Lipases chemoenzymatic synthesis

Poly(malic acid) is a biodegradable and bioadsorbable water-soluble polyester having a carboxylic acid in the side chain. The chemoenzymatic synthesis of poly(malic acid) was achieved by the lipase-catalyzed polymerization of benzyl (3-malolactonate, followed by the debenzylation. The molecular weight of poly(benzyl (3-malolactonate) increased on copolymerizafion with a small amount of (3-PL using lipase CR catalyst. ... 

Chemoenzymatic synthesis of biodegradable poly(malic acid) was performed by lipase-catalyzed polymerization of benzyl /J-malolactone, followed by the debenzylation [72]. The addition of a small amount of /J-PL (17 mol % for the monomer) increased Mw up to 3 x 104 [73]. 

An example for the application of enzymatic kinetic resolutions with high E values in natural product synthesis is the chemoenzymatic synthesis of the northern half of epothilones (also see Sect. 4.1). Various lipases and esterases could be found with outstanding enantioselectivity (up to >100) among these were lipase B from Candida antarctica, a lipase from Burkholderia cepacia, a lipase from Pseudomonas sp., and a lipase from Streptomyces diastochromogenes, all affording the desired (S)-configurated alcohol with >99% enantiomeric excess (Fig. 4) [65],... 

The 5 -(-)-2-cyclohexy 1-1,3-propanediol monoacetate (24) and the S-( )-2-phenyl-1,3-propanediol monoacetate (25) are key chiral intermediates for the chemoenzymatic synthesis of Monopril (26) (Fig. 10), a new antihypertensive drug which acts as an ACE inhibitor. The asymmetric hydrolysis of 2-cyclohexyl-1,3-propanediol diacetate (27) and 2-phenyl-1,3-propanediol diacetate (28) to the corresponding S-( - )-monoacetate (24) and S-( )-monoacetate (25) by porcine pancreatic lipase (PPL) and Chromobacterium viscosum lipase have been demon-... 

The asymmetric hydrolysis of (exo,exo)-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol, diacetate ester (37) to the corresponding chiral monoacetate ester (38) (Fig. 12B) has been demonstrated with lipases [61]. Lipase PS-30 from P. cepacia was most effective in asymmetric hydrolysis to obtain the desired enantiomer of monoacetate ester. The reaction yield of 75 M% and e.e. of >99% were obtained when the reaction was conducted in a biphasic system with 10% toluene at 5 g/liter of the substrate. Lipase PS-30 was immobilized on Accurel PP and the immobilized enzyme was reused (5 cycles) without loss of enzyme activity, productivity, or e.e. of product (38). The reaction process was scaled up to 80 liters (400 g of substrate) and monoacetate ester (38) was isolated in 80 M% yield with 99.3% e.e. The product was isolated in 99.5% chemical purity. The chiral monoacetate ester (38) was oxidized to its corresponding aldehyde and subsequently hydrolyzed to give chiral lactol (33) (Fig. 12B). The chiral lactol (33) obtained by this enzymatic process was used in chemoenzymatic synthesis of thromboxane A2 antagonist (35). 

Finally, chemoenzymatic synthesis has been used for the preparation of entiomerically pure 2/7-azirines. Thus, (i )-(+)-phenyl-2/7-azirine-2-methanol 873 and its (-acetate 874 were prepared by a lipase-catalyzed kinetic... 

Chemoenzymatic synthesis of a water-soluble polycarbonate having pendent carboxyl groups on the polymer main chain was achieved by lipase-catalyzed polymerization of 5-methyl-5-benzyloxycarbonyl-l,3-dioxan-2-one (MBC), followed by debenzylation.186 The copolymerization of MBC with TMC using lipase PF catalyst produced the random copolycarbonate.187... 

The first chemoenzymatic synthesis of organoselenium containing amines was recently reported by Andrade and Silva (Figure 14.7) [10]. Compounds containing a selenium atom have important antioxidant and anti inflammatory activities. Lipase mediated acylation of amine 13 gave the corresponding chiral amides 14 and amines 13 with excellent enantioselectivity (up to 99% ee). 

Kamal A, Chouhan G (2004) Chemoenzymatic synthesis of enantiomerically pure 1,2-diols employing immobilized lipase in the ionic liquid [bmim][PF6]. Tetrahedron Lett 45 8801-8805... 

The usefulness of a mutant dehydrogenase was demonstrated in a practical synthesis of 4-amino-2-hydroxy acids, which themselves are valuable as y-turn mimics for investigations into the secondary structure of peptides[146]. Chemoenzymatic synthesis of these compounds were achieved by lipase catalyzed hydrolysis of a a-keto esters to the corresponding a-keto acids followed by reduction employing a lactate dehydrogenase in one pot. Wild type lactate dehydrogenase from either Bacillus... 

Theil et al. developed a method for chemoenzymatic synthesis of both enantiomers of cispentacin [89]. frans-2-Hydroxymethylcyclopentanol, obtained by the sodium borohydride reduction of ethyl 2-oxocyclopentanecarboxylate, was monosilylated with tert-butyldimethylsilyl (TBDMS) chloride to afford 55. Lipase PS-catalysed transesterification with vinyl acetate in /erf-butyl methyl ether furnished the ester 56 and the alcohol 57. The deacetylated 58 was obtained by the Mitsunobu reaction with phthalimide, triphenylphosphine and diethyl azodicarboxylate (DEAD) to furnish the cis oriented 59 with inversion of configuration (not retention as mentioned in the original article) (Scheme 9). Desilylation, Jones oxidation and subsequent deprotection with aqueous methylamine gave the ( R,2S) enantiomer 5 [89]. The (15, 2/f) enantiomer was prepared by the same route from the silyl alcohol 57. 

V. (2009) Stereoselective chemoenzymatic synthesis of enantiopure l-(Heteroaryl)ethanamines by lipase-catalysed kinetic resolutions. Eur. J. 

Kamal, A., Ramesh Khanna, G.B., and Ramu, R. (2002) Chemoenzymatic synthesis of both enantiomers of fluoxetine, tomoxetine and nisoxetine lipase-catalyzed resolution of 3-aryl-3-hydroxypropanenitriles. Tetrahedron Asymmetry, 13, 2039-2051. 

Busto, E., Gotor-Fernandez, V., and Gotor, V. (2012) Asymmetric chemoenzymatic synthesis of ramatroban using lipases and oxidoreductases./. Org. Chem., 77, 4842 848. 

Kamal, A., Khanna, G. B. R., Ramu, R., and Krishnaji, T. (2003). Chemoenzymatic synthesis of duloxetine and its enantiomer Lipase-catalyzed resolution of 3-hydroxy-3-(2-thie-nyl) propanenitrile. Tetrahedron Lett., 44,4783-4787. 

My first paper in chemoenzymatic synthesis appeared in the fall of 1978 under the title "Synthesis of optically active alkynyl alcohols by microbial asymmetric hydrolysis of the corresponding acetates" [2,3]. As shown in Figure 24.1, asymmetric hydrolysis of ( )-l with Bacillus subtilis var. niger was only moderately successful, yielding the recovered (1 )-1 and the hydrolyzed (S)-2 of 7-96% ee [2, 3]. After 35 years of cooperative endeavor by biochemists as the suppliers of enz5unes and synthetic chemists as the users, it is now possible to employ various lipases and esterases as commercially available and bottled reagents for enantioselective synthesis of natural products, pharmaceuticals, and agrochemicals. 

Mangas-Sanchez J, Rodri guez-Mata M, Busto E, Gotor-Femandez V, Gotor V. Chemoenzymatic synthesis of rivastig-mine based on lipase-catalyzed processes. J. Org. Chem. 2009 74 5304-5310. 

An efficient chemoenzymatic synthesis of both enantiomers 142 and 143 of an LTD4 antagonist have been prepared by lipase-catalyzed asymmetrical hydrolysis of prochiral and racemic dithioacetal esters 144 having up to five bonds between die prochiral/chiral center and the ester carbonyl group. The e.e. of 98% and reaction yield of 45% were obtained using lipase PS-30 (Fig. 51). LTD4 antagonists have potential for the dierapeutic treatment of asthma [251]. 

An efficient chemoenzymatic route for the synthesis of optically active substituted indolines has been recently developed (Scheme 7.27), and also the alkoxycarbonyla-tion process is more efficient than the acylation reaction. Different lipases have been tested in the alkoxycarbonylation of these secondary amines, GALA being found to be the best biocatalyst for 2-substituted-indolines, and CALB for 3-methylindoline. The combination of lipases with a variety of allyl carbonates and TBME as solvent has allowed the isolation of the carbamate and amine derivatives in a high level of enantiopurity [51]. 

The first 10-step total asymmetric synthesis of herbarumin III (42) in 24% overall was reported in 2004 by Gurjar and coworkers who later synthesized the compound using the RCM approach. Thereafter, a chemoenzymatic asymmetric synthesis of 42 which fixed the hydroxyl stereocenters (C7 and C9) by lipase catalyzed irreversible transesterification was described. 

Epoxide hydrolases are less used than lipases however, in recent years the synthesis of chiral diols with these biocatalysts has emerged as an excellent methodology to develop new and interesting chemoenzymatic processes [13],... 

Chemoenzymatic polymerizations have the potential to further increase macro-molecular complexity by overcoming these limitations. Their combination with other polymerization techniques can give access to such structures. Depending on the mutual compatibility, multistep reactions as well as cascade reactions have been reported for the synthesis of polymer architectures and will be reviewed in the first part of this article. A unique feature of enzymes is their selectivity, such as regio-, chemo-, and in particular enantioselectivity. This offers oppormnities to synthesize novel chiral polymers and polymer architectures when combined with chemical catalysis. This will be discussed in the second part of this article. Generally, we will focus on the developments of the last 5-8 years. Unless otherwise noted, the term enzyme or lipase in this chapter refers to Candida antarctica Lipase B (CALB) or Novozym 435 (CALB immobilized on macroporous resin). 

Figure 24.2. Synthesis of positionally labeled, symmetrically structured TAGs of the MLM-type constituting MCFA at the end-positions, and EPA or DHA at the midposition, by a chemoenzymatic approach based on immobilized Candida antarctica lipase (CAL).

Chemoenzymatic strategies were recently also applied for the preparative-scale synthesis of the very rare and expensive research biochemicals D-myo-inositol-l-phosphate, and D- and L-l,3,4,5-myo-inositol tetrakisphosphates [127,167]. The approach uses commercial lipase from Pseudomonas sp. for the regio- and enantioselective acetylation (in vinyl acetate) of 4,6-di-O-benzyl-myo-inositol to lD-l-acetoxy-4,6-di-0-benzyl-myo-inositol (intermediate for D-IP,). and lipase from Candida antarctica for the enantioseparation of racemic 2,6-dibenzyl-myo-inositol by enantioselective C5-acetylation (in the synthesis of D- and L-1,3,4,5-IP4) (Fig. 12). 

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