- Identification of Inhibitors of Cholesterol Transport Proteins Through the Synthesis of a Diverse, Sterol-Inspired Compound Collection
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Cholesterol transport proteins regulate a vast array of cellular processes including lipid metabolism, vesicular and non-vesicular trafficking, organelle contact sites, and autophagy. Despite their undoubted importance, the identification of selective modulators of this class of proteins has been challenging due to the structural similarities in the cholesterol-binding site. Herein we report a general strategy for the identification of selective inhibitors of cholesterol transport proteins via the synthesis of a diverse sterol-inspired compound collection. Fusion of a primary sterol fragment to an array of secondary privileged scaffolds led to the identification of potent and selective inhibitors of the cholesterol transport protein Aster-C, which displayed a surprising preference for the unnatural-sterol AB-ring stereochemistry and new inhibitors of Aster-A. We propose that this strategy can and should be applied to any therapeutically relevant sterol-binding protein.
- Laraia, Luca,Olsen, Asger Hegelund,Whitmarsh-Everiss, Thomas
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supporting information
p. 26755 - 26761
(2021/11/17)
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- A synthetic approach to (±)-aristomakine
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We describe the synthesis of trans-11b-methyl-2,3,4,6,11,11b-hexahydro-1H-benzo[a]carbazol-3-ol (2) in five steps from the Wieland-Miescher ketone 3 in 17% overall yield. The N-benzyl analogue (trans-11-Benzyl-11b-methyl-2,3,4,6,11,11b-hexahydro-1H-benzo[a]carbazol-3-ol) 15 was likewise prepared. Attempts thus far to fashion (±)-aristomakine (1) from 2, 15, or derivatives have not been successful.
- Perni, Robert B.,Gribble, Gordon W.
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- One-pot synthesis of Wieland-Miescher ketone by enzymes
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We first report that lipase from porcine pancreas catalyzed Robinson annulation in the organic media to synthesize the Wieland-Miescher ketone. The promiscuous catalytic activity of lipase in the Robinson reaction is due to an important role played by lipase activity in both the Michael addition and Aldol reaction.
- Lai, Yi-Feng,Zhang, Peng-Fei
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p. 4077 - 4082
(2015/06/30)
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- Prolinamide/PPTS-catalyzed Hajos-Parrish annulation: Efficient approach to the tricyclic core of cylindricine-type alkaloids
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A series of Wieland-Miescher ketone analogues bearing highly functionalized substituents are efficiently constructed in high enantioselectivities and good yields using catalytic amounts of prolinamide and PPTS. We have successfully utilized this reaction as a key step to synthesize the tricyclic core of cylindricine type alkaloids. Georg Thieme Verlag Stuttgart.
- Zhang, Xiao-Ming,Wang, Min,Tu, Yong-Qiang,Fan, Chun-An,Jiang, Yi-Jun,Zhang, Shu-Yu,Zhang, Fu-Min
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scheme or table
p. 2831 - 2835
(2009/05/07)
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- Evaluating β-amino acids as enantioselective organocatalysts of the Hajos-Parrish-Eder-Sauer-Wiechert reaction
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A systematic study of the effect of substitution within the β-amino acid framework indicates that both β2- and β3- amino acids catalyse the Hajos-Parrish-Eder-Sauer-Wiechert reaction with poor to reasonable levels of enantioselectivity. These results led to the evaluation of the conformationally constrained β-amino acid (1R,2S)-cispentacin, which catalyses the Hajos-Parrish-Eder-Sauer-Wiechert reaction with comparable or higher levels of enantioselectivity to l-proline. The Royal Society of Chemistry.
- Davies, Stephen G.,Russell, Angela J.,Sheppard, Ruth L.,Smith, Andrew D.,Thomson, James E.
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p. 3190 - 3200
(2008/03/14)
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- Bimorpholine-mediated enantioselective intramolecular and intermolecular aldol condensation
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(Chemical Equation Presented) Monosalts of N-substituted bimorpholine derivatives are efficient organocatalysts in intramolecular and intermolecular aldol reactions. The properties of the catalysts can be tuned either by the selection of an appropriate acid for the salt formation or by the change of a substituent at the nitrogen atom. In aldol condensation, i-Pr-substituted bimorpholine is the most stereoselective catalyst affording products in high yield with enantioselectivities up to 95% ee.
- Kanger, Tonis,Kriis, Kadri,Laars, Marju,Kailas, Tiiu,Mueuerisepp, Aleksander-Mati,Pehk, Tonis,Lopp, Margus
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p. 5168 - 5173
(2008/02/08)
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- Synthesis and use of 3,3′-bimorpholine derivatives in asymmetric Michael addition and intramolecular aldol reaction
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The synthesis of 3,3′-bimorpholine and its N-alkyl derivatives is described. These new diamine derivatives were revealed to be efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitroalkenes with excellent enantioselectivity (up to 90% ee). The potential of these organocatalysts was also demonstrated for the highly enantioselective intramolecular aldol reaction affording the Wieland-Miescher ketone with tremendous enantioselectivity (up to 95% ee). Georg Thieme Verlag Stuttgart.
- Sulzer-Mosse, Sarah,Laars, Marju,Kriis, Kadri,Kanger, Tonis,Alexakis, Alexandre
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p. 1729 - 1732
(2008/02/08)
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- Enantioselective synthesis of Wieland-Miescher ketone through bimorpholine-catalyzed organocatalytic aldol condensation
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Novel bimorpholine-derived organocatalysts have been used for highly enantioselective intramolecular aldol reaction affording Wieland-Miescher ketone in high yield and enantioselectivity (up to 92% and 95%, respectively). Georg Thieme Verlag Stuttgart.
- Kriis, Kadri,Kanger, T?nis,Laars, Marju,Kailas, Tiiu,Müürisepp, Aleksander-Mati,Pehk, T?nis,Lopp, Margus
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p. 1699 - 1702
(2008/02/03)
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- Promotion of one-pot Robinson annelation achieved by gradual pressure and temperature manipulation under supercritical conditions
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The one-pot Robinson annelation from 2-methyl-cyclohexane-1,3-dione with 3-buten-2-one can be achieved in high yield (95%) and high selectivity (95%) by pressure and temperature manipulation using supercritical carbon dioxide in the presence of MgO catalyst, whose method could be applied for various ketones to synthesize fused polycyclic compounds.
- Kawanami, Hajime,Ikushima, Yutaka
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p. 5147 - 5150
(2007/10/03)
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- Solid-supported Robinson annulation under microwave irradiation.
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Robinson annulation on alumina occurred efficiently on heating with microwave irradiation.
- Takatori, Kazuhiko,Nakayama, Masayasu,Futaishi, Naoko,Yamada, Saori,Hirayama, Shinobu,Kajiwara, Masahiro
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p. 455 - 457
(2007/10/03)
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- Asymmetric one-pot Robinson annulations
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One-pot syntheses of ketol SS-5a, enone S-2 and optically active spiroenediones S-14, R-7 and S-15 are reported.
- Rajagopal,Narayanan,Swaminathan
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p. 4887 - 4890
(2007/10/03)
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- Steric and complexation effects on the 1,4-addition reaction of lithium dimethylcuprate with rigid α,β-unsaturated ketones
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Reaction of lithium dimethylcuprate with a series of substituted 10- methyl-l(9)-octal-2-ones in diethyl ether give 1,4-addition products with the same ring junction stereochemistry as the parent, unsubstituted α,β- unsaturated ketone. The reactivity of the system is modified by groups positioned axially and 1,3 with respect to the β-carbon of the enone. Alkoxy substituents are generally activating, particularly if they are syn with respect to the incoming methyl group.
- Vellekoop, A. Samuel,Smith, Robin A.J.
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p. 11971 - 11994
(2007/10/03)
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- Ring-Enlarging Annulatons. A One-Step Conversion of Cyclic Silyl Acyloins and ω-Alkynyl Acetals to Polycyclic Enediones
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A new sequence of cationic reactions that converts cyclic silyl acyloins and ω-alkynyl acetals to polycyclic enediones is reported.For example, treatment of bis-1,2-((trimethylsilyl)oxy)cyclobutene and 2-(ethylenedioxy)-5-heptyne with excess boron trifluoride etherate in methylene chloride for 2 days provides 4-acetyl-3,5,6,6a-tetrahydro-6a-methyl-1-(2H)-pentalenone in 58percent yield.This product is formed via a sequence involving a Mukaiyama aldol reaction, a pinacol ring expansion, and a 5-exo-dig alkynyl ketone cyclization.In the case of terminal alkynes, the last cyclization occurs in a 6-endo-dig fashion.The scope and limitations of this process are studied, and a number of bi- and tricyclic ring systems are formed.
- Balog, Aaron,Curran, Dennis P.
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p. 337 - 344
(2007/10/02)
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- Annulative Ring Expansions. Direct Conversion of ω-Alkynyl Acetals to Polycyclic Unsaturated Ketones
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Geminal acylation of ω-acetylenic acetals and bis(silyloxy)cycloalkenes under Lewis acid conditions preceded cationic cyclization of the alkyne onto the ketone to produce polycyclic unsaturated ketones.
- Sisko, Joseph,Balog, Aaron,Curran, Dennis P.
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p. 4341 - 4342
(2007/10/02)
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- A New Annulation Reagent, 2-Oxo-3-alkenylphosphonates. Reactions with Carbonyl-Stabilized Carboanions or Silyl Enol Ethers Leading to Cyclohexanones
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The reactions of 2-oxo-3-alkenylphosphonates with carbonyl-stabilized carbanions directly lead to 2-cyclohexen-1-ones through a sequence of Michael reaction and intramolecular Horner-Emmons olefination.On the other hand, the Lewis acid-mediated reactions with silyl enol ethers produce 1,5-diketones as Michael adducts, which then undergo cyclization on treatment with sodium hydride or triethylamine/zinc (II) bromide to afford 2-cyclohexen-1-ones or 2-phosphinyl-2-cyclohexen-1-ones, respectively.
- Wada, Eiji,Funakoshi, Junji,Kanemasa, Shuji
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p. 2456 - 2464
(2007/10/02)
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- Dependence of the Lewis Acid-induced Reaction of β-stannyl Ketones upon Substitution Pattern. 1,2-Alkyl Migration versus Cyclopropanation
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3-Stannylcyclohexanones fully substituted at 2 and 3 positions undergo a 1,2-alkyl migration and cyclopropanation.The balance of the reaction pattern depends upon the steric environment and migratory aptitude of the alkyl groups.
- Fujiwara, Jun,Yamamoto, Taro,Sato, Tadashi
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p. 1775 - 1778
(2007/10/02)
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- The Selective Protection of the 3-Ketone Functions of Steroids as Heptafluoro-p-tolyl Enol Ethers
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Conjugated and unconjugated 3-ketone functions in steroids react with octafluorotoluene at above 100 deg C in the presence of caesium fluoride to give heptafluoro-p-tolyl enol ethers.The related but unusually reactive Wieland-Miescher ketone (11) reacted at room temperature in the presence of tetra-n-butylammonium fluoride.Enones were regenerated from their derivatives by acidic hydrolysis.Hydrolysis of the derivative (10) of 4,5α-dihydroxytestosterone was slu but sodium methoxide regenerated the parent steroid.The methods have been applied in a synthesis of deuterium-labelled testosterone.
- Jarman, Michael,McCague, Raymond
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p. 1129 - 1134
(2007/10/02)
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- Aliphatic Liquid Crystals, 5 - The Influence of Angular 4a- and 8a-Methyl Groups on the Nematic Character of all-trans-Perhydro-2-phenanthrenol Esters
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The synthesis of the 4a- and 8a-methyl-7-hexylperhydro-2-phenanthrenol esters 2b - d and 3b - d is described.Compared to their methyl free counterparts 1b - d they posses lower clearing points and therefore narrower nematic ranges.The 8a-methyl derivatives are also prepared in the optically active form.
- Sucrow, Wolfgang,Brinkkoetter, Gustav
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p. 4330 - 4340
(2007/10/02)
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- Synthesis of a 4-Acylcyclohexa-2,5-dienone: 3,4-Dihydro-3,3,8a-trimethylnaphtalene-1,6(2H,8aH)-dione
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The synthesis is reported of 3,4-dihydro-3,3,8a-trimethylnaphtalene-1,6-(2H,8aH)-dione (11; R = Me).This is the first isolated 4-acylcyclohexa-2,5-dienone, a class of compounds postulated particularly as intermediates in the Fries and photo-Fries rearrangements.The dienone undergoes very easy acyl cleavage in the presence of bases or dilute acids, to form a phenolic acid (18).Similar cleavage, or a retro-Fries migration of the acyl group from the 4-position to the dienone ring oxygen, has prevented isolation of 4-acetyl-4-methylcyclohexa-2,5-dienone.Concentrated aqueous sulphuric acid causes rearrangement of the dienone to 3,4-dihydro-8-hydroxy-3,3,5-trimethylnaphtalen-1(2H)-one (13; R = Me), via recyclisation of 18.In trifluoroacetic acid solutions the same product (13, R = Me) is formed from the dienone by direct, formal dienone-phenol rearrangement.
- Waring, Anthony John,Zaidi, Javid Hussain
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p. 631 - 640
(2007/10/02)
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- Thermally induced crossed aldol condensations
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A relatively efficient, noncatalytic method for effecting crossed aldol condensations between cyclic ketones and aldehydes and between cyclic 1,3-diones and methyl vinyl ketone is reported.
- Findlay, John A.,Desai, Dixit N.,Macaulay, John B.
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p. 3303 - 3304
(2007/10/02)
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