Chemoenzymatic oxidation

Linear unsaturated and epoxidized polyesters via enzymatic polymerization were reported as well [58]. For this long-chain symmetrically unsaturated a,co-dicarboxylic acid dimethyl esters (C18, C20, C26) were synthesized using metathesis techniques from 9-decanoic, 10-undecanoic, and 13-tetradecanoic acid methyl esters, respectively. The dicarboxylic acid dimethyl esters were epoxidized via chemoenzymatic oxidation with hydrogen peroxide/methyl acetate and Novozym... 

More interestingly, the chemoenzymatic oxidation can be efficiently applied to complex molecules such as water-soluble cellulose, thus justifying further scientific interest and developments. 

Dioxygenases that are exploited at present do not provide general access to antipodal cis-diols and a combined chemoenzymatic strategy is required. While oxidation of bromobenzene (and other mono- and dihalogenated precursors) with TDO expressing cells gives the corresponding (—)-dihydrodiol in excellent... 

Chemoenzymatic processes involving oxidizing enzymes have been reported particularly for specific chemical syntheses. For example, industrially important amino acids can be deracemized by exploiting the enantioselectivity of amino acid oxidases a commercial process has recently been developed in which efficient... 

Very recently, the chemoenzymatic preparation of nootkatone from valencene was described [150]. Nootkatone was prepared from valencene by copper(I) iodide catalysed oxidation with tert-butyl hydroperoxide and hydroxylated at C-9 by Mucor plumbeus and Cephalosporium aphidicola. 

Combining whole-cell biocatalysis and radical polymerization, researchers at Imperial Chemical Industries (ICI) published a chemoenzymatic route to high-molecular-weight poly(phenylene) [86], This polymer is used in the fibers and coatings industry. However, since it is practically insoluble, the challenge was to make a soluble polymer precursor that could first be coated or spun, and only then converted to poly(phenylene). The ICI process starts from benzene, which is oxidized by Pseudomonas putida cells to cyclohexa-3,5-diene-l,2-diol (see Figure 5.17). The... 

The asymmetric hydrolysis of (exo,exo)-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol, diacetate ester (37) to the corresponding chiral monoacetate ester (38) (Fig. 12B) has been demonstrated with lipases [61]. Lipase PS-30 from P. cepacia was most effective in asymmetric hydrolysis to obtain the desired enantiomer of monoacetate ester. The reaction yield of 75 M% and e.e. of >99% were obtained when the reaction was conducted in a biphasic system with 10% toluene at 5 g/liter of the substrate. Lipase PS-30 was immobilized on Accurel PP and the immobilized enzyme was reused (5 cycles) without loss of enzyme activity, productivity, or e.e. of product (38). The reaction process was scaled up to 80 liters (400 g of substrate) and monoacetate ester (38) was isolated in 80 M% yield with 99.3% e.e. The product was isolated in 99.5% chemical purity. The chiral monoacetate ester (38) was oxidized to its corresponding aldehyde and subsequently hydrolyzed to give chiral lactol (33) (Fig. 12B). The chiral lactol (33) obtained by this enzymatic process was used in chemoenzymatic synthesis of thromboxane A2 antagonist (35). 

Fig. 21. Deracemization of p-nitrostyrene oxide by a chemoenzymatic process. Application to the synthesis of (R)-Nifenalol [211]...

Fig. 22. Fungal epoxide hydrolysis. Chemoenzymatic synthesis of (S)-2-methyl-heptene oxide [149]...

As a part of ongoing efforts to synthesize a potent, orally active anti-platelet agent, xemilofiban 1 [1], development of an efficient chemoenzymatic process for 2, the chiral yS-amino acid ester synthon (Fig. 1) was proposed. The scheme emphasized the creation of the stereogenic center as the key step. In parallel with the enzymatic approach, chemical synthesis of the / -amino acid ester synthon emphasized formation of a chiral imine, nucleophilic addition of the Reformatsky reagent, and oxidative removal of the chiral auxiliary. This chapter describes a selective amida-tion/amide hydrolysis using the enzyme Penicillin G amidohydrolase from E. coli to synthesize (R)- and (S)-enantiomers of ethyl 3-amino-5-(trimethylsilyl)-4-pen-tynoate in an optically pure form. The design of the experimental approach was applied in order to optimize the critical reaction parameters to control the stereoselectivity of the enzyme Penicillin G amidohydrolase. 

A polynucleoside with an unnatural polymeric backbone was synthesized by SBP-catalyzed oxidative polymerization of thymidine 5 -p-hydroxyphenylacetate [59]. Chemoenzymatic synthesis of a new class of poly(amino acid), poly(tyrosine) containing no peptide bonds, was achieved by the peroxidase-catalyzed oxidative polymerization of tyrosine ethyl esters, followed by alkaline hydrolysis [60]. 

Finally, a chemoenzymatic enantioconvergent procedure led to (S)-ibuprofen in four steps and 47% overall yield (Fig. 11.2-20). The latter compound is a widely used antiinflammatory drug and pain remedy and is one of the top ten drugs sold worldwide l,HH. In the key step, the conditions for the enantioconvergent hydrolysis of para-iso-butyl-a-methylstyrene oxide was optimized (elevated substrate concentration at +4 °C) to afford the non-reacted epoxide in >95 % ee[136l After separation from the epoxide, the formed diol (70% ee) was recycled via a two-step sequence via the corresponding bromohydrin, which was cyclized back to give ( )-epoxide. The latter material was subjected to repeated biocatalytic resolution in order to improve the economy of the process. 

Figure 16.2-53. Chemoenzymatic synthesis of 2-hydroxy-l-indanone. The racemic syn and anti diols were prepared by chemical dihydroxylation of indane. Asymmetric induction was achieved by microbial oxidation (MO) of these diols.

Figure 16.3-7. Chemoenzymatic Diels-Alder reactions. Ortho-quinones (dienes), derived from phenols by oxidation with tyrosinase, spontaneously react with dienophils.

Various pyrrolidines were prepared by using the chemoenzymatic approach. Thus, 2R,5S-dihydroxymethyl-3R,4A -dihydroxypyrrolidine (3) was prepared from the L-sorbose derivative 36 (Scheme 6). Thus, periodate oxidation of 2-azido-2-deoxythreitol (34) led to 2-azido-3-hydroxypropanal (35), which was treated with DHAP and FDP aldolase to... 

Theil et al. developed a method for chemoenzymatic synthesis of both enantiomers of cispentacin [89]. frans-2-Hydroxymethylcyclopentanol, obtained by the sodium borohydride reduction of ethyl 2-oxocyclopentanecarboxylate, was monosilylated with tert-butyldimethylsilyl (TBDMS) chloride to afford 55. Lipase PS-catalysed transesterification with vinyl acetate in /erf-butyl methyl ether furnished the ester 56 and the alcohol 57. The deacetylated 58 was obtained by the Mitsunobu reaction with phthalimide, triphenylphosphine and diethyl azodicarboxylate (DEAD) to furnish the cis oriented 59 with inversion of configuration (not retention as mentioned in the original article) (Scheme 9). Desilylation, Jones oxidation and subsequent deprotection with aqueous methylamine gave the ( R,2S) enantiomer 5 [89]. The (15, 2/f) enantiomer was prepared by the same route from the silyl alcohol 57. 

Still, there remain many open problems. It would be efficient to be able to prenylate or ferf-prenylate indole regioselectively at the benzene positions 4, 5 and 6 without having to rely on pre-functionalisation such as halogenation or hydroxylation. Here, deeper investigation of prenyl shifts and of CH functionalisation on indole is required. Enantioselective catalysis has to be explored further towards the synthesis of optically pure 3-prenylated or -tert-prenylated alkaloids. A chiral version of NBS would be helpful. In the case of conformationally flexible starting materials, the diastereoselectivity of oxidative cyclisations of tryptophan-derived diketopiperazines is still not convincing. In the area of chemoenzymatic synthesis, the number and availability of enzymes has to be enhanced and their substrate tolerance has to be elucidated in more detail. 

The chemoenzymatic synthesis of (13S)-hydroxy-18 2(9Z,ll ) was achieved in nine steps starting from (2 )-octenal. Of importance was the enzymatic conversion of (2 )-octenal to the (5)-cyanohydrin [5] with (S)-hydroxynitrile lyase cloned from Hevea brasiliensis (41). 13- Hydroxy-lO-oxo-18 1(11 ) was synthesized via a Kno-evenagel-type reaction of Isopropyl 11 - phenylsulfinyl-10-oxoundecanoate with hep-tanal to form y-hydroxyenone functionality together with carbon chain elongation (42). The regiospecific oxidation of a number of substituted unsaturated fatty esters with /7-benzoquinone in the presence of palladium(II) chloride under concomitant ultrasonic irradiation was reported. For example, methyl 9-hydroxy-18 1 (12Z) furnished methyl 9-hydroxy-12-keto-18 0 exclusively (43). 

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