Racemic compounds amination

The method is not restricted to secondary aryl alcohols and very good results were also obtained for secondary diols [39], a- and S-hydroxyalkylphosphonates [40], 2-hydroxyalkyl sulfones [41], allylic alcohols [42], S-halo alcohols [43], aromatic chlorohydrins [44], functionalized y-hydroxy amides [45], 1,2-diarylethanols [46], and primary amines [47]. Recently, the synthetic potential of this method was expanded by application of an air-stable and recyclable racemization catalyst that is applicable to alcohol DKR at room temperature [48]. The catalyst type is not limited to organometallic ruthenium compounds. Recent report indicates that the in situ racemization of amines with thiyl radicals can also be combined with enzymatic acylation of amines [49]. It is clear that, in the future, other types of catalytic racemization processes will be used together with enzymatic processes. 

The simple reaction of (natural) (/ ,7 )-dibenzoyltartaric anhydride (DBTAAN) with racemic primary amines and similar compounds yields tartarimides50. Especially notable about the H-NMR spectrum are the two sharp singlets corresponding to the two methine protons of the... 

The polymer of high molecular weight in the solid stage exhibited high crystallinity under a polarized microscope and insoluble in common organic solvents. When the polymer with high optical rotation was used as stationary phase or sorbent for the chromatographic resolution of racemic compounds, it showed the ability of resolution for many kinds of compounds, such as alcohols, amines, esters, and even hydrocarbons (28). 

In 1998, Machida et al. [45] and Hyun et al. [46] developed a new CCE-based CSP (covalently bonded to silica gel see Sect. 8.2). This CSP was used successfully for the chiral resolution of certain racemic compounds using a variety of mobile phases. The most important applications of this CSP are for the resolution of amino acids, amino esters, amino alcohols, amines, amides, quinolone antibacterials, and other drugs having primary amino groups [46-51,64,65]. The typical chromatograms of the chiral resolution of amino acids on (+)-(18-crown-6)-2,3,ll,12-tetracarboxylic acid CSP are shown in Figure 4. The enantiomeric resolution of the racemic compound on CCE-based CSPs are listed in Table 2. There is no report available on the chiral separations at the preparative scale using these CSPs. 

Because the steric effect contributes to the complex formation between guest and host, the chiral resolution on these CSPs is affected by the structures of the analytes. Amino acids, amino alcohols, and derivatives of amines are the best classes for studying the effect of analyte structures on the chiral resolution. The effect of analyte structures on the chiral resolution may be obtained from the work of Hyun et al. [47,48]. The authors studied the chiral resolution of amino alcohols, amides, amino esters, and amino carbonyls. The effects of the substituents on the chiral resolution of some racemic compounds are shown in Table 6. A perusal of this table indicates the dominant effect of steric interactions on chiral resolution. Furthermore, an improved resolution of the racemic compounds, having phenyl moieties as the substituents, may be observed from this Table 6. ft may be the result of the presence of n—n interactions between the CCE and racemates. Generally, the resolution decreases with the addition of bulky groups, which may be caused by the steric effects. In addition, some anions have been used as the mobile phase additives for the improvement of the chiral resolution of amino acids [76]. Recently, Machida et al. [69] reported the use of some mobile phase additives for the improvement of chiral resolution. They observed an improvement in the chiral resolution of some hydrophobic amino compound using cyclodextrins and cations as mobile phase additives. 

The most popular and commonly used chiral stationary phases (CSPs) are polysaccharides, cyclodextrins, macrocyclic glycopeptide antibiotics, Pirkle types, proteins, ligand exchangers, and crown ether based. The art of the chiral resolution on these CSPs has been discussed in detail in Chapters 2-8, respectively. Apart from these CSPs, the chiral resolutions of some racemic compounds have also been reported on other CSPs containing different chiral molecules and polymers. These other types of CSP are based on the use of chiral molecules such as alkaloids, amides, amines, acids, and synthetic polymers. These CSPs have proved to be very useful for the chiral resolutions due to some specific requirements. Moreover, the chiral resolution can be predicted on the CSPs obtained by the molecular imprinted techniques. The chiral resolution on these miscellaneous CSPs using liquid chromatography is discussed in this chapter. 

Many of the chiral molecules containing amide groups were bonded to a solid support for the preparation of CSPs [16-19]. The racemic compounds resolved on these CSPs include a-hydroxycarbonyls, /i-hydroxycarbonyls, amino acids, amino alcohols, amine, and derivatized and underivatized diols. The preliminary chiral diamide phase [(/V-foriuyl-L-valyl)aminopropyl)silica gel] has sufficient separability for racemic /Y-acylatcd a-amino acid esters but not in other types of enantiomer [16]. Most of the eluents used with these CSPs are of normal phase mode, including w-hcxanc, 2-propanol, chlorinated organic solvents, and acetonitrile. 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

S)-Methyl-3-(benzoylamino)butanoate (S)-72 is also available by enzymatic resolution with pig liver esterase. Alkylation and amination were run on the racemic compounds. One example of electrophilic amination is reported starting from rac-72 which is doubly deprotonated with LDA at low temperature (-60 °C to -45 °C). The enolate intermediate adopts an (E) configuration. After treatment at -70 °C with DTBAD (1.2 equiv.) in THF, the product 73 is obtained with 96% yield and an excellent diastereoselectivity de > 99 % in favor of the anri-diastereomer (Scheme 34). The absolute configuration of the created stereogenic center was assigned by chemical correlation with the known anti-2,3-diaminobutanoic acid. 

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. 

Various racemic compounds including alcohols, esters, amines, amino alcohols, carboxylic acids and amino acids... 

The brush-type of CSP was introduced by Pirkle who was one of the pioneers of modern enantioselective liquid chromatography [55]. The most frequently used 7i-acceptor phases are derived from the amino acids phenylglycine (DNBPG) (Fig. 6.8) or leucine (DNBLeu) covalently or ionically bonded to 3-aminopropyl silica gel [56, 57]. These CSPs are commercially available for analytical or preparative separation of enantiomers. Further CSPs based on amino acid or amine chiral selectors such as valine, phenylalanine, tyrosine [58] and l,2-tr s-diaminocyclohexane (DACH-DNB phase) [59] and 1,2-traus-diphenylethylene diamine (ULMO phase) [60] were also developed (Fig. 6.8). These CSPs have been applied for the preparative separation of the enantiomers of a few racemic compounds, but the number of reported preparative applications has remained very limited over the last 10 years. 

The late 1990s saw the development of an alternative methodology for the enzymatic resolution of racemic amines using transaminases. Transaminases are pyridoxal phosphate 50 dependent enzymes that catalyze the transfer of an amine group to a carbonyl compound (amine group acceptor), such as a ketone, aldehyde, or keto add (Figure 14.19). 

Just how determined you will see. They looked at salts of both amines with about fifty achiral acids of which eight proved to be conglomerates, three for 84 and five for 85 (this is about what would be expected - about 10%). Of these eight, two could not be separated by crystallisation because one salt 86 had crystal facets that acted as seeds for the other enantiomer while the conglomerate of another 87 was unstable and easily reverted to a racemic compound. 

The racemic compound is available by methods used (Disconnection Textbook, page 250) for the closely related benzodiazepines like diazepam, used in the treatment of depression. The one stereogenic centre is next to a primary amine, and the compound forms a crystalline salt with camphor sulfonic acid 98 (cf. 61). The maximum yield is 50%, but the amine (.S )-97 can be released from the salt simply by neutralisation.24 This is a classical resolution by crystallisation of diastereoisomers. 

Racemic compounds containing a carbonyl function can serve as good models for the study of diastereoselective reductive aminations using achiral amines as educts. Intermediates in these reactions ate imines. The related racemic amines are obtained with relatively low diastereose-lectivity11-14. 

A chemical reaction is carried out between the racemate and an optically active form (either laevo-or dextro-) of a substance capable of reacting with the racemate. This other optically active compound is usually derived from a natural source. To resolve the racemates of amines (or other bases) and alcohols, for example, use may be made of the naturally occurring d-tartaric acid (from wine tartar). The reaction with amines gives salts and esters are formed with alcohols. For the resolution of racemates of acids, use is frequently made of alkaloids such as quinine or stiychnine extracted from plants in which each of these alkaloids is present in an optically active form. The racemate mixture forms two diastereoisomers (compounds that are stereoisomers of each other, but are not enantiomers) of a derivative, with the optically active reagent used. If the... 

The importance of this reaction relies on the fact that the Betti bases can function as both excellent ligands and auxiliaries in asymmetric synthesis. The racemic Betti amines can be separated into their optical antipodes. In this respect, among the Betti bases from monochlorobenzaldehydes, only the dextro form of the ortho and meta chloro compounds could be resolved with satisfaction, while the levo antipodes are extremely difficult to obtain due to their higher solubilities. ... 

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