Organocatalytic Synthesis of Highly Substituted Furfuryl Alcohols and Amines

Clark, J. Stephen; Boyer, Alistair; Aimon, A.; Garcia, Paloma E.; Lindsay, David M.; Symington, Andrew D. F.; Danoy, Yves

doi:10.1002/anie.201207300

Cited by 56 publications

(31 citation statements)

References 52 publications

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“…In our original publication concerning the THT-catalysed reaction of ynenones to produce trisubstituted furfuryl alcohol derivatives, 10 we had shown that the propargylic alcohol 10 undergoes cyclisation to give the furanyl-substituted epoxide 11 in good yield (Scheme 2). This result served as the precedent for exploration of a general reaction in which a tetrahydrofuran or tetrahydropyran would be formed in tandem with a furan.…”

Section: Figure 1 Examples Of Natural Products and Bioactive Compoundmentioning

confidence: 99%

“…10 The reaction is proposed to occur by nucleophilic attack of the thioether catalyst on the alkyne to produce the zwitterionic allene 2 (Scheme 1). Cyclisation by intramolecular attack of the nucleophilic oxygen to give the furan then affords ylide 3 and subsequent proton transfer from the external acid (YH) provides the sulfonium salt 4.…”

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“…10 In contrast to conventional metal-mediated or condensation-based methods, organocatalytic methods for construction of furans are rare and have been relatively unexplored.…”

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Thioether-Catalysed Tandem Synthesis of Furans and Cyclic Ethers or Lactones

Klaus

Clark

2017

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Acyclic conjugated ynenediones tethered to an alcohol or carboxylic acid, are converted into furanylsubstituted cyclic ethers or lactones in a single step by treatment with the tetrahydrothiophene. Modest levels of diastereocontrol can be achieved in some cases where the presence of a substituent on the tether results in the creation of a second stereogenic centre upon formation of the cyclic ether or lactone.Key words Organocatalysis, thioether, furans, lactones, cyclic ethers, tandem cyclisation Substituted furans are important heteroaromatic systems that occur frequently as subunits in a wide range of complex natural products, 1 biologically active compounds and pharmaceutical products. 2 As a consequence of their chemical, physical and biological properties, furans have found widespread use as pharmacophores in the drug discovery process. The ubiquity of furans in both natural and non-natural bioactive compounds has served as a driver for development of new synthetic methods for the rapid and efficient construction of highly functionalised furans, and considerable time has been devoted to these endeavours.3 In addition to the various classical condensation-based methods, 4 a host of metal-mediated reactions using zinc, 5 copper, 6 palladium, 7 silver 8 and gold 9 complexes have been developed for the synthesis of furans.We have recently discovered a novel organocatalytic reaction for the synthesis of di-or trisubstituted furfuryl alcohol or amine derivatives by the treatment of fully conjugated ynenones or ynenediones with tetrahydrothiophene (THT) in the presence of an external oxygen or nitrogen nucleophile (Scheme 1). 10 In contrast to conventional metal-mediated or condensation-based methods, organocatalytic methods for construction of furans are rare and have been relatively unexplored. 11In our earlier work, we demonstrated that exposure of a range ynenones or ynenediones 1 to a substoichiometric amount of THT in the presence of an alcohol, carboxylic acid or sulfonamine produced the furfuryl alcohol/amine derivative 4 (Scheme 1). 10 The reaction is proposed to occur by nucleophilic attack of the thioether catalyst on the alkyne to produce the zwitterionic allene 2 (Scheme 1). Cyclisation by intramolecular attack of the nucleophilic oxygen to give the furan then affords ylide 3 and subsequent proton transfer from the external acid (YH) provides the sulfonium salt 4. The reaction probably then proceeds through an SN1 pathway rather than a concerted SN2 process, releasing THT back into the catalytic cycle and generating an oxocarbenium ion that is trapped by the external nucleophile (Y -) to deliver the final furan product 4. Scheme 1 Tetrahydrothiophene-catalysed synthesis of furfuryl alcohol and amine derivatives from ynenones bearing an electron-withdrawing substituentThe success of our original work prompted us to explore the application of the reaction to the synthesis of bicyclic or polycyclic natural products or synthetic bioactive compounds of the type shown in Figure 1, in which a furan ...

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Section: Figure 1 Examples Of Natural Products and Bioactive Compoundmentioning

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Thioether-Catalysed Tandem Synthesis of Furans and Cyclic Ethers or Lactones

Klaus

Clark

2017

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“…A few organocatalytic processes for the synthesis of furans have also been described, [11] including the tetrahydrothiophene-catalysed synthesis of highly substituted furfuryl alcohols and amines developed by our group recently. [12] Cyclopropanes, despite their ring strain, are found in many natural products including terpenes, pheromones, pyrethroid insecticides, fatty acid metabolites and unusual amino acids. [13] The cyclopropane group is also prevalent in pharmaceuticals and features in members of fluoroquinolone family of antibiotics, the antidepressant tranylcypromine, [14] antipsychotic substances [15] and anti-HIV agents.…”

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Synthesis of Cyclopropyl‐Substituted Furans by Brønsted Acid Promoted Cascade Reactions

et al. 2015

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“…28 The novel features of the procedure include the use of a simple thioether as the organocatalyst 13, the formation of a furan under neutral conditions rather than the anionic or acidic conditions employed in conventional syntheses, and the intermediacy of a versatile sulfonium ylide that has the potential to be intercepted directly by a variety of electrophiles instead of being protonated to give a sulfonium ion. The reaction proceeds with a wide range of substrates and nucleophiles to give highly decorated furans in good yield.…”

Section: Scheme 22mentioning

confidence: 99%