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Abstract
Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and an-algesic effects. Here, we present a scalable asymmetric synthesis of TTX and 9-epiTTX from the abundant chemical feed-stock furfuryl alcohol. The optically pure cyclohexane skeleton was assembled via a stereoselective Diels-Alder reaction. The dense heteroatom substituents were established sequentially by a series of functional group interconversions on highly oxygenated cyclohexane frameworks, including a chemoselective cyclic anhydride opening, and a decarboxylative hydrox-ylation. An innovative SmI2-mediated concurrent fragmentation, an oxo-bridge ring opening and ester reduction followed by an Upjohn dihydroxylation delivered the highly oxidized skeleton. Ruthenium-catalyzed oxidative alkyne cleavage and formation of the hemiaminal and orthoester under acidic conditions enabled the rapid assembly of TTX, anhydro-TTX, 9-epiTTX, and 9-epi lactone-TTX.
Supplementary materials
Title
Total Synthesis of Tetrodotoxin and 9-epiTetrodotoxin
Description
Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and an-algesic effects. Here, we present a scalable asymmetric synthesis of TTX and 9-epiTTX from the abundant chemical feed-stock furfuryl alcohol. The optically pure cyclohexane skeleton was assembled via a stereoselective Diels-Alder reaction. The dense heteroatom substituents were established sequentially by a series of functional group interconversions on highly oxygenated cyclohexane frameworks, including a chemoselective cyclic anhydride opening, and a decarboxylative hydrox-ylation. An innovative SmI2-mediated concurrent fragmentation, an oxo-bridge ring opening and ester reduction followed by an Upjohn dihydroxylation delivered the highly oxidized skeleton. Ruthenium-catalyzed oxidative alkyne cleavage and formation of the hemiaminal and orthoester under acidic conditions enabled the rapid assembly of TTX, anhydro-TTX, 9-epiTTX, and 9-epi lactone-TTX. The Supplementary material provided here contained all the relevant information about the paper.
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Supplementary weblinks
Title
Total Synthesis of Tetrodotoxin and 9-epiTetrodotoxin
Description
Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and an-algesic effects. Here, we present a scalable asymmetric synthesis of TTX and 9-epiTTX from the abundant chemical feed-stock furfuryl alcohol. The optically pure cyclohexane skeleton was assembled via a stereoselective Diels-Alder reaction. The dense heteroatom substituents were established sequentially by a series of functional group interconversions on highly oxygenated cyclohexane frameworks, including a chemoselective cyclic anhydride opening, and a decarboxylative hydrox-ylation. An innovative SmI2-mediated concurrent fragmentation, an oxo-bridge ring opening and ester reduction followed by an Upjohn dihydroxylation delivered the highly oxidized skeleton. Ruthenium-catalyzed oxidative alkyne cleavage and formation of the hemiaminal and orthoester under acidic conditions enabled the rapid assembly of TTX, anhydro-TTX, 9-epiTTX, and 9-epi lactone-TTX. The URL provided here contained all the relevant information about the paper on line.
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