Asymmetric hydroxyamination

This book is intended to provide an overview of several areas of research in which amination plays a key role, and to introduce the reader to new concepts that have been developed quite recently for generating new C - N bonds. As the pharmaceutical and chemical industries move rapidly away from the development of racemic compounds, the access to synthetic routes that lead efficiently to enantiomerically pure materials is becoming increasingly important. For this reason, most of the contributions in this book refer to asymmetric synthesis. However, no attempt has been made to present a comprehensive work, and important areas such as asymmetric hydroxyamination [1] have not been dealt with. Furthermore, it may be worth mentioning that viable, useful and comprehensive sources of information about the methodological approaches to electrophilic amination developed since 1985 have already been reported [2], and that a chapter in Houben-Weyl reviewing several aspects of the asymmetric electrophilic amination [3] compiles important contributions up to 1995. 

Scheme 15 Catalytic asymmetric hydroxyamination reactions of oxindoles with nitrosoarenes...

The reaction between epoxides and ammonia is a general and useful method for the preparation of P-hydroxyamines. " Ammonia gives largely the primary amine, but also some secondary and tertiary amines. The useful solvents, the ethanolamines, are prepared by this reaction. For another way of accomplishing this conversion, see 10-54. The reaction can be catalyzed with Yb(OTf)3 and in the presence of a-BINOL is l,l -bi-2-naphthol derivative gives amino alcohols with high asymmetric induction. A variation used Yb(OTf)3 at lOkbar or at ambient pressure. Lithium triflate can also be used. Primary and secondary amines give, respectively, secondary and tertiary amines, for example. 

Quinine and quinidine, as well as cinchonidine and cinchonine, are diastereo-meric pairs. However, at the critical sites—the P-hydroxyamine portions of the molecules—they are enantiomeric. Thus if quinine is used as the chiral catalyst in an asymmetric transformation (i.e., with one enantiomer being formed in excess), the other enantiomer is formed in excess when quinidine is used. Table 2 gives a representative example, the thiol addition reaction (19). 

Thiols may be enantioselectiveiy added in a conjugate fashion to a,p-unsaturated carbonyl compounds in the presence of chiral hydroxyamine catalysts e.g. chinchona alkaloids).242,244 249 252-261-269 In some cases ee of up to >80% were achieved e.g. Scheme 77).242-261-262 This methodology was utilized for the kinetic resolution of compound rat-86 Scheme 34) in a multigram scale.94 Related enantioselective 1,4-additions of thioacetates270-271 and selenophenols272 to enones are also known. Epoxidations, based on the asymmetric nucleophilic addition of peroxide anions to enones, are discussed separately.273... 

The [3-hydroxy amines are a class of compounds falling within the generic definition of Eq. 6A.6. When the alcohol is secondary, the possibility for kinetic resolution exists if the Ti-tartrate complex is capable of catalyzing the enantioselective oxidation of the amine to an amine oxide (or other oxidation product). The use of the standard asymmetric epoxidation complex (i.e., T2(tartrate)2) to achieve such an enantioselective oxidation was unsuccessful. However, modification of the complex so that the stoichiometry lies between Ti2 (tartrate) j and Ti2(tartrate)1 5 leads to very successful kinetic resolutions of [3-hydroxyamines. A representative example is shown in Eq. 6A.11 [141b,c]. The oxidation and kinetic resolution of more than 20 secondary [3-hydroxyamines [141,145a] provides an indication of the scope of the reaction and of some... 

More successful asymmetric reductions have been based on amine (particularly alkaloid) complexes of bis(dimethylglyoximato) cobalt(II), also known as cobaloxime(II) and represented Co(dmg)2 (compound VII). Cobaloxime-chiral amine complexes have been used to catalyze the hydrogenation of both olefinic and ketonic substrates (Fig. 24). It has been determined that hydroxyamine modifiers, for example, alkaloids such as quinine, quinidine, and cinchonidine, are most effective. The highest optical purity obtained thus far has been 71%, observed for reduction of benzil in benzene solution at 10° using quinine as the... 

Together with cinchona-PTC-mediated a-alkylations, the asymmetric nucleophilic a-substitution of carbonyl derivatives by using cinchona alkaloids as organocatalysts in nonbiphasic homogeneous conditions also have been extensively studied (e.g., arylation, hydroxylation, amination, hydroxyamination, and sulfenylation). 

All the examples reported so far for the enantioselective organocatalytic aminox-ylation (nucleophile attacks to the oxygen atom of the nitroso derivative) or hydro-xyamination (nucleophile attacks to the nitrogen atom of the nitroso derivative) have employed an enamine intermediate and nitrosobenzene, but O-selectivity is obtained in majority. In 2007, a selective a-hydroxyamination was disclosed with cinchona alkaloids by Jorgensen and coworkers (Scheme 6.43) [72]. They developed the organocatalytic asymmetric addition of a-aryl-a-cyanoacetates 133 to nitrosobenzene (144) catalyzed by (—(-quinine in high yields and moderate enantioselectivities up to 59% ee. 

An alternative approach to 1,4-addition affording / -amino acid derivatives, by use of Lewis acid-hydroxyamine hybrid reagents (LHHR), was also investigated [122]. LHHR were ten times more reactive than benzylhydroxyamine itself. This reagent-controlled asymmetric 1,4-addition using aluniinum-hydroxyamine complexes resulted in moderate enantioselectivity (43-71% ee) (Scheme 6.98). 

The transition metal-catalyzed asymmetric Michael addition reaction was first reported by Brunner employing the complex of Co(acac)2 and (S,S)-l,2-diphe-nyl-l,2-ethylenediamine (Scheme 12) [59, 60]. An enantiomeric excess of 66% was attained in the reaction of 6 and 7 giving R)-8 at -50 C in toluene. The dimeric copper complex 65 derived from salicylaldehyde and optically active (S)-hydroxyamines also promoted the reaction giving (S)-8 in 75% ee [61, 62, 63]. The second hydroxy group is considered to occupy the axial position of the monomeric intermediate. 

In a recent report, an asymmetric electrophilic hydroxyamination of a chiral A-acylsultam was used to give a nitrone which then underwent a cycloaddition reaction with styrene to ultimately produce, after several additional steps, (-)-allosedamine (178) [452]. 

Pinidine (188) was recently synthesized from methyl 6-ketoheptanoate. An asymmetric electrophilic hydroxyamination of a chiral N-acylsultam was used to form the piperidine ring, and hydrogenation of the nitrone gave the required cis-2,6 substitution [466]. 

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