Asymmetric total synthesis of naturally occurring (R)-(–)-enantiomer of tylophorine via intramolecular double Michael reaction

Ihara, Masataka; Takino, Yoshinobu; Tomotake, Mayumi; Fukumoto, Keiichiro

doi:10.1039/p19900002287

Cited by 33 publications

(12 citation statements)

References 19 publications

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“…No physical data were reported for this known compound. 26 However, the physical data were similar to those reported by Fukumoto 27 for the enantiomer ( 1 H NMR, CDCl 3 ).…”

Section: Experimental Sectionsupporting

confidence: 81%

Synthesis of Methylerythritol Phosphate Analogues and Their Evaluation as Alternate Substrates for IspDF and IspE from Agrobacterium tumefaciens

et al. 2014

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The methylerythritol phosphate biosynthetic pathway, found in most Bacteria, some parasitic protists, and plant chloroplasts, converts d-glyceraldehyde phosphate and pyruvate to isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), where it intersects with the mevalonate pathway found in some Bacteria, Archaea, and Eukarya, including the cytosol of plants. d-3-Methylerythritol-4-phosphate (MEP), the first pathway-specific intermediate in the pathway, is converted to IPP and DMAPP by the consecutive action of the IspD-H proteins. We synthesized five d-MEP analogues—d-erythritol-4-phosphate (EP), d-3-methylthrietol-4-phosphate (MTP), d-3-ethylerythritol-4-phosphate (EEP), d-1-amino-3-methylerythritol-4-phosphate (NMEP), and d-3-methylerythritol-4-thiolophosphate (MESP)—and studied their ability to function as alternative substrates for the reactions catalyzed by the IspDF fusion and IspE proteins from Agrobacterium tumefaciens, which covert MEP to the corresponding eight-membered cyclic diphosphate. All of the analogues, except MTP, and their products were substrates for the three consecutive enzymes.

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“…No physical data were reported for this known compound. 26 However, the physical data were similar to those reported by Fukumoto 27 for the enantiomer ( 1 H NMR, CDCl 3 ).…”

Section: Experimental Sectionsupporting

confidence: 81%

Synthesis of Methylerythritol Phosphate Analogues and Their Evaluation as Alternate Substrates for IspDF and IspE from Agrobacterium tumefaciens

et al. 2014

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“…Both the ( R )- and ( S )-tylophorine enantiomers have been synthesized selectively using the chiron approach, starting with either proline [41, 42], glutamic acid [6] or pyroglutamate [43] as well as the chiral auxiliary approach manifested in diastereoselective Grignard additions [44] and double Michael reactions [45], respectively. Recently, we reported the first catalytic asymmetric route to (S)-tylophorine [46].…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…The observed optical rotation of +15° for this compound is somewhat lower than that obtained by other research groups (vide infra). It has been noted that tylophorine decomposes at room temperature, with concomitant decrease in optical rotation, so this may be the source of the relatively lower optical rotation of Rapoport’s synthetic compound [45]. Interestingly, Rapoport and co-workers were unable to perform the de-oxygenation via chlorination/reduction on alcohol 8 .…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Phenanthroindolizidines and Phenanthroquinolizidines: Promising Alkaloids for Anti-Cancer Therapy

Chemler¹

2009

CBC

131

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The phenanthroindolizidine and phenanthroquinolizidine alkaloids, typified by tylophorine and cryptopleurine, are a family of plant-derived small molecules with significant therapeutic potential. The plant extracts have been used in herbal medicine and the isolated compounds have displayed a range of promising therapeutic activity such as anti-ameobicidal, anti-viral, anti-inflammatory and anti-cancer activity. Despite their therapeutic protential, no compounds in this class have fully passed clinical trials. Drawbacks include low in vivo anti-cancer activity, central nervous system toxicity and low natural availability. A number of biological effects of these compounds, such as protein and nucleic acid synthesis suppression, have been identified, but the specific biomolecular targets have not yet been identified. Significant effort has been expended in the synthesis and structure-activityrelationship (SAR) studies of these compounds with the hope that a new drug will emerge. This review will highlight important contributions to the isolation, synthesis, SAR and mechanism of action of the phenanthroindolizidine and pheanthroquinolizidine alkaloids.

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“…To extend our research on phenanthroindolizidine alkaloids as antiviral agents and further explore the effect of the α-C chirality upon antiviral activities, large amounts of (+)-tylophorine and (−)-tylophorine are needed. By far, both the (R)-and (S)-tylophorine enantiomers have been synthesized selectively using the chiral approach, starting with either proline, glutamic acid, or pyroglutamate, as well as the chiral auxiliary approach manifesting indiastereoselective Grignard additions and double Michael reactions [47,[52][53][54][55][56][57][58][59][60][61][62] . However, these reported approaches are not suitable for large-scale preparation due to low yields, harsh con ditions, or long steps.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of (S)-(+)-tylophorine and its seco analogues using free radical reaction

Wang

Cui

et al. 2009

Sci. China Ser. B-Chem.

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The synthesis of (S)-(+)-tylophorine and its seco analogues has been accomplished by using free radical reaction. (−)-N-(2,3,6,7-Tetramethoxyphenanthren-9-ylmethyl)-2-bromomethylpyrrolidine (7) and (−)-N-(2,3,6,7-tetramethoxyphenanthren-9-ylcarbonyl)-2-bromomethylpyrrolidine (9) have been obtained for the first time in three and two linear steps from 2,3,6,7-tetramethoxyphenanthrene-9-carboxylic acid (4), respectively. When bromide 7 was subjected to the action of tri-n-butyltin hydride and catalytic amount of azobisisobutyronitrile in acetonitrile at reflux, only a new structural N-((2,3,6,7-tetramethoxyphenanthren-9-yl)methyl)piperidine (2) was obtained in excellent yield, without expected (+)-tylophorine. As an alternative route, when bromide 9 was treated with azobisisobutyronitrile and tri-nbutyltin hydride in toluene at reflux, tylophorin-9-one (10) was provided in 33.6% yield. At the same time, a new structural (+)-N-((2,3,6,7-tetramethoxyphenanthren-9-yl)carbonyl)-2-methylpyrrolidine (11) was afforded as the main product in 65% yield. Notably, azobisisobutyronitrile plays dual roles in this reaction, and the possible mechanism has been described. Compounds 10 and 11 were reduced by lithium aluminum hydride to give (+)-tylophorine and (+)-N-((2,3,6,7-tetramethoxyphenanthren-9-yl) methyl)-2-methylpyrrolidine (3), respectively. free radical reaction, azobisisobutyronitrile, tri-n-butyltin hydride, (S)-(+)-tylophorine, seco analogues

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Asymmetric total synthesis of naturally occurring (R)-(–)-enantiomer of tylophorine via intramolecular double Michael reaction

Cited by 33 publications

References 19 publications

Synthesis of Methylerythritol Phosphate Analogues and Their Evaluation as Alternate Substrates for IspDF and IspE from Agrobacterium tumefaciens

Synthesis of Methylerythritol Phosphate Analogues and Their Evaluation as Alternate Substrates for IspDF and IspE from Agrobacterium tumefaciens

Phenanthroindolizidines and Phenanthroquinolizidines: Promising Alkaloids for Anti-Cancer Therapy

Synthesis of (S)-(+)-tylophorine and its seco analogues using free radical reaction

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