A Biomimetic Chromanol Cyclization Leading to α‐Tocopherol

Abstract

The diastereoselective formation of the chromanol ring is one of the most challenging reactions during the biosynthesis of tocopherols in photosynthetic organisms. We discovered the enzyme that catalyzes this transformation in the cyanobacteria Anabaena variabilis [1] and subsequently determined its substrate specificity [2] and recently cloned the tocopherol cyclase from the related Anabaena sp. into E. coli.[3] The enzymatic reaction mechanism was determined by isotopic labeling experiments, [4] which revealed that the reaction proceeds by si protonation of the double bond of 1 followed by re attack of the phenolic oxygen to yield g-tocopherol (2; Scheme 1).Two further observations suggest a concerted nonsynchronous cyclization, during which positive charge develops at the carbon atom that is trapped by the phenol (see 3, Scheme 2): 1) the tetrahydroisoquinolinium terpenoid 4 as a transition-state analogue is an excellent inhibitor (IC 50 = 1.4 nm) of tocopherol cyclase, [5] and 2) the epoxide of 1 cyclizes under acidic conditions yielding two compounds, the five-membered-ring "Baldwin" product and the six-membered ring analogue of the enzymatic product (4:6 ratio). [3,4]

Einhundert Jahre Vitamine – eine naturwissenschaftliche Erfolgsgeschichte

“…[222,223] Zudem wurden in den letzten Jahren organokatalytische [224] und andere Zugänge [225][226][227][228] unter Verwendung neuer Synthesemethoden verçffentlicht. [222,223] Zudem wurden in den letzten Jahren organokatalytische [224] und andere Zugänge [225][226][227][228] unter Verwendung neuer Synthesemethoden verçffentlicht.…”

“…Auf Grundlage dieser Erkenntnisse wurden biomimetische Routen für den Chromanolringschluss entwickelt. [222,223] Zudem wurden in den letzten Jahren organokatalytische [224] und andere Zugänge [225][226][227][228] unter Verwendung neuer Synthesemethoden verçffentlicht. Dies zeigt, dass die Synthese von RRR-92 noch immer ein aktuelles Forschungsthema ist.…”

Synthesis of Chiral 1,4‐Benzodioxanes and Chromans by Enantioselective Palladium‐Catalyzed Alkene Aryloxyarylation Reactions

“…To demonstrate the synthetic utility of this transformation, we investigated the synthesis of the a-tocopherol core structure [7] (Scheme 4). Formation of the main side products SP1 and SP2 in the synthesis of chroman 3fa.…”

“…[1] Fore xample,1 ,4-benzodioxane lignans represented by silybin A [2] are ag roup of natural products that exhibit aw ide range of interesting biological activities,s uch as hepatoprotective, anticancer,and antioxidant activity.Doxazosin [3] is aselective a1-adrenoceptor antagonist with a1 ,4-benzodioxane moiety that is used to treat high blood pressure and urinary retention associated with benign prostatic hyperplasia. a-Tocopherol [5] is the most significant member of the vitamin E family,w hich features ak ey chroman ring containing aq uaternary stereocenter.T he asymmetric synthesis of chiral 1,4-benzodioxanes [6] and chromans [7] has thus gained significant attention over the years.I np articular, several excellent metal-catalyzed asymmetric transformations have been developed, including an intramolecular Wacker-type cyclization, [8] allylic substitution, [9] aryl CÀOc oupling, [10] and allylic CÀHo xidation. a-Tocopherol [5] is the most significant member of the vitamin E family,w hich features ak ey chroman ring containing aq uaternary stereocenter.T he asymmetric synthesis of chiral 1,4-benzodioxanes [6] and chromans [7] has thus gained significant attention over the years.I np articular, several excellent metal-catalyzed asymmetric transformations have been developed, including an intramolecular Wacker-type cyclization, [8] allylic substitution, [9] aryl CÀOc oupling, [10] and allylic CÀHo xidation.…”

Gold‐Catalyzed Asymmetric Allylic Substitution of Free Alcohols: An Enantioselective Approach to Chiral Chromans with Quaternary Stereocenters for the Synthesis of Vitamin E and Analogues

“…However, while a variety of enantioselective approaches for the synthesis of the chiral chroman framework of a-tocopherol have been described (enzymatic methods, [11] Sharpless dihydroxylation, [12] palladium catalysis, [13] ruthenium catalysis, [14] organocatalysis, [15] or biomimetic cyclisation [16] ), novel, easy, and efficient methods are still indispensable. In retrosynthetic analysis (Scheme 1), (R)-vinylchroman 2 might be formed by an intramolecular enantioselective allylic alkylation of allylic alcohol 1.…”