Chiral synthons lipases

Tsuji T, Onishi T et al (1999) Lipase-catalyzed synthesis of a tri-substituted cyclopropyl chiral synthon a practical method for preparation of chiral l-alkoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane. Tetrahedron Asymmetry 10 3819-2825... 

Chiral carbon framework of the monoterpenoid secologanin, leading to powerful chiral synthons, from readily available meso-forms. Moderate results were obtained with lipases such as porcine liver esterase (PLE), delivering the (15,2/ )-mono-acetate at a yield of 78% with 96% ee (Fig. 10), though preparation of the enzyme seemed to be crucial for the appropriate result. In contrast, pig pancreatic lipase (PPL) was significantly more efficient in forming the (—)-(l/ ,25) enantiomer at a yield of 96% and 98% ee [86, 87]. 

A process utilizing a stereospecific ester cleavage yielding the product l -glycidylbutyrate in high optical purity has recently been scaled to commercial levels (63). The process catalyzed by porcine pancreatic lipase is shown in Fig. 19. R-glyddylbutyrate is a useful chiral synthon for a variety of commercial products, for example, p-blockers. 

Hydrolases catalyze the addition of water to a substrate by means of a nucleophilic substitution reaction. Hydrolases (hydrolytic enzymes) are the biocatalysts most commonly used in organic synthesis. They have been used to produce intermediates for pharmaceuticals and pesticides, and chiral synthons for asymmetric synthesis. Of particular interest among hydrolases are amidases, proteases, esterases, and lipases. These enzymes catalyze the hydrolysis and formation of ester and amide bonds. 

The lipase catalyzes the kinetic resolution of racemic amines, e.g. 1-phenyl-ethylamine (Fig. 19-21)[11. Products are intermediates for pharmaceuticals and pesticides. They can also be used as chiral synthons in asymmetric synthesis. As acylating agent ethylmethoxyacetate is used, because the reaction rate is more than 100 times faster than that with butyl acetate. Probably an enhanced carbonyl activity induced by the electronegative a-substituents accounts for the activating effect of the methoxy group. The lipase is immobilized on polyacrylate. The lowered activity caused by use of in organic solvent (tert-methylbutylether = MTBE) can be increased... 

Biotransformations are now firmly established in the synthetic chemist s armoury, especially reactions employing inexpensive hydrolytic enzymes for the resolution of racemates and for the desymmetrization of prochiral substrates. From a practical viewpoint, biocatalytic resolution is arguably the simplest method available to obtain synthetically useful quantities of chiral synthons. As an illustration of this point, many racemic secondary alcohols ROH can be resolved without prior derivatization by combining with a lipase and a volatile acyl donor (usually vinyl acetate) in an organic solvent, to effect irreversible transesterification once the desired degree of conversion has been reached, routine filtration to remove the enzyme and concentration of the filtrate affords the optically enriched products ROAcyl and ROH directly. 

The ZACA reaction of allyl alcohol with Me3Al afforded iodoalcohol (144) in good yield and enantioselectivity (Equation 61) [69]. The enantiopurity of (144) could be further improved by a combination with lipase-mediated reaction to provide useful chiral synthons (145) and (146) in high enantiopurity (Equations 62 and 63). 

Figure 41 Preparation of chiral synthons for antifungal and antitumor agents Lipase-catalyzed synthesis of enantiomerically pure alkyloxiranes.

Figure 42 Preparation of chiral synthon for polyether antibiotics Lipase-catalyzed enantioselec-tive hydrolysis of compounds 121 and 122.

Highly enantioselective esterification of (l ,S)-2-hydroxynonanoic acid with 1-butanol with C. rugosa lipase (CRL) in toluene in the presence of molecular sieves furnished the optically pure acid (Scheme 8) that has been used as a chiral synthon for the synthesis of the antirnicrobial agent (4 , ZS)-7-methox3i etradec-4-enoic acid [78]. 

A practical aspect of the use of enzymes for the preparation of chiral synthons is the fact that one can use enzymes such as lipases either in hydrolytic conditions or in organic solvents, and the most suitable method is a compromise between the solubility of the compound, the efficiency of the process, and the maximum enantioselection that can be achieved. In Scheme 65 two of these cases are presented [278,244] where esterification and hydrolysis can be compared. Interestingly, an opposite configuration of products is obtained when enzymatic hydrolysis of the ester or esterification of the alcohol is carried out. 

The usefulness of hydrolases like the immobilized lipase LIP to provide chiral substances for elaborated synthetic strategies is demonstrated in the example represented by Scheme 4. meso-UvA 8 was quantitatively acetylated to the monoacetate 9, an important intermediate in the preparation of synthon 10 used for prostaglandin syntheses [27]. 

Protease or lipase enzymes were useful for the regioselective aminoacylation of lobucavir. Lipase was also used for resolution of a synthon for the paclitaxel side chain. The paclitaxel side-chain ester was also prepared by reduction of a keto ester precursor. Enzymatic reduction of ketones to chiral alcohols is another reaction that has been widely applicable. C14-deacylase, ClO-deacety-lase, and C7-xylosidase were identified from microorganisms isolated from soil samples and were useful for converting complex mixtures of taxanes found in yew extracts primarily to 10-deacetyl baccatin III, a precursor for the semisynthesis of paclitaxel and analogs. 

The final compound is a mixture of two enantiomers (C2 is chiral) (Scheme 17.5). The use of lipases in 1991 to separate racemic mixture of a key synthon represents the cornerstone of the synthetic scheme leading to each enantiomer [40]. The two enantiomers of tetraconazole were separated using p cyclodextrin-mediated capillary electrophoresis in 2001 [42]. 

Kinetic Resolution of Alcohols. Primary alcohols may be resolved with moderate to good selectivities by Pseudomonas sp. lipase (PSL) using vinyl acetate [186] or acetic anhydride as the acyl dmior (Scheme 3.9). Whereas the selectivities achieved were moderate with alkyl and aiyl substituents, substrate modification via introduction of a bulky sulfur atom in helped considerably. In this way, chiral isoprenoid synthons having a Cs-backlxMie were obtained in >98% enantiomeric excess. 

The preparation of glycerol-based Ca-synthons and intermediates represents an interesting example where enzymatic transesterification is widely exploited. Alcoholysis of tributyrin with PPL was already shown to produce a chiral diglyceride (Fig. 3). Alcoholysis of trityl-protected dibutyrin with methanol in organic solvents shows some essential features about regio- and enantioselectivity in bifunctional compounds (Fig. 18) (25). Most lipases, such as lipases PS and AK and Novozym 435, first regioselectively produce the primary alcohol from the diester. With lipase AK, the reaction leads to effective kinetic resolution (A), whereas Novozym 435-catalyzed reaction (B) is not enantioselective. However,... 

Recently, Ogasawara and co-workers [54] disclosed an efficient synthesis of tiie enantiomerically pure tricyclic dienone 222 in both enantiomeric forms by employing lipase-mediated asymmetrization of the meso-synunetric precursor, and the novel palladium-mediated elimination reaction of the chiral monoacylated product. With this they show a new synthetic approach to A-ring synthon 189c (Scheme 13) [55]. Treatment of tricyclic diol 220, obtained from reduction of diketene 219, with two equivalents of vinyl acetate in acetonitrile in the presence of PSL furnished the monoacetate 221 in 79% yield after being stirred for 16 days at 28 C. The optically active acetate 221 was treated with ammonium formate in the presence of catalytic amounts of PdCl2(PPh3)2 to furnish the... 

---