With enantiomerically pure amine

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

An alternate approach, pioneered by Kunz and MacMillan, proceeds by reaction of sulfur ylides with a,(3-unsaturated iminium ions, formed by reaction of a,p-enals with enantiomerically pure amines. In this approach the sulfur ylide (9.87) reacts with a range of (3-aryl- and P-alkyl-substituted enals, including (9.88), in the presence of the dihydroindole (9.89) to give the cyclopropane with ees ranging from 89 to 96%. More recently, it has been shown that replacement of the carboxylate functional group in (9.89) with an isosteric tetrazolic acid gives an improved catalyst that effects cyclopropanation with 99% ees in all cases studied. 

It was found that the Ti-catalyzed hydroamination reactions of alkynes with enantiomerically pure amines possessing a chiral center adjacent to the nitrogen atom generally take place with partial racemization [304]. The extent of racemization at the corresponding chiral center seems to be influenced by the structure of the amine as well as the nature of the catalyst. The Cp 2TiMe2 was identified as one of the highly active racemization-free catalysts for this reaction (Scheme 14.128). 

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... 

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... 

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... 

This is a very simple and short method for the deprotection of N-Cbz and N-Bn groups, which is also applicable for N-Cbz protected amino acids and is compatible with Fmoc protecting groups, which remain unaffected under these conditions. Furthermore, the microwave protocol is fully compatible with enantiomerically pure amino acids and peptides, as no racemisation was observed in the resulting free amines. 

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). 

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. 

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]. 

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]. 

A convenient preparation of a new class of 1-L-a-amino acid derivatives of 2-phospholene oxides (405) involves amination of ( ) l-chloro-2-phospho-lene oxides (406) with enantiomerically pure L-a-amino acid esters (407) (Figure 71). ... 

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. 

An additional application of the observed trans diastereoselectivity in Michael reactions is demonstrated by performing this reaction with a c/5-4,5-diphenyloxazolidin-2-one as a chiral ammonia equivalent for the introduction of an amine functionality. This sequence, when carried out with enantiomerically pure (/ ,5)-4,5-diphenyloxazolidin-2-one, yielded diastereomerically and enantiomerially pure addition compounds which were separated by chromatography. ... 

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. 

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]. 

We already have a good idea how to resolve a carboxylic acid by making a salt with an enantiomerically pure amine. In this case the first amine you think of, phenylethylamine 2, works very well. Here is the asymmetric synthesis, carried out on a 50-100 g scale at Celltech.7 The hydrolysis of the dinitrile 35 is chemoselective because the intermediate 39 is formed. The salt with 2 crystallises in good yield (39% out of a possible 50%) and in excellent ee. 

Catalytic hydrogenation of the benzylic C-0 bond in 179 removes the second chiral centre and the hydroxy-ester 180 is prepared for coupling to an enantiomerically pure amine by conversion to the triflate 181. The coupling goes with inversion to give enalapril41182. 

While most methods for the synthesis of enantiomerically pure amines have employed kinetic resolution with the help of lipases or esterases, a method independent of kinetic resolution has been developed using the transamination of ketones catalyzed by co-transaminases ([Pg.880]

Lewis-acid catalyzed acetalization with enantiomerically pure alcohol 37 afford crystalline trans-aceXdX 63 in high yield (85% from oxazinone 61) and diastereoselectivity (96 4 trans/cis). Hydrogenolysis gave secondary amine 64 that was cleanly converted to imine ether 65 by a chlorination/elimination procedure. The diastereoselectivity of the subsequent imine hydrogenation was >99 1 (cis/trans). The resulting penultimate amine 5 was isolated as either the HCl or TsOH salt in 81% yield (Scheme 19). 

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