Chiral N-oxides

The virtue of performing the PKR in an enantioselective manner has been extensively elaborated during the last decade. As a result, different powerful procedures were developed, spanning both auxiliary-based approaches and catalytic asymmetric reactions. For instance, the use of chiral N-oxides was reported by Kerr et al., who examined the effect of the chiral brucine N-oxide in the intermolecular PKR of propargylic alcohols and norbornadiene [59]. Under optimized conditions, ee values up to 78% at - 60 °C have been obtained (Eq. 10). Chiral sparteine N-oxides are also able to induce chirality, but the observed enantioselectivity was comparatively lower [60]. 

Scheme 17 Enantioselective Allylation with axial chiral N-oxides...

Chiral N-Oxides 250) In the reaction of N-benzyl-N-methylamino amino acids with H202 in alkaline water solution, mixtures of diastereomeric N-oxides, containing new centers of chirality on nitrogen atoms, were obtained. The reaction was performed with the corresponding derivatives of (S)- [or (R)] alanine, (S)- [or (R)] leucine, (S)-[or (R)] phenylalanine, and (S)- [or (R)] proline, respectively. In the reaction a distinct stereoselectivity could be observed for alanine, leucine, and phenylalanine derivatives the formation of N(S)C(S), or correspondingly N C, diastereomer is favoured. The reaction of (S)-proline derivatives leads, however, exclusively to the N(R,C(S) stereoisomer (252) on the other hand, (R)-proline yielded stereoselectively the compound (253). 

Interestingly, completely different types of organocatalyst have been found to have catalytic hydrocyanation properties. Among these molecules are chiral diketo-piperazine [4, 5], a bicydic guanidine [6], and imine-containing urea and thiourea derivatives [7-13]. All these molecules contain an imino bond which seems to be beneficial for catalyzing the hydrocyanation process. Chiral N-oxides also promote the cyanosilylation of aldimines, although stoichiometric amounts of the oxides are required [14]. 

The Feng group showed that organic molecules without an imine bond also seem to be able to catalyze the cyanation of imines [14]. In the presence of (stoichiometric) amount of a chiral N-oxide, 19, addition of trimethylsilylcyanide to several types of aldimine gave the desired a-amino nitriles with enantioselectivity up to 73% ee [14]. For example, (S)-4a is obtained in 95% yield and with 58% ee (Scheme 5.10). In addition to medium enantioselectivity, a drawback of this method is the need for stoichiometric amounts of the chiral N-oxide. The use of trimethylsilylcyanide is also less recommendable than HCN from both atom-economical and industrial considerations. 

The suitability of a different type of organocatalyst, chiral N-oxides, for asymmetric allylation was discovered by the Nakajima group [176]. On the basis of the knowl-... 

Chiral N-oxides of type (S)-165 can be also used for diastereo- and enantioselec-tive allylation using ( )- and (Z)-crotyltrichlorosilanes [176]. For these substrates, high diastereoselectivity led to the anti-diastereomer when ( )-crotyltrichlorosilane, 158b, was used and the syn-diastereomer when the (Z)-substrate, 158c, was used (Scheme 6.77). For example, formation of the anti-diastereomer (R,R)-159e proceeded with 68% yield and excellent diastereoselectivity of d.r. (syn/anti) = 3 97. Enantiomeric excess for the major anti-diastereomer (R, )-159e was 86%. 

Two other types of catalysts have been investigated for the enantioselective Strecker-type reactions. Chiral N-oxide catalyst 24 has been utilized in the trimethylsilyl cyanide promoted addition to aldimines to afford the corresponding aminonitriles with enantioselectivities up to 73% ee [14]. Electron-deficient aldimines were the best substrates, but unfortunately an equimolar amount of catalyst 24 was used in these reactions. The asymmetric Strecker addition of trimethylsilyl cyanide to a ketimine with titanium-based BINOL catalyst 25 gave fast conversions to quarternary aminonitriles with enantiomeric excesses to 59%... 

Chiral N-oxides have also been employed as catalysts to promote aldol addition [62], but their true potential remains to be realized. Catalysis by N-oxides follows the same general trends that were established for the phosphoramide activators, though with reduced enantioselectivity. Thus, Nakajima [62] has demonstrated that the reaction of aldehydes 1 with silyl enol ethers 55, catalyzed by bidentate... 

An interesting case of N-oxidation is given by [2.2](2.5)furano(3,6)py-ridazinophane (67). Oxidation with /n-CPBA gave the chiral N-oxide 68 together with a smaller amount of diketone 69, resulting from furan ring... 

Pyridine Af-oxides have been utilized as asymmetric catalysts in the allylation of aldehydes <06JOC1458> and in the Strecker reaction <06T4071>. In the latter, the chiral N-oxides played a key role in the initial activation of the Si-C bond by coordinating an O atom to the Si atom of silyl cyanide and stabilizing the three-membered complex proposed by the... 

Previous reviews have dealt with metal-catalyzed [93] and stoichiometric [94] oxidation of amines in a broad sense. This section will be limited to the selective oxidation of tertiary amines to N-oxides. Amine N-oxides are synthetically useful compounds [95, 96] and are frequently used as stoichiometric oxidants in osmium-[97-99] manganese- [100] and ruthenium-catalyzed [101,102] oxidations, as well as in other organic transformations [103-105]. Aliphatic tert-amine N-oxides are usefid surfactants [96] and are essential components in hair conditioners, shampoos, toothpaste, cosmetics, and so on [106]. Chiral N-oxides have been used in asymmetric catalysis involving metal-free catalytic transformations [107] as well as metal-catalyzed reactions where the N-oxide serves as a ligand [107, 108]. Chiral tertiary amine N-oxides were recently used as reagents in asymmetric epoxidation of a,(3-unsaturated ketones [109]. 

L, and Rowlands, G.J. (2011) Facile synthesis of planar chiral N-oxides and their use in Lewis base catalysis. Chem. Commun., 433-435. 

Figure 15.4 Chiral phosphoramides used as Lewis-basic activators (79-81) and chiral N-oxides (82-84).

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