143901-35-3Relevant articles and documents
Biomimetic kinetic resolution: Highly enantio- and diastereoselective transfer hydrogenation of aglain ketones to access flavagline natural products
Stone, Steven D.,Lajkiewicz, Neil J.,Whitesell, Luke,Hilmy, Ahmed,Porco, John A.
, p. 525 - 530 (2015/01/30)
We have previously reported asymmetric syntheses and absolute configuration assignments of the aglains (+)-ponapensin and (+)-elliptifoline and proposed a biosynthetic kinetic resolution process to produce enantiomeric rocaglamides and aglains. Herein, we
Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors
Liu, Tao,Nair, Somarajan J.,Lescarbeau, Andre,Belani, Jitendra,Peluso, Stephane,Conley, James,Tillotson, Bonnie,OHearn, Patrick,Smith, Sherri,Slocum, Kelly,West, Kip,Helble, Joseph,Douglas, Mark,Bahadoor, Adilah,Ali, Janid,McGovern, Karen,Fritz, Christian,Palombella, Vito J.,Wylie, Andrew,Castro, Alfredo C.,Tremblay, Martin R.
, p. 8859 - 8878,20 (2020/09/16)
Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta[b]benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol has limited development potential due to poor druglike properties. Herein, we sought to develop a practical synthesis of key intermediates of silvestrol and explore structure-activity relationships around the C6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation-initiation machinery (i.e., complex 5′-untranslated region UTR) relative to simple 5′UTR was determined by a cellular reporter assay. Simplified analogues of silvestrol such as compounds 74 and 76 were shown to have similar cytotoxic potency and better ADME characteristics relative to those of silvestrol.
Total synthesis of (±)-rocaglamide via oxidation-initiated nazarov cyclization
Malona, John A.,Cariou, Kevin,Spencer, William T.,Frontier, Alison J.
, p. 1891 - 1908 (2012/04/23)
This article describes the evolution of a Nazarov cyclization-based synthetic strategy targeting the anticancer, antiinflammatory, and insecticidal natural product (±)-rocaglamide. Initial pursuit of a polarized heteroaromatic Nazarov cyclization to construct the congested cyclopentane core revealed an unanticipated electronic bias in the pentadienyl cation. This reactivity was harnessed in a successful second-generation approach using an oxidation-initiated Nazarov cyclization of a heteroaryl alkoxyallene. Full details of these two approaches are given, as well as the characterization of undesired reaction pathways available to the Nazarov cyclization product. A sequence of experiments that led to an understanding of the unexpected reactivity of this key intermediate is described, which culminated in the successful total synthesis of (+)-rocaglamide.
Total synthesis of the potent anticancer Aglaia metabolites (-)-silvestrol and (-)-episilvestrol and the active analogue (-)-4-desmethoxyepisilvestrol
Adams, Tim E.,Sous, Mariana El,Hawkins, Bill C.,Hirner, Sebastian,Holloway, Georgina,et al.
supporting information; experimental part, p. 1607 - 1616 (2009/07/30)
Total synthesis of the anticancer 1,4-dioxane containing natural products silvestrol (1) and episilvestrol (2) is described by an approach basedon the proposed biosynthesis of these novel compounds. The key steps in cluded an oxidative rearrangement of the protected D-glucose derivative 11 to afford the 1,4-dioxane 12, which could be elaborated to the coupling partner 5 and a photochemical [3 + 2] cycloadditon between the 3-hydroxyflavone 27 and methyl cinnamate followed by base-induced α-ketol rearrangement and reduction to give the cyclopentabenzofuran core 33. The core (-)-6 and 1,4-dioxane fragment 5 were united by a highly stereoselective Mitsunobu coupling with the modified azodicarboxylate DMEAD toafford the axial coupled product 36. Deprotection then gave episilvestr ol (2). Silvestrol (1) was synthesized by a coupling between core (-)-6 and the dioxane 44 followed by deprotection. Compound 1 was also synthesized from episilvestrol (2) by a Mitsunobu inversion. In addition, the analogue 4-desmethoxyepisilvestrol (46) was synthesized via the same route. It was found that 46 and episilvestrol 2 displayed an unexpected concentration-dependent chemical shift variation for the nonexchangeable dioxane protons. Synthetic compounds 1, 2, 38, 46, and 54 were tested against cancer cells lines, and it was found that the stereochemistry of the core was critical for activity. Synthetic analogue 4-desmethoxyepisilvestrol (46) was also active against lung and colon cancer cell lines.
ASYMMETRIC SYNTHESIS OF ROCAGLAMIDES VIA ENANTIOSELECTIVE PHOTOCYCLOADDITION MEDIATED BY CHIRAL BRONSTED ACIDS
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Page/Page column 49, (2008/06/13)
The present invention provides a new strategies for the synthesis of compounds of the rocaglamide family and related natural products. The synthetic approach generally involves photochemical generation of an oxidopyrylium species from a 3-hydroxychromone derivative followed by an enantioselective 1,3-dipolar cycloaddition of the oxidopyrylium species to a dipolarophile in the presence of a TADDOL derivative. This approach can be used for the formation of adducts containing an aglain core structure. Methods of the conversion of aglain core structures to aglain, rocaglamide and forbaglin ring systems are also provided. The present invention also relates to the use of rocaglamide/aglain/forbaglin derivatives for the manufacture of medicaments for use in the treatment of cancer or cancerous conditions, disorders associated with cellular hyperproliferation, or NF-κB-dependent conditions.
Enantioselective photocycloaddition mediated by chiral Bronsted acids: Asymmetric synthesis of the rocaglamides
Gerard, Baudouin,Sangji, Sheharbano,O'Leary, Daniel J.,Porco Jr., John A.
, p. 7754 - 7755 (2007/10/03)
Enantioselective syntheses of methyl rocaglate and the related natural products rocaglamide and rocaglaol are outlined. The approach involves enantioselective [3 + 2] photocycloaddition promoted by chiral Bronsted acids (TADDOLs) to afford an aglain precursor followed by a ketol shift/reduction sequence to the rocaglate core. Copyright
SYNTHESIS OF ROCAGLAMIDE NATURAL PRODUCTS VIA PHOTOCHEMICAL GENERATION OF OXIDOPYRYLIUM SPECIES
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Page/Page column 47-48; Sheet 12, (2008/06/13)
The present invention provides new strategies for the synthesis of compounds of the rocaglamide family and related natural products. In particular, the new biomimetic synthetic approach involves photochemical generation of an oxidopyrylium species from a
Synthesis of the Novel Anti-leukaemic Tetrahydrocyclopentabenzofuran, Rocaglamide and Related Synthetic Studies
Davey, Andrew E.,Schaeffer, Marcel J.,Taylor, Richard J. K.
, p. 2657 - 2666 (2007/10/02)
Two approaches to the rocaglamide tricyclic skeleton are described.The first, which employs an unusual dithianyl anion to carbonyl addition reaction, provides access to α-phenyl rocaglamide analogues.The second route involves an intramolecular keto aldehyde pinacolic coupling in the key step and can be used for the preparation of a whole range of rocaglamide analogues possessing both α- and β-phenyl substituents.A total synthesis of rocaglamide, in racemic form, is described using this second approach.The synthetic route commences with phloroglucinol, an inexpensive and readily-available starting material, and takes only 8/9 steps giving an overall yield > 6percent.The synthesis of 1-epi-rocaglamide 29b is also described.
