Desymmetrization, lipase-catalyzed

However, whatever the mechanism of action is, the effect of solvents on enzyme selectivity is sometimes really dramatic. For example, Hrrose et al. [42] reported that in the Pseudomonas species lipase-catalyzed desymmetrization of prochiral... 

Lipase-catalyzed desymmetrization was used to synthesize supellapyrone and its three stereoisomers, the female sex pheromone of the brown-banded cockroach Supella longipalpa ... 

Following lipase-catalyzed desymmetrization reactions of the substrate (e. g., 1) on the microtiter plates, an extraction step is necessary prior to MS analysis. This process is controlled by the Facts software (Figure 9.4. Four modules are controlled simultaneously the robot arm (RoMa), the carousel for storing the microtiter plates, the 96-pipette system (TeMo), and the 8-fold pipette head (Gemini). Iteration occurs within 12 min. 

Due to its structural complexity and interesting physiological activities as an antifungal agent and especially as an immunosuppressive drug, the macrolide rapamycin has been a target of many total syntheses [54-58]. In their approach, Ley and co-workers used a lipase-catalyzed desymmetrization of a meso diol (Fig. 3). In early studies, the selective acetylation of 7W w-2.4-dimethylpentane-1,5-diol was achieved by a PPL immobilized on celite with moderate yields and 92%... 

Figure 39 Lipase-catalyzed stereoselective resolution and desymmetrization of binaphthols 72.

An efficient synthesis of (R)- and (S)-1 -amino-2,2-difluorocycloropanecarboxylic acid (DFACC) 91 via lipase-catalyzed desymmetrization of prochiral diols 89 and prochiral diacetates 92 was recently reported.28 Thus, the lipase-catalyzed transesterification of 89 using vinyl acetate as acyl donor in benzene di-z-propyl ether (20 1) as organic solvent... 

Figure 46 Lipase-catalyzed desymmetrization of prochiral diols 89 and diacetates 92.28...

The first enzymatic desymmetrizations of prochiral phosphine oxides was recently reported by Kielbasinski et al.88 Thus, the prochiral bis(methoxycarbonylmethyl)-phenylphosphine oxide 93 was subjected to the PLE-mediated hydrolysis in buffer affording the chiral monoacetate (RJ-94 in 72% ee and 92% chemical yield. In turn, the prochiral bis(hydroxymethyl)phenylphosphine oxide 95 was desymmetrized using either lipase-catalyzed acetylation of 95 with vinyl acetate as acyl donor in organic solvent or hydrolysis of 97 in phosphate buffer and solvent affording the chiral monoacetate 96 with up to 79% ee and 76% chemical yield. 

Figure 47 Lipase-catalyzed desymmetrizations of prochiral phosphine oxides.

J-Flemandez, M. Johnson, V. D. Holland, L. H. McNulty, J. Capretta, A. Lipase-catalyzed stereoselective resolution and desymmetrization of binaphthols. Tetrahedron Asymmetry 2003, 14,289-291. 

SCHEME 13.21 Desymmetrization of meso-diacetate by lipase-catalyzed hydrolysis synthesis of C3-alditol derivatives. 

Kirihara, M., Kawasaki, M., Takuwa, T., et al. (2003) Efficient synthesis of (R)- and (S)-l-amino-2,2-difluorocyclopropanecarboxylic acid via lipase-catalyzed desymmetrization of pro-chiral precursors. Tetrahedron Asymmetry, 14, 1753-1761. 

Enzymatic resolution has been successfully applied to the preparation of optically active gem-difluorocyclopropanes (see Scheme 12.4). We succeeded in the first optical resolution of racemic gm-difluorocyclopropane diacetate, trans-43, through lipase-catalyzed enantiomer-specific hydrolysis to give (R,R)-(-)-44 with >99% ee (see equation 9, Scheme 12.4) [4a], We also applied lipase-catalyzed optical resolution to an efficient preparation of monoacetate cw-46 from prochiral diacetate m-45 (see equation 10, Scheme 12.4) [4a], Kirihara et al. reported the successful desymmetrization of diacetate 47 by lipase-catalyzed enantiomer-selective hydrolysis to afford monoacetate (R)-48, which was further transformed to enantiopure amino acid 15 (see equation 11, Scheme 12.4) [19]. We demonstrated that the lipase-catalyzed enantiomer-specific hydrolysis was useful for bis-gem-difluorocyclopropane 49. Thus, optically pure diacetate (R,S,S,R)-49 and (S,R,R,S)-diol 50, were obtained in good yields, while meso-49 was converted to the single monoacetate enantiomer (R,S,R,S)-51 via efficient desymmetrization (see equation 12, Scheme 12.4) [4b, 4e], Since these mono- and bis-gm-difluorocyclopropanes have two hydroxymethyl groups to modify, a variety of compounds can be prepared using them as building blocks [4, 22],... 

Resolution by transesterification. A procedure for the large-scale preparation of (15,25)-tran -2-methoxycyclohexanol, which is a key intermediate for the synthesis of tricyclic 3-lactam antibiotics, has been worked out." Monoprotected 1,2-diols and acetals of a-hydroxy aldehydes afford chiral acetates hy the lipase-catalyzed transesterification. a-Ketols are also resolved. Dimethyl /nejo-2,5-dibromoadipate is readily desymmetrized by the transesterification protocol, permitting the synthesis of chiral cA-2,5-disubstituted pyrrolidines. ... 

Wiktelius D, Johansson MJ, Luthman K, Kann N (2005) A biocatalytic route to P-chirogenic compounds by lipase-catalyzed desymmetrization of a prochiral phosphine-borane. Org Lett 7 4991 994... 

In contrast, lipase-catalyzed lactonization often leads to a product pattern that is different from that obtained by chemical catalysis (Scheme 3.20). The outcome depends on several parameters, i.e., the length of the hydroxy acid, the type of lipase, the solvent, the dilution, and even the temperature [255, 256]. In addition, when racemic or prochiral hydroxyacids are employed as substrates, a kinetic resolution [257,258] or desymmetrization may be accomplished with high selectivities [43]. It is obvious that enzymatic lactone formation is particularly easy with y-hydroxy derivatives, which lead to the formation of (favored) five-membered ring lactones. The most important synthetic aspect of enzymatic lactone formation, however, is the possibility of directing the condensation reaction towards the formation of macro-cyclic lactones and dilactones - i.e., macrolides and macrodiolides, respectively, which are difficult to obtain by chemical catalysis (Scheme 3.20) [44, 259]. This... 

SCH 51048 is a THF-based antifungal agent, which can be synthesized through the lipase-catalyzed desymmetrization of an adequate homoallylic diol. CAL-B have allowed the selective synthesis of the enantiopure (S)-monoacetate in 71% isolated yield at a 30 kg batch reaction using two equivalents of VinOAc in acetonitrile (MeCN) at 0°C after 6h (Figure 9.21) [176]. Complete conversion of the diol was observed, yielding byproduct diacetate in around 30%, which was separated by column chromatography. The desymmetrization of other 1,3-propanediol subunits has been... 

Lipase-catalyzed desymmetrization of prochiral diol intermediates forthe synthesis of antifungal and antitumor antibiotics. 

One of the reactions catalyzed by esterases and lipases is the reversible hydrolysis of esters (Figure 19.1, Reaction 2). These enzymes also catalyze transesterilications and the desymmetrization of mew-substrates (vide infra). Many esterases and lipases are commercially available, making them easy to use for screening desired biotransformations without the need for culture collections and/or fermentation capabilities.160 In addition, they have enhanced stability in organic solvents, require no co-factors, and have a broad substrate specificity, which make them some of the most ideal industrial biocatalysts. Alteration of reaction conditions with additives has enabled enhancement and control of enantioselectivity and reactivity with a wide variety of substrate structures.159161164... 

The proper stereochemistry was achieved by enzyme catalyzed desymmetrization of the prochiral 1,3-diol 30. Candida antarctica lipase (CAL)-catalyzed transesterification yielded the monoacetate 31, which gave rise to the methyl with the proper stereochemistry 32. The generation of the desired chiral epoxide 35 was achieved by asymmetric dihydroxylation employing AD-mix-a,42 followed by epoxide formation. Base-catalyzed etherification yielded the mixture of the enantiopure (+)-heliannuol A and (-)-heliannuol D. Unfortunately these compounds correspond to the opposite d/l series and correspond to the enantiomers of the natural products (-)-heliannuol A and (+)-heliannuol D (Fig. 5.6.A). 

Fig. 11.19. Desymmetrization of a meso-substrate 11 catalyzed by a lipase from Bacillus subtilis [82],...

DESYMMETRIZATION OF MESO ClS-3,5-DIACETOXYCYCLOPENTENE TO (1R,4S)-(+)-4-HYDR0XY-2-CYCL0PENTENYL ACETATE CATALYZED BY LIPASE B FROM C. ANTARCTICA... 

A procedure in Organic Syntheses used acetylcholine esterase from electric eel as the enantioselective catalyst [29], but the much less expensive and more common enzyme, C. antarctica lipase B can also be used for this reaction [30]. Desymmetrization of 15 g of diacetate vnthin 10 h requires 2 g of Novozym 435 ( US 40) or 18 mg of acetylcholine esterase from electric eel ( US 500). The procedure given below uses Novozym 435, which is C. antarctica lipase B immobilized on acrylic resin. Note that this immobilization is by ionic absorption, which is effective in organic solvents, but not in water, which this procedure uses. The lipase washes off the resin in water and cannot be recovered. Lipase from P. cepacia (Amano PS-30) also catalyzes this desymmetrization [31], but the yield was only -60% because the hydrolysis stopped for unknown reasons. 

Enantioselective hydrolysis catalyzed by lipase B from C. antarctica desymmetrized a meso diacetate to the chiral monoacetate. 

The enzyme-catalyzed kinetic asymmetric transformation (KAT) of a diastereomeric 1 1 syn anti mixture is limited to a maximum theoretical yield of 25% of one enantiomer. This important drawback has been overcome by the combination of the actions of a ruthenium complex and a lipase in a dynamic kinetic asymmetric transformation (DYKAT), the desymmetrization of racemic or diastereomeric mixtures involving interconverting diastereomeric intermediates, implying different equilibration rates of the stereoisomers. Thus, this strategy allows the preparation of optically active diols, widely employed in organic and medicinal chemistry, as they are an important source of chiral auxiliaries and ligands and they can be easily employed as precursors of much other functionality. 

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