- 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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p. 6530 - 6533
(2017/12/26)
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- Synthesis of Novel Oxime Sulfonate Derivatives of 2′(2′,6′)-(Di)chloropicropodophyllotoxins as Insecticidal Agents
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To discover novel natural-product-based pesticidal agents, we prepared a series of oxime sulfonate derivatives of 2′(2′,6′)-(Di)chloropicropodophyllotoxins by structural modification of podophyllotoxin. Their structures were well-characterized by proton nuclear magnetic resonance (1H NMR), high-resolution mass spectrometry (HRMS), optical rotation, and melting point. Moreover, the key steric structure of compound 5f was unambiguously determined by single-crystal X-ray diffraction. Additionally, their insecticidal activity was evaluated at 1 mg/mL against the pre-third-instar larvae of oriental armyworm (Mythimna separata Walker), a typical lepidopteran pest. Among all derivatives, compounds 4c, 5c, and 5d exhibited more promising insecticidal activity, with the final mortality rates greater than 60%, when compared to their precursor podophyllotoxin and the positive control, toosendanin. It demonstrated that introduction of the chlorine atom at the C-2′ or C-2′,6′ position on the E ring of picropodophyllotoxin or oxime sulfonate derivatives of picropodophyllotoxin was important for the insecticidal activity and introduction of a halogen (e.g., fluorine, chlorine, or bromine) atom-substituted phenylsulfonyl group on the oxime fragment of 2′(2′,6′)-(di)chloropicropodophyllones could lead to more promising compounds.
- Wang, Rong,Zhi, Xiaoyan,Li, Jie,Xu, Hui
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p. 6668 - 6674
(2015/08/18)
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- Insight into dihalogenation of E-ring of podophyllotoxins, and their acyloxyation derivatives at the C4 position as insecticidal agents
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Unexpected sequential E-ring dihalogenation of podophyllotoxin analogues is reported. It demonstrated that a chlorine/bromine atom was prior introduced at the C2′ position of podophyllotoxin, and the corresponding free rotation of E-ring around the C1-C1′
- Che, Zhiping,Yu, Xiang,Fan, Lingling,Xu, Hui
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supporting information
p. 5592 - 5598
(2013/10/01)
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- NEW PROCESS FOR PREPARING CYCLOLIGNANS
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The invention relates to a one-pot reaction for the preparation of a compound of Formula (I). The compound of Formula (I) may be further transformed into picropodophyllin and derivatives thereof.
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- Synthesis and quantitative structure-activity relationship (QSAR) study of novel isoxazoline and oxime derivatives of podophyllotoxin as insecticidal agents
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In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, 33 isoxazoline and oxime derivatives of podophyllotoxin modified in the C and D rings were synthesized and their structures were characterized by Proton nuclear magnetic resonance ( 1H NMR), high-resolution mass spectrometry (HRMS), electrospray ionization-mass spectrometry (ESI-MS), optical rotation, melting point (mp), and infrared (IR) spectroscopy. The stereochemical configurations of compounds 5e, 5f, and 9f were unambiguously determined by X-ray crystallography. Their insecticidal activity was evaluated against the pre-third-instar larvae of northern armyworm, Mythimna separata (Walker), in vivo. Compounds 5e, 9c, 11g, and 11h especially exhibited more promising insecticidal activity than toosendanin, a commercial botanical insecticide extracted from Melia azedarach. A genetic algorithm combined with multiple linear regression (GA-MLR) calculation is performed by the MOBY DIGS package. Five selected descriptors are as follows: one two-dimensional (2D) autocorrelation descriptor (GATS4e), one edge adjacency indice (EEig06x), one RDF descriptor (RDF080v), one three-dimensional (3D) MoRSE descriptor (Mor09v), and one atom-centered fragment (H-052) descriptor. Quantitative structure-activity relationship studies demonstrated that the insecticidal activity of these compounds was mainly influenced by many factors, such as electronic distribution, steric factors, etc. For this model, the standard deviation error in prediction (SDEP) is 0.0592, the correlation coefficient (R2) is 0.861, and the leave-one-out cross-validation correlation coefficient (Q2 loo) is 0.797.
- Wang, Yi,Shao, Yonghua,Wang, Yangyang,Fan, Lingling,Yu, Xiang,Zhi, Xiaoyan,Yang, Chun,Qu, Huan,Yao, Xiaojun,Xu, Hui
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p. 8435 - 8443
(2012/10/29)
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- Natural products-based insecticidal agents 6. Design, semisynthesis, and insecticidal activity of novel monomethyl phthalate derivatives of podophyllotoxin against Mythimna separata Walker in vivo
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To discover the more potent analogs, 12 novel monomethyl phthalate derivatives of podophyllotoxin were synthesized and preliminarily tested against the pre-third-instar larvae of Mythimna separata Walker in vivo at the concentration of 1 mg/mL. Compounds 8e-i showed the higher insecticidal activity than podophyllotoxin. Especially 8g exhibited the most potent insecticidal activity compared with toosendanin, a commercially available insecticide derived from Melia azedarach. The structure-activity relationships demonstrated that trans-lactone, 4β-substitution, 2β-chlorine substitution, and 4′-methoxy group were the important structural properties of podophyllotoxins for good insecticidal activity.
- Xu, Hui,He, Xiao-Qiang
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scheme or table
p. 4503 - 4506
(2010/11/24)
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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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- USE OF CYCLOLIGNANS FOR THE TREATMENT OF TYPE 2 DIABETES AND AS CONTRACEPTIVES
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There is disclosed use of certain cyclolignans for prophylaxis or treatment of diabetes mellitus type 2, nephropathy, retinopathy, macular degeneration, retinopathy of prematurity, central retinal vein occlusion, branch retinal vein occlusion, rubeotic gl
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Page/Page column 14; 19
(2008/06/13)
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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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- A novel enzymatic dehydrogenation of podophyllotoxin congeners by yeast cells
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The biotransformation of aryltetralin lignans to arylnaphthalene lignans in presence of yeast is described. Podophyllotoxone, an oxidation product of podophyllotoxin on incubation with yeast from different sources produced dehydropodophyllotoxin, an important representative of arylnaphthalene lignans.
- Kamal, Ahmed,Damayanthi
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p. 657 - 662
(2007/10/03)
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- Reassignment of the configuration of several keto-cyclolignans prepared from podophyllotoxin
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The configuration of several keto-cyclolignans related to podophyllotoxin has been reviewed. Under basic catalysis, the configuration at the C-atom in α-position to the lactone carbonyl group in podophyllotoxone is inverted instead of the C-atom in α- pos
- Del Corral,Gordaliza,Lopez,Del Olmo,Castro,Lopez
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p. 1793 - 1796
(2007/10/02)
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- UNAMBIGUOUS CONFIGURATIONAL AND CONFORMATIONAL DETERMINATION OF THURIFERIC ACID
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The stereochemistry of thuriferic acid has been checked on the basis of spectral, chemical and molecular modelling findings.Under basic catalysis, the carbon alfa to the lactone carbonyl group in podophyllotoxone must be inverted instead of the carbon alf
- Lopez-Perez, Jose L.,Olmo, Ester del,Pascual-Teresa, Beatriz de,Merino, Marta,Martin, Sara,Feliciano, Arturo San
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p. 6343 - 6348
(2007/10/02)
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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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- 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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- 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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- 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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- 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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- Antitumor Agents. 78. Inhibition of Human DNA Topoisomerase II by Podophyllotoxin and α-Peltatin Analogues
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It has been reported that the action of etoposide (VP-16) (14) as an antitumor agent is mediated through its interaction with DNA topoisomerase II which results in DNA breakage inside the cell.In order to understand the mechanism of action as well as structure-activity relationships of 14, several novel, synthetic and some naturally occurring analogues related to podophyllotoxin were examined for inhibition of the DNA topoisomerase II activity.Compound 2 exhibited enhanced activity and compound 5 slightly diminished activity relative to 14.A 4β-substituted ether at the C ring and O-demethylation at the E ring appear to enhance activity.
- Thurston, Lee S.,Irie, Hiroshi,Tani, Shohei,Han, Fu-Sheng,Liu, Zong-Chao,et al.
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p. 1547 - 1550
(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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