Hajos-Wiechert ketone

In a route towards new estrogens which bind to the /1-unit of the K+-channel located on the surface of the endothelium, L.F. Tietze et al. described the synthesis of a novel enantiopure B-Nor-steroid, applying multiple Pd-catalyzed transformations [141] (Scheme 38). A combination of a Suzuki-Miyaura and a Heck reaction using a 2-bromobenzylchloride derivative and a boronic ester, derived from the enantiopure Hajos-Wiechert ketone [142-... 

Scheme 1.13 Calculations for the formation of the Hajos-Wiechert ketone with relative gas-phase energies (kcal moV0[14]...

Tietze and his co-workers prepared estradiol and a number of other steroid derivatives using a compact sequential Heck reaction approach. Compound 51 was obtained from the known Hajos-Wiechert ketone derivative 50 in 3 steps. Heck reaction with palladium(II) acetate in the presence of triphenylphosphine gave intermediate 52, the precursor of the second Heck reaction. Additional steps converted steroid analog 53 into estradiol (54). 

An inspection of this steroid substructure encouraged us to synthesize the enantiomerically pure dienes from the easy to make Hajos-Wiechert ketone (Scheme 10), which offered themselves as highly selective chiral templates which can be used in three different ways. 

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. 

The mechanism of the Hajos-Wiechert reaction has not been without controversy. The original paper by Hajos and Parrish proposed two possible mechanisms. The first, via the carbinolamine 7, proposed addition of proline to a ketone, followed by a nucleophilic attack of the pendant, remote enol [transition state 8]. Calculations by Houk and Clemente show that this is one of the higher energy pathways. The second proposed mechanistic pathway proceeded via an enamine intermediate, followed by carbon-carbon bond formation via transition state 9 and a hydrogen transfer between nitrogen 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. ... 

Lastly, the figure below lists a number of other natural products for which Hajos-Parrish ketone and other derivatives from the Hajos-Wiechert reaction were employed as chiral building blocks to achieve partial or complete total synAeses. 

Inspired by the proline-catalyzed Robinson annulation pioneered by Wiechert, Hajos, Parrish and coworkers [39], they were able to construct cyclohexanones of type 2-107 with up to four stereogenic centers with excellent enantio- and di-astereoselectivity from unsaturated ketones 2-104 and acyclic (l-ketoesters 2-105 in the presence of 10 mol% phenylalanine-derived imidazohdine catalyst 2-106. The final products can easily be converted into useful cyclohexanediols, as well as y- and e-lactones. 

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... 

In addition to catalyzing the well-known Hajos-Parrish-Eder-Sauer-Wiechert reaction (Scheme 3 Eq. 1), we found in early 2000 that proline also catalyzes intermolecular aldolizations (e.g. Eq. 2). Thereafter, our reaction has been extended to other substrate combinations (aldehyde to aldehyde, aldehyde to ketone, and ketone to ketone Eqs. 3-5) and to enolexo-aldolizations (Eq. 6 Northrup and MacMillan 2002a ... 

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... 

The as)rmmetric proline-catalyzed intramolecular aldol cyclization, known as the Hajos-Par-rish-Eder-Sauer-Wiechert reaction [106,107], was discovered in the 1970s [108,109,110,111]. This reaction, together with the discovery of nonproteinogenic metal complex-catalyzed direct asymmetric aldol reactions (see also Sect 5.5.1) [112,113,114], led to the development by List and co-workers [115,116] of the first proline-catalyzed intermolecular aldol reaction. Under these conditions, the reaction between a ketone and an aldehyde is possible if a large excess of the ketone donor is used. For example, acetone reacts with several aldehydes in dimethylsulfoxide (DMSO) to give the corresponding aldol in good yields and enantiomeric excesses (ee) (O Scheme 17) [117]. 

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). 

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. 

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. 

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. 

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. 

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... 

In the 1970s, Hajos and Parrish and Wiechert and coworkers independently reported that the Michael addition of 2-methylcyclopentane-l,3-dione to vinyl ketone in water gives the corresponding conjugated addition product without the use of a basic catalyst. A similar... 

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]. 

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