- Asymmetric total synthesis of (-)podophyllotoxin
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Asymmetric synthesis of podophyllotoxin is achieved through tandem conjugate addition of S (-) benzyl phenyl sulfoxide to but-2-en-4-olide.
- Hadimani, Shreeshailkumar B.,Tanpure, Rajendra P.,Bhat, Sujata V.
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- Chemoenzymatic Total Synthesis of Deoxy-, epi-, and Podophyllotoxin and a Biocatalytic Kinetic Resolution of Dibenzylbutyrolactones
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Podophyllotoxin is probably the most prominent representative of lignan natural products. Deoxy-, epi-, and podophyllotoxin, which are all precursors to frequently used chemotherapeutic agents, were prepared by a stereodivergent biotransformation and a biocatalytic kinetic resolution of the corresponding dibenzylbutyrolactones with the same 2-oxoglutarate-dependent dioxygenase. The reaction can be conducted on 2 g scale, and the enzyme allows tailoring of the initial, “natural” structure and thus transforms various non-natural derivatives. Depending on the substitution pattern, the enzyme performs an oxidative C?C bond formation by C?H activation or hydroxylation at the benzylic position prone to ring closure.
- Lazzarotto, Mattia,Hammerer, Lucas,Hetmann, Michael,Borg, Annika,Schmermund, Luca,Steiner, Lorenz,Hartmann, Peter,Belaj, Ferdinand,Kroutil, Wolfgang,Gruber, Karl,Fuchs, Michael
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p. 8226 - 8230
(2019/05/21)
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- Asymmetric Chemoenzymatic Synthesis of (?)-Podophyllotoxin and Related Aryltetralin Lignans
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(?)-Podophyllotoxin is one of the most potent microtubule depolymerizing agents and has served as an important lead compound in antineoplastic drug discovery. Reported here is a short chemoenzymatic total synthesis of (?)-podophyllotoxin and related aryltetralin lignans. Vital to this approach is the use of an enzymatic oxidative C?C coupling reaction to construct the tetracyclic core of the natural product in a diastereoselective fashion. This strategy allows gram-scale access to (?)-deoxypodophyllotoxin and is readily adaptable to the preparation of related aryltetralin lignans.
- Li, Jian,Zhang, Xiao,Renata, Hans
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supporting information
p. 11657 - 11660
(2019/08/02)
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- Total synthesis of podophyllotoxin and select analog designs via C–H activation
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An account of our previously disclosed total synthesis of the aryltetralin lignan natural product podophyllotoxin, a building block used in the synthesis of the FDA-approved anticancer drug etoposide, is disclosed. A C–H activation disconnection was viewed as being amenable to the preparation of E-ring modified analogs but proved challenging to execute. Various insights into palladium-catalyzed C–H arylation reactions on complex scaffolds are reported ultimately leading to the implementation of this strategy and the synthesis of compounds inaccessible by semisynthetic means.
- Ting, Chi P.,Tschanen, Esther,Jang, Esther,Maimone, Thomas J.
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p. 3299 - 3308
(2019/05/15)
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- Divergent Asymmetric Syntheses of Podophyllotoxin and Related Family Members via Stereoselective Reductive Ni-Catalysis
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A nickel-catalyzed reductive cascade approach to the efficient construction of diastereodivergent cores embedded in podophyllum lignans is developed for the first time. Their gram-scale access paved the way for unified syntheses of naturally occurring podophyllotoxin and other members.
- Xiao, Jian,Cong, Xiao-Wei,Yang, Gui-Zhen,Wang, Ya-Wen,Peng, Yu
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p. 1651 - 1654
(2018/03/23)
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- Catalytic Enantioselective Synthesis of (-)-Podophyllotoxin
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The first catalytic enantioselective total synthesis of (-)-podophyllotoxin is accomplished by a challenging organocatalytic cross-aldol Heck cyclization and distal stereocontrolled transfer hydrogenation in five steps from three aldehydes. Reversal of se
- Hajra, Saumen,Garai, Sujay,Hazra, Sunit
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supporting information
p. 6530 - 6533
(2017/12/26)
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- Ci-H bond arylation in the synthesis of aryltetralin lignans: A short total synthesis of podophyllotoxin
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A short total synthesis of podophyllotoxin, the prototypical aryltetralin lignan natural product, is reported. Key to the success of this synthetic pathway is a Pd-catalyzed C(sp3)-H arylation reaction enabled by a conformational biasing element to promote C-C reductive elimination over an alternative Ci-N bond-forming pathway. This strategy allows for access to the natural product in five steps from commercially available bromopiperonal, and sheds light on subtle conformational effects governing reductive elimination pathways from high-valent palladium centers. Testing a new tactic: In a concise synthesis of podophyllotoxin with a crucial palladium-catalyzed arylation step, subtle conformational effects govern reductive elimination pathways from the high-valent palladium center. This route to aryltetralin lignan derivatives may be of interest in drug discovery.
- Ting, Chi P.,Maimone, Thomas J.
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p. 3115 - 3119
(2014/04/03)
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- Synthesis and antimitotic and tubulin interaction profiles of novel pinacol derivatives of podophyllotoxins
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Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl group with either the 7α (podo) or 7β (epipodo) configuration. Along with pinacols, some C-7 alkylidene and C-7 alkyl derivatives were also prepared. Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7β-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7α-isopropyl-7-deoxypodophyllotoxin (20), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series.
- Abad, Andrés,López-Pérez, José L.,Del Olmo, Esther,García-Fernández, Luis F.,Francesch, Andrés,Trigili, Chiara,Barasoain, Isabel,Andreu, José M.,Fernand Díaz,San Feliciano, Arturo
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experimental part
p. 6724 - 6737
(2012/09/25)
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- Concise stereoselective synthesis of (-)-podophyllotoxin by an intermolecular iron(III)-catalyzed Friedel-Crafts alkylation
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(Chemical Equation Presented) Without further ado, the building blocks 1-3 were combined in three C-C bond-forming reactions to provide the enantiomerically pure natural product (-)-podophyllotoxin (4). The stereogenic center at C1 was generated in the key reaction, a diastereoselective iron(III)-catalyzed intermolecular Friedel-Crafts alkylation.
- Stadler, Daniel,Bach, Thorsten
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supporting information; body text
p. 7557 - 7559
(2009/03/12)
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- ANTINEOPLASTIC COMPOUNDS
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A compound of general formula (I), wherein Ar, R1, R2, R3 and R4 take various meanings with the proviso that R2 and R3 are not both H, for use in the treatment of cancer.
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Page/Page column 40-42
(2008/06/13)
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- Silenes in organic synthesis: A concise synthesis of (±)-epi- picropodophyllin
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A concise, seven step synthesis of the aryl tetralin lignan lactone epi-picropodophyllin from piperonal is described. The key steps are a silene diene Diels-Alder reaction and the Hosomi-Sakurai reaction of the resultant silacyclohexene. The Royal Society
- Pullin, Robert D. C.,Sellars, Jonathan D.,Steel, Patrick G.
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p. 3201 - 3206
(2008/04/01)
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- A concise stereocontrolled formal total synthesis of (+/-)-podophyllotoxin using sulfoxide chemistry.
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A short stereoselective formal total synthesis of (+/-)-podophyllotoxin has been carried out from a sulfoxide, using a one-pot tandem conjugate addition/aldol/electrophilic aromatic substitution reaction to form a tetralin, which was converted into picrop
- Casey, Mike,Keaveney, Claire M
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p. 184 - 185
(2007/10/03)
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- Enzyme-assisted asymmetric total synthesis of (-)-podophyllotoxin and (- )-picropodophyllin
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Described is the first catalytic, asymmetric synthesis of (-)- podophyllotoxin and its C2-epimer, (-)picropodophyllin. Asymmetry is achieved via the enzymatic desymmetrization of advanced meso diacetate 20, through PPL-mediated ester hydrolysis. A second key feature of the synthesis is the strategically late introduction of the highly oxygenated natural ring E through an arylcopper species. The successful implementation of this approach augers well for the introduction of other functionalized rings E for future SAR work. The synthesis begins from piperonal, which is fashioned into isobenzofuran (IBF) precursor 14 in three steps (bromination, acetalization, and halogenmetal exchange/hydroxymethylation). Interestingly, treatment of 14 with HOAc in commerical dimethyl maleate (contains 5% dimethyl fumarate) leads to a nearly equimolar mixture of fumarate-(15) and maleate-IBF Diels- Alder adducts (16 and 17), indicating that IBF 11 reacts about 15 times faster with dimethyl fumarate than with dimethyl maleate. With scrupulously pure dimethyl maleate a 2.8:1 endo:exo mixture of maleate DA adducts is still obtained. On the other hand, the desired meso diester 16 is obtained pure and in nearly quantitative yield by employing neat dimethyl acetylene dicarboxylate as the dienophile, followed by catalytic hydrogenation. Reduction (LiAlH4) of 16 provides meso diol 19, which is then treated with Ac2O, BzCl, and PhCH2COCl to provide the corresponding meso diesters, 20- 22. Screening of these meso benzoxabicyclo[2.2.1]heptyl substrate candidates across a battery of acyl transfer enzymes leads to an optimized match of diacetate 20 with PPL. Even on 10-20 g scales, asymmetry is efficiently introduced here, yielding the key chiral intermediate, monoacetate 25 (66% isolated yield, 83% corrected yield, 95% ee). Protecting group manipulation and oxidation (Swern) provide aldehyde 27b, which undergoes efficient retro- Michael ring opening to produce dihydronaphthalene 30, in which the C3 and C4 stereocenters are properly set. Following several unsuccessful approaches to the intramolecular delivery of ring E (via Claisen rearrangement, Heck- type cyclization, or radical cyclization), a highly diastereoselective, intermolecular conjugate addition of the arylcopper reagent derived from (3,4,5-trimethoxy)phenylmagnesium bromide and CuCN to acyl oxazolidinone 50 was developed (85% yield, only the required α-stereochemistry at C1 is observed). The conjugate addition product is converted to (-)- picropodophyllin in two steps (lactonization, SEM deprotection) or to (-)- podophyllotoxin, in three steps, through the introduction of a C2- epimerization step, under Kende conditions, prior to the final conjugate addition.
- Berkowitz, David B.,Choi, Sungjo,Maeng, Jun-Ho
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p. 847 - 860
(2007/10/03)
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- Asymmetric total synthesis of (-)-podophyllotoxin
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(-)-Podophyllotoxin of 98% optical purity has been synthesized in eight steps and in 15% overall yield. The key step, Diels-Alder addition of the o-quinonoid pyrone 2 [6,7-methylenedioxy-1-(3,4,5-trimethoxyphenyl)-2-benzopyran-3-one] to the chiral dienophile 5 [5-(-)-menthyloxyfuran-2(5H)-one], proceeds with very high regio-, endo- and facial selectivity.
- Bush, Edward J.,Jones, David W.
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p. 151 - 155
(2007/10/03)
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- Azepines by Photochemical Ring Enlargement of 9-Azidopodophyllotoxin- and 9-Azido-9'-demethylepipodophyllotoxin Derivatives
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The azepines 5a-5c were obtained by photochemical nitrene rearrangement of the azides 1e/1f and 4b/4c in cyclohexene, but not in other solvents.They are ring expansion products of podophyllotoxin (1a) and resemble steganacin (9), but show only low biological activity.The triazenes 7a/8a and the aziridine 8b are also less active than 1a. - Keywords: Podophyllotoxin / Podophyllotoxin azides / Nitrene rearrangement
- Laatsch, Hartmut,Ernst, Bernd Peter,Hoffmann, Dieter
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p. 1773 - 1778
(2007/10/03)
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- Process for preparing pure podophyllotoxin
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A process for preparing crystalline, anhydrous podophyllotoxin from a podophyllotoxin product comprises dissolving the product in a non-aromatic and non-halogenated solvent which has a boiling point at atmospheric pressure not exceeding 130° C., and which
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- A Mild Method for Selective Cleavage of Tetrahydropyranyl Ethers in the Presence of Other Acid-Labile Functionalities
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A mild method for selective cleavage of tetrahydropyranyl ethers in the presence of other acid sensitive functionalities such as acetonides, methoxymethyl ethers, methylenedioxy ethers, mesitylaldehyde acetals and t-butyldimethylsilyl ethers using Lewis acid-thiol system is described.
- Nambiar, Krishnan P.,Mitra, Abhijit
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p. 3033 - 3036
(2007/10/02)
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- Synthesis of Podophyllum Lignans via an Isolable o-Quinonoid Pyrone
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The 2-benzopyran-3-one 10 is a stable, isolable and useful Diels-Alder diene; its methyl 4-benzoyloxycrotonate adduct 23 formed regioselectively and stereoselectively in acetonitrile is reduced with H2/Pd to give 31 with inversion of C-1 stereochemistry.T
- Jones, David W.,Thompson, Adrian M.
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p. 2533 - 2540
(2007/10/02)
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- Synthesis of (+/-)-4-Deoxypodophyllotoxin, (+/-)-Podophyllotoxin and (+/-)-Epipodophyllotoxin
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6,7-Methylenedioxy-1-(3',4',5'-trimethoxyphenyl)-2-benzopyran-3-one 1 and dimethyl fumarate in acetonitrile give mostly the C-2 exo-CO2Me adduct 4 which is transformed in four steps into epipodophyllotoxin 10a.Attempted addition of dimethyl maleate to 1 p
- Jones David W.,Thompson, Adrian M.
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p. 2541 - 2548
(2007/10/02)
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- BIOTRANSFORMATION OF PODOPHYLLUM LIGNANS IN CELL SUSPENSION CULTURES OF FORSYTHIA INTERMEDIA
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Biotransformation studies using cell suspension cultures of Forsythia intermedia showed these are capable of rapidly oxidizing the aryltetralin lactone lignan podophyllotoxin into podophyllotoxone.Smaller amounts of the stereoisomer picropodophyllone were
- Broomhead, A. Jane,Dewick, Paul M.
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p. 1511 - 1517
(2007/10/02)
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- Comprehensive Synthetic Route to Eight Diastereomeric Podophyllum Lignans
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An oxabicyclo compound, 9, prepared in 47percent yield through an isobenzofuran intermediate was converted with excellent regio- and stereocontrol to eight (+/-)-lignan lactones of the podophyllotoxin series.One of the eight, epiisopicropodophyllin, 36, t
- Forsey, Steven P.,Rajapaksa, Dayananda,Taylor, Nicholas J.,Rodrigo, Russell
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p. 4280 - 4290
(2007/10/02)
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- Intermediates for the production of podophyllotoxin and related compounds and processes for the preparation and use thereof
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There are disclosed intermediates which can be converted into podophyllotoxin and related compounds, which are known antineoplastic agents. There are also disclosed processes for the preparation of such intermediates, and processes for the conversion of t
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- Asymmetric Total Synthesis of (-)-Podophyllotoxin
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Using a diastereoselective addition of the appropriate aryllithium to a naphtalene-containing chiral oxazoline leads to advanced intermadiate 11 in the podophyllotoxin series.The latter is obtained in a 92:8 de.Transformation of the oxazoline moiety to the requisite lactone 18 followed by invoking the Kende route to the target gave natural (-)-podophyllotoxin in 94 percent ee.The overall yield of the sequence, accomplished in 24 steps, was 5 percent.
- Andrews, Robert C.,Teague, Simon J.,Meyers, A. I.
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p. 7854 - 7858
(2007/10/02)
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- A SHORT VERSATILE SYNTHESIS OF ARYLTETRALIN LIGNANS INCLUDING DEOXYISOPODOPHYLLOTOXIN AND EPI-ISOPODOPHYLLOTOXIN
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Cyclisation of tandem conjugate addition products (10), (15), and (20), prepared by reaction of anions derived from benzyl phenyl and benzyl t-butyl sulphides with but-2-en-4-olide, affords a series of aryltetralin lignans belonging to either the 'normal' or the 'retro' lactone series.Desulphurisation of compound (15) followed by cyclisation, or desulphurisation of the cyclised product (22b), affords deoxyisopodophyllotoxin (5), while treatment of compound (22b) with mercury(II) trifluoroacetate yields epi-isopodophyllotoxin (6).
- Pelter, Andrew,Ward, Robert S.,Pritchard, Martyn C.,Kay, I. Trevor
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p. 1615 - 1624
(2007/10/02)
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- Synthesis of Podophyllum Lignans via an Isolable o-Quinonoid Pyrone
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The 2-benzopyran-3-one (7) is a stable, isolable, and useful Diels-Alder diene; its adduct (10) formed with dimethyl fumarate is transformed in three steps into methyl epipodophyllate (14) which gives epipodophyllotoxin (2) (81percent) by direct lactonisation (ZnCl2-tetrahydrofuran-4 Angstroem molecular sieves).
- Jones, David W.,Thompson, Adrian M.
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p. 1797 - 1798
(2007/10/02)
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- Process for the isolation and purification of podophyllotoxin
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A process for obtaining purified podophyllotoxin from an impure podophyllotoxin containing starting material comprising forming a solution of the starting material, forming a solid complex of podophyllotoxin and an aromatic or heteroaromatic compound other than benzene, and separating the solid complex from the solution.
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- Studies on the Constituents of the Seeds of Hernandia ovigera L. V. Syntheses of Epipodophyllotoxin and Podophyllotoxin from Desoxypodophyllotoxin
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Epipodophyllotoxin (EPT) and podophyllotoxin (PT) were prepared from desoxypodophyllotoxin (DPT), obtained from the seeds of Hernandia ovigera L. (Hernandiaceae).EPT was obtained together with dehydrodesoxypodophyllotoxin (I) by a radical bromination of D
- Yamaguchi, Hideo,Arimoto, Masao,Nakajima, Syunji,Tanoguchi, Mariko,Fukada, Yoshinari
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p. 2056 - 2060
(2007/10/02)
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- TOTAL SYNTHESIS OF (+/-)-PODOPHYLLOTOXIN AND (+/-)-EPIPODOPHYLLOTOXIN
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A novel approach to (+/-)-epipodophyllotoxin (2c) and hence also to (+/-)-podophyllotoxin (1c) is described, involving as a key-step the stereoselective ring closure of the TMS-ester derived from 17a to the tetralin derivative 30c with mesyl chloride.
- Eyken, J. Van der,Clercq, P. de,Vandewalle, M.
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p. 4297 - 4308
(2007/10/02)
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- TOTAL SYNTHESIS OF (+/-)-PODOPHYLLOTOXIN AND (+/-)-EPIPODOPHYLLOTOXIN.
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A novel approach to (+/-)-epipodophyllotoxin (2) and hence also (+/-)-podophyllotoxin (1) is described, involving as a key-step the stereoselective ring closure of the TMS-ester derived from 14a to the tetralin derivative 15 with mesyl chloride.
- Eycken, J. Van der,Clercq, P. De,Vandewalle, M.
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p. 3871 - 3874
(2007/10/02)
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- SYNTHESIS OF DEOXYISOPODOPHYLLOTOXIN AND EPIISOPODOPHYLLOTOXIN.
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Cyclisation of the tandem conjugate addition products 1-3 by displacement of either the OH or SPh group provides a short efficient synthesis of lignan lactones including compounds of the clinically important podophyllotoxin series.
- Pelter, Andrew,Ward, Robert S.,Pritchard, Martyn C.,Kay, I. Trevor
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p. 6377 - 6380
(2007/10/02)
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- BIOSYNTHESIS OF PODOPHYLLUM LIGNANS - I. CINNAMIC ACID PRECURSORS OF PODOPHYLLOTOXIN IN PODOPHYLLUM HEXANDRUM
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Feeding experiments in Podophyllum hexandrum plants have established that phenylalanine, cinnamic acid and ferulic acid are good precursors of the two major aryltetralin lignans podophyllotoxin and 4'-demethylpodophyllotoxin.Sinapic and 3,4,5-trimethoxycinnamic acids were poorly utilized, showing that the substitution pattern of the pendent aryl ring is built up after coupling of the two phenylpropane units.Degradation studies on podophyllotoxin derived from ferulic acid show that the two halves of the lignan molecule are equally labelled supporting a biosynthetic sequence involving oxidative coupling of two similar phenylpropane precursors having the substitution pattern of ferulic acid.Although 3,4-methylenedioxycinnamic acid was readily incorporated, degradative studies prove that this compound is not incorporated intact, but via a metabolic sequence in which the methylenedioxy carbon atom enters the C1-pool and then labels the methylenedioxy and methoxyl substituents of podophyllotoxin.The rest of the skeleton is incorporated via ferulic acid, presumably by way of caffeic acid.Key Word Index - Podophyllum hexandrum; Podophyllaceae; aryltetralin; lignans; biosynthesis; podophyllotoxin.
- Jackson, David E.,Dewick, Paul M.
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p. 1029 - 1036
(2007/10/02)
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