- Imidazotetrazines as Weighable Diazomethane Surrogates for Esterifications and Cyclopropanations
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Diazomethane is one of the most versatile reagents in organic synthesis, but its utility is limited by its hazardous nature. Although alternative methods exist to perform the unique chemistry of diazomethane, these suffer from diminished reactivity and/or correspondingly harsher conditions. Herein, we describe the repurposing of imidazotetrazines (such as temozolomide, TMZ, the standard of care for glioblastoma) for use as synthetic precursors of alkyl diazonium reagents. TMZ was employed to conduct esterifications and metal-catalyzed cyclopropanations, and results show that methyl ester formation from a wide variety of substrates is especially efficient and operationally simple. TMZ is a commercially available solid that is non-explosive and non-toxic, and should find broad utility as a replacement for diazomethane.
- Svec, Riley L.,Hergenrother, Paul J.
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supporting information
p. 1857 - 1862
(2019/12/27)
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- Syntheses of Gibberellins A15 and A24, the Key Metabolites in Gibberellin Biosynthesis
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Gibberellins (GAs) are essential phytohormones involved in numerous aspects of plant growth and development. Notably, the biochemistry and genetics of GA biosynthesis, which is associated with their endogenous regulation, have been largely resolved; however, a crucial unsolved question remains: the precise mechanism of the stepwise oxidation and subsequent removal of C-20 from C20 precursors, leading to bioactive C19 gibberellins, is still unresolved. To satisfy numerous requests from biologists, practical preparations of certain GAs that were isolated in miniscule quantities are highly demanded. Herein, we report the first practical syntheses of GA15 and GA24, the key C20 metabolites in gibberellin biosynthesis, from commercially available GA3. The protocols are robust and offer the capacity to produce GA24 and GA15 under gram scales in high overall yields and thus aid in further biological and related studies.
- Bon, David J.-Y. D.,Mander, Lewis N.,Lan, Ping
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p. 6566 - 6572
(2018/05/30)
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- Synthesis and anti-proliferative activity of allogibberic acid derivatives containing 1,2,3-triazole pharmacophore
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Sixty novel allogibberic acid derivatives containing 1,2,3-triazole pharmacophore were designed and synthesized. The key chemical processes include aromatization of the A ring in gibberellins, formation of allogibberic azides and its copper mediated Huisgen 1,3-dipolar cycloaddition with alkynes. A number of hybrids containing α,β-unsaturated ketone moiety exhibited excellent in vitro cytotoxic activities. Some of the hybrids were more selective to MCF-7 and SW480 cell lines with IC50 values at least 8-fold more cytotoxic than cisplatin (DDP). The most potent compounds C43 and C45 are more cytotoxic than cisplatin (DDP) against all tested five tumor cell lines, with IC50 values of 0.25–1.72 μM. Mechanism of action studies indicated that allogibberic-triazole derivative C45 could induce the S phase cell cycle arrest and apoptosis in SMMC-7721 cell lines.
- Wu, Ming-Jiang,Wu, Dong-Mei,Chen, Jing-Bo,Zhao, Jing-Feng,Gong, Liang,Gong, Ya-Xiao,Li, Yan,Yang, Xiao-Dong,Zhang, Hongbin
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supporting information
p. 2543 - 2549
(2018/06/20)
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- Synthesis and biological evaluation of pharbinilic acid and derivatives as NF-κB pathway inhibitors
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A 7-step synthesis of pharbinilic acid, a member of the gibberellin family of natural products and the first naturally occurring allogibberic acid, is reported. An efficient decarboxylative aromatization reaction enables the synthesis of pharbinilic acid and related analogs for evaluation as modulators of NF-κB activity. Remarkably, one analog displays a 2 μM IC50 in an NF-κB activity assay and inhibits an endogenous NF-κB-regulated pathway.
- Annand,Bruno,Mapp,Schindler
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supporting information
p. 8990 - 8993
(2015/05/27)
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- Synthesis of sesquiterpene-inspired derivatives designed for covalent binding and their inhibition of the NF-κB pathway
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A significant portion of bioactive secondary metabolites are endowed with reactive functionalities that can engage in covalent interactions with their target. Sesquiterpene lactones in particular are rich in Michael acceptors that react with cysteines. Several polycyclic scaffolds derived from total synthesis or readily available polycyclic terpenes were used as the starting point in the synthesis of a library aiming to project mildly reactive functionalities (Michael acceptors or chloroacetates) with diverse geometries. Screening of the library for inhibition of the NF-κB pathway revealed several potent inhibitors that are chemically readily accessible.
- Duplan, Vincent,Serba, Christelle,Garcia, Jose,Valot, Gaelle,Barluenga, Sofia,Hoerle, Melanie,Cuendet, Muriel,Winssinger, Nicolas
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supporting information
p. 370 - 375
(2014/01/06)
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- EXPEDITIOUS SYNTHESIS OF GIBBERLLIN A5 AND ESTERS THEREOF
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An expeditious synthesis of gibberellin A5 (GA5) esters is presented, from which GA5 may be prepared. The synthesis offers an inexpensive route of few steps to these compounds, starting from gibberellin A3 (GA3) esters in the presence of a metal hydride.
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Page/Page column 16-17; 20
(2010/04/25)
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- Synthesis of gibberellin derivatives with anti-tumor bioactivities
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A series of gibberellin based molecules were designed and synthesized. Gibberellin derivatives bearing two α,β-unsaturated ketone units showed strong anticancer activities in MTT assay towards a number of human cancer cell lines including HT29, A549, HepG
- Chen, Jingbo,Sun, Zhuxian,Zhang, Yanli,Zeng, Xianghui,Qing, Chen,Liu, Jianping,Li, Liang,Zhang, Hongbin
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scheme or table
p. 5496 - 5499
(2010/05/02)
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- Confirmation of structure and synthesis of three new 11β-OH C20 gibberellins from loquat fruit
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Three new 11β-hydroxy C20 gibberellins have been isolated from immature loquat fruit and their structures were established as 11β-hydroxy-GA12, 11β-hydroxy-GA15 and 11β-hydroxy-GA53, respectively, by direct GC-M
- Phuoc, Le Than,Mander, Lewis N.,Koshioka, Masaji,Oyama-Okubo, Naomi,Nakayama, Masayoshi,Ito, Akiko
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p. 4835 - 4851
(2008/12/20)
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- Some Rearrangements of Gibberellins Catalysed by Tetracyanoethylene
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Tetracyanoethylene in methanol has been shown to catalyse the rearrangement of ring A of gibberellic acid to give the 3β-methyl ether of gibberellenic acid and 19-2α-isolactone whilst 13-hydroxygibberellin 16,17-epoxides are converted to 8:13-isogibberellins.
- Hanson, James R.,Uyanik, Cavit
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p. 2850 - 2861
(2007/10/03)
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- Unexpected C-arylation of a gibberellin: A cautionary note on the radical deoxygenation of homoallylic secondary alcohols
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Aryl 3-O-thionocarbonates (7a-c), upon treatment with tributyltin hydride and a catalytic amount of AIBN in benzene at reflux, do not undergo deoxygenation as expected, but instead afford the 10-arylated bis-γ-lactones (8a-c) in high yields.
- Mander, Lewis N.,Sherburn, Michael S.
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p. 4255 - 4258
(2007/10/03)
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- Concise synthesis of 3-hydroxy-Δ1.10-12,16-cyclogibberellin 12 dimethyl ester - A trachylobagibberellin analogue
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Chemical synthesis of a trachylobagibberellin analogue - 3-hydroxy-Δ1.10-12,16-cyclogibberellin dimethyl ester 4 from gibberellin acid GA3 3 was described herein. The key step is the decomposition of the tosylhydrazone 11 to construct the novel [3.2.1.02.7]octane system.
- Nie,Xie,Lin,Song,Pan
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p. 4053 - 4062
(2007/10/03)
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- Highly Selective Epimerization of the 3β-Hydroxyl Function of Gibberellin Derivatives with a Base in an Aprotic Medium: Efficient Preparation of Methyl Esters of 3-epi-GA3 and 3-epi-GA1
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Methyl esters of 3-epi-GA3 and 3-epi-GA1 were efficiently prepared from methyl esters of GA3 and GA1, respectively, by highly selective epimerization of the 3-hydroxyl function with a base in a low-polar aprotic medium.
- Seto, Hideharu,Akamatsu, Mitsuhiro,Yoshida, Shigeo
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p. 2342 - 2343
(2007/10/03)
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- Regio- und stereospezifische Addition von Diazomethan an Gibberellinsaeure: Ein neuer effektiver Weg zu 1,2-Methylengibberellinen
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A new pathway to 1α,2α-methylenegibberellines via pyrazoline intermediates is reported.In contrast to the addition of diazomethane to the Δ1-double bond of corresponding enones in the case of 1 "Umpolung" of the regioselectivity with cis-addition from the α-side to give pyrazoline ester 4 is observed.Subsequent photolysis of 4 leads to the 1,2-cyclopropyl derivative 6.THe structure of the key compounds 4 and 6 are confirmed especially by n.m.r. and X-Ray analysis.
- Voigt, B.,Porxel, A.,Voigt, D.,Adam, G.,Kutschabsky, L.
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p. 227 - 230
(2007/10/02)
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- Substitution Reactions of the 3-Epimeric Methanesulphonates of Methyl Gibberellate
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Whereas displacement of the 3β-(axial)-methylsulphonyloxy group from methyl gibberellate with lithium chloride or buffered aqueous acetone proceeds predominantly with syn rearrangement to afford the 1β-chloro- or 1β-hydroxy-gibberellin, the corresponding 3α-(equatorial) epimer reacts with simple inversion of configuration.This affords on the one hand a facile route to the 1-hydroxygibberellins and, on the other, a means of labelling gibberellins at C-3.
- Duri, Zvitendo J.,Hanson, James R.
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p. 603 - 607
(2007/10/02)
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- Allylic Chlorination of Gibberellins A3 and A7 Methyl Esters and of Gibberellin A3: Preparation of Gibberellin A5
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A high-yield conversion of gibberellin A3 to gibberellin A5 is described.With thionyl chloride, gibberellin A3 methyl ester gives mainly 1β-chlorogibberellin A5 methyl ester; the isomeric 3α-chloro-1-ene was the main product from the reaction with toluene-p-sulphonyl chloride and lithium chloride.Each product is reduced by tri-n-butylstannane and acetylated to give the same mixture of the 13-acetates of gibberellin A5 methyl ester and of the isomeric 1(10)-ene-19,2-lactone.Hydrolysis of gibberellin A5 methyl ester 13-acetate gives gibberellin A5 in 20percent overall yield from gibberellin A3. 2H1>Gibberellin A5 is obtained in the same way by using tri-n-butyl2H1>stannane in the reduction step.Analogous chlorination products of gibberellin A7 methyl ester and of gibberellin A3 are described.
- Bearder, John R.,Kirkwood, Paul S.,MacMillan, Jake
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p. 672 - 678
(2007/10/02)
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- CHLOROETHOXY(TRIMETHYL)SILANE : A HARD-BASE TRAP WHICH PRESERVES TMS ETHER GROUPS AND IMPROVES THE WITTIG METHYLENATION OF GIBBERELLINS
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A reagent, 2-chloroethoxy(trimethyl)silane (CETS), has been devised which ensures the preservation of TMS ether groups during Wittig methylenation in protic media and which makes this formerly capricious reaction with 16-keto gibberellins a reliable and straightforward procedure.
- Mander, Lewis N.,Turner, John V.
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p. 4149 - 4152
(2007/10/02)
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- Reaction of Methyl Gibberellate with Triphenylphosphine and Carbon Tetrachloride
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Treatment of methyl gibberellate and its 3-epimer with triphenylphosphine and carbon tetrachloride containing acetone or pyridine, gave the 1β-chloro- and 1β,13-dichloro-Δ2-derivatives respectively as the major products.The 3-chloro-compounds were obtained as minor products.The 1-bromo-compounds were obtained with carbon tetrabromide.The structures of these compounds were established by location of the label in the products from methyl 3-epi-gibberellate.
- Duri, James Z.,Fraga, Braulio M.,Hanson, James R.
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p. 3016 - 3019
(2007/10/02)
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- Mechanism and Stereochemistry of Conjugate Reduction of Enones from Gibberellins A3 and A7
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Conjugate reduction of the methyl esters of 3-didehydrogibberellin A3 13-acetate and of 3-didehydrogibberellin A7, in aprotic solvents by borohydride (or borodeuteride), is shown to introduce hydrogen (or deuterium) at the 1β- and 3β-positions in the products, 3-epi-gibberellin A1 13-acetate and 3-epi-gibberellin A4 methyl esters.The third hydrogen (or deuterium) comes from the proton (or deuteron) source used in the work-up.A mechanism for conjugate reduction of enones is proposed.The products from the borodeuteride reduction of 3-didehydrogibberellin A7 methyl ester with proton and deuteron work-up were chemically converted into -, -, and -gibberellin A4 and the stereochemistries of the deuterium atoms were determined from the deuterium content of the metabolites, formed from these labelled gibberellins in cultures of Gibberella fujikuroi, mutant B1-41a.
- Beale, Michael H.,MacMillan, Jake
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p. 877 - 884
(2007/10/02)
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