Enantiomerically Pure Amines with Lipase

33 Synthesis of Enantiomerically Pure Amines through Transamination 

Each enantiospecific co-transaminase can be applied for the synthesis of (S)- or (J )-amines (Stirling, 1992) by  

Both (R)- and (S)-amino transferase are available forthe synthesis of enantiomerically pure amines from racemic amines. Degrees of conversion were at or close to 50% for resolutions, and enantioselectivities customarily reached 99% e.e. for the amine product from both resolutions or syntheses from ketones (Stirling, 1992 Matcham, 1996). The donor for resolutions of amine racemates was usually pyruvate whereas either isopropylamine or 2-aminobutane served as donors for reduction of ketones. The products range from i- and D-amino acids such as i-aminobutyric acid (see Section 7.2.2.6) and i-phosphinothricin (see Section 7.4.2) to amines such as (S)-MOIPA (see Section 7.4.2). 

The major disadvantage of the transamination technology is an equilibrium constant K often near unity. As K 1 would limit the net conversion of substrates to around 50%, the key to efficient transamination technology lies in overcoming the problem of incomplete conversion of the 2-keto acid precursor to the desired amino 

L-Aspartic acid Oxaloacetic acid Pyruvic acid 

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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). 

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]

In addition, Jacobs et al. have developed the DKR of benzylic amines in the presence of a combination of palladium supported on an alkaline earth-type support such as BaS04 with a lipase. Hence, this heterogeneous catalytic system has allowed various benzylic amines to be transformed into their corresponding enantiomerically pure amides with excellent yields and enantioselectivities of >99% ee, as shown in Scheme 8.70. 

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. 

Starting with tropone 330, the azido compound 331 was first synthesized, as shown in Scheme 55. Then, compound 331 was chemoselectively reduced to unsaturated amine 332 by Lindlar catalyst, and this material was elaborated to the meso carbamate 333, ready for enzymatic asymmetrization. Treatment of 333 with Amano P-30 lipase in the presence of isopropenyl acetate resulted in formation of the enantiomerically pure (>98% ee) monoacetate 334, the common intermediate to both calystegines 337 and ent-337. Using conventional chemistry, elaboration of the functional groups within tropane 334... 

Various methods for the preparation of enantiomerically pure P4-P3 mimetics had been published before this work. Among these were the classical co-crystallization with chiral amines [7, 8], the derivatization as diastereoisomeric amides [6, 9, 10], the synthesis of chiral intermediates following Evans methodology [10-12], or the use of lipase-catalyzed reactions [13], and the asymmetric hydrogenation of unsaturated derivatives [8, 14],... 

Scheme 5.6, Equation 5.1) [19]. Although the acidity of the a-proton is much greater than that of the oxoesters, the presence of a tertiary amine has been shown to be indispensable for quantitative conversion. Biochemical transesterification has also been reported for the DKR of a variety of chiral trifluoroethyl thioesters [20]. The DKR of trifluoroethyl thioesters, using either lipase-catalysed hydrolysis [20b,d,e] or transesteriflcation with 4-morpholine ethanol [20c], has allowed the isolation of enantiomerically pure profen esters based on (S)-naproxen, (S)-fenoprofen and (S)-suprofen in >75% yield with up to 95% ee. Some oxoester with relatively higher... 

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