Optically pure secondary amines

Scheme 7. Chemoenzymatic preparation of optically pure secondary amines via hydrolysis of an racemic oxalamic ester linker...

All of the examples discussed so far focus on the resolution of primary amines however, secondary amines are also important building blocks in the synthesis of biologically active compounds. The development of general, efficient methods for the production of optically pure secondary amines has remained a challenge. However, there are a few reported methods for enzyme mediated kinetic resolution of secondary amines. 

The preparation of optically pure secondary amines was accomplished via the resolution of oxalamic esters 43 to give acids 44 and ultimately amines 45 [22]. Excellent selectivities ( >200) were obtained using a variety of proteases. Back ground chemical hydrolysis was suppressed by keeping the pH between 7.0 and 7.5 (Figure 14.16). 

Since simple ketones typically coordinate more weakly to metals than olefins, many Rh-phosphane complexes may show poor activity for the hydrogenation of simple ketones. However, the catalytic properties of cyclometalated half-sandwich Rh(lII) complexes 99-101, isolated or prepared in situ firom metal precursors and optically pure secondary amines, were evaluated, among which the complex 100 showed the highest productivity in the reduction of acetophenone with a i-PrOH/t-BuOK reductant system (Fig. 26) [93]. The complex 99 afforded good yield of alcohol products from acetophenone, but the enantioselectivity was low, while the cyclometalated imine 101 was almost inactive. The rhodacycle 100, which was formed in situ, efficientiy catalysed the reduction of substrates 102 (92 % ee), 103 (93 % ee) and 104 (91 % ee), with substrate 103 showing total chemoselectivity. For substrates 105,106 and 107, however, lower ee values were observed (<85 %). 

This acylating agent has also been used in the resolution of indolines see Gotor-Fernandez, V., Rebolledo, F. and Gotor, V., Chemoenzymatic preparation of optically active secondary amines a new efficient route to enantiomerically pure indolines. Tetrahedron Lett., 2006,17, 2558. 

Moreover, reduction of alkyl aryl ketones can be used to access optically pure secondary aryl alkyl amines, as illustrated in an enantioselective synthesis of SDZ-ENA-713 (ll)60 and as we have demonstrated in a related process (Scheme 16.8). 

The dynamic kinetic resolution (DKR) of secondary alcohols and amines (Scheme 11.11) is a prominent, industrially relevant, example of chemo-enzymatic chemistry in which a racemic mixture is converted into one enantiomer in essentially 100% yield and in high ee. This is in sharp contrast to enzyme-catalyzed kinetic resolutions that afford the desired end-product in a yield of at most 50%, while 50% of the starting material remains unreacted. In DKR processes, hydrolases are typically employed as the enantioselective acylation catalyst (which can be either R or S selective) while a concurrent racemization process racemizes the remaining substrate via an optically inactive intermediate. This ensures that all starting material is converted into the desired end-product. The importance of optically pure secondary alcohols and amines for the pharmaceutical industry triggered the development of a number of approaches that enable the racemization of sec-alcohols and amines via their corresponding ketones and imines, respectively [42],... 

Enantiomerically pure 2-substituted cyclopentanamines are obtained from racemic cyclopentanones by reductive amination the ketone is condensed with an optically active 1-phenylethylamine, the imine mixture hydrogenated with Raney nickel, and the optically active, diastereoisomerically pure secondary amine is hydrogenolysed with palladium-on-carbon to give the enantiomerically pure 2-substituted cyclopentanamine. ... 

Polymers derived from natural sources such as proteins, DNA, and polyhy-droxyalkanoates are optically pure, making the biocatalysts responsible for their synthesis highly appealing for the preparation of chiral synthetic polymers. In recent years, enzymes have been explored successfully as catalysts for the preparation of polymers from natural or synthetic monomers. Moreover, the extraordinary enantioselectivity of lipases is exploited on an industrial scale for kinetic resolutions of secondary alcohols and amines, affording chiral intermediates for the pharmaceutical and agrochemical industry. It is therefore not surprising that more recent research has focused on the use of lipases for synthesis of chiral polymers from racemic monomers. 

Careful inspection of the reported photocatalytic reactions may demonstrate that reaction products can not be classified, in many cases, into the two above categories, oxidation and reduction of starting materials. For example, photoirradiation onto an aqueous suspension of platinum-loaded Ti02 converts primary alkylamines into secondary amines and ammonia, both of which are not redox products.34) ln.a similar manner, cyclic secondary amines, e.g., piperidine, are produced from a,co-diamines.34) Along this line, trials of synthesis of cyclic imino acids such as proline or pipecolinic acid (PCA) from a-amino acids, ornithine or lysine (Lys), have beer. successfuL35) Since optically pure L-isomer of a-amino acids are available in low cost, their conversion into optically active products is one of the most important and practical chemical routes for the synthesis of chiral compounds. It should be noted that l- and racemic PCA s are obtained from L-Lys by Ti02 and CdS photocatalyst, respectively. This will be discussed later in relation to the reaction mechanism. 

Ridha, T., Ben Hassine, B. and Genet, J.P., Synthesis of optically pure imines using microwave activation and application to the preparation of new secondary amines, Compt. Rend. Acad. Sci. Ser. II Fas. C, 2000, 3, 35-42. 

The ionic chiral auxiliary approach was also applied to the enantioselective photocylization of tropolone. Irradiation of salt crystals of tropolone ether carboxylic acid 29 with several chiral amines afforded the enantiomerically enriched secondary products 31 [52]. The best results were obtained with optically pure 1-phenylethylamine and l-amino-2-indanol, which gave optical yields in the 60-80% ee range depending on the extent of conversion. 

It was shown by Shonenberger et al. that thermal decomposition of the separated diastereomeric (a-methylbenzyl) urea derivatives produced by the reaction of [19] and chiral secondary amines is a convenient technique for the retrieval of the optically pure amines (93). 

The Curtius rearrangement of the acyl azide derived from optically pure a-methoxy-a-(trifluoro-methyl)phenylacetic acid (MTPA 48) also proceeds with retention of configuration, giving a-methoxy-a-(trifluoromethyl)benzyl isocyanate (49 equation 26). The isocyanate (49) is useful for the determination of the enantiomeric composition of optically active primary and secondary amines. 

In the recent literature numerous reactions in which enamines are used for synthesis of enantiomerically pure compounds (EPC) can be found . Optically active enamines from substituted pyrrolidine (e.g. 27, R = CH20Me, CH20SiMe3, or 28, R = Me, CH20Me), or from piperidine , such as 29, (S)-phenylethylamine (30) " and stanna-N,0-heterocyclic amine (31) , are used. The cyclohexanenamines seem to be the preferred test compounds for this kind of reaction, whereas enamines of open-chain ketones and aldehydes have been investigated only rarely . Enamines from carbonyl compounds and secondary amines are obtained with azeotropic removal of water or by die Weingarten method with TiC. A titanium chloride-catalysed variation in which perfluorinated alkyl groups can be introduced is also known " . 

Optically pure opine-type secondary amine carboxylic acids were synthesized from amino acid and its analog and a-keto acids such as glyoxylate, pyruvate, and 2-oxobutyrate, by using ODH with a regeneration of NADH by formate dehydrogenase (FDH) [13,24]. 

Optically pure opine-tjrpe secondary amine carboxylic acids were also synthesized from amino acids and their analogs, such as L-methionine, L-isoleucine, L-leucine, L-valine, L-phenylalanine, L-alanine, L-threonine, L-serine, and L-phenylalaninol, and a-keto acids, such as glyoxylic, pyruvic, and 2-oxobutyric acids, using the enzyme with regeneration of NADH with FDH from Moraxella sp. C-1 [13]. The absolute configuration of the nascent asymmetric center of the opines was of the D stereochemistry with > 99.9% e.e. One-pot synthesis of N-[l-D-(carboxyl)ethyl]-L-phenylalanine from phenylpyruvic and pyruvic acid by using ODH, FDH, and phenylalanine dehydrogenase (PheDH) from Bacillus sphaericus... 

The highly selective asymmetric addition of organolithiums to acyclic imines and N-aryl group oxidative removal provided a facile and efficient synthetic route to the optically active 1-substituted tetrahydroisoquinoline (TIQ) 81 [74] (Scheme 24), (R)-(-i-)-salsohdine (84) [71] (Scheme 25), and optically pure a-amino acid derivatives 88 bearing a bulky a-substituent [75] (Scheme 26). The reaction of organoiithium reagents with the acyclic imine 78 and subsequent cy-clization of the secondary amine under Moffat oxidation conditions, after oxidative hydroboration of 79, gave 80 (Scheme 24). 

The solution to the problem of catalysts for a general reaction of acyclic secondary amines with aryl halides began with the use of Kumada s phosphinoether ligand 1 (Eq. With palladium catalysts bearing Kumada s ligand, high yields were observed for this type of amination reaction. However, the ligand is extremely expensive in its commercially available optically pure form, and the synthesis is multistep. Nevertheless,... 

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