Prolines oxazolidinone

Reaction progress kinetic analysis offers a reliable alternative method to assess the stability of the active catalyst concentration, again based on our concept of excess [e]. In contrast to our different excess experiments described above, now we carry out a set of experiments at the same value of excess [ej. We consider again the proline-mediated aldol reaction shown in Scheme 50.1. Under reaction conditions, the proline catalyst can undergo side reactions with aldehydes to form inactive cyclic species called oxazolidinones, effectively decreasing the active catalyst concentration. It has recently been shown that addition of small amounts of water to the reaction mixture can eliminate this catalyst deactivation. Reaction progress kinetic analysis of experiments carried out at the same excess [e] can be used to confirm the deactivation of proline in the absence of added water as well to demonstrate that the proline concentration remains constant when water is present. 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

Hence, if the proline-catalyzed aldol reaction between acetone and 4-nitrobenzal-dehyde in DM SO is carried out using 5 mol% proline, decarboxylation occurs and [3 + 2] cycloaddition between the resulting ylide and benzaldehyde gives a 1,3-oxazolidinone as the maj or side product [98]. Therefore, it is important that if catalyst loadings are to be reduced, either the carboxylic acid should be unable to decarbox-ylate (e.g. Appendix 7.B, Entries 12 [97, 98], 35 [99]) or else must be replaced by an isostere [101, 102] (e.g. Appendix 7.B, Entries 7 [103, 104], 8-10 [105], 11 [106], 28 [107]). Alternatively, the relative rate of the aldol reaction can be increased in order to minimize the concentration of iminium ion in solution and remove it from equilibrium before decarboxylation can take place. 

An important feature of this reaction is that in contrast to most other catalytic asymmetric Mannich reactions, a-unbranched aldehydes are efficient electrophiles in the proline-catalyzed reaction. In addition, with hydroxy acetone as a donor, the corresponding syn-l, 2-aminoalcohols are furnished with high chemo-, regio-, diastereo-, and enantioselectivities. The produced ketones 14 can be further converted to 4-substituted 2-oxazolidinones 17 and /i-aminoalcohol derivatives 18 in a straightforward manner via Baeyer-Villiger oxidation (Scheme 9.4) [5]. 

The a-amination of aldehydes and subsequent reduction to form oxazolidinones (Scheme 7.6) was developed by the Jorgensen group [7]. In the presence of 10 mol% L-proline as catalyst a variety of aldehydes reacted with azodicarboxylates, 3a and 3a, affording the oxazolidinones 7 after subsequent reduction with borohydride and cyclization. Selected examples of the synthesis of products 7, which were obtained in yields up to 92% and with enantioselectivity up to 95% ee, are shown in Scheme 7.6. 

Proline-based palladium complex 106 has been shown to catalyze the Diels-Alder reaction of 1,2-dihydropyridine 85 and oxazolidinone 99 to give 103 in similar enantiomeric excess as the chromium(m) complex 102<2005TL5677>. Alteration of the dienophile to pyrazolidin-3-one 107 improves the enantioselectivity of the reaction and gives product 108 in 97% ee (Scheme 29). 

The direct a-amination of aldehydes by azodicarboxylates as the electrophilic nitrogen source can be catalyzed by, for example i-proline 3a, to give the a-hydrazino aldehydes 4 having (R -configuration in moderate to good yields and with excellent enantioselectivities (89-97% ee) (Scheme 2.27) [4]. The optically active a-hydrazino aldehydes 4 are prone to racemization, and it was found beneficial to reduce them directly with NaBFU to stereochemical stable compounds which, by treatment with NaOH, can cyclize to form the N-amino oxazolidinones 5 in a one-pot process. The N-amino group in 5 could be cleaved with Zn/acetone to give the oxazolidinone 6 (Scheme 2.27). 

Scheme 2.27 Direct enantioselective a-amination of aldehydes catalyzed by L-proline, and further transformations to optically active oxazolidinones. (For experimental details see Chapter 14.8.1).

More recently, Amedjkouh and Ahlberg138 have described another route to 108 and derivatives (Scheme 81). Condensation of proline or pyroglutamic acid with chloral rendered crystalline bicyclic oxazolidinones as a single enantiomer. Reaction with pyrrolidine followed by reduction of the amide gave diamine 108 in 77% yield. Both enantiomers of pyroglutamic acid are commercially available at moderate cost. Thus this route represents a practical protocol for both enantiomers of 4. 

Seebach, D. Beck, A. K. Badine, D. M. Limbach, M. Eschenmoser, A. Treasury-wala, A. M. Hobi, R. Prikoszovich, W. Linder, B. Are oxazolidinones really unproductive, parasitic species in proline catalysis - Thoughts and experiments pointing to an alternative view, Helv. Chim. Acta 2007, 90, 425-471. 

Sharma, A. Sunoj, R. Enamine versus oxazolidinone What controls stereoselectivity in proline-catalyzed asymmetric aldol reactions , Angew. Chem. Int. Ed. 2010, 49, 6373-6377. 

Other Oxazolidine as well as Thiazolidine Derivatives for Branching Amino Acids. The cyclic derivative of alanine and other amino acids employed most frequently for a-allq lation is not (1) but rather the benzaldehyde acetal (5), either with a benzoyl or with a Cbz group on nitrogen. These compounds were used for the preparation of 2-methyl-2-aminobutanoic acid, a-methylphenylalanine, a-methyllysine, 2-methylaspartic acid, and 2-methylglutamic acid. Bicyclic compounds containing oxazolidinone rings such as (6) (from alanine, leucine, and phenylalanine) and (7) (from azetidinecaiboxylic acid, proline, " hydroxyproline, and cysteine ) have also been applied to the synthesis of branched amino acids. 

Enantiomerically pure spiro oxindoles (Scheme 35) were prepared by using solid-supported N-cinnamoyl Evans oxazolidinone (164) [265]. Thus, chiral oxazolidi-none prepared from L-tyrosine was attached to a Merrifield resin and then N-acylated with the required unsaturated acyl chloride such as cinnamoyl chloride (not shown). The resin (165) was then suspended in aqueous dioxane and treated with proline and N-phenyl isatin at 80-90 °C overnight to give a highly substituted spiro compound (167). 

Now we are prepared to illustrate these experimental protocols of reaction progress kinetic analysis using data from reaction calorimetric monitoring of the aldol reaction shown in Scheme 27.1. We turn hrst to the issue of catalyst stability using our same excess protocol. In these aldol reactions, it was noted that the active catalyst concentration can be effectively decreased by the formation of oxazolidinones between proline and aldehydes or ketones, and that addition of water can suppress this catalyst deactivation. Same excess reactions carried out in the absence of water and in the presence of water are shown in Figure 27.3a and Figure 27.3b, respectively. The plots do not overlay in the absence of water, but they do when water is present. The overlay in these same [e] experiments in Figure 27.3b means that the total concentration of active catalyst within the cycle is constant and is the same in the two experiments where water is present. 

Hydrolysis. The anomeric acetate is the only hydrolyzable group in polyacetyl amino sugars on treatment with Si02-Me0H. Oxazolidinones such as those derived from proline are similarly cleaved, allowing for a very simple purification of the end products in a synthetic approach to a-alkylprolines. 

In the past Lewis acid-catalyzed [4+2] cycloaddition reactions of chiral alkyl acrylates have been systematically studied. Chiral auxiliaries derived from camphor, menthol and amino acids or from carbohydrates have been developed. Stereochemical and theoretical aspects of these chiral inductors have been intensively reviewed (see. Chapter 6). Asymmetric Diels-Alder reactions of chiral acrylamides derived from Ca-symmetrical secondary amines lead selectively to the cycloadducts in the presence of Lewis acids such as AICI3. In reactions of chiral auxiliaries derived from (iS)-proline and (iS)-prolinol excellent endo/exo selectivities and diastereoselectivities were obtained in the presence of catalytic amounts of Et2AlCl or TiCL. Cycloadducts of chiral crotonoyl derivatives derived from oxazolidinones 62, sultam 63 or for example (S)-lactate IS were obtained with high selectivities in the presence of Lewis acids such as Et2AICl. 

Another issue is the formation of oxazolidinones, which has been the subject of study by several research groups and is considered to be part of a parasitic equilibrium for proline-catalysed aldol reactions. More recent studies have indicated that this parasitic equilibrium may not be true, and that reversible oxazolidinone formation may help keep proline in solu-tion. Figure 5.3 illustrates a generalised mechanism for proline catalysis involving enamine intermediates. As aforementioned, the formation of oxazolidinones may or may not be part of a parasitic equilibrium. 

Among the available methods for the stereoselective synthesis of quaternary proline analogues (7)/ the direct a-functionalisation of (5 )-proline-derived oxazolidinone 5 proposed by Seebach et al. in 1983 has been extensively used in the last thirty years for the production of many bioactive compounds (Scheme 11.1)/ Both a-allq lation and a-condensation reactions proceed stereoselectively with retention of configuration, exemplifying the concept of self-reproduction of chirality . More recently, Germanas and coworkers introduced the cheaper oxazolidinone 6, derived from the condensation of (S)-proline 1 with trichloroacetaldehyde (Scheme 11.1). ... 

Recently, kinetic and specdoscopic studies gave a mechanistic explanation of the role of water in the aldol reaction with aromatic aldehydes. While the addition of water increases the catalyst concentration by suppression the formation of parasitic species such as the oxazolidinone, decreases the relative concentration of key minimum intermediates by Le Chatelier s principle, shifting the equilibrium towards proline (1). The net effect on the reaction rate of these opposing roles would differ when different substrates are used in the reaction, with the intrinsic rate per active catalysts species within the cycle being suppressed by the added water in the aldol reaction of acetone with aromatic aldehydes [37]. 

Fig. 4.47 Intermediate heterocyclic oxazolidinone formed by reaction of proline 1 with ketone...

An alternative process has been postulated occurring through the formation of corresponding heterocyclic oxazolidinone (see Fig. 4.47) by reaction of proline... 

SCHEME 2.4. Seebach s oxazolidinone pathway for proline catalysis. 

The regio- and the stereoselectivity of proline-catalyzed a-electrophilic substitution of carbonyl compounds can therefore be successfully explained by the oxazolidinone model, although the diastereoselectivity of the aldol and Mannich reactions was not taken into account in Seebach s discussion. Moreover, the model also could explain the autoinductive effects observed by Blackmond in the proline-catalyzed nitroso aldol and a-amination reactions of aldehydes [29, 31], by simply assuming that the oxazolidinone product acts as a base in the rate-determining enamine formation step. Kinetic resolution of proline, leading to chirality amplification effects, would be accounted for by the greater thermodynamic stability of the matched oxazolidinone product. In fact, the formation of Seebach s oxazolidi-nones, rather than enamines or iminium ion intermediates, from ketones and proline in DMSO solution had been described by List et al. in 2004 [23], but they concluded that this was a parasitic equilibrium leading to an unproductive intermediate. On the other hand, the product oxazolidinone in the proline-catalyzed a-amination of... 

Moyano, Rios, and co-workers [38] have shown that the beneficial effect of hydrogen-bond donors in proline-catalyzed aldol reactions in nonpolar solvents [39] is due both to the facilitation of proline solubilization by formation of an oxazolidinone with the ketone and to the stabilization of the iminium carboxylate zwitterionic form that is the direct precursor of the reactive enamine intermediate,... 

SCHEME 2.6. Proline deactivation by oxazolidinone formation from electron-deficient aldehydes. 

McQuade and co-workers [41] found that while the rate of proline-catalyzed a-aminoxylation of aldehydes in chloroform or ethyl acetate is significantly increased by the presence of a bifunctional urea, this effect is not observed when the catalyst is a 2-pyrrolidine-tetrazole, which cannot form an oxazolidinone. On the other hand, a similar rate acceleration was observed when the catalyst was the preformed Seebach oxazolidinone derived from proline and hexanal, or the soluble trans-A- tert- saiy di-methylsilyloxy)proline. NMR studies also showed that the role of the urea was to promote both (a) pro line solubilization by formation of the oxazolidinone (not by direct... 

In the course of their seminal study on the amine-catalyzed cyclopropanation of a,(3-unsaturated aldehydes by p-oxosulfonium ylides, Kunz and MacMillan [89] found that while first- and second-generation oxazolidinones failed to promote the reaction, proline afforded the expected product in good yields and poor enantiose-lectivity (Scheme 2.15). 

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