Lipases epoxy esters

In the case of biocatalysis, enzymes [3] and catalytic antibodies [4] have attracted most attention. Since enzymes are inherently the more active catalysts, they have been used most often. Indeed, many industrial processes for the enantioselective production of certain chiral intermediates are based on the application of enzymes, as in the lipase-catalyzed kinetic resolution of an epoxy-ester used in the production of the anti-hypertensive therapeutic Diltiazem [5]. Recently, it has been noted that there seems to be a trend in industry to use enzymes more often than in the past... 

Also, in Andeno s diltiazem synthesis (Scheme 27), an early enantioselective enzymatic hydrolysis of an epoxy ester by a lipase is the key step, creating the necessary optically active intermediate 44 [106]. 

An alternative approach is to perform a resolution of the epoxy ester (10), which can be accomplished with a lipase from Serratia marcescens (Scheme 2) [30,31]. This approach allows for resolution of an early intermediate that can then be used to prepare just the desired diastereoisomer. Alternatives are to resolve precursors to the epoxy functionality [32]. 

The types of enzymes used by organic chemists vary widely and include such well-known biocataiysts as lipases, esterases, oxidoreductases, oxinitrilases, transferases and aldolases [4]. An example which illustrates the industrial application of a lipase concerns the kinetic resolution of a chiral epoxy ester used as the key intermediate in the synthesis of the calcium antagonist Diltiazem, a major therapeutic in the treatment of high blood pressure [6] (Fig. 1). In developing the industrial process for the production of this drug, many different lipases were screened, but only the bacterial lipase from Serratia marescens showed both a sufficiently high activity and enantioselectivity. The intermediate is produced industrially on a scale of 50 tons/year. 

Scheme 2.55 Resolution of epoxy esters by porcine pancreatic lipase...

Scheme 2.71 Lipase-catalyzed resolution of an epoxy-ester on industrial scale...

Another interesting synthetic application is the lipase-catalyzed preparation of en-antiomerically pure epoxy esters as intermediates of the calcium channel blocker diltiazem [283] (Scheme 67). 

Both saturated (50) and unsaturated derivatives (51) are easily accepted by lipases and esterases. Lipase P from Amano resolves azide (52) or naphthyl (53) derivatives with good yields and excellent selectivity. PPL-catalyzed resolution of glycidyl esters (54) is of great synthetic utiUty because it provides an alternative to the Sharpless epoxidation route for the synthesis of P-blockers. The optical purity of glycidyl esters strongly depends on the stmcture of the acyl moiety the hydrolysis of propyl and butyl derivatives of epoxy alcohols results ia esters with ee > 95% (30). 

W. Ladner and G. M. Whitesides, Lipase-catalyzed hydrolysis as a route to esters of chiral epoxy alcohols, J. Am. Chem. Soc. 1984, 106, 7250-7251. 

The catalyst was the unsupported lipase from Pseudomonas cepacia. The reaction was as selective in SCCO2 as it was in hexane but was much slower in SCCO2. The S ester formed preferentially, in 46% e.e. (after 63% conversion), leaving the R acid in 78% e.e. Later experiments compared the eflfectiveness of the crude enzyme with the epoxy- and Celite-stabilized enzymes (82). All three were stable to exposure to SCCO2 and greater rates of reaction were found with the immobilized versions, but the conversions dropped greatly when the catalyst was reused. 3-Hydroxy esters can be used as intermediates for the preparation of optically active pharmaceuticals such as propranolol, a (5-blocker (82). 

Palomo JM, Munoz G, Fernandez-Lorente G et al. (2003) Modification of Mucor miehei lipase properties via directed immobilization on different heterofunctional epoxy resins. Hydrolytic resolution of (R,S)-2-butyroyl-2-phenylacetic acid. J Mol Catal B Enzym 21 201-210 Palomo JM, Ortiz C, Fernandez-Lorente G et al. (2005) Lipase-lipase interaction as a new tool to immobilize and modulate the lipase properties. Enzyme Microb Technol 36 447-454 Park EY, Sato M, Kojima S (2006) Fatty acid methyl ester production using Upase-immobilizing silica particles with different particle sizes and different specific surface areas. Enzyme Microb Technol 39(4) 889-896... 

Unsaturated fatty alcohols can also be epoxidized by lipase-catalyzed perhydrol-ysis (16). Interestingly, the outcome of the reaction depends on the ester applied for peroxy acid generation (Fig. 5). Fatty acid esters such as butyric acid ethylester react to epoxyalkanolacylates in a three-step one-pot reaction. Carbonic acid esters such as diethyl carbonate also form peroxy acids (percarbonic acid derivatives) and epox-idize the unsaturated alcohol however, in a water-containing environment, they are obviously not stable enough to esterify the hydroxyl group. Thus, the end product is the epoxy alcohol. 

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