Hajos—Parrish reaction

The originally proposed stereochemical model by Hajos and Parrish was rejected by M.E. Jung and A. Eschenmoser. They proposed a one-proline aldolase-type mechanism involving a side chain enamine. The most widely accepted transition state model to account for the observed stereochemistry was proposed by C. Agami et al. suggesting the involvement of two (S)-(-)-proline molecules. Recently, K.N. Houk and co-workers reexamined the mechanism of the intra- and intermolecular (S)-(-)-proline catalyzed aldol reactions. Their theoretical studies, kinetic, stereochemical and dilution experiments support a one-proline mechanism where the reaction goes through a six-membered chairlike transition state. 

The first enantioselective total synthesis of tetracyclic sesquiterpenoid (+)-cyclomyltaylan-5a-ol, isolated from a Taiwanese liverwort, was accomplished by H. Hagiwara and co-workers. They started out from Hajos-Parrish ketone analogue, (S)-(+)-4,7a-dimethyl-2,3,7,7a-tetrahydro-6/-/-indene-1,5-dione, that could be synthesized from 2-methylcyclopentane-1,3-dione and ethyl vinyl ketone in an acetic acid-catalyzed Michael addition followed by an intramolecular aldol reaction. The intramolecular aldol reaction was carried out in the presence of one equivalent (S)-(-)-phenylalanine and 0.5 equivalent D-camphorsulfonic acid. The resulting enone was recrystallized from hexane-diethyl ether to yield the product in 43% yield and 98% ee. Since the absolute stereochemistry of the natural product was unknown, the total synthesis also served to establish the absolute stereochemistry. 

Wicha and co-workers reported the enantioseiective synthesis of the CD side-chain portion of enf-vitamine D3. The key step in their approach was the amino acid mediated asymmetric Robinson annulation between 2-methyi-cyciopentane-1,3-dione and 1-phenyisuifanyi-but-3-en-2-one. During their optimization studies they found that the annuiation is most efficient if the reaction is carried out in the presence of (S)-(-)-phenylalanine and D-camphorsuifonic acid, giving the product in 69% yieid and 86.2% ee. The opticai purity of the enone couid be improved to 95.6% by recrystaiiization from methanoi. 

The first total synthesis of barbacenic acid, a bisnorditerpene containing five contiguous stereocenters, was achieved by A. Kanazawa et. al. They started out from a Wieland-Miescher ketone analogue that could be synthesized with high yield and excellent enantioselectivity by the procedure of S. Takahashi. According to this procedure, the Michael addition product 2-methyl-2-(3-oxo-pentyl)-cyclohexane-1,3-dione was cyclized in the presence of (S)-(-)-phenylalanine and D-camphorsulfonic acid. 

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Houk s involvement in proline-catalyzed asymmetric induction began in a similar way. Occasionally something very interesting appears in the literature, especially so if it is amendable to elucidation by computational methods, Houk recalls. We are especially interested in synthetic methods where the experimentalist is unclear of just how things work. This was Ihe case with the proline work. We saw the work of Barbas and List on the aldol reaction, and we were aware of the Hajos-Parrish reaction. So we started computations on simple models, and then looked at the Hajos-Parrish reaction, and we came upon an explanation for its stereoselectivity. This was all done without communicating with any of the experimentalists. ... 

The Hajos-Parrish reaction can be regarded as the enantioselective version of the Robinson annulation. In the early stages of the synthetic effort targeting the mixed polyketide-terpenoid metabolite (-)-austalide B, L.A. Paquette and co-workers used this transformation to prepare the key bicyclic precursor in enantiopure form. Ethyl vinyl ketone was reacted with 2-methyl-1,3-cyclopentanedione in the presence of catalytic amounts of L-valine to afford the bicyclic diketone with a 75% ee. 

Hajos-Parrish reaction Enantio-enriched bicyclic enones from 1,5-diketones. 192... 

EIGURE 2.5. Agami s two-proline transition state model for the Hajos-Parrish reaction (1986). 

Further experimental support to the Houk-List mechanism was provided by the observation that when the Hajos-Parrish reaction was carried out with a 25 mol% of proline and in the presence of a 3 vol% of H20 in DMSO at rt, after 4 days under argon, rigorously excluding air and moisture, more than 90% incorporation of had taken place on the aldol product [23]. 

The Houk-List model was also applied to explain the origin of stereoselectivity in proline-catalyzed intermolecular aldol reactions [19c, 24]. Contrary to the Hajos-Parrish reaction, there is no restriction on the approach of the electrophile. Interestingly enough, theoretical calculations strongly favour an anti proline enamine... 

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. 

Discovery of the proline-catalyzed intramolecular aldol reaction - the Hajos-Parrish-... 

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. 

Case Study 4 The Hajos-Parrish-Eder-Wiechert-Sauer Reaction 405 References 406... 

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... 

Enamine catalysis involves a catalytically generated enamine intermediate that is formed via deprotonation of an iminium ion and that reacts with various electrophiles or undergoes pericyclic reactions. The first example of asymmetric enamine catalysis is the Hajos-Parrish-Eder-... 

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 ... 

Hajos-Parrish-Eder-Wiechert-Sauer Reaction... 

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