Organocatalytic Oxidations

On the other hand, Jprgensen et al. have reported an interesting a-arylation of aldehydes with electron-rich aromatic compounds such as A-(4-hydroxyphenyl)-4-methylbenzenesulfonamide through a novel anodic oxidation/organocatalytic protocol [95]. As depicted in Scheme 2.29, the reaction firstly involves the... 

A new mode of oxidative organocatalytic activation has been reported, termed organo-SOMO catalysis, which has been successfully applied using an enantioselective intramolecular a-arylation of aldehydes via catalytic oxidative radical cyclization (Eq. 9.25) [101]. In this approach, the exposure of an aryl-tethered aldehyde (124) to a chiral secondary amine catalyst 125 and a suitable oxidant leads to enantio-enriched 126 ... 

This approach has been extended to the enantioselective construction of multiple C—C bonds and contiguous stereocenters. In this way, an oxidative organocatalytic polycyclization reaction of suitable functionalized aldehydes such as 127 afforded di- to hexacyclization products in good yields and useful enantioselectivities (Eq. 9.26) [102] ... 

The catalytic asymmetric epoxidation of a,p-unsaturated aldehydes has also been an important challenge in iminium catalysis and for chemical synthesis in general. More recently, Jprgensen and coworkers have developed an asymmetric organocatalytic approach to ot, (3-epoxy aldehydes using pyrrolidine catalyst 20 and H2O2 as the stoichiometric oxidant. The reaction appears to be extremely general and will likely receive wide attention from the chemical synthesis community (Scheme 11.6b). 

Figure 6.6 Structurally diverse Bronsted acids (1 mol% loading) screened in the cooperative Bronsted acid-type organocatalytic system (1 mol% thiourea 9) utilizing the ethanolysis (12 equiv. EtOH) of styrene oxide as model reaction.

Scheme 6.27 Typical P-alkoxy alcohols obtained from the highly regioselective alcoholysis of styrene oxides catalyzed by thiourea 9 and mandelic acid 20 in a cooperative organocatalytic system.

Scheme 6.28 Mechanistic proposal for the regioselective alcoholysis of styrene oxides utilizing a cooperative Bronsted acid-type organocatalytic system comprised of thiourea 9 and mandelic acid 20.

A simple route to 1,2-diols by organocatalytic enantioselective a-oxidation of aldehydes with singlet molecular oxygen, catalysed by protected diarylprolinols, has been reported. The oxidation produced (/-hydroxy ketones, which are reduced with boro-hydride to the diols. The 1,2-diols were isolated in high yields with up to 98% ee. The oxidant was photo or chemically generated 102.242... 

The vast majority of organocatalytic reactions proceeds via covalent formation of the catalyst-substrate adduct to form an activated complex. Amine-based reactions are typical examples, in which amino acids, peptides, alkaloids and synthetic nitrogen-containing molecules are used as chiral catalysts. The main body of reactions includes reactions of the so-called generalized enamine cycle and charge accelerated reactions via the formation of iminium intermediates (see Chapters 2 and 3). Also, Morita-Baylis-Hillman reactions (see Chapter 5), carbene-mediated reactions (see Chapter 9), as well as asymmetric ylide reactions including epoxidation, cyclopropanation, and aziridination (see Chapter 10), and oxidation with the in situ generation of chiral dioxirane or oxaziridine catalysts (see Chapter 12), are typical examples. 

One drawback for the direct organocatalytic a-oxidation of aldehydes and ketones is the use of nitrosobenzene, which is an expensive oxygen source . This has led to further investigations in order be able to use other oxidants. Recently, Cordova et al. [20] reported that r-a-methyl proline could incorporate O2 in the a-position of an aldehyde. The presence of tetraphenylporphyrin (TPP) as sensitizer was necessary to promote the formation of singlet 02 as the electrophilic species. Although, the enantioselectivities obtained were only moderate (54-66% ee), this represents undoubtedly a very intriguing alternative to the use of nitrosobenzene in this type of reaction. 

Oxidation reactions - notably alkene epoxidations - were some of the first asymmetric organocatalytic processes to develop into generally useful synthetic methods applicable to a range of substrates [1], This chapter surveys these reactions, with emphasis placed on the most practical and general. Some recent, very useful oxidation reactions involving a-oxidation of carbonyl compounds are covered elsewhere (see Chapter 2). 

The information contained in this chapter has demonstrated the enormous power and versatility of organocatalytic oxidation processes. However, challenges still remain in addition to the substrate limitations highlighted for several of the transformations and moderate current levels of enantioselectivity for some of the processes, catalyst loadings are often high compared to metal-catalyzed reactions, and non-environmentally friendly oxidants are sometimes required. Thus, further progress in the development of more selective and more active catalysts is eagerly anticipated. 

Brown SP, Brochu MP, Sinz CJ, MacMillan DWC (2003a) The direct and enantioselective organocatalytic alpha-oxidation of aldehydes. J Am Chem Soc 125 10808-10809... 

Based on our previously developed organocatalytic Mannich methodology (Enders et al. 2005b) we planned a synthetic strategy towards (+)-polyoxamic acid (49) starting from a suitable Mannich base, which would utilize a diastereoselective reduction of the ketone functionality to the corresponding secondary alcohol and an oxidation step to con-... 

The suitability of organocatalytic reactions for larger-scale production processes of chiral building blocks has also already been demonstrated in some cases. Notably, different types of bond formation have been reported, comprising several carbon-carbon bond formations as well as oxidation processes. An overview about asymmetric organocatalytic processes with an industrial impact is given in Table 1. These syntheses comprise asymmetric organocatalytic reactions which have been scaled... 

Direct organocatalytic asymmetric aldol reaction of a-aminoaldehydes 35 with other substituted aldehydes furnishes S-hydroxy-a-aminoaldehydes with high anti-stereoselectivity. This procedure is of importance for the synthesis of a-aminosugars and derivatives. Additionally, the oxidation of aldehydes gives rise to highly enantiomerically enriched ant/-/3-hydroxy-a-amino acids (O Scheme 28) [156]. 

Copper amine oxidase (CAO) enzymes carry out the aerobic oxidation of primary amines to aldehydes (Scheme 14.8a). While copper is present in the active site, substrate oxidation proceeds by an organocatalytic pathway involving an o-quinone cofactor via a transamination mechanism (Scheme 14.8b). 

Likewise, [bis(acyloxy)iodo]arenes can be used as the oxidants in organocatalytic, asymmetric epoxidation of a,p-unsaturated aldehydes using chiral imidazolidinone catalyst 207 [266]. In a specific example, the... 

Additional examples of oxidations at a nitrogen center inciude the foiiowing the PhI(OAc)2-induced oxidation of aromatic amines to imines appiied for deprotection of protected amino diois [512], N-acylation of 1,3-disubstituted thioureas using PhI(OAc)2 [513], PhI(OAc)2-promoted oxidation of 1,2-dicarbethoxyhydrazine to diethyl azodicarboxylate as a key step in an organocatalytic Mitsunobu... 

---