Nucleophilic substitution of protected β-bromoethyl cyclohexadiene-cis-diol as an alternative to direct microbial oxidation of β-functionalized phenethyl substrates

Hudlický, Tomáš; Endoma, Mary Ann A.; Butora, Gabor

doi:10.1039/p19960002187

Cited by 18 publications

(15 citation statements)

References 17 publications

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“…As previously described in our earlier publications on the preparation of ent -oxycodone [30,31], the synthesis began with the microbial dihydroxylation of phenethyl acetate 8 (Scheme 2) via a whole cell fermentation with E. coli JM109 (pDTG601A) to afford the known intermediate cyclohexadiene diol 7 (obtained in 5gL −1 yield) [52,53], which was subjected to a selective reduction of the more accessible alkene to afford the known diol 9 (85% yield) [54,55]. The distal, less hindered, hydroxyl in diol 9 was protected with tert -butyl dimethylsilyl chloride and the free allylic alcohol was then subjected to a Mitsunobu reaction with iodo phenol 10 [56], derived from isovanillin, to furnish the coupled product ether 6 (45% yield over two steps).…”

Section: Resultsmentioning

confidence: 99%

Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate

2019

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The total synthesis of (+)-10-keto-oxycodone was attained from phenethyl acetate in a stereoselective manner. Absolute stereochemistry was established via enzymatic dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) that furnished the corresponding cis-cyclohexadienediol whose configuration corresponds to the absolute stereochemistry of the ring C of (+)-10-keto-oxycodone. Intramolecular Heck reaction was utilized to establish the quaternary carbon at C-13, along with the dibenzodihydrofuran functionality. The C-14 hydroxyl and C-10 ketone were installed via SmI2-mediated radical cyclization, and oxidation of a benzylic alcohol (obtained from an intermediate nitrate azide), respectively. The synthesis of (+)-10-keto-oxycodone was completed in a total of 14 operations (21 steps) and an overall yield of ~2%. Experimental and spectral data are provided for key intermediates and new compounds.

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Section: Resultsmentioning

confidence: 99%

Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate

2019

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“…The synthesis began with the microbial dihydroxylation of phenethyl acetate 3 to afford an intermediate cyclohexadiene diol, which was subjected to a selective reduction of the less hindered alkene to afford the known diol 4 (Scheme ). The coupling of diol 4 with bromoisovanillin was accomplished by a Mitsunobu reaction at the more reactive allylic alcohol functionality to afford ether 5 .…”

Section: Figurementioning

confidence: 99%

“…The synthesis began with the microbial dihydroxylation of phenethyla cetate 3 to afford an intermediate cyclohexadiene diol, [8] which was subjected to as elective reduction of the less hindered alkene to afford the known diol 4 (Scheme 1). The couplingo fd iol 4 with bromoisovanillin was accomplished by aM itsunobu reaction at the more reactive allylic alcohol functionality to afford ether 5.Asubsequent intramolecular Heck reaction of 5 allowed the assembly of the ABC rings of galanthamine present in the intermediate aldehyde 6.T he aldehyde functionality was convertedt oc arbamate 7 by reductive amination with methylaminef ollowed by protection of the resulting amine with Boc group.…”

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confidence: 99%

Chemoenzymatic Total Synthesis of (+)‐Galanthamine and (+)‐Narwedine from Phenethyl Acetate

Endoma‐Arias

Hudlický

2016

Chemistry A European J

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The stereoselective total synthesis of unnatural (+)-galanthamine starting from phenethyl acetate is described. Chirality was introduced via microbial dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) to the corresponding cis-cyclohexadi-enediol, configuration of which provided the absolute stereochemistry of the ring C of (+)-galanthamine. Intramolecular Heck cyclization was used to form the quaternary carbon and dibenzofuran functionality. The synthesis of (+)-galanthamine was completed in a total of ten steps and an overall yield of 5.5 %. Experimental and spectral data are provided for all new compounds.

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“…Toluene dioxygenase (TDO) catalyzes the biotransformation of benzonitrile to cis-(1S,2R)-1,2-dihydroxy-3-cyanocyclohexane-3,5-diene, [53] (2-cyanoethyl)benzene to (5S,6R)-1-(2-cyanoethyl)-5,6-dihydroxycyclohexa-1,3-diene [54] and trans-cinnamonitrile to (trans-cinnamonitrile)-cis-2,3-dihydrodiol. [55] CDO catalyzes the transformation of benzonitrile to cis-dihydroxy-cyclohexadienecarbonitrile and benzyl cyanide to 1-(cis-1,2-dihydroxy-3,5-cyclohexadienyl)-acetonitrile (main product 98%), 2-(cis-2,3-dihydroxy-4,6-cyclohexadienyl)-acetonitrile, and 1-(cis-3,4-dihydroxy-1,5-cyclohexadienyl)-acetonitrile.…”

Section: Substrate Rangementioning

confidence: 99%

“…Differently, the toluene dioxygenase-catalyzed dihydroxylation of benzonitrile and (2-cyanoethyl)benzene results in cis-diols with very high enantiomeric excess. [53,54] It was also shown before that the enantiomeric excess of the products from CDO-catalyzed reactions can be significantly different from those of TDO-catalyzed reactions. [18] Our results can be a basis for future work to learn about the differences in enantiomeric excess.…”

Section: Substrate Rangementioning

confidence: 99%

Recombinant Chlorobenzene Dioxygenase from Pseudomonas sp. P51: A Biocatalyst for Regioselective Oxidation of Aromatic Nitriles

Yildirim

Franko

Wohlgemuth³

et al. 2005

Adv Synth Catal

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An efficient biocatalyst was developed for the cis-dihydroxylation of aromatic nitriles. The chlorobenzene dioxygenase (CDO) genes of Pseudomonas sp. strain P51 were cloned under the strict control of the Palk promoter of Pseudomonas putida GPo1. Escherichia coli JM101 cells carrying the resulting plasmid pTEZ30 were used for the biotransformation of benzonitrile in a 2-L stirred tank bioreactor. Use of a stable expression system resulted in an average specific activity and an average volumetric productivity of 1.47 U/g cdw and 120 mg of product/h/L, respectively. The values represent a three-fold increase compared to the results of the similar biotransformations with E. coli JM101 (pTCB144) where the genes of CDO were expressed under the control of lac promoter. The productivity of the cis-dihydroxylation process was limited by product toxicity. Removal of the products at toxic concentrations by means of an external charcoal column resulted in an additional increase in product concentration by 43%. E. coli JM101 (pTEZ30) was further used for the regio-and stereospecific dihydroxylations of various monosubstituted benzonitriles, benzyl cyanide, and cinnamonitrile. Biotransformations resulted in products with 42.9 -97.1% enantiomeric excess. Initial enzymatic activities and isolated yields were obtained in the range of 1.7 -4.7 U/g cdw and of 3 -62%, respectively.

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Nucleophilic substitution of protected β-bromoethyl cyclohexadiene-cis-diol as an alternative to direct microbial oxidation of β-functionalized phenethyl substrates

Cited by 18 publications

References 17 publications

Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate

Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate

Chemoenzymatic Total Synthesis of (+)‐Galanthamine and (+)‐Narwedine from Phenethyl Acetate

Recombinant Chlorobenzene Dioxygenase from Pseudomonas sp. P51: A Biocatalyst for Regioselective Oxidation of Aromatic Nitriles

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