Proline catalyzed a-aminoxylation

Proline-catalyzed a-aminoxylation reaction in the synthesis of biologically active compounds 13ACR289. 

Chirality amplification in the proline-catalyzed a-aminoxylation of aldehydes was uncovered and analyzed by Blackmond and co-workers in 2004 [29]. These researchers found that, contrary to what happens in proline-catalyzed aldol reactions, when the reaction was carried out with non-enantiopure proline, the enantiomeric excess of the product was higher than that expected from a linear relationship, and this enantiomeric excess rose over the course of the reaction. These results were rationalized by assuming an autoinductive behavior of the a-aminoxylation product, which formed a new catalytic species via enamine formation with proline, with the additional hypothesis of a matched interaction of L-Pro with the (/ )-enantiomer of the product (Scheme 2.3). 

SCHEME 23. Blackmond s mechanism for product induction and kinetic resolution in the proline-catalyzed a-aminoxylation of 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... 

The synthesis of functionalized tetrahydro-1,2-oxazines 76 from nitroolefins 75 and nitrosoarenes has been studied by Zhong and coworkers. This enantio and diastereoselective organocatalytic process takes place via a domino sequence comprising an initial proline-catalyzed enantioselective aminoxylation of the starting material taking place by addition of the enamine onto the 0=N nitroso bond, followed by a final aza-Michael addition (Scheme 3.20) [57]. The same group has reported a very similar reaction starting from 2-alkylidene derivatives of malonic ester [58]. 

Chiral non-racemic 0-(2-ketoalkyl) A-phenylhydroxylamines such as 115 (equation 84) can be prepared through catalytic enantioselective a-aminoxylation of carbonyl compounds catalyzed by proline. This reaction proceeds with a variety of ketones and aldehydes although it has been tried only with a nitrosobenzene component ... 

Hayashi, Y. Yamaguchi, H., Sumiya, T. and Shoji, M. Direct Proline-catalyzed Asymmetric a-Aminoxylation of Ketones. Angew. Chem. Int. Ed. 2004, 43, 1112 -1114. 

Table 6.1 Proline-catalyzed direct asymmetric a-aminoxylation of aldehydes.

Recently, some extensive research has been devoted to exploring a diastereo-selective and enantioselective route for the synthesis of a-hydroxyaldehydes or a-hydroxyketones because they are important building blocks for the construction of complex natural products and biologically active molecules [91]. In parallel with the transition-metal-catalyzed asymmetric nitroso-aldol reaction [92], much interest has also been expressed towards the proline-catalyzed direct asymmetric a-aminoxylation of aldehydes or ketones for the synthesis of optically active a-hydroxyladehydes and a-hydroxyketones [93]. Wang [94] and Huang [95] independently reported an L-proline-catalyzed asymmetric a-aminoxylation reaction in ionic liquids, whereby it was found tliat aldehydes and ketones could undergo... 

Very recently, Pericas reported a new strategy to immobihze trans-4-hydroxypro-line onto an insoluble Merrifield-type polymer by exploiting Cu(I)-catalyzed 1,3-dipolar cycloaddition ( click chemistry ) [42]. The supported catalyst 25 was successfully employed in the a-aminoxylation of ketones and aldehydes (Scheme 8.13). Under the optimized reaction conditions (20mol%/cat, 2 equiv. ketone, DMF, 23 °C, 3 h), the reaction of cyclohexanone with nitrosobenzene catalyzed by 25 gave the product in 60% yield and 98% ee (Scheme 8.13 Equation a). It should be noted that the reaction rates of cyclic ketones with supported catalyst are faster than those reported with (S)-proline. The use of a supported catalyst allowed for a simplification of the work-up procedure, as the product could often be obtained after simple filtration of the catalyst and evaporation of the solvents. Furthermore, 25 was recycled up to three times without any decrease in either the chemical and/or stereochemical efficiency. 

SCHEME 2.8. MacQuade s merging of Seebach and Blackmond pathways for proline-catalyzed aldehyde a-aminoxylation. 

Aldehydes and ketones could be asymmetrically a-amino-oxylated [36, 37] or a-aminated [38] to corresponding poly-functional compounds 8 and 9 by proline-catalyzed reactions with nitrosobenzene or diethyl azodicarboxylate in molten imidazoUum salts (Scheme 22.5). As compared to those in common solvents, the yields of a-aminoxylation products 8 of both aldehydes and ketones improved significantly in the IL medium and the enantioselectivity was excellent Yields and enantiomeric enrichment of hydrazino-aldehydes 9 were somewhat lower. The ionic environment considerably accelerated the processes and the (S)-proline/IL system could be quantitatively recovered after completion of the aminoxylation reaction and reused (5-6 times) without any loss of catalytic performance. Aldehyde-derived products 8 and 9 (R = H) could be reduced to chiral 1,2-diol derivatives 10 or configurationally stable heterocycles 11, which are valuable intermediates in asymmetric synthesis. 

The easy detection of the end of the a-aminoxylation reaction catalyzed by (S)-proline (21) has allowed the in situ transformation of compounds 97 into interesting chiral functionalized compounds through the use oftandemone-potprocesses [118]. This synthetic strategy has been applied to the formal synthesis of HRV 3C-protease inhibitor (lR,2S)-thysanone [119], the synthesis of the atorvastatin side chain (a building block present in the statin family that acted as cholesterol regulator) [120], and the synthesis of the lactone moiety ofcompactin and mevinolin [121]. 

Even different chiral dihydro-1,2-oxazine derivatives were obtained when the enantioselective a-aminoxylation reaction was catalyzed by tetrazole proline derivative 24, in which the in sim formed aldehyde 66 reacted subsequently with vinylphosphonium salt derivatives or Grignard reagents [89]. 

Not only derivatives from proline are able to catalyze this transformation but also binaphthyl-based chiral secondary amine 67 (5 mol%) has been applied in the a-aminoxylation of both aldehyde and ketone substrates [99]. 

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