Enzyme-Based Organic Synthesis. Cheanyeh Cheng
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Название: Enzyme-Based Organic Synthesis
Автор: Cheanyeh Cheng
Издательство: John Wiley & Sons Limited
Жанр: Химия
isbn: 9781118995150
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Scheme 2.30 Peroxidation of linoleic acid with soybean lipoxygenase and subsequent production of its methyl ester.
Scheme 2.31 Mn‐LO mediated peroxidation of linoleic acid.
Manganese lipoxygenase (Mn‐LO) from the fungus Gäumannomyces graminis has been reported for the peroxidation of linoleic acid to give a major product (13R)‐hydro‐peroxy‐(9Z,11E)‐octadecadienoic acid (13R‐HPOD) and a new minor product (11S)‐hydroperoxy‐(9Z,12Z)‐octadecadienoic acid(11S‐HPOD) in a ratio of 1:5 (Scheme 2.31) [134]. An initial abstraction of the pro‐S hydrogen from C‐11 of linoleic acid is proceeded by Mn‐LO to produce a linoleoyl radical. This radical is reversibly oxygenated at C‐11 and further converted into (11S)‐HPOD. Alternatively, this radical is irreversibly oxygenated at C‐13 position to form (13R)‐HPOD. Similar transformations with lipoxygenase enzymes have been described by other research groups [129, 130]. An iron mini‐lipoxygenase from Cyanobacterium Cyanthece sp. (CspLOX2) was also reported by Feussner et al. to catalyze similar reactions [135].
Instead of the direct synthesis of enantiomerically pure hydroperoxides, enantioselective kinetic resolution using enzymes for racemic hydroperoxides is another effective method to reach the goal. The kinetic resolution of racemic hydroperoxides by horseradish peroxidase (HRP)‐catalyzed reduction for aryl hydroperoxides shows that both the catalytic efficiency and the stereoselectivity of HRP are highly dependent on the structure of the hydroperoxides (Scheme 2.32) [124, 136]. Other enzymes such as selenosubtilisin was also used for catalyzing the reduction of aryl hydroperoxides with thios via the catalytic cycle of glutathione peroxidase [137]. This reaction has also been applied for the kinetic resolution of racemic aryl hydroperoxides to form enantiopure hydroperoxides and alcohols [138, 139], and their corresponding enantioselectivity of enantiopure hydroperoxides and alcohols are shown in Scheme 2.33 [137].
Scheme 2.32 Kinetic resolution of aryl hydroperoxides by HRP.
Scheme 2.33 Enantioselectivities of the selenosubtilisin‐catalyzed kinetic resolution of hydroperoxides [137].
2.2 Reduction Reactions
2.2.1 Reduction of Aldehydes and Ketones
Chiral alcohols are important building blocks and among the most valuable key intermediates for the production of pharmaceuticals and fine chemicals [140–143]. As an alternative to chemical processes, an efficient and powerful method to prepare enantiopure alcohols is the use of NAD(P)H‐dependent ADHs to perform the asymmetric hydrogenation of prochiral ketones without protective groups that are common in traditional organic synthesis [144, 145]. Although asymmetric reduction of ketones to optically pure alcohols has become quite mature in asymmetric synthesis during the last decade, it is still the most interesting strategy in preparing single enantiomers of alcohols by recent advancement in genetic engineering, coupled enzyme reaction, reaction design, and the availability of a variety of ADH. At least 150 different ADHs are available from various commercial sources, which allow the most suitable ADH to be selected for a specific substrate to access the desired (S)‐ or (R)‐enantiomer. The following are a concise introduction of the synthetic strategies used for the preparation of optically pure alcohol recently.
Since serine‐threonine kinase, a polo‐like kinase 1 (PLK1), is a key regulator of mitotic progression and cell division in eukaryotes and is highly expressed in tumor cells, it is considered a potential target for cancer therapy. To synthesize the most promising PLK1 inhibitor candidates, thiophene‐benzimidazole and imidazopyridine, for chemotherapy, enantioselective reduction of o‐chloroacetophenone is preferred to produce the chiral key intermediate, (S)‐1‐(o‐chlorophenyl)‐ethanol, for their synthesis (Scheme 2.34) by whole‐cell catalyst of recombining E. coli and recombining S. cerevisiae [146]. The recombinant xylose reductase was from Candida tenuis.
Scheme 2.34 Asymmetric reduction of ketone precursor o‐chloroacetophenone with recombining microorganism toward chiral alcohol product.
Aprepitant (Emend®), a trichiral compound, is a neurokinin‐1 (NK‐1) receptor antagonist that has been approved by the United States and Europe to treat moderately and highly emetogenic chemotherapy for the prevention of acute and delayed chemotherapy‐induced nausea and vomiting. According to its structure (Figure 2.2), 3,5‐bis(trifluoromethyl) acetophenone was used as the starting material to synthesize asymmetrically the key intermediate, chiral (1R)‐[3,5‐bis(trifluoromethyl)phenyl] ethanol, of aprepitant (Scheme 2.35) [147–149]. In the synthesis, a novel bacterial strain Leifsonia xyli HS0904 was isolated from soil that exhibits R‐stereospecific СКАЧАТЬ