Lipase-catalyzed lactonizations

Mei, Y., Kumar, A., and Gross, R.A. (2002) Probing water-temperature relationships for lipase-catalyzed lactone ring-opening polymerizations. Macromolecules, 35.14, 5444-5448. 

A compilation of the lipase-catalyzed lactone, cyclic ester related monomers and copolymers, the enzymes used, and the corresponding citation(s) are given in Table 4.4. 

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... 

Lipase-catalyzed intermolecular condensation of diacids with diols results in a mixture of macrocycUc lactones and liuear oligomers. Interestingly, the reaction temperature has a strong effect on the product distribution. The condensation of a,(D-diacids with a,(D-dialcohols catalyzed by Candida glindracea or Pseudomonas sp. Upases leads to macrocycUc lactones at temperatures between 55 and 75°C (91), but at lower temperatures (<45°C) the formation of oligomeric esters predorninates. Optically active trimers and pentamers can be produced at room temperature by PPL or Chromobacterium viscosum Upase-catalyzed condensation of bis (2,2,2-trichloroethyl) (+)-3-meth5ladipate and 1,6-hexanediol (92). 

Asymmetric alcoholyses catalyzed by lipases have been employed for the resolution of lactones with high enantioselectivity. The racemic P-lactone (oxetan-2-one) illustrated in Figure 6.21 was resolved by a lipase-catalyzed alcoholysis to give the corresponding (2S,3 S)-hydroxy benzyl ester and the remaining (3R,4R)-lactone [68]. Tropic acid lactone was resolved by a similar procedure [69]. These reactions are promoted by releasing the strain in the four-membered ring. 

Various cyclic esters have been subjected to hpase-catalyzed ring-opening polymerization. Lipase catalyzed the ring-opening polymerization of 4- to 17-membered non-substituted lactones.In 1993, it was first demonstrated that medium-size lactones, 8-valerolactone (8-VL, six-membered) and e-caprolactone (e-CL, seven-membered), were polymerized by lipases derived from Candida cylindracea, Burkholderia cepacia (lipase BC), Pseudomonas fluorescens (lipase PF), and porcine pancreas (PPL). °... 

On the other hand, the macrolides showed unusual enzymatic reactivity. Lipase PF-catalyzed polymerization of the macrolides proceeded much faster than that of 8-CL. The lipase-catalyzed polymerizability of lactones was quantitatively evaluated by Michaelis-Menten kinetics. For all monomers, linearity was observed in the Hanes-Woolf plot, indicating that the polymerization followed Michaehs-Menten kinetics. The V, (iaotone) and K,ax(iaotone)/ m(iaotone) values increased with the ring size of lactone, whereas the A (iactone) values scarcely changed. These data imply that the enzymatic polymerizability increased as a function of the ring size, and the large enzymatic polymerizability is governed mainly by the reachon rate hut not to the binding abilities, i.e., the reaction process of... 

Lipase catalysis is often used for enantioselective production of chiral compounds. Lipase induced the enantioselective ring-opening polymerization of racemic lactones. In the lipase-catalyzed polymerization of racemic (3-BL, the enantioselec-tivity was low an enantioselective polymerization of (3-BL occurred by using thermophilic lipase to give (/ )-enriched PHB with 20-37% enantiomeric excess (ee). ... 

Polyester syntheses have been achieved by enzymatic ring-opening polymerization of lactide and lactones with various ring-sizes. Here, we focus not only on these cyclic esters but also other cyclic monomers for lipase-catalyzed ringopening polymerizations. Figure 8 summarizes cyclic monomers for providing polyesters via lipase catalysis. 

Lipase catalyzed the ring-opening polymerization of medium-size lactones, d-valerolactone (<5-VL, six-membered) and -caprolactone (c-CL, seven-mem-bered). Lipases CC, PF and PPL showed high catalytic activity for the polymerization of <5-VL [74,75]. The molecular weight of the polymer obtained in bulk at 60 °C was relatively low (less than 2000). 

Lipases catalyze the polymerization of lactones [Duda et al., 2002 Gross et al., 2001 Kobayashi, 1999 Kobayashi et al., 2001]. The reaction mechanism is similar to that for the enzymatic polymerization of hydroxyacids (Sec. 2-17a-2). Lipase reacts with lactone to produce enzyme-activated hydroxyacid and some of the latter reacts with water to produce hydroxyacid (Eqs. 7-81). Hydroxyacid and enzyme-activated hydroxyacid react to initiate polymerization (Eq. 7-82). Propagation proceeds by nucleophilic attack of... 

The natural substrates of lipases are triglycerides and, in an aqueous environment, lipases catalyze their hydrolysis into fatty acids and glycerol. In anhydrous media, lipases can be active in the reverse reaction [19]. In fact, in the acylation step, acids, lactones, (cyclic) carbonates [20, 21], cyclic amides [22, 23], (cyclic) thioesters [24, 25], and cyclic phosphates [26] have been found to act as suitable acyl donors. In the deacylation step, apart from water, lipases also accept alcohols [27], amines [28, 29], and thiols [30] as nucleophiles although the specificity of lipases is lower for amines and thiols than for water and alcohols [31]. 

In lipase-catalyzed ROP, it is generally accepted that the monomer activation proceeds via the formation of an acyl-enzyme intermediate by reaction of the Ser residue with the lactone, rendering the carbonyl more prone to nucleophilic attack (Fig. 3) [60-64, 94]. Initiation of the polymerization occurs by deacylation of the acyl-enzyme intermediate by an appropriate nucleophile such as water or an alcohol to produce the corresponding co-hydroxycarboxylic acid or ester. Propagation, on the other hand, occurs by deacylation of the acyl-enzyme intermediate by the terminal hydroxyl group of the growing polymer chain to produce a polymer chain that is elongated by one monomer unit. 

Randomness in Copolymerizations of Lactones with Lipase-Catalyzed ROP... 

In addition to lactones, lactides and glycolides are highly interesting monomers for evaluation in lipase-catalyzed ROP. Lactide is the cyclic dimer of lactic acid and can occur in three stereo-configurations L-lactide, D-lactide, and D,L- or meso-lactide (Fig. 6). In analogy, glycolide is the cyclic dimer of glycolic acid but is... 

A second route (route B in Fig. 1) relies on an initiation process with an (meth)acryl hydroxyl compound and is adopted from the chemical ROP of lactones. The controlled character of these polymerizations ensures a virtually quantitative initiation and thus incorporation of hydroxy-functional initiator (e.g., acrylate) into the polymer chain. However, this is not automatically the case for lipase-catalyzed ROP due to the different mechanism. The latter follows an activated monomer mechanism in which the lipase activates any carbonyl group of a carboxylic acid derivative present in the system. It has recently been shown that acrylation using hydroxy-functional acrylate initiators like hydroxy ethyl(meth)acrylate (HEMA or... 

While diketene remains a very important synthetic precursor, there has been increasing interest in the chemistry of a-methylene-/3-lactones, 3-methylene-2-oxetanones. However, unlike diketene, which can be readily synthesized by the dimerization of aldehydic ketenes, there are few methods for the synthesis of a-methylene-/3-lactones in the literature. Recent strategies for the preparation of the compounds are discussed in Section 2.05.9.2. The kinetic resolution of racemates of alkyl-substituted a-methylene-/3-lactones has been carried out via a lipase-catalyzed transesterification reaction with benzyl alcohol (Equation 21) <1997TA833>. The most efficient lipase tested for this reaction was CAL-B (from Candida antarctica), which selectively transesterifies the (A)-lactone. At 51% conversion, the (R)-f3-lactone, (R)-74, and (A)-/3-hydroxy ester, (S)-75, were formed in very high enantio-selectivities (up to 99% ee). 

Lactonization and Polycondensation. The lipase-catalyzed intramolecular transesterification of a range of w-hydroxy esters has been investigated extensively - and was observed to be very dependent on the chain length of the substrate (eq 16). 

A preparatively useful synthesis of (R)-lipoic acid involves Baeyer-Villiger monooxygenase-catalyzed biotransformation of 2-(2-acetoxyethyl)cyclohexanone 351 to the key precursor, that is, chiral lactone 352 (Scheme 68) < 1997BMCL253, 1995CC1563>. The enzyme-catalyzed lactone 352 was then converted by a standard reaction procedure into the desired acid on enantioselective esterification of racemic lipoic acid, using C. rugosa lipase. 

Lipase-catalyzed ring-opening polymerization of nine-membered lactone, 8-octanolide (OL), has been reported.165 Lipases CA and PC showed the high catalytic activity for the polymerization. Racemic fluorinated lactones with a ring size from 10 to 14 were enantioselectively polymerized by lipase CA catalyst to give optically active polyesters.166... 

The lipase-catalyzed copolymerization of lactones often afforded random copolyesters, despite the different enzymatic polymerizability of lactones in some cases.165 167g-174 So far, the random copolymers were enzymatically obtained from combinations of d-VL-e-CL, e-CL-OL, e-CL-PDL, and OL-DDL. The formation of the random copolymers suggests that the intermolecular transesterifications of the polyesters frequently took place during the copolymerization. By utilizing this specific lipase catalysis, random ester copolymers were synthesized by the lipase-catalyzed polymerization of macrolides in the presence of poly-(e-CL).175... 

In addition lipase-catalyzed ROP of lactones was successfully used to synthesize macromers by using hydroxyl moieties of carbohydrates as sites for initiation [68, 69, 88], Specifically, ethylglucopyranoside (EGP) was used as a multifunctional initiator and e-CL/trimethylene carbonate (TMC) as monomers for lipase-catalyzed ROPs. Initiation of ROP occurred selectively from the 6-hydroxyl position forming macromers with a carbohydrate head group with three remaining hydroxyl groups that remained available for other enzymatic or chemical transformations (Scheme 4.13). 

Lipase-catalyzed synthesis of polyesters came to the focus after two major breakthroughs in 1984, novel lipase-catalyzed polycondensation to give oli-goesters in 1993, discovery of the catalysis for ring-opening polymerization of lactones. 

Namekawa, S., Suda, S., Uyama, H., and Kobayashi, S. (1999) Lipase-catalyzed ring-opening polymerization of lactones to polyesters and its mechanistic aspects. Int. J. Biol. Macromol., 25 (1-3), 145-151. 

Nobes, G.A.R., Kazalauskas, R.J., and Marchessault, R.H. (1996) Lipase-catalyzed ring-opening polymerization of lactones a novel route to poly(hydroxyalkanoate) s. Macromolecules, 29 (14), 4829-4833. 

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