Block enzymatic synthesis

Zhu, D., Mukherjee, C. and Hua, L. (2005) Green synthesis of important pharmaceutical building blocks enzymatic access to enantiomerically pure a-chloroalcohols. Tetrahedron Asymmetry, 16 (19), 3275—3278. 

Rare or unnatural monosaccharides have many useful applications as nonnutritive sweeteners, glycosidase inhibitors and so on. For example, L-glucose and L-fructose are known to be low-calorie sweeteners. In addition, rare or unnatural monosaccharides are potentially useful as chiral building blocks for the synthesis of biologically active compounds. Therefore, these compounds have been important targets for the development of enzymatic synthesis based in the use of DHAP-dependent aldolases alone or in combination with isomerases. Fessner et al. showed that rare ketose-1-phosphates could be reached not only by aldol addition catalyzed by DHAP-dependent aldolases, but by enzymatic isomerization/ phosphorylation of aldoses [35]. Thus, for example, L-fructose can be prepared... 

Enzymatic polymerization has been combined with various chemical polymerizations for the synthesis of block copolymers. The choice of chemical polymerization generally depends on the applied strategy for the block copolymer synthesis. These can be divided into three main approaches, as shown in Fig. 4 for the example of enzymatic ROP. It has to be noted that some of these strategies have also been applied for enzymatic polycondensations. 

Initial reports on chemoenzymatic block copolymer synthesis focus on the enzymatic macroinitiation from chemically obtained hydroxy-functional polymers (route A in Fig. 4). The first report on enzymatic macroinitiation was published by Kumar et ah, who used anionically synthesized hydroxy-functional polybutadiene of various molecular weights ranging from 2600 to 19,000Da (Fig. 5) [16]. In a systematic study, the authors investigated the efficiency of the macroinitiation of CL and PDF by Novozym 435 as a function of the polybutadiene macroinitiator. The reaction profile showed that polybutadiene consumption steadily increased with the reaction... 

While all previous examples employ enzymatic ROP, there are two reports on block copolymer synthesis employing enzymatic poly condensation. The first one was published by Sharma et al. and describes the synthesis and solid-state properties of polyesteramides with poly(dimethylsiloxane) (PDMS) blocks [21]. The polycondensation was carried out with various ratios of dimethyl adipate. 

Fig. 6 Left Strategy for consecutive chemoenzymatic and simultaneous one-pot block copolymer synthesis combining enzymatic ROP and ATRP. Right Influence of ATRP-catalyst system on the conversion of CL in the enzymatic ROP of MMA at 60 °C using ATRP-3 as initiator filled squares reaction in absence of ATRP-catalyst open circles CuBr/PMDETA (1 1 1 ratio with respect to initiator) jiWed triangles CuBr/dNbpy (1 2.1 1 ratio with respect to initiator) open inverted triangles CuBr (1 1 ratio with respect to initiator) yiHed diamonds CuBr2 (1 1 ratio to initiator). CL conversion was determined with H-NMR [26]...

S. Amann, G. Drager, C. Rupprath, A. Kirschning, and L. Elling, (Chemo)enzymatic synthesis of dTDP-activated 2,6-dideoxysugars as building blocks of polyketide antibiotics, Carbohydr. Res., 335 (2001) 23-32. 

Fig. 16 (a) Enzymatic synthesis of building blocks for arachidonic acid metabolites, (b) Che-moenzymatic synthesis of constanolactones C/D... 

Fig. 21 Enzymatic synthesis of unnatural amino acids as building blocks for omapatrilat. (a-c) Enzymatic approaches to 6-oxonorleucine analogs...

These additional metabolic processes may not significantly stabilize the 0-1 glucose ester bond from non-enzymatlc hydrolysis, but they may block enzymatic processes such as B-glucosldase hydrolysis or the reverse reaction in the synthesis of the 0-glucose ester. Thus, the formation of these more complex metabolites may result in detoxification of the xenobiotic. 

Several biosyntheses involve assembling building blocks such as amino acids and carboxylic acids. Parts of these assembly processes can show some substrate flexibility, allowing the enzymatic synthesis of un-natural analogues of normal fungal metabolites. One of the earliest examples was the variation of the penicillin side-chain brought about by replacing the phenylacetic acid of penicillin G with phenoxyacetic acid as in penicillin V. 

In the present chapter, the current status of enzymatic polyester synthesis is described. For information on the enzymatic synthesis of chiral polyesters and polyester block copolymers using enzymatic polymerizations please refer to Chapters 11 and 12 respectively. 

Villarroya, S., Thurecht, K.J., Heise, A., and Howdle, S.M. (2007) Supercritical C02 an effective medium for the chemo-enzymatic synthesis of block copolymers Chem. Commun. (Camb.j, 37, 3805-3813. 

Modification of Enzymatic Blocks to Form Macroinitiators 316 Enzymatic Synthesis of Graft Copolymers 319 Summary and Outlook 320 References 320... 

Fluorouracil (5-FU) requires enzymatic conversion to the nucleotide (ribosylation and phosphorylation) in order to exert its cytotoxic activity these reactions are illustrated in Figure 51-5. The interaction between FdUMP and TS blocks the synthesis of thymidine triphosphate (TTP), a necessary constituent of DNA. The folate cofactor, 5,10-methylenetetrahydrofolate, and FdUMP form a covalently bound ternary complex with TS. The transfer of the methylene group and two hydrogen atoms from folate to FdUMP is blocked in the inhibited complex of TS-FdUMP-folate by the stability of the fluorine carbon bond on FdUMP sustained inhibition of the enzyme results. In... 

It is generally accepted that the eROP of CL is initiated by a nucleophilic attack of a hydroxy compound on the enzyme activated monomer (8-10). Various hydroxy-fimctionalized (macro)initiators have been reported in the past for the enzymatic synthesis of functionalized polymers and block copolymers, respectively (8-11). As outlined above, only a high initiation efficiency of the dual initiator in the eROP leads to high block copolymer yield. This efficiency mainly depends on two factors side reactions caused by competitive water initiation and the initiator design. We achieved the reduction of the water initiation by developing a thorough drying protocol prior to the enzymatic reaction (12). In order to study the influence of the initiator structure, several dual... 

We investigated the chemoenzymatic synthesis of block copolymers combining eROP and ATRP using a bifunctional initiator. A detailed analysis of the reaction conditions revealed that a high block copolymer yield can be realized under optimized reaction conditions. Side reactions, such as the formation of PCL homopolymer, in the enzymatic polymerization of CL could be minimized to < 5 % by an optimized enzyme (hying procedure. Moreover, the structure of the bifunctional initiator was foimd to play a major role in the initiation behavior and hence, the yield of PCL macroinitiator. Block copolymers were obtained in a consecutive ATRP. Detailed analysis of the obtained polymer confirmed the presence of predominantly block copolymer structures. Optimization of the one-pot procedure proved more difficult. While the eROP was compatible with the ATRP catalyst, incompatibility with MMA as an ATRP monomer led to side-reactions. A successfiil one-pot synthesis could only be achieved by sequential addition of the ATRP components or partly with inert monomers such as /-butyl methacrylate. One-pot block copolymer synthesis was successful, however, in supercritical carbon dioxide. Side reactions such as those observed in organic solvents were not apparent. 

Enzymatic Synthesis of At lysine Ethylene Acetal. (S)-2-Amino-5-(l,3-dioxolan-2-yl)-pentanoic acid (5 )-allysine ethylene acetal (7) (Fig. 3A) is one of three building blocks used in an alternative synthesis of Omapatrilat (1). It previously had been prepared via an eight-step chemical synthesis from 3,4-dihydro [2H] pyran (16). An alternate synthesis of (7) was demonstrated by reductive amination of ketoacid acetal (8) using phenylalanine dehydrogenase (PDH) from Thermoactinomyces intermedins (17). The reaction required ammonia and NADH NAD produced during the reaction was recycled to NADH by the oxidation of formate to CO using formate dehydrogenase (FDH). 

Yamagishi T, Mori J-I, Haruki T, Yokomatsu T (2011) A chemo-enzymatic synthesis of optically active l,l-diethoxyethyl(aminomethyl)phosphinates useful chiral building blocks for phosphinyl dipeptide isosteres. Tetrahedron Asymmetry 22 1358-1363... 

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