31883-98-4Relevant academic research and scientific papers
Identification, Synthesis, and Characterization of a Major Circulating Human Metabolite of TRPV4 Antagonist GSK2798745
Behm, David J.,Briand, Jacques,Erhard, Karl,Graczyk-Millbrandt, Grazyna,Holt, Dennis A.,Lawhorn, Brian G.,Mcatee, John J.,Pero, Joseph E.,Rivero, Ralph A.,Roberts, Andrew D.
supporting information, p. 1498 - 1502 (2021/09/13)
GSK2798745, an antagonist of the transient receptor potential vanilloid 4 (TRPV4) ion channel, was recently investigated in clinical trials for the treatment of cardiac and respiratory diseases. Human plasma and urine samples collected from healthy volunteers following oral administration were analyzed to identify circulating and excreted metabolites of the parent drug. One major circulating metabolite (1) was found in pooled human plasma samples, accounting for approximately half of the observed drug-related material. Isolation of metabolite 1 from urine samples followed by MS and NMR studies led to a putative structural assignment of 1 where hydroxylation of GSK2798745 occurred on the central ring, producing a penta-substituted cyclohexane structure containing three stereocenters. Two unique chemical syntheses of the proposed structure were developed to confirm the identity of metabolite 1 and provide access to gram quantities for biological characterization.
Highly Enantioselective Construction of Hajos-Wiechert Ketone Skeletons via an Organocatalytic Vinylogous Michael/Stetter Relay Sequence
Jia, Zhi-Long,Wang, Yao,Zhao, Chuan-Gang,Zhang, Xiao-Hai,Xu, Peng-Fei
supporting information, p. 2130 - 2133 (2017/04/27)
A highly enantioselective supramolecular iminium-catalyzed vinylogous Michael addition/Stetter relay sequence has been developed. This transformation provided a series of Hajos-Wiechert-type fused bicyclic diones with three continuous stereogenic centers in good yields with excellent enantioselectivities. The obtained products can be easily transformed into other structures with potential synthetic value.
Regioselective Iridium-Catalyzed Asymmetric Monohydrogenation of 1,4-Dienes
Liu, Jianguo,Krajangsri, Suppachai,Singh, Thishana,De Seriis, Giulia,Chumnanvej, Napasawan,Wu, Haibo,Andersson, Pher G.
supporting information, p. 14470 - 14475 (2017/10/24)
A highly efficient regio- and enantioselective monohydrogenation of 1,4-dienes has been realized using an iridium catalyst with a chiral N,P-ligand under mild conditions. The substrate scope was studied and included both unfunctionalized as well as functionalized substituents on the meta- or para-position. Substrates having substituents with functionalities such as silyl protected alcohols or ketals were monohydrogenated in high regioselectivity and high enantiomeric excess (up to 98% ee).
Expedient route to the functionalized calyciphylline a- Type skeleton via a michael addition- RCM strategy
Sladojevich, Filippo,Michaelides, Iacovos N.,Darses, Benjamin,Ward, John W.,Dixon, Darren J.
, p. 5132 - 5135 (2011/12/15)
An efficient, robust, and scalable strategy to access the functionalized core of calyciphylline A-type alkaloids has been developed starting from commercially available 3-methylanisole. Key features of this approach are an intramolecular Michael addition/allylation sequence and a ringclosing metathesis step.
A concise, stereocontrolled total synthesis of rippertenol
Snyder, Scott A.,Wespe, Daniel A.,Von Hof, J. Marian
supporting information; experimental part, p. 8850 - 8853 (2011/08/04)
The first total synthesis of the unique terpene rippertenol, a molecule with dense stereochemical complexity arrayed on a compact framework largely devoid of functional groups, is described. Key elements include orchestrated and unique applications of aldol condensations, Diels-Alder chemistry, and a ring expansion to advance a chiral starting material containing a single chiral center into the final target in a concise and diastereocontrolled manner.
Synthesis of cyclohexadienylstannanes - Novel example of vinylic SRN1 mechanism: A theoretical and experimental study
Dorn, Viviana B.,Badajoz, Mercedes A.,Lockhart, María T.,Chopa, Alicia B.,Pierini, Adriana B.
, p. 2458 - 2462 (2008/09/20)
The reaction of trimethyltinsodium (1) with 1-(diethoxyphosphoryl)oxy-1,3-cyclohexadienes in liquid ammonia under irradiation affords the corresponding 1-trimethylstannylcyclohexadienes. We suggest that these reactions occur by an SRN1 mechanism. On the other hand, 2-(diethoxyphosphoryl)oxy-1,3-cyclohexadiene reacts very slowly towards 1 and the substitution product decomposes under the reaction conditions employed. Thus, structurally similar compounds do not behave in the same way under ET conditions. We suggest that this behavior is mainly due to differences in spin density of their radical anions, which affect their fragmentation rates. Our results are supported by computational calculations.
Identification of m-Mentha-3(8),6-diene (isosylveterpinolene) in black pepper oil
Nussbaumer, Cornelius,Cadalbert, Riccardo,Kraft, Philip
, p. 53 - 58 (2007/10/03)
m-Mentha-3(8),6-diene (= isosylveterpinolene; 5), which has not been found in nature before, was shown by GC/MS analysis and co-injection with a synthetic sample to be present to the extent of 0.12-0.17% in black and green pepper oil. The synthetic reference 5 was prepared by deconjugation of 3- methylcyclohex-2-en-1-one (1), subsequent alkylation with lithium 2-lithio- 2-methylpropanoate, and decarboxylative dehydration of the resulting hydroxycarboxylic acid 3 employing dimethylformamide dimethyl acetal. On polar GC columns, 5 was eluted between p-cymene and terpinolene, and was characterized by an MS similar to that of terpinolene, but with the fragment m/z 121 (59, [M - Me]+) being less intense than that of the molecular ion at m/z 136 (67, M+). Since m-mentha-3(8),6-diene was also found to the extent of 0.24% in the headspace of ground black peppercorns, it can be considered to be of genuine natural origin, and thus is the first established example of a naturally occurring m-menthadiene.
Concise total syntheses of the sesquiterpenoids (-)-homalomenol A and (-)-homalomenol B
Piers, Edward,Oballa, Renata M.
, p. 8439 - 8447 (2007/10/03)
The conjugate additions of the organocopper(I) reagents 22 and 27 to the enantiomerically homogeneous bicyclic enone 4 provided, after epimerization (NaOMe, MeOH) of the resultant product mixtures and appropriate chromatographic separations, the bicyclo[4.3.0]nonan-2-ones 24 and 28. Compounds 24 and 28 were readily converted, via two synthetic steps in each case, into the sesquiterpenoids (-)-homalomenols B (2) and A (1), respectively.
Mechanism of acid-catalyzed photoaddition of methanol to 3-alkyl-2-cyclohexenones
Schuster, David I.,Yang, Jie-Min,Woning, Jan,Rhodes, Timothy A.,Jensen, Anton W.
, p. 2004 - 2010 (2007/10/03)
Contrary to a previous report, it is concluded that formation of methanol adducts to 3-methyl-2-cyclohexenones and of deconjugated enones on irradiation of the enones in acidified solutions proceeds via protonation of the intermediate enone ?,?* triplet excited state and not by protonation of a relatively long-lived ground state trans-cyclohexenone.A rate constant for protonation of the triplet state of 3-methyl-2-cyclohexenone by sulfuric acid of 1.7*109 M-1 s-1 was determined by laser flash photolysis in ethyl acetate.Based on quantum efficiencies of product formation, a rate constant of ca. 108 M-1 s-1 was estimated for protonation of the enone triplet by acetic acid, which is too small to cause measurable reduction in the triplet state lifetime in the mM concentration range used in the preparative studies.The intermediate carbocation can be trapped by methanol, or revert to starting enone or the exocyclic deconjugated enone by loss of a proton.Since products revert to starting materials in an acid-catalyzed process, there is an acid concentration at which the yields of products are optimal.This concentration is ca. 6mM for acetic acid, but it is only 0.1 mM for p-toluenesulfonic or sulfuric acids.Product formation could be quenched using 1-methylnaphthalene and cyclopentene as triplet quenchers; in the latter case, formation of photoadducts was observed to compete with formation of methanol adducts.Quenching rate constants were determined by laser flash studies. - Key words: laser flash photolysis, kinetic absorption spectroscopy (KAS), photoacoustic calorimetry (PAC), protonation of triplet states, trans-cyclohexenones.
Thermolysis of alkylated 2-cyclohexenones and related monoterpenoid ketones
Lange, Gordon L.,Pereira, Vincent A.,Weedle, Michael
, p. 1639 - 1644 (2007/10/02)
2-Cyclohexenone and three methylated cyclohexenones were thermolyzed at 400 deg C for 20 hours to give conversions to products in the range 11 to 45 percent.When three monoterpenes containing the cyclohexenone moiety were thermolyzed under the same conditions the conversions were over 75 percent.The major products formed were alkylated benzenes, alkylated phenols, and double bond isomers of the starting enones.Mechanisms are proposed to account for these products.
