131692-90-5Relevant academic research and scientific papers
Synthesis and evaluation of colletoic acid core derivatives
Ling, Taotao,Gautam, Lekh Nath,Griffith, Elizabeth,Das, Sourav,Lang, Walter,Shadrick, William R.,Shelat, Anang,Lee, Richard,Rivas, Fatima
supporting information, p. 126 - 132 (2016/02/05)
Cortisol homeostasis has been linked to the pathogenesis of metabolic syndrome (MetS), since it stimulates hepatic gluconeogenesis and adipogenesis. MetS is classified as a constellation of health conditions that increase the risk of type 2 diabetes and cardiovascular disease. Intracellular cortisol levels are regulated by 11β-hydroxysteroid dehydrogenase (type 1 and type 2) in a tissue dependent manner. The type 1 enzyme (11β-HSD1) is widely expressed in glucocorticoid targeted tissues and is responsible for the conversion of cortisone to the active cortisol. Local reduction of cortisol regeneration presents a potential strategy for MetS treatment. Recently we disclosed the total synthesis of (+)-colletoic acid as a potent 11β-HSD1 inhibitor. Herein, we describe our improved processing chemistry for the synthesis of the colletoic acid core to access a diverse number of derivatives for evaluation against 11β-HSD1. The Evan's chiral auxiliary was utilized to construct the acyclic precursor 12 to afford the acorane core 9 using a modified Heck reaction in excellent chemical yields. The colletoic acid core derivatives showed modest activity against 11β-HSD1 and will serve for further biological evaluation.
Enantiodivergent Fluorination of Allylic Alcohols: Data Set Design Reveals Structural Interplay between Achiral Directing Group and Chiral Anion
Neel, Andrew J.,Milo, Anat,Sigman, Matthew S.,Toste, F. Dean
supporting information, p. 3863 - 3875 (2016/04/09)
Enantioselectivity values represent relative rate measurements that are sensitive to the structural features of the substrates and catalysts interacting to produce them. Therefore, well-designed enantioselectivity data sets are information rich and can provide key insights regarding specific molecular interactions. However, if the mechanism for enantioselection varies throughout a data set, these values cannot be easily compared. This premise, which is the crux of free energy relationships, exposes a challenging issue of identifying mechanistic breaks within multivariate correlations. Herein, we describe an approach to addressing this problem in the context of a chiral phosphoric acid catalyzed fluorination of allylic alcohols using aryl boronic acids as transient directing groups. By designing a data set in which both the phosphoric and boronic acid structures were systematically varied, key enantioselectivity outliers were identified and analyzed. A mechanistic study was executed to reveal the structural origins of these outliers, which was consistent with the presence of several mechanistic regimes within the data set. While 2- and 4-substituted aryl boronic acids favored the (R)-enantiomer with most of the studied catalysts, meta-alkoxy substituted aryl boronic acids resulted in the (S)-enantiomer when used in combination with certain (R)-phosphoric acids. We propose that this selectivity reversal is the result of a lone pair-π interaction between the substrate ligated boronic acid and the phosphate. On the basis of this proposal, a catalyst system was identified, capable of producing either enantiomer in high enantioselectivity (77% (R)-2 to 92% (S)-2) using the same chiral catalyst by subtly changing the structure of the achiral boronic acid.
Gold(l)-catalyzed formation of furans by a Claisen type rearrangement of ynenyl allyl ethers
Istrate, Florin M.,Gagosz, Fabien
, p. 878 - 885 (2011/09/20)
A series of ynenyl allyl ethers were rearranged into polysubstituted furans in the presence of a gold(I) catalyst. It is proposed that the transformation involves a Claisen-type rearrangement that allows the efficient creation of quaternary centers under mild experimental conditions.
Generation of medium-ring cycloalkynes by ring expansion of vinylogous acyl triflates
Tummatorn, Jumreang,Dudley, Gregory B.
supporting information; experimental part, p. 1572 - 1575 (2011/04/26)
Reductive cyclization of aryl and vinyl iodides tethered to vinylogous acyl triflates (VATs) induces a ring-expanding fragmentation to provide cyclic alkynyl ketones, including strained nine-membered cycloalkynes, in fair to excellent yield. The tandem cy
Improved catalysts for the iridium-catalyzed asymmetric isomerization of primary allylic alcohols based on charton analysis
Mantilli, Luca,Gerard, David,Torche, Sonya,Besnard, Celine,Mazet, Clement
supporting information; experimental part, p. 12736 - 12745 (2011/02/21)
An improved generation of chiral cationic iridium catalysts for the asymmetric isomerization of primary allylic alcohols is disclosed. The design of these air-stable complexes relied on the preliminary mechanistic information available, and on Charton analyses using two preceding generations of iridium catalysts developed for this highly challenging transformation. Sterically unbiased chiral aldehydes that were not accessible previously have been obtained with high levels of enantioselectivity, thus validating the initial hypothesis regarding the selected ligand-design elements. A rationale for the high enantioselectivities achieved in most cases is also presented. Achieving enantioselectivity: An improved generation of chiral cationic iridium catalysts for the asymmetric isomerization of primary allylic alcohols is disclosed. The design of these air-stable complexes relies on preliminary mechanistic information and on Charton analyses using two preceding generations of iridium catalysts developed for this highly challenging transformation (see figure).
Total synthesis and biological evaluation of the cytotoxic resin glycosides ipomoeassin A-F and analogues
Nagano, Takashi,Pospisil, Jiri,Chollet, Guillaume,Schulthoff, Saskia,Hickmann, Volker,Moulin, Emilie,Herrmann, Jennifer,Mueller, Rolf,Fuerstner, Alois
supporting information; experimental part, p. 9697 - 9706 (2010/04/29)
A multitasking C-silylation strategy using the readily available compound 26 as a surrogate for cinnamic acid represents the key design element of a total synthesis of all known members of the ipomoeassin family of resin glyosides. This protecting group maneuver allows the unsaturated acids decorating the glucose subunit of the targets to be attached at an early phase of the synthesis, prevents their participation in the ruthenium-catalyzed ring-closing metathesis (RCM) used to form the macrocyclic ring, and protects them against reduc tion during the hydrogenation of the resulting cycloalkene over Wilkinson's catalyst. As the C-silyl group can be concomitantly removed with the O-TBS substituent using tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) in acetonitrile, no separate protecting group manipulations were necessary in the final stages, thus contributing to a favorable overall "economy of steps". In addition to the naturally occurring ipomoeassins, a small set of synthetic analogues has also been prepared by "diverted total synthesis". The cytotoxicity of these compounds was assayed with two different cancer cell lines. The recorded data confirm previous findings that the acylation- and oxygenation pattern of these amphiphilic glycoconjugates is highly correlated with their biological activity profile. Ipomoeassin F turned out to be the most promising member of the series, showing IC50 values in the low nanomolar range.
Synthesis of functionalized furans via gold(I)-catalyzed Claisen-type rearrangement
Istrate, Florin M.,Gagosz, Fabien L.
, p. 730 - 733 (2008/09/17)
(Chemical Equation Presented) Gold(I)-catalyzed cyclization of pentenynyl allyl ethers allows the rapid construction of functionalized furans. The concerted oxy-Claisen-type mechanism induces a complete selectivity of the process and allows the easy forma
Novel selective PPARδ agonists: Optimization of activity by modification of alkynylallylic moiety
Havranek, Miroslav,Sauerberg, Per,Mogensen, John P.,Kratina, Pavel,Jeppesen, Claus B.,Pettersson, Ingrid,Pihera, Pavel
, p. 4144 - 4149 (2008/03/11)
Y-shaped molecules bearing alkynylallylic moieties were found to be potent and selective PPARδ activators. The alkynylallylic moiety was synthesized from alkyn-1-ols by hydroalumination followed by a cross-coupling reaction. Series of active compounds 6 w
Total syntheses of ipomoeassin B and E
Fuerstner, Alois,Nagano, Takashi
, p. 1906 - 1907 (2007/10/03)
A concise, flexible, and efficient total synthesis of the cytotoxic resin glycosides ipomoeassin B (1) and ipomoeassin E (2) is reported which features the advantages of a novel protecting group strategy employing (Z)-3-dimethyl(phenyl)silyl-2-propenoic acid as cinnamic acid surrogate. The use of this readily available compound allowed the macrocycle of the glycolipids to be formed by ring closing olefin metathesis (RCM) with the aid of the second generation Grubbs carbene complex 12. The resulting E/Z mixture could be selectively hydrogenated using Wilkinson's catalyst [RhCl(PPh3)3] without affecting the unsaturated esters in the periphery of the compound, before the C-silyl group was cleaved off with TASF [tris(dimethylamino)sulfonium difluorotrimethylsilicate] under notably mild conditions to release the required cinnamate moiety. Other key steps of the synthesis route comprise the formation of the disaccharide linkage by the trichloroacetimidate method, the formation of the chiral acid segment 19 via a VO(acac)2-catalyzed, tert-BuOOH-induced oxidative rearrangement of the optically pure furyl alcohol (-)-15 (Achmatowicz-type reaction), and a reductive cleavage of the 4,6-O-p-methoxybenzylidene acetal in 5 with NaBH3CN and Me3SiCl (TMSCl), the regiochemical course of which was found to be opposite to that previously reported in the literature for sterically less encumbered substrates. Copyright
Stereoselective Lewis acid mediated [1,3] ring contraction of 2,5-dihydrooxepins as a route to polysubstituted cyclopentenes
Nasveschuk, Christopher G.,Rovis, Tomislav
, p. 3264 - 3267 (2007/10/03)
(Chemical Equation Presented) A room-temperature diastereoselective [1,3] rearrangement results from treatment of 2,5-dihydrooxepins with EtAlCl 2 (see scheme). A modular synthesis of dihydrooxepins allows substituents to be incorporated at any
