Synthetic Studies on Cephalotaxus Alkaloids. A synthesis of (.+-.)-Cephalotaxine.

Ikeda, Masazumi; Okano, M.; Kosaka, Keigo; Kido, Masaru; Ishibashi, Hiroyuki

doi:10.1248/cpb.41.276

Cited by 43 publications

(15 citation statements)

References 2 publications

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“…The racemic approaches have embodied several key transformations, including Nazarov cyclization, [19] photo-stimulated S RN 1 cyclization, [20] Claisen rearrangement, [21,22] oxidative ring contraction, [23] acylnitroso Diels-Alder cycloaddition, [24,25] transannular N-conjugate addition, [26,27] intramolecular alkyne hydroamination, [28] and reductive ring expansion of tetrahydrosioquinoline intermediates. [29,30] Non-racemic routes have featured electrophilic aromatic substitution, [31] Heck arylation, [32,33] Pummerer-electrophilic aromatic substitution cascade, [34][35][36] and acid catalyzed ring expansion of cyclobutanol derivatives. [37] On the other hand, the significance of the complex Cephalotaxus esters (e.g., 2-5) extends beyond that of 1 on several levels, the most prominent being their exceedingly potent antiproliferative properties.…”

mentioning

confidence: 99%

Synthesis of Antiproliferative Cephalotaxus Esters and Their Evaluation against Several Human Hematopoietic and Solid Tumor Cell Lines: Uncovering Differential Susceptibilities to Multidrug Resistance

Eckelbarger

Wilmot

Epperson

et al. 2008

Chemistry A European J

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Deoxyharringtonine (2), homoharringtonine (3), homodeoxyharringtonine (4), and anhydroharringtonine (5) are reported to be among the most potent members of the antileukemia alkaloids isolated from the Cephalotaxus genus. Convergent syntheses of these four natural products are described, each involving novel synthetic methods and strategies. These syntheses enabled evaluation of several advanced natural and non-natural compounds against an array of human hematopoietic and solid tumor cells. Potent cytotoxicity was observed in several cell lines previously not challenged with these alkaloids. Variations in the structure of the ester chain within this family of alkaloids confer differing activity profiles against vincristine-resistant HL-60/RV+, signalling new avenues for molecular design of these natural products to combat multi-drug resistance.

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mentioning

confidence: 99%

Synthesis of Antiproliferative Cephalotaxus Esters and Their Evaluation against Several Human Hematopoietic and Solid Tumor Cell Lines: Uncovering Differential Susceptibilities to Multidrug Resistance

Eckelbarger

Wilmot

Epperson

et al. 2008

Chemistry A European J

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“…The second approach was more efficient and started with (S)-cyclopentenol (284) obtained in 96% ee set up via enantioselective Noyori's hydrogenation of propargylic ketone 280 using (S,S)-1,1 0 -bi-2-naphthol 281 to give 282. 126 130 The phosphoramidite ligand 296 provided the chirality during the [3 þ 2] cycloaddition, delivering compound (þ)-297 in 91% ee (chiral HPLC). 125 Dihydroxylation of silyl enolate (S)-285 afforded the diol 286 as a single diastereoisomer, which was protected as an acetonide.…”

Section: Asymmetric Catalysismentioning

confidence: 99%

“…130, 138 The intermediate ABCD ketone (þ)-149 was prepared from unnatural D-proline (R)-140 used to furnish the C ring with C4 atom and to control the C5 tetrasubstituted stereogenic center set in 319 (Scheme 31). 130, 138 The intermediate ABCD ketone (þ)-149 was prepared from unnatural D-proline (R)-140 used to furnish the C ring with C4 atom and to control the C5 tetrasubstituted stereogenic center set in 319 (Scheme 31).…”

Section: Ikeda's Formal Synthesis (1999)mentioning

confidence: 99%

Cephalotaxus Alkaloids

Pérard-Viret

Quteishat

Alsalim

et al. 2017

The Alkaloids: Chemistry and Biology

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Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. Significant activity against leukemia in mice was demonstrated for extracts of Cephalotaxus. Cephalotaxine (CET) (1), the major alkaloid of this series was isolated from Cephalotaxus drupacea species by Paudler in 1963. The subsequent discovery of promising antitumor activity among new Cephalotaxus derivatives reported by Chinese, Japanese, and American teams triggered extensive structure elucidation and biological studies in this family. The structural feature of this cephalotaxane family relies mainly on its tetracyclic alkaloid backbone, which comprises an azaspiranic 1-azaspiro[4.4]nonane unit (rings C and D) and a benzazepine ring system (rings A and B), which is linked by its C3 alcohol function to a chiral oxygenated side chain by a carboxylic function alpha to a tetrasubstituted carbon center. The botanical distribution of these alkaloids is limited to the Cephalotaxus genus (Cephalotaxaceae). The scope of biological activities of the Cephalotaxus alkaloids is mainly centered on the antileukemic activity of homoharringtonine (HHT) (2), which in particular demonstrated marked benefits in the treatment of orphan myeloid leukemia and was approved as soon as 2009 by European Medicine Agency and by US Food and Drug Administration in 2012. Its exact mechanism of action was partly elucidated and it was early recognized that HHT (2) inhibited protein synthesis at the level of the ribosome machinery. Interestingly, after a latency period of two decades, the topic of Cephalotaxus alkaloids reemerged as a prolific source of new natural structures. To date, more than 70 compounds have been identified and characterized. Synthetic studies also regained attention during the past two decades, and numerous methodologies were developed to access the first semisynthetic HHT (2) of high purity suitable for clinical studies, and then high grade enantiomerically pure CET (1), HHT (2), and analogs.

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“…A Pd(II) -promoted [3+2] methylenecyclopentane anellation of nitrostyrene 125 with acetate 126 allows the fi rst carbacyclic unit to be built up (Scheme 3.71 ) [144] .…”

Section: Arene -Fused Piperidine Compoundsmentioning

confidence: 99%