Proline annulation

Comparison witli tlie Hajos-Parrisb asymmetric version of tlie Robinson annulation [81] iSdieme 7.25iaj) shows tlie following distinct differences between tlie two metliods. Firstly, tlie cydoalkenone in tlie CuiOTf)2/ligand 18-catalyzed procedure is tlie Midiael acceptor, whereas tlie cydoalkanone is tlie Midiad donor in tlie proline-mediated annulation. Secondly, tlie asymmetric induction occurs in tlie 1,4-addition step in tlie new metliod, in contrast to tlie asymmetric aldol-cydization in tlie Hajos-Parrisb procedure. 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

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. 

What is described as a domino Knoevenagel-hetero-Diels-Alder reaction , involving the reaction of the glucose-derived aldehyde 93 with a 1,3-dicarbonyl compound in presence of either proline or ethylenediammonium acetate, leads to the doubly annulated 5 6 6-fused compound 94 (Scheme 30) <2004S1150>. If the dicarbonyl compound is Meldmm s acid, however, the sequence is completed by spontaneous elimination of acetone and carbon dioxide from the Diels-Alder adduct, to give compound 95 <2005ASC1353>. 

In 1986, Puchot et al.104 studied the nonlinear correlation between the enantiomeric excess of a chiral auxiliary and the optical yield in an asymmetric synthesis, either stoichiometric or catalytic. Negative NLEs [(—)-NLEs] were observed in the asymmetric oxidation of sulfide and in [.S ]-proline-mediated asymmetric Robinson annulation reactions, while a positive NLE [(+)-NLEs]... 

Comparison with the Hajos-Parrish asymmetric version of the Robinson annulation [81] (Scheme 7.25(a)) shows the following distinct differences between the two methods. Firstly, the cycloalkenone in the Cu(OTf)2/ligand 18-catalyzed procedure is the Michael acceptor, whereas the cycloalkanone is the Michael donor in the proline-mediated annulation. Secondly, the asymmetric induction occurs in the 1,4-addition step in the new method, in contrast to the asymmetric aldol-cyclization in the Hajos-Parrish procedure. 

The product in entry 1 of Scheme 2.10 is commonly known as the Wieland-Miescher ketone and is a useful starting material for the preparation of steroids and terpenes. The Robinson annulation to prepare this ketone can be carried out enantioselectively by using the amino acid L-proline to form an enamine intermediate. The 5-enantiomer of the product is obtained in high enantiomeric excess.89 This compound and the corresponding product obtained from cyclopentane-1,3-dione90 are key intermediates in the enantiose-lective synthesis of steroids.91... 

Keywords 2-formylcycloalkanone, methyl vinyl ketone, proline, Robinson annu-lation, asymmetric annulation, spiro compound... 

In an extension to the above methodology, a sequential 1,2-addition, dehydration, and in situ ring closure via a 67t-electron electrocyclic cyclization has been described in the context of the pharmacologically relevant natural products warfarin A, the arisugacins, merulidial, and isovelleral (Scheme 20) <2005CAR1287>. Carbohydrate-derived a,3-unsaturated enals were coupled with 4-hydroxycoumarin 188 and 4-hydroxy-6-methylpyran-2//-one 191 in the presence of proline catalysts to provide pyrone-annulated products of types 190 and 192. Stereoselective electrocyclic ring closure was observed only when hydroxyl functionality (at any of R -k ) on the enal was acyl protected. 

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... 

This i-proline-mediated annulation received a considerable synthetic and mechanistic interest [41]. It was demonstrated that other amino acids, such as (R)-phenylalanine, could replace in some cases advantageously the i-proline [42]. Earlier applications in total syntheses appeared, however, as singular events, as in Woodward s synthesis of erythromycin (Scheme 1.5) [27]. Remarkably, in this synthesis a racemic lceto aldehyde 5 could be used for aldolization with D-proline... 

There are many other examples of highly efficient catalytic asymmetric syntheses. These include the asymmetric dihydroxylation of alkenes and certain homogeneous catalyzed hydrogenations. The latter will be discussed in the context of redox reactions in Sections 17.3.2 and 17.4.7. Further examples for catalytic asymmetric syntheses also mentioned in this book are the proline-catalyzed cyclohexenone annulations in Figure 12.19. 

Bui, T., Barbas, C. F. A proline-catalyzed asymmetric Robinson annulation reaction. Tetrahedron Lett. 2000, 41, 6951-6954. 

Davies and co-workers [12, 35] have exploited one particular aspect of the asymmetric cyclopropanation of alkenes with vinyl diazoacetates, namely, application to substrates suitable for subsequent Cope rearrangement. Cyclopropanation of dienes with predominant cfs-1,2-divinyl diastereoselection makes possible subsequent facile [3,3]-sigmatropic rearrangement with entry to 1,4-cycloheptadienes or bicyclic dienes. Two such examples employing cyclopenta-diene and penta-l,3-diene as substrates and the rhodium(II) prolinate catalyst, Rh2(2S-TBSP)4 in Fig. 1, are shown in Eq. (6) and Eq. (7),respectively cfs-l,2-di-vinylcyclopropanes are presumed to be intermediates in these annulation reactions. In contrast, ethyl diazoacetate and styrene with the prolinate catalyst (Fig. 

Efficient L-proline-catalyzed Robinson annulation was reported in the early 1970s by two separate groups in industry one at Schering in Germany [27] and the other at... 

Application of aza-annulation with cyclic enamino esters was reported in the synthesis of angiotensin converting enzyme inhibitor A58365A (323, Scheme 27).90 Aza-annulation of proline derivative 319, which was obtained in 4 steps from L-pyroglutamic acid, with a-methyleneglutaric anhydride (320) led to the formation of indolizidinone 321 as a mixture of diastereomers. Esterification followed by oxidation with DDQ gave 322, which was converted in 4 steps to the desired target 323. 

Scheme 5.3 Single-step proline-catatysed Robinson annulation.

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. 

This is by far the largest class of organocatalytic domino processes and leads to a great diversity of highly functionahzed and complex molecules. In terms of Class 1 processes that lead to cyclization. Class lA are the most populous. For example, Barbas and Bui described a Robinson annulation for the synthesis of the Wieland-Miescher ketone discussed in Sect. 1.5.1.1 using L-proline 45 (Scheme 1.37) [54]. 

Although asymmetric organocatalysis is now considered as a powerful tool for the synthesis of chiral compounds this research held experimented its own revolution. It was restricted after the seventies only to the nse of simple a-amino acids as catalyst for the Robinson annulations and above all with the application of proline to the enantioselective intermolecular aldol reaction. 

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