HYDROXYHEXANOIC ACID

Lipase CA also polymerized hydrophobic oxyacids efficiently. The DP value was beyond 100 in the polymerization of 16-hydroxyhexadecanoic acid, 12-hydroxy dodecanoic acid, or 10-hydroxy decanoic acid under vacuum at high temperature (90°C) for 24 h, whereas the polyester with lower molecular weight was formed from 6-hydroxyhexanoic acid under similar reaction conditions. This difference may be due to the lipase-substrate interachon. 

L-6-Hydroxynorleucine, a different key chiral intermediate used for synthesis of the vasopeptidase inhibitor Omapatrilat (Vanlev ), was prepared in 89% yield and > 99% optical purity by reductive amination of 2-keto-6-hydroxyhexanoic acid using glutamate dehydrogenase from beefliver (Hanson, 1999) (Figure 13.22). In an alternative process, racemic 6-hydroxynorleucine produced by hydrolysis of 5-(4-hydroxybutyl)hydantoin was treated with D-amino acid oxidase to prepare a mixture containing 2-keto-6-hydroxyhexanoic acid and L-6-hydroxynorleucine followed by the reductive amination procedure to convert the mixture entirely to L-6-hydroxynorleucine, with yields of 91-97% and optical purities of > 99%. 

Chemical synthesis and isolation of 2-keto-6-hydroxyhexanoic acid required several steps. In a second, more convenient process (Fig. 2), the ketoacid was prepared by treatment of racemic 6-hydroxynorleucine [produced by hydrolysis of 5-(4-hydroxybutyl)hydantoin (3)] with D-amino acid oxidase and catalase. After the e.e. of the remaining L-6-hydroxynorleucine had risen to >99%, the reductive animation procedure was used to convert the mixture containing 2-keto-6-hydroxyhexanoic acid and L-6-hydroxynorleucine entirely to L-6-hy-droxynorleucine with yields of 91-97% and e.e. of >98%. Sigma porcine kidney D-amino acid oxidase and beef liver catalase or Trigonopsis variabilis whole cells (source of oxidase and catalase) were used successfully for this transformation [22],... 

GC-MS chromatograms in Fig. 4 show that the low molecular weight PCL products were rapidly utilized by compost microorganisms. The unaged PCL films contained some low molecular weight products, i.e., 6-hydroxyhexanoic acid, caprolactone, and its cyclic dimer and trimer (Fig. 4, a). These products were also identified after aging in sterile mineral medium. However, after 2 weeks in... 

Fig. 4. GC-MS chromatograms of low molecular weight products extracted from PCL a) before aging and b) after 2 weeks in biotic mineral medium. The identity of the numbered peaks is Peak l=caprolactone peak 2=6-hydroxyhexanoic acid peak4=cyclic dimer peak 7=cyclic trimer peaks 3,5 and 6=phthalates...

L-6-Hydroxynorleucine is a key intermediate used for the synthesis of a vasopepti-dase inhibitor. It was synthesized from 2-keto-6-hydroxyhexanoic acid by reductive amination using beef liver GluDH and GDH from Bacillus sp. for regeneration of NADH (Fig. 36) [155]. The educt of the reaction, 2-keto-6-hydroxyhexanoic acid is in equilibrium with 2-hydroxytetrahydropyran-2-carboxylic acid. 

Fig. 36 Conversion of 2-keto-6-hydroxyhexanoic acid to L-6-hydroxynorleucine. Reductive ami-nation is carried out by glutamate dehydrogenase (GluDH), coenzyme regeneration by glucose dehydrogenase (GDH)...

The other components in the pyrolysate include fragments resulting from two units of 6-hydroxyhexanoic acid. One such component responsible for about 17% of the analyzed portion of the pyrolysate with the mass spectrum shown in Figure 10.1.3 was tentatively assigned as 6-hex-5-enoyloxyhexanoic acid. 

PPL catalyzed the polymerization of methyl esters of 5-hydroxypentanoic and 6-hydroxyhexanoic acids.149 In the polymerization of the latter in hexane at 69 °C for more than 50 days, the polymer with DP up to 100 was formed. Relationships between solvent type and polymerization behaviors were systematically investigated hydrophobic solvents such as hydrocarbons and diisopropyl ether were suitable for the enzymatic production of high molecular weight polymer. Pseudomonas sp. lipase catalyzed the polymerization of ethyl esters of 3- and 4-hydroxybu-tyric acids, 5- and 6-hydroxyhexanoic acids, 5-hy-droxydodecanoic acid, and 15-hydroxypentadecanoic acid.157 Oxyacid vinyl esters were demonstrated as new monomers for polyester production under mild reaction conditions, yielding the corresponding polyesters with A/n of several thousands.276... 

Hakkarainen [19,36] Poly(vinyl chloride)/ polycaprolactone-carbonate blend Thermo-oxidation, hydrolysis 6-Hydroxyhexanoic acid, caprolactone PDMS-DVB... 

Abiotic hydrolysis of linear, crosslinked and porous PCL resulted in formation of 6-hydroxyhexanoic acid (HHA) and water-soluble oligomers [73]. As seen in Fig. 4 the introduction of crosslinks considerably increased the hydrolysis rate and formation of monomeric 6-hydroxyhexanoic acid. This was mainly explained by the lower degree of crystallinity for the crosslinked PCL homopolymer. 

PCL was also degraded to 6-hydroxyhexanoic acid during enzymatic hydrolysis by Lipase Asahi derived from Chromobacterium viscosum and Hp-ase F derived from Rhizopus niveus [74]. In another study formation of oligomers during biotic hydrolysis of PCL was shown by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) [50]. Enzymatic degradation of copolymers of 3-hydroxybutyric acid (3HB) and... 

Fig. 4 Migration of 6-hydroxyhexanoic acid from different polycaprolactone homopolymers during hydrolysis in phosphate buffer (A) porous structure, ( ) linear disc and (x) network. Reprinted from [73] with permission of Taylor Francis. Taylor Francis (2007)...

Fig. 5 GC-MS chromatograms of the low molecular weight products extracted from poly- caprolactone films (a) unaged film (b) after 2 weeks in abiotic medium and (c) after 2 weeks in biotic medium. The identity of numbered peaks is 1 = caprolactone 2 = 6-hydroxyhexanoic acid 4 = cyclic dimer 7 = cyclic trimer and 3,5,6 = phthalates. Reprinted from [60] with permission of Wiley-VCH Verlag GmbH Co. Wiley-VCH Verlag Gmbh 8c Co (2002)...

Figure 8 shows the amount of 3-(2-hydroxyethoxy)-propanoic acid (HPA) and 6-hydroxyhexanoic acid (HHA) migrating from the CL/DXO copolymers as a function of copolymer composition and hydrolysis time. Figure 8a shows that the amount of HPA released from the materials increased both as a function of hydrolysis time and as the DXO-content in the copolymer increased. In the case of HHA release the situation was more complicated and the largest amount of HHA was released from the copolymers with intermediate CL-contents (Fig. 8b). In relation to the CL- content, the largest amount of HHA was released from the DXO-rich copolymers (Fig. 8c). This was explained by the faster hydrolysis rate of DXO-units, which also enhances the release of HHA.

Fig. 9 The relative amount of 6-hydroxyhexanoic acid (HHA) and 3-(2-hydroxyethoxy)-propanoic acid (HPA) formed during hydrolysis of a DXO/CL/DXO triblock copolymer, b CL/DXO multiblock copolymer, c Random crosslinked CL/DXO copolymer and d PCL homopolymer. All of the copolymers had 60 mol % CL imits and 40 mol % DXO imits. The polymers were hydrolyzed for different times in phosphate buffer pH 7.4 and 37 °C. After the predetermined hydrolysis times the monomeric degradation products were extracted by solid-phase extraction and analyzed by GC-MS. Reprinted from [160] with permission of American Chemical Society. American Chemical Society (2007)...

Fig.1 The amount of 6-hydroxyhexanoic acid that migrated from PVC/PCL-PC to water and buffer solution after different aging times at 37 °C and 70 °C. The amount of 6-hydroxyhexanoic acid is given as mg/g of PVC/PCL-PC blend. Reprinted from [28] with permission of Elsevier. Elsevier (2003)...

Fig. 3 GC-MS chromatograms showing the low-molecular-weight compounds migrat- ing from PVC/PCL-PC diming steam sterilization. Some 6-hydroxyhexanoic acid (main product) and hexadecanoic acid migrated from all the PVC/PCL-PC samples. If diphenyl carbonate was used for the synthesis of PCL-PC phenol and acetophenone impurities were also present and released from the material (chromatogram above). When another synthetic route was developed, no phenol or acetophenone was detected (chromatogram below)...

---