Aminolysis chiral amines

Over the past years, interest in the preparation of chiral amines and amides by enzymatic ammonolysis or aminolysis reactions [4] has greatly increased for academic and industrial sectors. The role that the enzymatic acylation of amines or ammonia plays for the preparation of some pharmaceuticals is noteworthy [5]. 

In recent years, a great variety of primary chiral amines have been obtained in enantiomerically pure form through this methodology. A representative example is the KR of some 2-phenylcycloalkanamines that has been performed by means of aminolysis reactions catalyzed by lipases (Scheme 7.17) [34]. Kazlauskas rule has been followed in all cases. The size of the cycle and the stereochemistry of the chiral centers of the amines had a strong influence on both the enantiomeric ratio and the reaction rate of these aminolysis processes. CALB showed excellent enantioselec-tivities toward frans-2-phenylcyclohexanamine in a variety of reaction conditions ( >150), but the reaction was markedly slower and occurred with very poor enantioselectivity with the cis-isomer, whereas Candida antarctica lipase A (GALA) was the best catalyst for the acylation of cis-2-phenylcyclohexanamine ( = 34) and frans-2-phenylcyclopropanamine ( =7). Resolution of both cis- and frans-2-phenyl-cyclopentanamine was efficiently catalyzed by CALB obtaining all stereoisomers with high enantiomeric excess. 

Calixarene esters are easily available by alkylation with ethyl bromoacetate and are often used as starting materials for the introduction of chiral groups at the narrow rim. Their aminolysis by chiral amines led to chiral calixarene derivatives in high yields. Water soluble calix[4]arene amino acid derivatives 9a,b obtained in this way, were successfully used as a pseudostationary phase... 

In contrast to the facile in-situ racemization of sec-alcohols via Ru-catalysts (Schemes 3.14 and 3.17), which allows dynamic resolution, the isomerization of ot-chiral amines requires more drastic conditions. Hydrogen transfer catalyzed by Pd [283, 284], Ru [285, 286] Ni, or Co [287] is slow and requires elevated temperatures close to 100°C, which still requires the spatial separation of (metal-catalyzed) racemization from the lipase aminolysis [288]. 

The resolution of racemic ethyl 2-chloropropionate with aliphatic and aromatic amines using Candida cylindracea lipase (CCL) [28] was one of the first examples that showed the possibilities of this kind of processes for the resolution of racemic esters or the preparation of chiral amides in benign conditions. Normally, in these enzymatic aminolysis reactions the enzyme is selective toward the (S)-isomer of the ester. Recently, the resolution ofthis ester has been carried out through a dynamic kinetic resolution (DKR) via aminolysis catalyzed by encapsulated CCL in the presence of triphenylphosphonium chloride immobilized on Merrifield resin (Scheme 7.13). This process has allowed the preparation of (S)-amides with high isolated yields and good enantiomeric excesses [29]. 

The generalized application of the aminolysis of halophosphanes has been the method of choice for the preparation of a wide variety of chiral phosphinous amides by starting from enantioenriched primary amines [36]. The aminolysis reaction occurs efficiently even when the halophosphane is placed in the coordination sphere of a metal, as in the palladium and platinum complexes of the type ds-M(Ph2PCl2)2Cl (M=Pd, Pt) [37,38]. 

Now let us turn to an examination of the A-[Co(en)2(Ala-(S)-AlaOMe)]3+ products. When 0.03 M (S)-AlaOMe was used RP-HPLC gave 50% A-RS and 50% ASS after 8 s, building to 76% A-RS and 24% ASS at the conclusion of the reaction (500 s). With 0.06 M (S)-AlaOMe the result was 32% A-RS and 68% ASS (4 s) building to 58% A-R-S and 42% ASS (24 s) with 0.06 M (R)-AlaOMe the comparison were 34% A-R-S (4 s) building to 55% (24 s), i.e., nearly the same distributions. These results require the A-R ester to react with (S)- or CR)-AlaOMe to give the A-R-S (or A-R-R) product at a considerably faster rate (via k4) than does the A-S ester to give ASS (or A-S-R). Also, either differences between the rate constants for epimerization and aminolysis cancel the effect of chirality of the amine base or the rate constants themselves are little affected by the amine chirality. Subsequent analysis on other systems found the latter explanation to hold. 

A chiral recognition was observed in aminolysis of 3-acyl-4(R)-methoxycarbonyl-l,3-thiazolidine-2-thione, a derivative of (R)-cysteine, by racemic amines to give an optically active amide [(S)-excess] and amine [(R)-excess]264). In the reaction of cyclic meso-1,3-diols with chiral N-protected phenylalanyl chlorides, Yamada et al.26S) observed the preferential formation of one of the two possible diastereomeric monoesters, which has been used for the synthesis of optically active steroids 266) and prostaglandins 267). 

Several other examples were summarized by Nagao et al. (82TL201). Thus a significant chiral recognition was realized in the aminolysis of 3-acyl-(4/ )-methoxycarbonyl-l,3-thiazolidine-2-thiones [4(/ )-AMCTT] (14) with racemic amines. In this reaction, (4/ )-AMCTT (14) showed a preferential reactivity to the (S)-amine. 

Aminolysis of mei o-epoxides is facilitated by Sc(OTf)3. In the presence of bipyridyldiol 8 chiral products are obtained/ mei o-A-Acylaziridines react with Me3SiN3 to provide (3-azido amines, and a chiral Bronsted acid (e.g., 9) renders the ring opening asymmetrical/ ... 

Amides of lactic acid with secondary amines, e.g., 5 and 6, have been used as chiral ligands for the molybdenum-catalyzed epoxidation of alkenes (Section D.4.5.2.2.). They are easily obtained by aminolysis of the lactic esters4. 

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