Enantiomerically pure amine

Reaction of benzylideneaniline with optically active methyl p-tolyl sulphoxide 449 in the presence of lithium diethylamide produces the corresponding jS-anilinosulphoxide 450 with 100% asymmetric induction. Its reductive desulphurization with Raney nickel leads to the enantiomerically pure amine 451524 (equation 270). When the same optically active... 

Symmetrical N, N -disubstituted imidazolium salts are usually obtained by addition of paraformaldehyde on a bis-imine of glyoxal under acidic conditions. A one-pot procedure has been developed. Several enantiomerically pure amines were used to prepare the corresponding symmetrical salts 6 (Scheme 4) [12,13]. 

One of the potentially most useful aspects of the imine anions is that they can be prepared from enantiomerically pure amines. When imines derived from chiral amines are alkylated, the new carbon-carbon bond is formed with a bias for one of the two possible stereochemical configurations. Hydrolysis of the imine then leads to enantiomerically enriched ketone. Table 1.4 lists some examples that have been reported.118... 

Enantiomerically pure amines are extremely important building blocks for biologically active molecules, and whilst numerous methods are available for their preparation, the catalytic enantioselective hydrogenation of a C=N bond potentially offers a cheap and industrially viable process. The multi-ton synthesis of (S)-metolachlor fully demonstrates this [108]. Although phospholane-based ligands have not proven to be the ligands of choice for this substrate class, several examples of their effective use have been reported. 

Analogous to the reactions of chiral alcohols, enantiomerically pure amines can be prepared by (D)KR of the racemate via enzymatic acylation. In the case of alcohols the subsequent hydrolysis of the ester product to the enantiomerically pure alcohol is trivial and is generally not even mentioned. In contrast, the product of enzymatic acylation of an amine is an amide and hydrolysis of an amide is by no means trivial, often requiring forcing conditions. 

By analogy with the enantioselective reduction of prochiral ketones to chiral alcohols an attractive method for producing enantiomerically pure amines would be enantioselective reductive amination of a ketone via enzymatic reduction of an imine intermediate (Scheme 6.11). Unfortunately the required enzymes-amine... 

To obtain an asymmetric induction during C-C bond formation, one needs an enantiomerically pure amine compound. 

Synthesis of Enantiomerically Pure Amines through Transamination... 

While kinetic resolution with the help of lipases or esterases has seen the greatest success for the synthesis of enantiomerically pure amines, the same target can be reached by employing co-transaminases (co-TA) to reductively transaminate ketones to either (S)- or (K)-amines, depending on the transaminase. The reaction is shown in Figure 7.22 with acetophenone and (S)-transaminase as an example (Shin, 1998, 1999). 

Both (R)- and (S)-amino transferase are available forthe synthesis of enantiomerically pure amines from racemic amines. Degrees of conversion were at or close to 50% for resolutions, and enantioselectivities customarily reached > 99% e.e. for the amine product from both resolutions or syntheses from ketones (Stirling, 1992 Matcham, 1996). The donor for resolutions of amine racemates was usually pyruvate whereas either isopropylamine or 2-aminobutane served as donors for reduction of ketones. The products range from i- and D-amino acids such as i-aminobutyric acid (see Section 7.2.2.6) and i-phosphinothricin (see Section 7.4.2) to amines such as (S)-MOIPA (see Section 7.4.2). 

Either (S)-specific aminopeptidase catalyzed hydrolysis of racemic PGA11 or crystallization-induced asymmetric transformation of racemic PGA with (.S l-mandelic acid as resolving agent12 can be used to prepare (R)-PGA. As a result of its ready availability on large scale within DSM, we envisaged the application of (R)-PGA for the production of enantiomerically pure amine functionalized compounds using the chirality transfer concept. Obviously, (S)-phenylglycine amide is also available and can be used for the preparation of the opposite enantiomer of the amines described. 

In this chapter, recent applications of (W)-phcnylglycine amide (1) in asymmetric synthesis are presented (Figure 25.2). The first section deals with diastereoselective Strecker reactions for the preparation of a-amino acids and derivatives, whereas the second section focuses on diastereoselective allylation of imines for preparation of enantiomerically pure homoallylamines. This latter class of compounds is a well-known intermediate for the synthesis of, for example, many types of amines, amino alcohols, and P-amino acids. The final section describes reduction of imines providing enantiomerically pure amines. (S)-3,3-Dimethyl-2-butylamine and (S)-l-aminoindane will be presented as leading examples. The results described in this chapter originate from a longstanding cooperation in the field of chiral technology development between DSM Pharma Chemicals and Syncom B.V. 

More applications of this chirality transfer approach to enantiomerically pure amines using (R)-or (,S )-phcnylglycinc amide are under investigation. 

The enantiomerically pure amines 82 and 84 are for example prepared by resolution of the racemic 8-benzyl-rfs-2,8-diazabicyclo[4.3.0]nonane 79 using natural R,R(+)-tartaric acid, whereupon the diastereomerically pure i ,i -tartrate of the R, /<-enantiomer is crystallized from dimethylformamide (DMF) and can be purified by recrystallization from methoxyethanol. The target S,S-enantiomer contained in the mother liquor is first converted into the free base, which is then, for the purpose of further purification, precipitated with S,S(-)-tartaric add to give the diastereomerically pure S,S-tartrate. The S,S-enantiomer 83 is then liberated with sodium hydroxide solution. The R,R-enantiomer 81 is obtained in the same way. Separation of the enantiomers can also be carried out with high optical yields in an aqueous/alcoholic solution [140]. The hydrogenolytic debenzylation of 81 and 83 produces the corresponding pure R,R- and, S, S —2,8-diazabicyclo[4.3,0]no-nanes 82 and 84 (Scheme 14.2) [129]. 

Sulfinyl sultam 82 was also used in the synthesis of enantiopure sulfinimines 85, useful precursors in the synthesis of enantiomerically pure amine, as well as a- and P-aminoacid derivatives.109 Interestingly, the addition of one equivalent of water to the sulfinylated HMDS 84 prior to the addition of the aldehyde was necessary to convert enolizable aldehyde into enantiomerically pure sulfinimines 85, which cannot be obtained by the Davis procedure. Thus, both enolizable and noneno-lizable aldehydes can afford enantiomerically pure aryl and alkyl sulfinimine 85 in good yield (Scheme 26). 

Enantioselective catalysis promoted by enantiomerically pure amines (aminocatalysis) is the subject of considerable interest due to the ubiquitous presence and ready availability of these compounds in the chiral pool. In this context amino acids have always played a key role. One of the most successful and versatile chiral organic catalysts, proline, was... 

Thus, as shown in Fig. 4-10, three isomeric enantiomerically pure amines can be prepared from the same starting material by the appropriate choice of the reaction conditions [76]. 

An enantiomerically pure aldehyde, (lR,2R,3R)-2,7,7-trimethylbicyclo[3.1.1]hep-tane-2-aldehyde, is produced from a-pinene by rhodium-catalyzed hydroformylation [79, 80]. Initially, reaction with ferrocene under acidic conditions leads to a 1 1 mixture of diastereoisomeric cations, but on standing for a few hours at room temperature, isomerization by rotation around the ferrocene — cationic carbon bond to the thermodynamically more stable cation (with configuration (R) at the cationic center) occurs (Fig. 4-11). An enantiomerically pure amine is available by trapping of this cation by azide and reduction [75]. Analogously, the isomeric aldehyde with the bicyclo [2.2.1] heptane structure is formed by hydroformylation of a-pinene with cobalt catalysts [79, 80] and was used as the starting material for an isomeric series of chiral amines [75]. 

Bartoli et al. [31] reported the formation of enantiomerically pure amines and hydroxylamines from optically active nitroalkanes with allylic and benzylic Grignard reagents. The intermediate nitrones (see Table 3, entry 7) were mixtures of E- and Z-isomcrs from the protected nitroalkanes. Although the regiochemistry is complicated, the stereochemistry of the double bond was affected by the nature of the Grignard reagent. The major isomer was always the R-isomer. 

Table 4. Se signal dispersions in Hz (at 76.3 MHz) of 1 1 mixtures of racemic a-phenylselenenylbutanoic acid and enantiomerically pure amines (in CDCl3) ...

The product class of enantiomerically pure amines is of considerable importance in both pharmaceutical and agrochemical applications. For instance, enantiopure aryl-alkyl amines are utilized for the synthesis of intermediates for pharmaceutically active compounds such as amphetamines and antihistamines. Several chemical as well as biotransformation methods for the asymmetric synthesis/dynamic kinetic resolution [29] or separation of enantiomers of chiral amines have been described. These are illustrated in Scheme 4.5 for (S)-a-methylbenzylamine [30]. 

Amino acids and their derivatives represent an obvious source of chiral organic catalysts, which has been fully exploited by synthetic organic chemists [32], especially in the field of aminocatalysis, such as enantioselective catalytic processes promoted by enantiomerically pure amines [33],... 

The iridium catalyzed asymmetric hydrogenation of quinolines provides a con venient and efficient way to enantiomerically pure amines with bisphosphines, N,P ligands and S,P ligands. However, the reactivities and enantioselectivities were generally substrate dependent. There is no omnipotent ligand for every substrate. 

Hydroamination with Enantiomerical Pure Amines 367 Table 11.3 Catalytic kinetic resolution of chiral aminopentenes [52, 124]. 

Several methods for the resolution of racemic amines are reported in the literature, and among them, we at first evaluated the formation and preferential crystallisation of diastereomeric salts with chiral acids (e.g. camphorsulphonic acid) [19]. This method proved to be efficient in many cases, and allowed the recovery of the wanted enantiomerically pure amine after the opportune neutralisation [15]. 

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