Double Hetero-Michael Addition of <i>N</i>-Substituted Hydroxylamines to Quinone Monoketals: Synthesis of Bridged Isoxazolidines

Baek

Biotech & Bioengineering

et al. 2015

Tyrosinase is a binuclear copper-containing metalloprotein that leads the fast and regio-selective o-hydroxylation of monophenols to o-diphenols. However, the subsequent second oxidation to produce o-quinones, i.e., melanin precursors, from the o-diphenols has restricted its use to the production of functional o-diphenol derivatives. Herein, we present a combined strategy for the effective inhibition of melanin formation in tyrosinase reaction, which allows the use of tyrosinase as a monophenol monooxygenase. The o-diphenolic products were protected from being oxidized in the tyrosinase reaction by borate ions and L-ascorbic acid (LAA). Borate-o-diphenol complexes were favorable formed at high pH and consequentially protected the o-diphenolic products from the catecholase activity of tyrosinase. LAA not only directly reduced the byproduct, o-quinones, into o-diphenols but also assisted the completion of the tyrosinase reaction cycle by removing a hydroxyl group attached to the copper metal cluster at the active site of the met-form tyrosinase. The regio-selective o-hydroxylation of 7,4'-dihydroxyisoflavone (daidzein) to produce 7,3',4'-trihydroxyisoflavone (3'-ODI) was successfully carried out by whole E. coli cell biotransformation with heterologously expressed tyrosinase from Bacillus megaterium. The yield of this o-hydroxylation of 5 mM daidzein in one-pot 400 mL reaction was ca. 100% in 90 min and the productivity was 16.3 mg 3'-ODI · L(-1) · h(-1) · DCW mg(-1), which is considerably higher than that of other monooxygenases. The method effectively abolished melanin synthesis, so that the o-diphenolic product remained stable without enzyme inactivation. Other monophenolic phytochemicals such as resveratrol and genistein could be subjected to the same strategy. After 1 h, 1 mM of genistein and resveratrol were both converted to orobol and piceatannol, respectively, with ca. 95% conversion yield. These results support the strong potential of tyrosinase as a monooxygenase for regio-selective o-hydroxylation of various monophenolic compounds.

Section: Resultsmentioning

confidence: 99%

Using tyrosinase as a monophenol monooxygenase: A combined strategy for effective inhibition of melanin formation

Baek

Biotech & Bioengineering

et al. 2015

“…The usefulness of compound 196 was demonstrated by synthesis into aminocyclitol derivative 199 in few steps (Scheme 22). [71] It was observed by Zheng and co-workers that when quinone monoketal 200 was treated with N,N'-dimethylhydrazine dihydrochlorine then unexpected nucleophilic chlorination took place and there was the formation of chlorinated phenol 202. It was observed that the same kind of reaction in the presence of DBU generally give pyrazolidine.…”

Section: Reactions Of Para-quinols and 25-cyclo-hexa-dienone Monoketalmentioning

confidence: 99%

“…The usefulness of compound 196 was demonstrated by synthesis into aminocyclitol derivative 199 in few steps (Scheme 22). [71] …”

Section: Reactions Of Para‐quinols and 25‐cyclo‐hexa‐dienone Monoketalmentioning

confidence: 99%

Molecular Complexity from Aromatics: Recent Advances in the Chemistry of paraQuinol and Masked para‐Quinone Monoketal

Chandra

Patel

2020

ChemistrySelect

Synthesis of complex organic molecules from simple, cheap, and readily available starting materials is one of the most challenging and desirable factors in organic synthesis. In the last two decades, various methods have been developed for the de-aromatization reaction of planar aromatics compounds which lead to reactive intermediates like 2,5-cyclohexadienone ketal and para-quinol having a non-planar framework. Recently, there is an upsurge of interest in the development of the chemistry of these intermediates due to their inherent dual electrophilic and nucleophilic character. The presence of diverse functionality makes them important scaffolds and thus these are intensively utilized for the development of methodologies towards the synthesis of the highly functionalized and diverse chemical framework. These synthons have also been used in the total synthesis of many natural products. Interestingly, these are also adaptable for asymmetric synthesis. This review is a summary of the recent development of methods for 2,5-cyclohexadienone ketal and para-quinol synthesis and their application in natural product synthesis.

“…Prior work mainly focused on Lewis acid‐catalyzed annulation reactions of QMAs with alkenes to construct bridged rings [10] . A few examples of base‐promoted double nucleophilic additions involving β‐keto esters, [11a,b] nitropropionate ester, [11c] N‐substituted hydroxylamines, [11d] and enamino esters [11e,f] have been described, and deprotonation by a strong base to enhance the nucleophilicity is generally required for these transformations (Scheme 1B, path a). Recently, the Rh‐catalyzed C−H activation approach has enabled the annulation of QMAs with several aromatics or alkenes tethered with proper directing groups (e.g, N ‐methoxybenzamide) [12a] to give bridged azacyclic compounds [12] .…”

Section: Introductionmentioning

confidence: 99%

Pyrrolidine‐Catalyzed Annulations of Quinone Monoacetals with Naphthols: Synthesis of 2‐Oxabicyclo[3.3.1]nonane Skeletons, Transformations and Reaction Mechanism

Xiao

et al. 2021

Adv Synth Catal

Herein, we report the pyrrolidine‐catalyzed annulation reaction of p‐quinone monoacetals with naphthols at room temperature. The reaction is also extended to including 4‐hydroxycoumarin, 4‐hydroxy‐1‐methylcarbostyril, 4‐hydroxycarbostyril, and several β‐ketoesters as the nucleophiles, thereby providing a collection of bridged cyclic compounds bearing 2‐oxabicyclo[3.3.1]nonane skeletons in 41–96% yields. The reaction can be adapted to gram‐scale synthesis, and several transformations of the obtained bridged cyclic products are demonstrated for the preparation of polycyclic compounds that may find utility in related fields. Mechanism studies indicate the engagement of iminium intermediate in the reaction, and a bridged ring enamine intermediate can be observed by NMR.