Enantiomerically pure chiral amines applications

The asymmetric synthesis of enantiomerically pure primary amines has received considerable attention in recent years due to applications of the chiral amines, either as chiral auxiliaries for the synthesis of optically active molecules [33] or as a deri-vatizing agent for the resolution of racemic carboxylic acids [34], Hydroboration -amination is also a convenient synthetic route to epimerically clean amine derivatives in a simple one-stage reaction. Interestingly, rrans-2-phenylcyclopentylamine (cypenamine), which is an antidepressant [35], can be obtained as a pure isomer in good yields by the hydroboration of 1-methylcyclopentene [7,10,36] (Scheme 13). 

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

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. 

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 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]. 

Enantiomerically pure oxazolines and oxazolidinones have found widespread application in organic synthesis as chiral auxiliaries. They have been mainly used for the synthesis of enantiomerically pure amino acids but also as chiral auxiliaries to produce non-racemic enolates as pioneered by Evans.The reaction types proceeding with high stereocontrol include enolate alkylation, enolate oxidation, enolate halogenation, enolate amination, enolate acylation, aldol reaction and Diels-Alder reactions. 

In 1971, an interesting application of the chlorobridged Pd(II) complexes with orthometallated chiral amines was demonstrated by Otsuka and co-workers resolution of racemic chiral phosphincs. The binuclear species reacts with tertiary phosphines or arsines to form two equivalents of mononuclear complexes (Scheme 3). If both the phosphines and the orthometallated palladium complexes were chiral, the mononuclear products could be a mixture of diastereomers. With appropriate combinations of the chiral racemic phosphines and the enantiomerically pure orthometallated palladium species, one of the two enantiomers of the phosphines reacts with the palladium complex selectively to give a specific diastereomer of the mononuclear palladium complexes, leaving the other enantiomer of the phosphine unreacted. 

Intramolecular rhodium-catalyzed carbamate C-H insertion has broad utility for substrates fashioned from most 1° and 3° alcohols. As is typically observed, 3° and benzylic C-H bonds are favored over other C-H centers for amination of this type. Stereospecific oxidation of optically pure 3° units greatly facilitates the preparation of enantiomeric tetrasubstituted carbinolamines, and should find future applications in synthesis vide infra). Importantly, use of PhI(OAc)2 as a terminal oxidant for this process has enabled reactions with a class of starting materials (that is, 1° carbamates) for which iminoiodi-nane synthesis has not proven possible. Thus, by obviating the need for such reagents, substrate scope for this process and related aziridination reactions is significantly expanded vide infra). Looking forward, the versatility of this method for C-N bond formation will be advanced further with the advent of chiral catalysts for diastero- and enantio-controlled C-H insertion. In addition, new catalysts may increase the range of 2° alkanol-based carbamates that perform as viable substrates for this process. 

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