Lactones enzyme-catalyzed polymerization

In 1993, Kobayashi et al. first reported the successful lipase-catalyzed ROP of lactones [82]. Although, initially only oHgo-poly(BL) (250 < M < 1050) were prepared after several weeks using an equal quantity of lipase to BL monomers, some time later a much-improved enzyme-catalyzed polymerization of BL was reported which used thermophilic lipases to yield an optically active poly(BL) that was enriched with R-repeating units and had a M ranging from 900 to 3900 [83]. 

The first attempts at ROP have been mainly based on anionic and cationic processes [4,5]. In most cases, polyesters of low molecular weight were recovered and no control on the polymerization course was reported due to the occurrence of side intra- and intermolecular transesterification reactions responsible for a mixture of linear and cyclic molecules. In addition, aliphatic polyesters have been prepared by free radical, active hydrogen, zwitterionic, and coordination polymerization as summarized in Table 2. The mechanistic considerations of the above-mentioned processes are outside the scope of this work and have been extensively discussed in a recent review by some of us [2 ]. In addition, the enzyme-catalyzed ROP of (di)lactones in organic media has recently been reported however, even though this new polymerization procedure appears very promising, no real control of the polyesters chains, or rather oligomers, has been observed so far [6]. 

This method exclusively yields macrocyclic polyesters without any competition with linear polymers. Furthermore, the coordination-insertion ROP process can take part in a more global construction set, ultimately leading to the development of new polymeric materials with versatile and original properties. Note that other types of efficient coordination initiators, i.e., rare earth and yttrium alkoxides, are more and more studied in the framework of the controlled ROP of lactones and (di)lactones [126-129]. These polymerizations are usually characterized by very fast kinetics so as one can expect to (co)polymerize monomers known for their poor reactivity with more conventional systems. Those initiators should extend the control that chemists have already got over the structure of aliphatic polyesters and should therefore allow us to reach again new molecular architectures. It is also important to insist on the very promising enzyme-catalyzed ROP of (di)lactones which will more likely pave the way to a new kind of macromolecular control [6,130-132]. 

In addition to (substituted) lactones various cyclic esters related monomers were polymerized via enzyme-catalyzed ROP. 

Ethyl glucoside as a multifunctional initiator for enzyme-catalyzed regioselective lactone ring-opening polymerization. J. Am. Chem. Soc.,... 

Garcia-Arrazola, R., Gimeno, M., and Barzana, E. (2007) Use of liquid 1,1,1,2-tetrafluoroethane as solvent media for enzyme-catalyzed ringopening polymerization of lactones. Macromolecules, 40 (12), 4119-4120. 

Inspired by the fmding that HiC is active for polycondensation polymerizations, studies were performed to assess HiC activity for lactone ringopening polymerizations (Scheme 2). HiC-catalyzed ROP was carried out in either bulk or toluene. To determine the relationship between reaction temperature and enzyme activity for lactone ring-opening polymerizations, e-caprolactone (1) in bulk was taken as the model system. 

The mechanism for the lipase-catalyzed polymerization of lactones was first presented by Uyama et al. [67]. The proposed mechanisms for the lipase-catalyzed polymerization of lactones proceeded via an acyl-enzyme intermediate (enzyme-activated monomer, EM) at a serine residue of the catalytic site of lipase as the principal reaction course (Scheme 9) [67,88-90]. The key step is the reaction of the lactone with lipase involving the ring opening of... 

The mechanism of enzyme-catalyzed ROP was first proposed by Uyama et al. [54]. Here, the catalyhc site of lipase is the serine residue, which forms a complex with the lactone, leading to the formation of an enzyme-monomer complex (EMC). The rate-determining step in the overall polymerization was believed to be the formation of EMC (also known as an enzyme-activated monomer ). 

Srivastava, R.K. and Albertsson, A.-C. (2006) Enzyme-catalyzed ring-opening polymerization of 7-membered ring lactones leading to terminal functionalized and tri-block polyesters. Macromolecules, 39(1), 46 54. 

This review aims at reporting on the synthesis of aliphatic polyesters by ROP of lactones. It is worth noting that lactones include cyclic mono- and diesters. Typical cyclic diesters are lactide and glycolide, whose polymerizations provide aliphatic polyesters widely used in the frame of biomedical applications. Nevertheless, this review will focus on the polymerization of cyclic monoesters. It will be shown that the ROP of lactones can take place by various mechanisms. The polymerization can be initiated by anions, organometallic species, cations, and nucleophiles. It can also be catalyzed by Bronsted acids, Lewis acids, enzymes, organic nucleophiles, and bases. The number of processes reported for the ROP of lactones is so huge that it is almost impossible to describe aU of them. In this review, we will focus on the more... 

Lipases are enzymes of the hydrolase family and, in nature, hydrolyze fatty acid esters in aqueous environment. It is worth recalling that the hydrolysis of esters is a reversible reaction. Chemists thus often use lipases to catalyze the reverse reaction, i.e., the esterification and the ROP of lactones. In 1993, the groups of Kobayashi [91] and Knani [92] reported independently the hpase-catalyzed ROP of sCL and 8-valerolactone. The aliphatic polyesters were functionalized by a carboxylic group at one chain-end and a hydroxyl group at the other chain-end. Accordingly, the polymerization was initiated and terminated by water present in the reaction media. 

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... 

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. 

Conventional ring-opening polymerization of cyclic anhydrides, carbonates, lactones, and lactides require extremely pure monomers and anhydrous conditions as well as metallic catalysts, which must be completely removed before use, particularly for medical applications. To avoid these difficult restrictions, an enzymatic polymerization may be one of the more feasible methods to obtain the polyesters. This method was first reported by two independent groups (Kobayashi [152] and Gutman [153]) who showed that lipases, enzymes capable of catalyzing the hydrolysis of fatty acid esters, can polymerize various medium-sized lactones. 

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