One-Pot Sequential Two-Step Photo-Biocatalytic Deracemization of sec-Alcohols Combining Photocatalytic Oxidation and Bioreduction
Rudzka, Aleksandra
;
Antos, Natalia
;
Reiter, Tamara
, et al.
ACS Catal.,2024,14(3):1808-1823.
DOI:
10.1021/acscatal.3c05100
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Abstract: Chiral alcohols are versatile building blocks and are of particular interest in the asym. synthesis of nonracemic active pharmaceutical ingredients, agrochems., fragrances, flavors, natural products, etc. Herein, we report on a "one-pot sequential two-step" concurrent oxidation-reduction photobiocatalytic process to synthesize enantiomerically enriched alcs. In this regard, an efficient photocatalytic system based on irradiation with 440 nm blue LEDs in the presence of 9-fluorenone as a metal-free photocatalyst and mol. oxygen as the terminal oxidant in dry DMSO as the hydrogen peroxide-neutralizing agent was used to oxidize a broad range of racemic (hetero)benzylic alcs. into prochiral ketones quantitively (>99% conv.). The in situ formed carbonyl compounds were subsequently converted into the corresponding chiral alcs. via a sequential biocatalytic transhydrogenation catalyzed by lyophilized E. coli cells overexpressing highly stereoselective and stereocomplementary recombinant alc. dehydrogenases (ADHs) originated from Rhodococcus ruber (E. coli/ADH-A) or Rhodococcus erythropolis (E. coli/ReADH) to obtain (S)-alcs. and Lactobacillus kefir (E. coli/Lk-ADH) or KRED-110 to obtain (R)-alcs., resp. Overall, the elaborated photobiocatalytic deracemization of racemic alcs. using a 9-fluorenone-O2-blue LED-DMSO-E. coli/ADH system carried out on a semipreparative scale (0.25 mmol; 63 mM final concentrate in 4 mL) at room temperature yielded nonracemic aryl alcs. with 82-99.9% conv., in up to 92% isolated yield, with 97-99.9% ee and complementary chirality.
Keywords:
photoredox catalysis ;
biocatalysis ;
alcoholdehydrogenases ;
nonstereoselective oxidation ;
asymmetricbioreduction ;
one-pot sequential cascades ;
chiralalcohols
Purchased from AmBeed:
2646-71-1
Physicochemical properties and cytochromes P-450 kinetics of the trifluoroacetamido derivative of phenacetin
Cure, Hannah L
;
Shell, Thomas A
;
Results Chem.,2024,13,101918.
DOI:
10.1016/j.rechem.2024.101918
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Abstract: Substituting hydrogen atoms with fluorine alters physicochemical properties often resulting in improved drug action relative to the parent molecule. The high electronegativity of fluorine changes the electron density distribution of the molecule; however, the substitution does not significantly change the size of the molecule because hydrogen and fluorine have similar atomic radii. A trifluoroacetamido derivative (TFA-phenacetin) of phenacetin, an analgesic antipyretic drug, was synthesized to compare its lipophilicity to the parent molecule by determining octanol–water partition coefficients. TFA-phenacetin is over seven times more lipophilic than phenacetin, which suggests that TFA-phenacetin would have better bioavailability relative to phenacetin. The kinetics of cytochromes P-450 (CYP) catalyzed oxidation of phenacetin and TFA-phenacetin were compared using Sprague Dawley (SD) rat liver microsomes. Phenacetin and TFA-phenacetin have the same apparent binding affinity for the SD rat liver microsome CYP proteome and undergo CYP catalyzed oxidation at the same rate in the presence of SD rat liver microsomes.
Keywords:
Phenacetin ;
Fluorine derivative ;
Lipophilicity
Purchased from AmBeed:
2646-71-1 ;
111-87-5
Biocatalytic hydrogen-transfer to access enantiomerically pure proxyphylline, xanthinol, and diprophylline
Pawe? Borowiecki
;
Aleksandra Rudzka
;
Tamara Reiter
, et al.
Bioorg. Chem.,2022,127,105967.
DOI:
10.1016/j.bioorg.2022.105967
PubMed ID:
35777234
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Abstract: Alcohol dehydrogenases (ADHs; EC 1.1.1.1) have been widely used for the reversible redox reactions of carbonyl compounds (i.e., aldehydes and ketones) and primary or secondary alcohols, often resulting in optically pure hydroxyl products with high added value. In this work, we report a concise chemoenzymatic route toward xanthine-based enantiomerically pure active pharmaceutical ingredients (API) – proxyphylline, xanthinol, and diprophylline employing various recombinant short-chain ADHs with (R)- or (S)-selectivity as key biocatalysts. By choosing the appropriate ADH, the (R)- as well as the (S)-enantiomer of proxyphylline was prepared in excellent enantiomeric excess (99–99.9% ee), >99% conversion, and the isolated yield ranging from 65% to 74%, depending on the used biocatalyst (ADH-A from Rhodococcus ruber or a variant derived from Lactobacillus kefir, Lk-ADH-Lica). In turn, E. coli/ADH-catalyzed bioreduction of the carbonylic precursor of xanthinol and diprophylline furnished the corresponding (S)-chlorohydrin in >99% ee, >99% conversion, and 80% yield (in the case of Lk-ADH-Lica); while the (R)-counterpart was afforded in 94% ee, 64% conversion, and 41% yield (in the case of SyADH from Sphingobium yanoikuyae). After further chemical functionalization of the key (S)-chlorohydrin intermediate, the desired homochiral (R)-xanthinol (>99% ee) was obtained in 97% yield and (S)-diprophylline (>99% ee) in 90% yield. The devised biocatalytic method is straightforward and thus might be considered practical in the manufacturing of title pharmaceuticals.
Keywords:
Biocatalysis ;
Alcohol dehydrogenases ;
Asymmetric bioreduction ;
Chiral alcohols ;
Xanthines ;
Enantiomeric APIs
Purchased from AmBeed:
2646-71-1
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