Butyrolactone, lipase

Five-membered unsubstituted lactone, y-butyrolactone (y-BL), is not polymerized by conventional chemical catalysts. However, oligomer formation from y-BL was observed by using PPL or Pseudomonas sp. lipase as catalyst. Enzymatic polymerization of six-membered lactones, 8-VL and l,4-dioxan-2-one, was reported. 8-VL was polymerized by various lipases of different origins. The molecular weight of the enzymatically obtained polymer was relatively low (less than 2000). 

Five-membered unsubstituted lactone, y-butyrolactone, is not polymerized by conventional chemical catalysts. On the other hand, oligomer formation from y-butyrolactone was observed by using PPL or Pseudomonas sp. lipase as catalyst [23,69]. 

The biotechnological synthesis of lactones has reached a high standard. Besides microbial production, lactones can also be enzymatically produced. For instance, a lipase-catalysed intramolecular transesterification of 4-hydroxy-carboxylic esters leads enantioselectively (ee>80%) to (S)-y-lactones the chain length may vary from C5 to Cl 1 [13]. y-Butyrolactone can be produced in that way with lipase from Mucor miehei [30]. 

The copolymer of 12-hydroxydodecanoic acid/P-butyrolactone was synthesized at 45 °C in toluene, using Porcine pancreatic lipase [29], After 72 h, the molecular weight of the obtained copolymer in 70% yield was M = 1800. Electrospray... 

As well as the above-described intermolecular alcoholysis of esters, the intramolecular version has been successfully utilized for the synthesis of lactones from racemic hydroxy carboxylic acid esters (25-41, 64—66) (Table 11.1-22). High selectivity in the pig pancreas lipase-catalyzed enantiomer-differentiating lactonization of y-hydroxy carboxylic acid esters with formation of butyrolactones substituted in... 

Enzymatic desymmetrization of substituted 1,3-propanediols has been used as key step in the synthesis of y-butyrolactones by Itoh and coworkers, Scheme (8) [54],The diols 43 were treated with lipase PS (Pseudomenas sp.) in the presence of vinyl acetate as acyl donor to afford acetates 44 in excellent chemical yields and very high enantiomeric excesses (90-98%). These monoacetates were then converted into hydroxy nitriles 46 using a three step procedure. Tosylation of the hydroxyl group of 44, followed by treatment with potassium cyanide in dimethyl sulfoxide at 80°C gave the corresponding acetates 45. The acetoxy groups of 45 were finally hydrolysed with lithium hydroxide in a... 

Fukuyama also presented an alternative route to the advanced intermediate 114 as shown in Scheme 18 with an early introduction of the protected amino functionality. Reaction of y-butyrolactone with the Grignard reagent derived from 1,4-dibromobutane (120) afforded diol 121. Mesylation of the primary hydroxyl functionality with concomitant elimination of the tertiary one was followed by reaction with methylamine and protection of the resulting secondary amine to give alkene 122. Ozonolysis of the double bond in 122 and subsequent intramolecular aldol condensation of the resulting ketoaldehyde afforded cycohexenone 123. Rubottom oxidation and acetylation gave 124, which served as substrate in the lipase-... 

Lipase catalysis is often used for the enantioselective production of chiral compounds indeed, lipase has been known to induce an enantioselective ROP of racemic lactones. In the lipase-catalyzed polymerization of racemic j8-butyrolactone (/3-BL), the enantioselectivity was low rather, an enantioselective polymerization of /3-BL occurred by employing a thermophilic lipase to yield the (R)-enriched polymer with 20-37% enantiomeric excess (e.e.) [101]. The enantioselectivity was greatly improved by copolymerization with seven- or 13-membered nonsubstituted lactones, using the lipase CA catalyst, whereby the e.e.-value reached almost 70% for the copolymerization of /3-BL with DDL [102]. It should be noted that, in the case of the lipase CA catalyst, the (S)-isomer was reacted preferentially to produce the (S)-enriched, optically active copolymer. The lipase CA-catalyzed copolymerization of i5-CL (six-membered) with DDL proceeded enantioselectively, to yield the (R)-enriched optically active polyester with an e.e.-value of 76%. 

The use of isolated enzymes in organic solvents has already found its niche in organic synthetic laboratories, both in academia and industry (14, 75). Enzymes have emerged as very useful tools for the synthesis of optically active lactones by enantioselective lactonization of racemic yhydroxy esters, cohydroxy esters, and 5-hydroxy esters into enantioenriched y-butyrolactones, colactones, and 5-lactones, respectively (76,77,78). Isolated enzymes, such as lipases (20) and esterases (27) have also been exploited for preparing optically active four-, five- and six-membered lactones by enantioselective ring-opening... 

Four-membered ring lactones 3-propiolactone (P-PL) [68-70], P-butyrolactone (P-BL) [71-76], benzyl P-malolactonate (BBM) [77] and a-methyl-P-propiolactone (MPL) [78, 79] were polymerised using different lipases (Table 12.5). 

The five-membered unsubstituted lactone y-butyrolactone (y-BL) may not polymerize when using a conventional chemical catalyst. However, it was reported that only an oligomer was produced by the ring-opening polymerization of y-BL using PPL or lipase from Pseudomonas sp. [11,36]. 

Five membered, unsubstituted, lactone 7-butyrolactone (y-BL) was polymerised by PPL or PCL [16, 73] into small oligomers with a degree of polymerisation (DP) of 8-11. In the Pseudomonas sp, lipase catalysed polymerisation of y-VL and y-CL, less than 10% conversion was observed at 60 °C for 480 hours [75]. Unsubstituted and substituted six membered lactone 6-valerolactone (6-VL) [26, 69, 79-80] and a-methyl-6-valerolactone (MVL) [81] were polymerised using Rhizopus japonicus lipase, CCL, PFL, PPL and CAL enzymes. For unsubstituted 5-VL, the reactions were run for 5-10 days and the highest molecular weights obtained were in the range of 2,000 Da. CAL catalysed polymerisation of a-methyl-6-valerolactone yielded polyester with a M of up to 11,400 at 60 °C in 24 hours. 

An alternative enzymatic synthesis of 2(S)-mercapto-Y-butyrolactone (19) was also attempted as shown in Figure 8. Surprisingly, there are relatively few examples of enzymatic resolution of thiols, however, we were encouraged by the work of C ti (76) to investigate the lipase mediated hydrolysis of racemic thioacetate 20 (9). 

Reagents and conditions (a) Mucor meihei lipase, nBuOH, toluene-H20 Figure 8. Enzynwitic synthesis of2(S)-mercapto-Y-butyrolactone (19)... 

Cyclophostin (87) was prepared in 6 steps and 15% overall yield from hydroxymethyl butyrolactone (86) (Scheme 21). The cyclophostin (87) was then converted into cyclipostin P (88), a potent naturally occurring hormone sensitive lipase (HSL) inhibitor, using a one pot dealkylation-alkylation process. ... 

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