Intramolecular reactions Hajos-Wiechert reaction

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]. 

This type of interesting phenomenon has also been observed in non-organometallic reactions. The Hajos-Wiechert intramolecular aldol reaction of the triketone to the bicyclic aldol exhibits a nonlinear relation between the enantiomeric purity of the (S)-proline catalyst and the en-antioselectivity (Scheme 44) (75). With the partially resolved amino acid, the cyclization affords the product in an ee lower than anticipated. The reaction occurring via an enamine intermediate again may be interpreted in terms of participation of two proline molecules in the productdetermining transition state. 

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... 

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). 

Prior to the determination of the aldolase mechanism and the development of catalytic antibodies for the aldol reaction, Hajos and Parrish and independently Wiechert et al. discovered that (5)-proline catalyzes the intramolecular aldol reaction of cyclic triketones (Scheme 6.7). This is not only a catalytic effect the reaction proceeds with high yields and large enantiomeric excess. 

We next turn our attention to the intramolecular aldol reaction, typified by the Hajos-Parrish-Wiechert-Eder-Sauer reaction (Scheme 6.7). Houk ° first examined the intramolecular proline-catalyzed aldol reaction of 4-methyl-2,6-hexadione... 

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]. 

Impressive results have been obtained by Hajos, Wiechert and coworkers [261] in enantiosdective Robinson simulations of triketones catalyzed by ( -pro-line 1.64 (R = COOH). This type of asymmetric intramolecular aldol reaction is quite general under aminoacid catalysis [261, 775]. Asymmetric hydrocyanation of aldehydes is catalyzed by dipeptides, among which 3.4 is the most efficient. Asymmetric epoxidation of chalcone by alkaline H2O2 >s catalyzed by polyami-noacids [578, 776], but this reaction is not veiy general [777]. 

Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

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 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). 

Covalent strategy enamine catalysis Intramolecular process Hajos-Parrish-Eder-Sauer-Wiechert reaction... 

Interestingly, the stereoselectivity of reactions of cyclohexanone vith iso-butyraldehyde and benzaldehyde vere first predicted by using density functional theory calculations on models based on Houk s calculated transition state of the Hajos-Parrish-Eder-Sauer-Wiechert reaction [125]. The transition states of inter- and intramolecular aldol reactions are almost super-imposable and readily explain the observed enantiofacial selectivity. Relative transition state energies vere then used to predict the diastereo- and enan-tioselectivity of the proline-catalyzed reactions of cyclohexanone vith iso-butyraldehyde and benzaldehyde. The predictions are compared vith the experimental results in Scheme 4.30. The good agreement clearly validates the theoretical studies, and provides support for the proposed mechanism. Additional density functional theory calculation also support a similar mechanism [126, 127]. 

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... 

In 1971, Hajos and Wiechert independently reported intramolecular desym-metrization cyclization via the aldol reaction. Hajos mentioned that the intramolecular aldol reaction of 2-methyl-2-(3-oxobutyl)-l,3-cyclopentanedione (2) could smoothly afford bicycUc diketone 3 catalyzed by L-proline (1) in N,N-dimethylformamide (DMF), in excellent yield and with 93% ee. Further dehydration of 3 yielded the unsaturated diketone 4 (Scheme 36.1) [5a]. In Wiecherf s work, diketone 4 could be obtained directly from 2 by employing perchloric acid in refluxing acetonitrile (Scheme 36.1) [5bj. 

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]. 

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]. 

As stated above, the studies of Wieland and Miescher, as well as Woodward, on the intramolecular aldol reaction of diketones and dialdehydes were encouraged by this previous work. Wieland, Miescher, and Woodward studied the application of the intramolecular aldol reaction, catalyzed by secondary amine salts, to the synthesis of steroids and believed that their aldolizations proceed via enamine intermediates [ 10]. This was corroborated by the mechanistic studies carried out by Spencer in 1965 [11]. Based on these works, Hajos and Parrish (1974) andEder, Sauer, and Wiechert... 

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). 

The Hajos and Wiechert research groups looked at a number of other potential proline based catalysts for their intramolecular Robinson annulation. (. -(-)-Hygrinic acid, Af-methylproline 13, was examined, but only the racemic intermediate ketol product 2 was obtained. In a similar manner, the proline methyl ester 14 also produced the racemic ketol intermediate. No reaction was observed with the piperidine analog 15. The homo-proline analog 16 gave the enantiomeric product. An explanation for this change in selectivity has not been provided yet. Please note that the use of (i )-proline provides the enantiomeric product. 

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)). 

Class 1 aldolase mimics consist of amino acid catalysts that presumably activate the donor via enamine formation and the acceptor through a hydrogen bond with an acid functionality. Repotted hrst by Wiechert et al. and then by Hajos and Parrish,-proline was found to catalyze intramolecular asymmetric aldol reactions. However, the... 

---