Asymmetric aminohydroxylation reactions

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

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. 

Synthesis of the taxol side chain involves the asymmetric aminohydroxylation reaction (Scheme 1.16). 

The asymmetric aminohydroxylation reaction provides ready access to 1,2-amino alcohol derivatives and is a useful alternative not only to the AD methodology but also to peroxide-based approaches. The power of both the approaches in synthesis is helped by the development of the mnemonic device, which allows the stereochemical outcome of the reactions to be predicted with a large degree of certainty. 

Although the first, albeit stoichiometric, example of this asymmetric aminohydroxylation reaction had already been observed in 1980 [5], the discovery of the titanium catalyzed asymmetric epoxidation (AE) [6] at about the same time probably also interfered with an earlier development of today s catalytic asymmetric aminohydroxylation (AA) process. 

It is also important to note that the obtained regioselectivity of this aminoacetoxylation reaction is opposite to the one observed in the seminal Sharpless asymmetric aminohydroxylation reaction (Sharpless AA reaction) [120]. Although processes of palladium(IV) catalysis currently cannot induce enantioselectivity, future development should render this unique reactivity complementary to existing enantioselective transformations. 

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. 

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. 

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... 

By reactions of different 13,4-triazine derivatives, C-ribosyl imidazo[2,l-/][13,4]triazines <99JCS(P1)2929> and C-ribosyl 13.4-triazolo[3,4-/ [13,4]triazines <99JCS(P1)2937> have been synthesized as inhibitors of adenosine and AMP deaminases. Catalytic asymmetric aminohydroxylation with amino substituted 13,4-triazine and 133-tiiazine derivatives, as nitrogen sources, has been described <99AG(E)1080>. 

Alkenes are oxidized to 2-amino ketones in an osmium-catalysed oxidation with CAT. The reaction can also be carried out as a sequential process consisting of asymmetric aminohydroxylation and subsequent oxidation to enantiopure 2-amino ketones.107... 

There remain still quite a few conceptual advances to be discovered in the asymmetric aminohydroxylation, broadening further the scope and limitations of this process. On the other hand, the utility of the AA is demonstrated in many applications now, giving ample proof that this reaction has become an indispensable tool in organic synthesis. 

With cis-vic-aminohydroxylations of unsymmetrical alkenes, however, it may be a problem that two regioisomers occur—a complication that does not occur with cis-vic-dihydroxylations. The addition of (DHQ)2-PHAL or (DHQD)2-PHAL (Figure 17.21, part I) in a cis-vic-aminohydroxylation will also cause asymmetric catalysis. The related reactions are known as asymmetric aminohydroxylations. 

Another substrate class, for which the outcomes of a radical and a carbocationic process are opposite, are indoles (Fig. 85) [418], Indeed, when oxaziridines 315a or 315c were treated with indoles 314c in the presence of 2 or 10 mol% of C11CI2/ TBAC oxazolidinoindolines 316c were obtained as the exclusive products in 53-90% yield. The reaction is applicable to 2-, 3-, and 2,3-disubstituted indoles. Chiral indole derivatives acylated with (S)-proline units at nitrogen underwent asymmetric diastereoselective aminohydroxylation reactions with 86-91% de. Tricyclic hemiaminals derived from tryptamine derivatives could be transformed to pyrrolidinoindolines, which are core structures of a number of alkaloids. 

Angert, K. B. Sharpless, Angew. Chem. Int. Ed. Engl. 1996,35,2813 (c) H. C. Kolb, K. B. Sharpless, Asymmetric Aminohydroxylation in Transition Metals for Organic Synthesis, Vol. 2 M. Beller, C. Bolm (Eds.) WILEY-VCH, Weinheim, 1998,243 - 260 (d) G. Schlingloff, K. B. Sharpless, Asymmetric Aminohydroxylation in Asymmetric Oxidation Reactions A Practical Approach T. Katsuki (Ed.) Oxford University Press, Oxford, in press. 

In 1975 Sharpless and coworkers discovered the stoichiometric aminohydrox-ylation of alkenes by alkylimido osmium compounds leading to protected vicinal aminoalcohols [1,2]. Shortly after, an improved procedure was reported employing catalytic amounts of osmium tetroxide and a nitrogen source (N-chlo-ro-N-metallosulfonamides or carbamates) to generate the active imido osmium species in situ [3-8]. Stoichiometric enantioselective aminohydroxylations were first reported in 1994 [9]. Finally, in 1996 the first report on a catalytic asymmetric aminohydroxylation (AA) was published [10]. During recent years, several reviews have covered the AA reaction [11-16]. 

Schlingloff G, Sharpless KB (2001) Asymmetric aminohydroxylation. In Katsuki T (ed) Asymmetric oxidation reactions. Oxford UP, Oxford, p 104... 

In 2001, K. B. Sharpless won the Nobel Prize in Chemistry for his work on asymmetric aminohydroxylation and asymmetric epoxidation °. These stereoselective oxidation reactions are powerful catalytic asymmetric methods that have revolutionized synthetic organic chemistry. 

Sharpless and co-workers first reported the aminohydroxyIation of alkenes in 1975 and have subsequently extended the reaction into an efficient one-step catalytic asymmetric aminohydroxylation. This reaction uses an osmium catalyst [K20s02(OH)4], chloramine salt (such as chloramine T see Chapter 7, section 7.6) as the oxidant and cinchona alkaloid 1.71 or 1.72 as the chiral ligand. For example, asymmetric aminohydroxylation of styrene (1.73) could produce two regioisomeric amino alcohols 1.74 and 1.75. Using Sharpless asymmetric aminohydroxylation, (IR)-N-ethoxycarbonyl-l-phenyl-2-hydroxyethylamine (1.74) was obtained by O Brien et al as the major product and with high enantiomeric excess than its regioisomeric counterpart (R)-N-ethoxycarbonyl-2-phenyl-2-hydroxyethylamine (1.75). The corresponding free amino alcohols were obtained by deprotection of ethyl carbamate (urethane) derivatives. 

SCHEME 13.118 Application of the Sharpless asymmetric aminohydroxylation and of the aza-Achmatowicz reaction to the synthesis of a l,5-dideoxy-l,5-iminoalditol. 

K.B. Sharpless (1941-) studied at Stanford and was first appointed atMIT but is now at the Scripps Institute in California. His undoubted claim to fame rests on the invention of no fewerthan three reactions of immense significance AE (asymmetric epoxidation) and AD (asymmetric dihydroxylation) are discussed in this chapter. The third reaction, AA (asymmetric aminohydroxylation) has still to reach the perfection of the first two. 

Chiral amines and K20sC>2(0H)4 are also used to catalyze the Sharpless asymmetric aminohydroxylation. The stoichiometric oxidant in aminohydroxylation is a deprotonated /V-lialoamide, whose mechanistic behavior is very similar to NMO. The reaction proceeds by a mechanism essentially identical to that of Sharpless dihydroxylation. 

Solvent selection can markedly influence the product ratios of a reaction. In the catalytic asymmetric aminohydroxylation of styrene, the ratio of the acetamide products rose from 0.9 1 to 6.1 1 when the reaction was run in aqueous acetonitrile instead of aqueous n-PrOH (Figure 4.11) [34]. Solvent polarity can influence asymmetric induction, particularly during peptide coupling. When the racemic azlactone 15 was condensed with L-lysine methyl ester (16, Figure 4.12), the D,L-product predominated in relatively nonpolar solvents, and the L,L-product predominated in polar solvents and at lower temperatures [35]. 

There is a marked rate acceleration in the presence of a tertiary amine or pyridine [19, 41]. This finding provided the background for the asymmetric dihy-droxylation (AD) and, later, the asymmetric aminohydroxylation (AA) reactions as it is this ligand acceleration effect (LAE) that ensures the reaction pathway involving the ligand. 

Catalytic asymmetric aminohydroxylation using Os(VIII) and Sharpless cinchona alkaloid ligand has been applied to a,p- and P,Y-unsaturated phosphonate substrates (Scheme 48). The reaction only works for the aryl substituted examples (287) and although initial e.e. s are sometimes low, they can be increased to >90% by a single recrystallisation. The phosphonic acid analogue... 

The Sharpless asymmetric hydroxylation can take one of two forms, the initially developed asymmetric dihydroxylation (AD)1 or the more recent variation, asymmetric aminohydroxylation (AA).2 In the case of AD, the product is a 1,2-diol, whereas in the AA reaction, a 1,2-amino alcohol is the desired product. These reactions involve the asymmetric transformation of an alkene to a vicinally functionalized alcohol mediated by osmium tetraoxide in the presence of chiral ligands (e.g., (DHQD)2-PHAL or (DHQ)2-PHAL). A mixture of these reagents (ligand, osmium, base, and oxidant) is commercially available and is sold under the name of AD-mix p or AD-mix a (vide infra). 

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