Aminohydroxylations

Two methods that are particularly convenient for large-scale synthesis of aziridines are discussed below. Both utilize readily available chloramine salts, such as chloramine-T, as sources of nitrogen. The first method involves direct olefin azir-idination catalyzed by phenyltrimethylammonium tribromide (PhNMe3+Br3 PTAB) [42]. In the second method, 1,2-hydroxysulfonamides, conveniently obtained by osmium-catalyzed aminohydroxylation of olefins, are converted into aziridines by one-pot cyclodehydration. 

Two procedures have been developed for the aminohydroxylation of a, 3-unsat-urated amides Procedure A for products that are insoluble in the reaction mixture and Procedure B for soluble products (Scheme 12.17) [48]. These differ only in that the former requires a 10-25% excess of chloramine-T and t-BuOH as the cosolvent, while the latter uses only one equivalent of the chloramine salt and MeCN as the cosolvent. The excess of chloramine-T in Procedure A allows better turnover near the end of the reaction, and the trace amount of p-toluenesulfonamide byproduct can be removed by recrystallization. However, elimination of the necessity to remove p-toluenesulfonamide far outweighed the inconvenience of slightly longer reaction times needed in procedure B without the use of excess chloramine salt. 

Both regioisomers were observed in aminohydroxylation of almost all the substrates that were examined. By taking advantage of their high combined yields, as well as the racemic nature of the aminohydroxylation products, a one-pot, two-step synthesis of sulfonyl aziridines through the cyclodehydration of hydroxysulfona-mides was developed (Scheme 12.18). 

The generality of this method for large-scale preparations was demonstrated for the syntheses of toluenesulfonyl aziridines from aminohydroxylation products of N-substituted cinnamamides (Table 12.9). The results of synthesis of other sulfo-nyl aziridines are summarized in Tables 12.10 and 12.11. 

Mehrmann SJ, Abdel-MagidAF, Maryanoff CA, Medaer BP (2004) Non-Salen Metal-Catalyzed Asymmetric Dihydroxylation and Asymmetric Aminohydroxylation of Alkenes. Practical Applications and Recent Advances. 6 153-180 De Meijere, see Wu YT (2004) 13 21-58 Manage S, see Fontecave M (2005) 15 271-288... 

Amino-Hydroxylation. A related reaction to asymmetric dihydroxylation is the asymmetric amino-hydroxylation of olefins, forming v/c-ami noalcohols. The vic-hydroxyamino group is found in many biologically important molecules, such as the (3-amino acid 3.10 (the side-chain of taxol). In the mid-1970s, Sharpless76 reported that the trihydrate of N-chloro-p-toluenesulfonamide sodium salt (chloramine-T) reacts with olefins in the presence of a catalytic amount of osmium tetroxide to produce vicinal hydroxyl p-toluenesulfonamides (Eq. 3.16). Aminohydroxylation was also promoted by palladium.77... 

Subsequently, stoichiometric asymmetric aminohydroxylation was reported.78 Recently, it was found by Sharpless79 that through the combination of chloramine-T/Os04 catalyst with phthalazine ligands used in the asymmetric dihydroxylation reaction, catalytic asymmetric aminohydroxylation of olefins was realized in aqueous acetonitrile or tert-butanol (Scheme 3.3). The use of aqueous rerr-butanol is advantageous when the reaction product is not soluble. In this case, essentially pure products can be isolated by a simple filtration and the toluenesulfonamide byproduct remains in the mother liquor. A variety of olefins can be aminohydroxylated in this way (Table 3.1). The reaction is not only performed in aqueous medium but it is also not sensitive to oxygen. Electron-deficient olefins such as fumarate reacted similarly with high ee values. 

In 1975, Sharpless et al. reported that imino-osmium trioxides underwent aminohydroxylation (Scheme 54).208,209 t0 perform aminohydroxylation with high efficiency, regio-, chemo-, and enantioselectivity must be addressed. This had made the practical realization of aminohydroxylation difficult. However, the development of asymmetric dihydroxylation, as described in the preceding section, propelled the study of asymmetric aminohydroxylatyion forward and, in 1996, Sharpless et al. reported a highly enantioselective version of catalytic aminohydroxylation... 

Figure 9 The proposed catalytic cycle of asymmetric aminohydroxylation.

The reactions with a combination of (DHQ)2-PHAL [or (DHQD)2-PHAL] and /V-halosulfo-namides can be successfully applied to trans-olefins. Especially when the substrates are a,j3-unsaturated esters, high regioselectivity as well as good enantioselectivity is realized (Scheme 55).210,211 The use of an /V-halosulfonamide bearing a smaller A-substituent increases the enantioselectivity.211 n-Propanol/water (1 1) is the solvent of choice. Aminohydroxylation of silyl enol ethers has been successfully performed with DHQD-CL or (DHQD)2-PYR, to give the corresponding a-amino ketones.212... 

A-chloro carboxamides can also be used as nitrogen sources, but the reaction must be performed at 4 °C or below to avoid Hofmann degradation of the carboxamides. The regioselectivity of the reaction is dependent on the ligand and the solvent used PHAL and AQN ligands again show opposite selectivity to each other (Scheme 57).204 The aminohydroxylation using... 

The asymmetric oxidation of organic compounds, especially the epoxidation, dihydroxylation, aminohydroxylation, aziridination, and related reactions have been extensively studied and found widespread applications in the asymmetric synthesis of many important compounds. Like many other asymmetric reactions discussed in other chapters of this book, oxidation systems have been developed and extended steadily over the years in order to attain high stereoselectivity. This chapter on oxidation is organized into several key topics. The first section covers the formation of epoxides from allylic alcohols or their derivatives and the corresponding ring-opening reactions of the thus formed 2,3-epoxy alcohols. The second part deals with dihydroxylation reactions, which can provide diols from olefins. The third section delineates the recently discovered aminohydroxylation of olefins. The fourth topic involves the oxidation of unfunc-tionalized olefins. The chapter ends with a discussion of the oxidation of eno-lates and asymmetric aziridination reactions. 

The /Tamino alcohol structural unit is a key motif in many biologically important molecules. It is difficult to imagine a more efficient means of creating this functionality than by the direct addition of the two heteroatom substituents to an olefin, especially if this transformation could also be in regioselective and/ or enantioselective fashion. Although the osmium-mediated75 or palladium-mediated76 aminohydroxylation of alkenes has been studied for 20 years, several problems still remain to be overcome in order to develop this reaction into a catalytic asymmetric process. 

As for the mechanism of asymmetric aminohydroxylation, it has been proposed that there are at least two catalytic cycles in the reaction system (Scheme 4-38).77b It is also suggested that both electronic and steric factors play important roles in the reaction. In the first cycle, in which the turnover occurs, effects of the ligand on selectivity are possible. For the ligand-independent... 

Scheme 4-38. Proposed mechanism for asymmetric aminohydroxylation. Sequence of steps in the first catalysis cycle (left) (1) addition (a1), (2) reoxidation (O), (3) hydrolysis (h1) in the second catalysis cycle (right) (1) addition (a2), (2) hydrolysis (h2), (3) reoxidation (O). The first cycle proceeds with high ee, the second with low ee. L = chiral ligand X = CH3SO2. ... 

TABLE 4-16. Influence of Ligand and Solvent on the Regioselectivity in Asymmetric Aminohydroxylation Reaction of Four Styrene Substrates7 9b... 

TABLE 4-17. Asymmetric Aminohydroxylation Using TeoCNNaCl as the Nitrogen Source... 

The catalytic asymmetric aminohydroxylation of a variety of styrene derivatives, vinyl aromatics, and some other olefins using osmium tetroxide... 

Several methods have been developed for the synthesis of the taxol side chain. We present here the asymmetric construction of this molecule via asymmetric epoxidation and asymmetric ring-opening reactions, asymmetric dihydroxylation and asymmetric aminohydroxylation reaction, asymmetric aldol reactions, as well as asymmetric Mannich reactions. 

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