- Synthesis of seven-membered oxacycles. Part 2: The furan approach
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We describe an efficient new approach for the synthesis of seven-membered oxacycles that is based on the oxidation of a furan ring with singlet oxygen followed by an intramolecular Michael addition.
- Fall, Yagamare,Vidal, Beatriz,Alonso, David,Gómez, Generosa
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- Total Synthesis Confirms the Molecular Structure Proposed for Oxidized Levuglandin D2
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Levuglandins (LG)D2 and LGE2 are γ-ketoaldehyde levulinaldehyde derivatives with prostanoid side chains produced by spontaneous rearrangement of the endoperoxide intermediate PGH2 in the biosynthesis of prostaglandins. Covalent adduction of LGs with the amyloid peptide Aβ1-42 promotes formation of the type of oligomers that have been associated with neurotoxicity and are a pathologic hallmark of Alzheimer’s disease. Within 1 min of their generation during the production of PGH2 by cyclooxygenation of arachidonic acid, LGs are sequestered by covalent adduction to proteins. In view of this high proclivity for covalent adduction, it is understandable that free LGs have never been detected in vivo. Recently a catabolite, believed to be an oxidized derivative of LGD2 (ox-LGD2), a levulinic acid hydroxylactone with prostanoid side chains, was isolated from the red alga Gracilaria edulis and detected in mouse tissues and in the lysate of phorbol-12-myristate-13-acetate-treated THP-1 cells incubated with arachidonic acid. Such oxidative catabolism of LGD2 is remarkable because it must be outstandingly efficient to prevail over adduction with proteins and because it requires a unique dehydrogenation. We now report a concise total synthesis that confirms the molecular structure proposed for ox-LGD2. The synthesis also produces ox-LGE2, which readily undergoes allylic rearrangement to Δ6-ox-LGE2
- Cheng, Yu-Shiuan,Yu, Wenyuan,Xu, Yunfeng,Salomon, Robert G.
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- NUCLEIC ACID-POLYPEPTIDE COMPOSITIONS AND USES THEREOF
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Disclosed herein are compositions and pharmaceutical formulations that comprise a binding moiety conjugated to a modified polynucleic acid molecule and a polymer. Also described herein include methods for treating a cancer which utilize a composition or a
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- Stereoselective synthesis of marine macrolide Aspergillide D
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A formal stereoselective synthesis of the naturally occurring 16-membered macrolide aspergillide D is described. The origins of the chiral centers are ribose, lactic acid and the Sharpless asymmetric epoxidation protocol. The foremost reactions involved a
- Talakokkula, Anil,Baikadi, Karunakar,Venkat Narsaiah
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- Platinum-catalyzed α,β-unsaturated carbene formation in the formal syntheses of frondosin B and liphagal
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Formal syntheses of tetracyclic terpenoids frondosin B and liphagal are described. Both synthetic routes rely on the use of platinum-catalyzed α,β-unsaturated carbene formation for the key C-C bond forming transformations. The successful route toward frondosin B utilizes a formal (4 + 3) cycloaddition, while the liphagal synthesis features the vinylogous addition of an enol nucleophile as a key step. Both synthetic routes are discussed, revealing insights into structural requirements in the catalytic a,β-unsaturated carbene reaction manifold.
- Huynh, Khoi Q.,Seizert, Curtis A.,Ozumerzifon, Tarik J.,Allegretti, Paul A.,Ferreira, Eric M.
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supporting information
p. 294 - 297
(2017/11/28)
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- γ-Lactone Synthesis via Palladium(II)-Catalyzed Lactonization of Unactivated Methylene C(sp3)-H Bonds
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A palladium(II)-catalyzed intramolecular lactonization of unactivated methylene C(sp3)-H bonds using PIP bidentate auxiliary is described. This method provides an efficient and concise pathway to synthesize functionalized γ-lactones.
- Liu, Bin,Shi, Bing-Feng
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supporting information
p. 2396 - 2400
(2016/09/28)
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- Photooxidizing chromium catalysts for promoting radical cation cycloadditions
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The photooxidizing capabilities of selected CrIII complexes for promoting radical cation cycloadditions are described. These complexes have sufficiently long-lived excited states to oxidize electron-rich alkenes, thereby initiating [4+2] processes. These metal species augment the spectrum of catalysts explored in photoredox systems, as they feature unique properties that can result in differential reactivity from the more commonly employed ruthenium or iridium catalysts. Spotlight on chromium: Selected CrIII complexes were investigated for promoting radical cation cycloadditions. These species have sufficiently long-lived excited states to oxidize electron-rich alkenes, thereby initiating [4+2] processes. These metal complexes augment the spectrum of catalysts explored in photoredox systems, featuring properties that can result in differential reactivity from the more common Ru or Ir catalysts.
- Stevenson, Susan M.,Shores, Matthew P.,Ferreira, Eric M.
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supporting information
p. 6506 - 6510
(2015/06/08)
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- Synthesis and biological evaluation of nitric oxide-donating analogues of sulindac for prostate cancer treatment
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A series of analogues of the non-steroidal anti-inflammatory drug (NSAID) sulindac 1 were synthesised tethered to nitric oxide (NO) donating functional groups. Sulindac shows antiproliterative effects against immortal PC3 cell lines. It was previously demonstrated that the effect can be enhanced when tethered to NO releasing groups such as nitrate esters, furoxans and sydnonimines. To explore this approach further, a total of fifty-six sulindac-NO analogues were prepared and they were evaluated as NO-releasing cytotoxic agents against prostate cancer (PCa) cell lines. Compounds 1k and 1n exhibited significant cytotoxic with IC50 values of 6.1 ± 4.1 and 12.1 ± 3.2 μM, respectively, coupled with observed nitric oxide release.
- Nortcliffe, Andrew,Ekstrom, Alexander G.,Black, James R.,Ross, James A.,Habib, Fouad K.,Botting, Nigel P.,O'Hagan, David
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supporting information
p. 756 - 761
(2014/01/23)
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- Synthesis of the atropurpuran A-ring via an organocatalytic asymmetric intramolecular Michael addition
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The asymmetric synthesis of the A-ring fragment 2a-b of atropurpuran 1 has been achieved in 15 steps with up to 70% ee via an organocatalytic intramolecular Michael addition of nitroalkene 10. The absolute configuration of the two contiguous carbon center
- Chen, Huan,Zhang, Dan,Xue, Fei,Qin, Yong
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p. 3141 - 3148
(2013/05/09)
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- Sterically controlled alkylation of arenes through iridium-catalyzed C-H borylation
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Complementary chemistry: A one-pot method for the site-selective alkylation of arenes controlled by steric effects is reported. The process occurs through Ir-catalyzed C-H borylation, followed by Pd- or Ni-catalyzed coupling with alkyl electrophiles. This selectivity complements that of the typical Friedel-Crafts alkylation; meta-selective alkylation of a broad range of arenes with various electronic properties and functional groups occurs in good yield with high site selectivity. Copyright
- Robbins, Daniel W.,Hartwig, John F.
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supporting information
p. 933 - 937
(2013/02/25)
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- Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression
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Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment, targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenaline, is not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogues that interact with α4β2 nicotinic acetylcholine receptors (nAChRs) as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450-related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.
- Liu, Jianhua,Yu, Li-Fang,Eaton, J. Brek,Caldarone, Barbara,Cavino, Katie,Ruiz, Christina,Terry, Matthew,Fedolak, Allison,Wang, Daguang,Ghavami, Afshin,Lowe, David A.,Brunner, Dani,Lukas, Ronald J.,Kozikowski, Alan P.
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p. 7280 - 7288
(2011/12/15)
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- Comparative molecular field analysis and synthetic validation of a hydroxyamide-propofol binding and functional block of neuronal voltage-dependent sodium channels
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Voltage gated sodium channels represent an important therapeutic target for a number of neurological disorders including epilepsy. Unfortunately, medicinal chemistry strategies for discovering new classes of antagonist for trans-membrane ion channels have
- Brown, Milton L.,Eidam, Hilary A.,Paige, Mikell,Jones, Paulianda J.,Patel, Manoj K.
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scheme or table
p. 7056 - 7063
(2009/12/24)
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- Synthesis of enantiopure bicyclic α,α-disubstituted spirolactams via asymmetric Birch reductive alkylation
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The synthesis of enantiopure bicyclic α,α-disubstituted spirolactams is described using a diastereoselective Birch reductive alkylation as the key step. Hydrogenation of the resultant alkylated cyclohexadienes followed by intramolecular cyclization provides access to enantiopure 8-azaspiro[5.6]dodecan-7-ones.
- Gueret, Stephanie M.,O'connor, Patrick D.,Brimble, Margaret A.
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supporting information; experimental part
p. 963 - 966
(2009/07/11)
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- Solid-phase synthesis of [5.5]-spiroketals
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An efficient and reliable multi-step synthesis of 251 natural product-like [5.5]-spiroketals on solid supports has been developed. As central key step, a double intramolecular hetero-Michael (DIHMA) reaction to alkynones was applied. The sequence allows for introduction of numerous substituents on the scaffold and for variation of stereochemistry. [5.5]-Spiroketals bearing an additional ketone were obtained in high overall yields. Further diversification was achieved by reduction of the ketone and reductive amination using polymer-supported borohydride, Grignard reaction and conversion to oxime derivatives in the solution phase.
- Sommer, Stefan,Kuehn, Marc,Waldmann, Herbert
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supporting information; experimental part
p. 1736 - 1750
(2009/08/14)
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- Diastereoselective synthesis of cyclopentapyridazinones via radical cyclization: Synthetic studies toward halichlorine
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(Equation Presented) The pyridazinone ring system serves as an excellent scaffold for the diastereoselective preparation of novel cis-fused cyclopentapyridazinones utilizing the directed 5-exo radical cyclization approach. This overall approach was succes
- Keck, Gary E.,Neumann, Stacey A.
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supporting information; experimental part
p. 4783 - 4786
(2009/05/31)
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- Introduction of functional groups into peptides via N-alkylation
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An optimized protocol for the mild and selective Fukuyama-Mitsunobu reaction was used for mono- and di-N-alkylation on solid support. Thereby, nonfunctionalized aliphatic and aromatic residues are quickly introduced into transiently protected, primary ami
- Demmer,Dijkgraaf,Schottelius,Wester,Kessler
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scheme or table
p. 2015 - 2018
(2009/04/18)
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- Cyclization reactivities of fluorinated hex-5-enyl radicals
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A kinetic study of the effect of fluorine substitution on the rates and regiochemistry of hex-5-enyl radical cyclization is reported. One or more fluorines on or proximate to the double bond of the radical have relatively little electronic effect on eithe
- Dolbier Jr., William R.,Rong, Xiao X.,Bartberger, Michael D.,Koroniak, Henryk,Smart, Bruce E.,Yang, Zhen-Yu
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p. 219 - 231
(2007/10/03)
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- Intramolecular anodic olefin coupling reactions and the use of vinylsilanes
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Intramolecular anodic olefin coupling reactions involving vinylsilane groups have been studied. It was found that the previously successful predictive model for olefin coupling reactions based on an electrophilic attack of a radical cation onto an olefin did not successfully predict product formation for olefin coupling reactions involving vinylsilane terminating groups. Instead, these reactions were best described by viewing the initial addition of the radical cation to an olefin as if it occurred in a reversible "radical-like" fashion. In addition, reactions using a temporary silicon tether were shown to be compatible with the formation of quaternary carbons with control of relative stereochemistry. These reactions helped highlight the compatibility of the anodic olefin coupling reactions with extremely sensitive substrates. Finally, the results reported suggest that the mass balance of the intramolecular anodic olefin coupling reaction depends on the ease with which the initially formed cyclized product undergoes the second oxidation step.
- Hudson, Christine M.,Moeller, Kevin D.
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p. 3347 - 3356
(2007/10/02)
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- [3,3]Sigmatropic ring expansion of cyclic thionocarbonates. VII. On the formation of 8-membered thionocarbonates as the intermediates
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In order to clarify the reaction mechanism of [3,3]sigmatropic ring expansion of cyclic thionocarbonates, the 8-membered thionocarbonates (6 and 7) were synthesized by treatment of the corresponding diol monothionocarbonates (5 and 13) with lithium bis(tr
- Harusawa,Tomii,Takehisa,Ohishi,Yoneda,Kurihara
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p. 2279 - 2282
(2007/10/02)
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- Formation of 14-membered carbocycles by intramolecular Michael addition on ynones and enones
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The base-catalyzed intramolecular Michael addition of substituted malonates on ynones or enones proceeds efficiently to give the 14-membered carbocycles.
- Girard, Suzanne,Deslongchamps, Pierre
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p. 1265 - 1273
(2007/10/02)
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- Cyclic ethers as educts for the synthesis of lepidoptra pheromones
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ω-Iodo(trialkylsiloxy)alkanes 2 prepared by ring opening of cyclic ethers with iodotrimethylsilane, are useful starting materials for the synthesis of pheromone components. Reaction with triphenylphosphine to give the corresponding Wittig reagent and subsequent coupling with lithium (Z)-dihex-1-enylcuprate gives (Z)-alken-1-ols 5 and 7, after deprotection, in good yields. The direct coupling of 2 with alkynes failed because of competition reactions, however, the more stable ω-iodo-1-(tert-butyldimethylsiloxy)alkanes were able to undergo C,C-coupling with alkynes. The thus formed 1-(tert-butyldimethylsiloxy)-5-decyne (13c) was hydrogenated and deprotected to give (E)-5-decen-1-ol (15c).
- Poleschner,Heydenreich,Martin
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p. 1231 - 1235
(2007/10/02)
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- A new method for the stereocontrolled synthesis of silyl dienol ethers using (naphtalene) chromium tricarbonyl catalyzed isomerization
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Various tert-butyldimethylsilyl dienol ethers of type 4 were synthesized in a highly stereoselective manner for the first time. Treatment of (1Z)-1-[[(tert-butyldimethylsilyl)oxy] methyl] butadiene derivatives 1 with 20 mol % of (naphthalene) Cr(CO)3
- Sodeoka, Mikiko,Yamada, Hiroyoshi,Shibasaki, Masakatsu
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p. 4906 - 4911
(2007/10/02)
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- Synthesis and Reactions of Iodo Lactams
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The synthesis of a series of iodo lactams has been achieved by a new cyclization method that depends on generating N,O-bis(trimethylsilyl)imidate derivatives as intermediates.Treatment of an unsaturated amide with trimethylsilyl triflate in pentane and then iodine in tetrahydrofuran gives the iodo lactam.Some reactions of this new difunctional group with bases, nucleophiles, and Michael acceptors leading to functionalized or elaborated lactams are presented.In general, iodo lactams undergo direct SN2 reactions with reactive (but weakly basic) nucleophiles like azide and triphenylphosphine and elimination or decomposition in the presence of bases or basic nucleophiles.Sodium hydride may be used to generate an N-acylaziridine intermediate, which can be opened with azide to deliver an azido lactam with overall retention of stereochemistry.Silver-assisted solvolysis of iodo lactams gives the hydroxy lactams with retention of configuration, probably also because of participation by the lactam nitrogen.The sodium salt of 5-(iodomethyl)-2-pyrrolidinone (3), generated at -20 deg C, undergoes an annulation reaction with unsaturated esters (but not sulfones), leading to pyrrolizidine derivatives.
- Knapp, Spencer,Levorse, Anthony T.
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p. 4006 - 4014
(2007/10/02)
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- Cleavage of Tetrahydrofuran by tert-Butyldimethylsilyl Iodide and Further Transformations of the Resulting 1-Silyloxy-4-Iodobutane
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Tetrahydrofuran is readily cleaved by tert-butyldimethylsilyl iodide generated in situ by reaction of the chloride with sodium iodide in acetonitrile to give the corresponding 1-silyloxy-4-iodobutane, which in turn undergoes a number of useful functionalizations of the iodo group including substitutions with hetero nucleophiles, such as amine, thiolate sulfinate, and phosphite and carbon nucleophiles such as enolate and acetylide, with survival of the silyloxy group.
- Nystroem, Jan-Erik,McCanna, Terrence D.,Helquist, Paul,Amouroux, Roger
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- RHODIUM CARBENOID MEDIATED CYCLISATIONS. PART 2. SYNTHESIS OF CYCLIC ETHERS
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Alkylation of the dianion of methyl acetoacetate with the t-butyldimethylsilyl protected α,ω-halogeno alcohols (1)-(9) gives the β-keto esters (1) which are converted into the diazo alcohols (3) by diazo transfer and desilylation.Rhodium carbenoid cyclisa
- Heslin, Julie C.,Moody, Christopher J.
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p. 1417 - 1424
(2007/10/02)
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- SHORT INTRAMOLECULAR DIELS-ALDER APPROACH TO FUNCTIONALIZED SPIRODECANES
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The intramolecular Diels-Alder reaction of a (5'-hexynyl)cyclopentadiene provides a 1,2-tetramethylene-bridged norbornadiene which undergoes selective monohydrogenation followed by ozonolysis to provide the title compounds.
- Nystroem, Jan-E.,McCanna, Terrence D.,Helquist, Paul,Iyer, Ramnath S.
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p. 5393 - 5396
(2007/10/02)
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- A PROCEDURE FOR "IODOLACTAMIZATION"
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Treatment of an unsaturated amide with TMS-OTf, then iodine in THF gives the iodolactam.
- Knapp, Spencer,Rodriques, Karen E.,Levorse, Anthony T.,Ornaf, Raphael M.
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p. 1803 - 1806
(2007/10/02)
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- A SIMPLE ROUTE TO SPIROKETALS VIA ALKYLATION OF DIHYDROPYRAN
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3,4-Dihydro-2H-pyran was alkylated, via its 2-lithio derivative, with several O-protected β- or γ-iodo alcohols in excellent yields.Acidic treatment of the resultant 2-substituted dihydropyrans produced both the deprotection of the hydroxyl group and the
- Amouroux, Roger
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p. 1489 - 1492
(2007/10/02)
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