Redox Deracemization Of 1,3,4,9-tetrahydropyrano[3,4-b]Indoles

Enantiopure a-substituted cyclic ethers are ubiquitous structural motifs in natural products and biologically active molecules.The most frequently adopted synthetic strategy is enantioselective inter-or intramolecular C-C bond formation involving oxocarbenium ion intermediates.In such reaction patterns,the enantioselectivity as well as reaction efficiency are typically susceptible to the electronic and substituent effects of either nucleophile or electrophile partners.Therefore,current methods in many cases suffer from relatively obvious restriction of substrate applicability.Therefore,developments of simple and efficient way to synthesize such compounds are required.In recent years,Redox Deracemization has achieved rapid developments.Accordingly,we envisioned that the direct and complete transformation of racemic ethers into a single enantiomer of exactly the same species in theoretically 100%yield,known as the deracemization of ethers,would be an ideal technology to access chiral ethers with diverse skeletons and substituents.However,redox-driven deracemization techniques to date rely heavily on enzyme catalysis in highly specific reaction profiles to avoid the incompatibility of oxidant with reductant.Nonenzymatic chemically catalytic deracemization studies remain elusive,and overwhelmingly focus on alcohol or amine substrates,whose oxidized intermediates are stable and isolable ketones and imines,respectively.Therefore,this article mainly discusses how to use redox deracemization to obtain optically active a-substituted cyclic ethers.The direct redox deracemization of racemic a-substituted ethers involving an initial oxidation followed by an enantioselective reduction represents an ideal supplement because the enantiocontrol should be less susceptible to the regional variation of the electronic or substituent effect of oxidized 1,1-disubstituted cyclic oxocarbenium ion.Very recently,we have reported the first redox deracemization of ethers enabled by an "acetal pool" strategy,allowing for a-substituted 6H-benzo[c]chromenes,1H-isochromenes,and isochromans being effectively deracemized.This paper mainly studies the application of redox deracemization in a-substituted cyclic ethers of other structural motifs.First,we choes racemic a-substituted 1,3,4,9-tetrahydropyran[3,4-b]Anthraquinone(THPIs)derivatives as our substrate because Chiral a-substituted THPIs are common structural motifs in many synthetic pharmaceuticals.However,to our knowledge,the catalytic enantioselective synthesis is scarely reported.Seidel disclosed the exclusive approach through catalytic enantioselective oxa-Pictet-Spengler reaction of tryptophol with aryl-aldehydes,and the stereoselectivity was controlled via an elegant anion binding/ion pair formation process.We envisioned that direct redox deracemization of ?-substituted THPIs would be a good solution to obtain Chiral a-substituted THPIs.Initially,the redox deracemization of a-phenyl substituted THPI was selected as the model reaction,in which DDQ was used for the oxidation process,and chiral phosphoric acid-catalyzed asymmetric transfer hydrogenation for enantioselective reduction process.A series of reaction conditions investigated,including additive,catalyst,Solvent,reducing Agent,temperature,addition Sequence,oxidant.Further an ideal conditions was obtained.Next,we extended the scope of the substrate and found that different a-substituents,including phenyl,thiophene,furan,naphthol,all can be efficiently converted.The method exhibits good compatibility with the regional variation of electronic or substituent effect of substrates in high yields and excellent ee.Finally,we further validated the reaction mechanism by separating intermediates and further testing.In summary,a highly enantioselective one-pot redox deracemization of a-substituted THPIs enabled by the "acetal pool" strategy has been established.In such process,DDQ was used as the oxidant to destroy the stereocenter,and chiral phosphoric acidcatalyzed asymmetric transfer hydrogenation of a 1,1-disubstituted cyclic oxocarbenium ion was in charge of regenerating the stereocenter.The protic EtOH additive proved to be crucial to harmonizing the complete ether oxidation with the enantioselective reduction.The method exhibits good compatibility with the regional variation of electronic or substituent effect of substrates in high yields and excellent ee,thus providing a practical and efficient supplement to tradition strategy through enantioselective C-C bond construction of oxocarbenium ions.And it also provides a new idea for the synthesis of optically pure a-substituted cyclic ethers.