Hajos-Eder-Sauer-Wiechert reaction

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]. 

The delicateness of the aldol protocol has perhaps been one of the factors why enamine catalysis of the aldol reaction did not emerge nntil the 1970s. The Hajos-Parrish-Eder-Sauer-Wiechert reaction [30] (Scheme 16) was an important early example of an intramolecular enamine-catalyzed aldol reaction. However, it was not nntil 2000 when List, Barbas and Lemer demonstrated that the same reaction can also be performed in an intermolecular fashion, using proline as a simple enamine catalyst [26]. 

Scheme 16 The Hajos-Parrish-Eder-Sauer-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. 

In addition to the many intermolecular asymmetric (organo)catalytic aldol reactions, analogous intramolecular syntheses are also possible. In this connection it is worthy of note that the first example of an asymmetric catalytic aldol reaction was an intramolecular reaction using an organic molecule, L-proline, as chiral catalyst. This reaction - which will be discussed in more detail below - is the so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction [97-101], which was discovered as early as the beginning of the 1970s. 

Triketone (29) undergoes an intramolecular aldol reaction - the Hajos-Parrish-Eder-Sauer-Wiechert reaction - to give (30) and subsequently enone (31), in high ee with the stereochemistries indicated being found for D-proline catalysis.128 Now ahomochi-ral /3-amino acid, (1 W,2.S )-cispentacin (32) has been found to give comparable ee, and indeed does so for the cyclohexyl substrate also. 

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 ... 

S.C. PanandB. List s paper spans the whole field of current organocat-alysts discussing Lewis and Brpnsted basic and acidic catalysts. Starting from the development of proline-mediated enamine catalysis— the Hajos-Parrish-Eder-Sauer-Wiechert reaction is an intramolecular transformation involving enamine catalysis—into an intermolecular process with various electrophilic reaction partners as a means to access cY-functionalized aldehydes, they discuss a straightforward classification of organocatalysts and expands on Brpnsted acid-mediated transformations, and describe the development of asymmetric counteranion-directed catalysis (ACDC). 

Recent experiments and computations, however, suggest that the rate-limiting step of the Hajos-Parrish-Eder-Sauer-Wiechert reaction is not the step forming the new C-C bond. Meyer and Houk determined the kinetic isotope... 

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). 

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

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. 

HAJOS-PARRISH-EDER-SAUER-WIECHERT REACTION... 

One of the milestones in the development of organocatalysis is the intramolecular aldol reaction catalyzed by proline developed independently by two industrial research groups at Hoffmann-La Roche and Schering (Scheme 1.3). This reaction, also known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction, was reported in 1971 and is based on the foundations of stoichiometric enamine chemistry by Stork and the mechanistic conclusions driven by Langebeck himself on some enzymatic reactions, and outlines for the first time the reversible formation of a nucleophilic enamine as the key intermediate participating in the catalytic cycle. 

The foundations of this concept (enamine activation) lie in the fundamental studies by Stork and Robinson covering the stoichiometric use of enamine nucleophiles for the formation of C-C bonds. The Hajos-Parrish-Eder-Sauer-Wiechert reaction reported in 1971 (Scheme 2.2), which consisted of a... 

Scheme 11.39 Hajos-Parrish-Eder-Sauer-Wiechert reaction catalysed by (5 )-pro-line 1 and by constrained cis- and trans-pyrrolidines 37.

The next breakthrough was made by Pracejus in 1960 who also used alkaloids as catalysts, namely 0-acetlyquinine in the addition of methanol to phenylmethylke-tene in an impressive ee of 74 % [20]. Then in 1973 the (5)-proUne (27) catalysed Robinson annulation was discovered by Hajos and Parrish and independently by Wiechert and co-workers [21, 22]. High levels of enantioselectivity of up to 93 % were observed using 3 mol% of catalyst in the transformation which later became known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction (Scheme 4.9). 

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