Chiral compounds, Amino acids Heterocycles

Chiral a-amino acids, a-methyl amino acids and ahphatic or aromatic a-hydroxycarboxylic acids, chiral iV-alkyl, iV-carbamyl, and iV-formyl amino acids, dipeptides and heterocyclic compounds... 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

Ugi I, Horl W, Hanusch-Kompa C, Schmid T, Herdtweck E (1998) MCR 6 chiral 2, 6-piperazinediones via Ugi reactions with alpha-amino acids, carbonyl compounds, isocyanides and alcohols. Heterocycles 47(2) 965-975... 

Carbohydrate-derived auxiliaries exhibit an efficient stereoselective potential in a number of nucleophilic addition reactions on prochiral imines. a-Amino acids, P amino acids and their derivatives can be synthesized in few synthetic steps, and with high enantiomeric purity. A variety of chiral heterocycles can readily be obtained from glycosyl imines by stereoselective transformations, providing evidence that carbohydrates have now been established as useful auxiliaries in stereoselective syntheses of various interesting classes of chiral compounds. 

The examples outlined in this chapter show that carbohydrates are efficient stereodifferentiating auxiliaries, which offer possibilities for stereochemical discrimination in a wide variety of chemical reactions. Interesting chiral products are accessible, including chiral carbo- and heterocycles, a- and 3-amino acid derivatives, 3-lactams, branched carbonyl compounds and amines. Owing to the immense material published since the time of the earlier review articles on carbohydrates in asymmetric synthesis [9,10], the examples discussed in this chapter necessarily focused on the use of carbohydrates as auxiliaries covalently linked to and cleavable from the substrate. Given the scope of this chapter, a discussion of other interesting asymmetric reactions has not been permitted — for example, reactions in which carbohydrate-derived Lewis acids, such as cyclopentadienyl titanium carbohydrate complexes, exhibit stereocontrol in aldol reactions [180]. Similarly, processes in which in situ glycosylation induces reactivity and stereodifferentiation — for example, in Mannich reactions of imines [181] — have also been excluded from this discussion. 

The approach exploiting a chiral centre that is already in the synthon is effective in a number of cases. The chiral moiety in the synthon diverts a reaction at a nearby prochiral centre in favour of one enantiomer (asymmetric induction). An excellent example of the latter is the Schollkopf method (4 in Scheme 6.3, see also 5 in Scheme 6.7) hydrogenation of azlactones (3 in Scheme 6.3) using a homogeneous chiral catalyst is one route illustrating the former approach. Use of chiral five-membered heterocyclic compounds (e.g., 6 and 7) offers an alternative successful approach to asymmetric amino-acid synthesis. 

The synthetic polymers based on N-acryloyl amino acid-derivatives developed by Blaschke in the 1970 and transferred to silica-bonded phases in the 1980 are especially useful for the separation of 5- and 6-membered N- and O-heterocycles with chiral centers (Review in Kinkel, 1994). Their wide chemical variety has been intensively exploited by Bayer Healthcare for their portfolio of chiral molecules. One example of this approach has been published in a joint work of Merck and Bayer (Schulte, 2002). This work explicitly shows how important it is to screen different intermediates in addition to the final dmg compound. Due to different selectivities and solubilities, the productivity for the preparative separation can be dramatically different. 

BromocycUzation reactions are well known for their ability to facilitate the construction of chiral compounds. An example this chemistry outlined the preparation of tetrahydropyrroles (Scheme 3.13) [13]. A chiral phosphoric acid was used to provide the stereocontrol, and NBS served as the bromine source. Using this system, a range of gamma-amino alkenes were converted into nitrogen heterocycles in high yield with moderate to good selectivity. 

Heterocycles of high enantiomeric purity are used to prepare other optically active compounds for example, to obtain chiral amino acids some optically active derivatives of hydantoin or aziridine have been employed [68]. 

N-Tfa- and iV-Fmoc-a-amino ketones have been synthesized56 by reaction of some N -heterocycles or benzene with chiral AM Tfa- and Fmoc-a-aminoacyl)benzotriazoles [e.g. (49)] in the presence of aluminium trichloride. Full preservation of chirality was reported. Aromatic side-chains in some of the (a-amineacyl)benzotriazole compounds gave a competitive intramolecular cyclization, again with retention of chirality [e.g. (49) to (50)]. A full report57 on the intramolecular acylation of aromatics with Meldrum s acid derivatives catalysed by metal trifluoromethanesulfonates under mild reaction conditions has appeared [e.g. (51) to (52)]. The method tolerates many functional groups and was extended to the synthesis of 1-tetralones, 1-benzosuberones and donepezil (53). 

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