An Antimalarial Alkaloid From Hydrangea. Xxi. Synthesis and Structure of Febrifugine and Isofebrifugine

Baker, B. R.; McEvoy, Francis J.; Schaub, Robert E.; Joseph, Joseph P.; Williams, James H.

doi:10.1021/jo01130a006

Cited by 31 publications

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“…Koepfli et al [19] were first to report structure elucidation studies on febrifugine and isofebrifugine using oxidative and degradative experiments. Based upon this work, they proposed the relative configuration 4 [21]. Production of a ring-opened aldehyde during oxidation made them to suggest the presence of a piperidine ring.…”

Section: Structure Elucidationmentioning

confidence: 97%

“…Based upon this work, they proposed the relative configuration 4 [21]. [19], (4) Baker et al [21], (5) Hill and Edwards [22], (6) Barringer et al [23], and (7) Kobayashi et al [24]. However, structural elucidation of these compounds remained a puzzling task because of the ready interconversion of 1 and 2 by a reversible Michael reaction.…”

Section: Structure Elucidationmentioning

confidence: 99%

“…In addition to their difference in stereochemistry, structural difference between these two alkaloids can be inferred from their infrared spectra [21]. Febrifugine and isofebrifugine are related to each other by their isomerization through a w-aminoenone.…”

Section: Chemical and Physical Properties Of Febrifuginementioning

confidence: 99%

See 2 more Smart Citations

Febrifugine and Its Analogs: Studies for Their Antimalarial and Other Therapeutic Properties

Ningthoujam¹,

Talukdar

Nath

et al. 2015

Studies in Natural Products Chemistry

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Section: Structure Elucidationmentioning

confidence: 97%

Section: Structure Elucidationmentioning

confidence: 99%

See 1 more Smart Citation

Febrifugine and Its Analogs: Studies for Their Antimalarial and Other Therapeutic Properties

Ningthoujam¹,

Talukdar

Nath

et al. 2015

Studies in Natural Products Chemistry

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“…[1][2][3][4] It is well known that d-1 and d-2 are related to each other's isomerization via waminoenone 5,6) (3) (Chart 1). Among reported methods [7][8][9][10][11][12][13][14][15][16][17][18][19][20] of d-1, we had believed that our method 10,13) was widely applicable to the synthesis of the derivatives needed to study the structure-activity relationship of d-1. However, we could not successfully prepare some derivatives because our method involved uncontrollable trans-cis isomerization in the final step.…”

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confidence: 99%

Concise Synthesis of dl-Febrifugine

Takeuchi

Oshige

Azuma

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Racemic compound (1) of the antimalarial agents febrifugine (d-1) was synthesized using an stereoselective Michael reaction of an w w-amidoenone (5) which was prepared by the Wittig reaction of piperidinediol (7).Key words total synthesis; stereoselective Michael reaction; Wittig reaction; febrifugine; antimalarial activity Febrifugine (d-1) is an antimalarial agent that has been isolated from Dichroa febrifuga and Hydrangea umbellate along with isofebrifugine (d-2).1-4) It is well known that d-1 and d-2 are related to each other's isomerization via waminoenone 5,6) (3) (Chart 1). Among reported methods [7][8][9][10][11][12][13][14][15][16][17][18][19][20] of d-1, we had believed that our method 10,13) was widely applicable to the synthesis of the derivatives needed to study the structure-activity relationship of d-1. However, we could not successfully prepare some derivatives because our method involved uncontrollable trans-cis isomerization in the final step. In recent our study, we found that cis form of N-protected febrifugine derivatives (cis-4) also afforded a mixture of trans-4 and cis-4 form under the presence of acid by the isomerization (Chart 2). 21)From those findings, we planed a synthetic strategy via an w-amidoenone (5) as a key intermediate, which would afford trans piperidine derivative (trans-6) by the intramolecular Michael reaction with the stereoselectivity (Chart 3). In this paper, we describe a novel synthesis of dl-febrifugine (dl-1).The synthesis of the key intermediate, w-amidoenone (5), was achieved to utilize the Wittig reaction of 2-hydroxypiperidine derivative which we have developed in our synthetic study of deoxyfebrifugine.22) The Wittig reaction of 2,3-piperidinediol (7), which was easily prepared in 84% yield from tetrahydropyridine (8) by Oxone ® -acetone oxidation, 23) afforded (E)-w-amidoenone (E-5) in which the double bond had E configuration based on the coupling constant (Jϭ16 Hz) of olefinic protons in 1 H-NMR. The Michael reaction of trans-5 (E-5) with BF 3 · OEt 2 afforded the Michael adduct (trans-6). N-Cbz febrifugine (10) was afforded by successive reactions, silylation of the hydroxy and ketone group, bromination, and coupling with 4(3H)-quinazolinone. Hydrogenolysis of 10 gave dl-1 which was identical with the reported one by mp or 1 H-NMR data (Chart 4). In the Michael reaction of E-5 with BF 3 · OEt 2 , we could obtain the furan derivative (9) and 1,4-diketone derivative (11) along with trans-6. It is known that 9 and 11 can be transformed from cis-6 by acid.24) Decreasing yield of trans-6 with the prolongation of the reaction time or heat of reaction mixture suggests that there is an equilibrium relationship via E-5 between trans-6 and cis-6 in the presence of Lewis acid (Table 1).Herein, we could develop the the synthetic method for dlfebrifugine derivatives in high total yield and short steps without using the very expensive, toxic, or dangerous reagents used in other reports. [25][26][27][28][29][30] We are now progress the asymmetric synthesis using this me...

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“…[1][2][3][4] The plane structure 5) of (ϩ)-1 and (ϩ)-2 was first proposed in 1950. Subsequently, their relative 6) and absolute 7) structures were proposed, based on Baker's synthetic work. [8][9][10] The relative configuration 11) of (ϩ)-1 was corrected in 1973 and then the absolute structures 12,13) of (ϩ)-1 and (ϩ)-2 were corrected in 1999.…”

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confidence: 99%

Re-revision of the Stereo Structure of Piperidine Lactone, an Intermediate in the Synthesis of Febrifugine

Takeuchi

Azuma

Abe

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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An Antimalarial Alkaloid From Hydrangea. Xxi. Synthesis and Structure of Febrifugine and Isofebrifugine

Cited by 31 publications

References 0 publications

Febrifugine and Its Analogs: Studies for Their Antimalarial and Other Therapeutic Properties

Febrifugine and Its Analogs: Studies for Their Antimalarial and Other Therapeutic Properties

Concise Synthesis of dl-Febrifugine

Re-revision of the Stereo Structure of Piperidine Lactone, an Intermediate in the Synthesis of Febrifugine

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