (72) and Hajos and Parrish at Hoffmann-La Roche 13,14) independently reported a proUne-catalyzed intramolecular aldol reaction of the triketone 16 as the key step in the synthesis of the diketone 17, a highly important intermediate in steroid synthesis. Remarkably, Hajos and Parrish obtained the diketone 18 in excellent yield and enantioselectivity with only 3 mol% of catalyst (Scheme 5). Acid-mediated dehydratiOTi then furnished the targeted 17. The accepted transition state for this reaction is believed to include one proline molecule as elucidated by List and Houk 21, 34). 

At the same time Eder, Sauer and Wiechert of Schering A.G. in 1971 published a one-pot reaction for the asymmetric synthesis of chiral bicyclics. The group affected this transformation from prochiral triketones in the presence of chrial amines or amino acids such as proline (similar to Hajos and Parrish). The (5)-amine or (5)-amino acid induces (5)-configuration bicyclics, while the (/ )-configuration outcomes varies. The best results for this annulation are shown in the synthesis of 41 and 44. The reaction is performed in the presence of (5)-proline and perchloric acid. The reaction mixture is heated under reflux to give the products in good 87% and 83% yields, respectively, and 84% and 71% ee, respectively. 

Around 1970, chemists at Schering (Ulrich Eder, Gerhard Sauer, Rudolf Wiechert) and concurrently at Hoffmann-La Roche (Zoltan Hajos, David Parrish) had found an improved Michael addition of 2-ethylcyclopentane-l,3-di-one [61] to methyl vinyl ketone. If water is used in place of methanol, and catalytic amounts of potassium hydroxide are present, then the yield is increased from 54 to 81%. [62, 63] The higher homologues can be synthesised in an analogous manner as well. [64] Robinson annulation, in presence of 30 mole% proline, leads in good yield to a bicydic hydroxy-ketone. After dehydration, crystallisation and reduction with sodium borohydride, the enantiomerically pure bicydic ketone is obtained, which is required for Coreys synthesis. 

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