Wieland-Miescher ketone, Hajos-Wiechert reaction

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. 

For the Hajos-Eder-Sauer-Wiechert reaction [2a, b], which was found in the 70ties, Barbas III et al. recently reported an optimized protocol [10], This reaction furnishes the chiral Wieland-Miescher ketone. It has now been shown, that this synthesis (which comprises three reactions) can be carried out as a one-pot synthesis (49% yield 76% ee Scheme 4) [10], Prolin functions as an efficient catalyst for all three reaction steps (Michael-addition, cyc-lization, dehydratization). A very interesting theoretical study of the mechanism of this reaction has been recently published by the Houk group [11]. 

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). 

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. 

Developed in the early 1970s, this reaction, also called the Hajos-Parrish reaction or Hajos-Parrish-Ender-Sauer-Wiechert reaction, is one of the earliest processes for the stereoselective synthesis of Wieland-Miescher ketone, an important building block for steroids and terpenoid synthesis. This reaction is a proline mediated asymmetric variation to the Robinson annulation. Hajos and Parrish of Hoffmann-La Roche Inc. in 1971 and 1974 published an asymmetric aldol cyclization of triketones such as that of structure 39, which affords optically active annulation products in the presence of catalytic amounts of (S)-proline (Z-proline). One of the early examples is the synthesis of 41 from the triketone 39 (a product of the Michael addition of MVK to the corresponding 2-methylcyclopentane-l,3-dione), the reaction is performed in two steps first by ring formation in the presence of 3 mol % of (iS)-proline in DMF to afford the ketol 40 in 100% yield after crystallization with 93% ee and then by reaction with toluenesulfonic acid to give the dehydrated adduct 41. The formation of the Wieland-Miescher Ketone 44 follows the same synthetic route, starting from the tri-ketone 42 to give the end product in 75% optical purity and 99.8% of optical yield. 

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. 

Reactions 1 and 2 show the initial work by Hajos and Parrish. After an initial Michael reaction, usually with methyl vinyl ketone, starting material 1 was obtained in quantitative yield. Compound 1 was treated with 3 mol% proline in DMF at room temperature to give intermediate 2 upon further reaction with toluenesulfonic acid, the dehydrated product 3 is obtained. In an analogous manner, enantioenriched Wieland-Miescher ketone 4 was obtained in a lesser optical yield. Reactions 3 and 4 show the one-pot reaction discovered by Eder, Sauer and Wiechert. The yields and optical purity of the compounds obtained were similar to those of Hajos and... 

The preparation of Wieland-Miescher ketone has sparked additional interest since the Hajos-Wiechert reaction provides it in lesser purity than the corresponding hydrindane derivative. The groups of Furst and Harada have reported two crystallization protocols for Wieland-Miescher ketone based on recrystallization fi om ether or a 10 1 ether/ethyl acetate blend these protocols, although time consuming, appear to be scaleable. ... 

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