6654-36-0Relevant academic research and scientific papers
Family of Structurally Related Bioconjugates Yields Antibodies with Differential Selectivity against Ketamine and 6-Hydroxynorketamine
Kyzer, Jillian L.,Wenthur, Cody J.,Worob, Adam,Zheng, Zhen
, p. 4113 - 4122 (2021/11/01)
The dissociative-hypnotic compound ketamine is being used in an increasingly wide range of therapeutic contexts, including anesthesia, adjunctive analgesia, treatment-resistant depression, but it also continues to be a notable substance of abuse. No specific antidotes exist for ketamine intoxication or overdose. Immunopharmacotherapy has demonstrated the ability to offer overdose protection through production of highly specific antibodies that prevent psychoactive drug penetration across the blood-brain barrier, although antiketamine antibodies have not yet been assessed or optimized for use in this approach. Moreover, generation of specific antibodies also provides an opportunity to address the role of 6-hydroxynorketamine metabolites in ketamine's rapid-acting antidepressant effect through selective restriction of metabolite access to the central nervous system. Hapten design is a critical element for tuning immune recognition of small molecules, as it affects the presentation of the target antigen and thus the quality and selectivity of the response. Here, we report the synthesis and optimization of carrier protein and conjugation conditions for an initial hapten, norketamine-N-COOH (NK-N-COOH), to optimize vaccination conditions and assess the functional consequences of such vaccination on ketamine-induced behavioral alterations occurring at dissociative-like (50 mg/kg) doses. Iterating from this initial approach, two additional haptens, ketamine-N-COOH (KET-N-COOH) and 6-hydroxynorketamine-N-COOH (HNK-N-COOH), were synthesized to target either ketamine or 6-hydroxynorketamine with greater selectivity. The ability of these haptens to generate antiketamine, antinorketamine, and anti-6-hydroxynorketamine immune responses in mice was then assessed using enzyme-linked immunosorbent assay (ELISA) and competitive surface plasmon resonance (SPR) methods. All three haptens provoked immune responses in vivo, although the KET-N-COOH and 6-HNK-N-COOH haptens yielded antibodies with 5- to 10-fold improvements in affinity for ketamine and/or 6-hydroxynorketamine, as compared to NK-N-COOH. Regarding selectivity, vaccines bearing a KET-N-COOH hapten yielded an antibody response with approximately equivalent Kd values against ketamine (86.4 ± 3.2 nM) and 6-hydroxynorketamine (74.1 ± 7.8 nM) and a 90-fold weaker Kd against norketamine. Contrastingly, 6-HNK-N-COOH generated the highest affinity and most selective antibody profile, with a 38.3 ± 4.7 nM IC50 against 6-hydroxynorketamine; Kd values for ketamine and norketamine were 33- to 105-fold weaker, at 1290 ± 281.5 and 3971 ± 2175 nM, respectively. Overall, these findings support the use of rational hapten design to generate antibodies capable of distinguishing between structurally related, yet mechanistically distinct, compounds arising from the same precursor molecule. As applied to the production of the first-reported anti-6-hydroxynorketamine antibodies to date, this approach demonstrates a promising path forward for identifying the individual and combinatorial roles of ketamine and its metabolites in supporting rewarding effects and/or rapid-acting antidepressant activity.
DIBALH: From known fundamental to an unusual reaction; Chemoselective partial reduction of tertiary amides in the presence of esters
An, Duk Keun,Heo, Yu Jin,Jaladi, Ashok Kumar,Kim, Hyun Tae
, p. 33809 - 33813 (2021/12/09)
This study presents a quick and reliable approach to the chemoselective partial reduction of tertiary amides to aldehydes in the presence of readily reducible ester groups using commercial DIBALH reagent. Moreover, the developed method was also extended to multi-functional molecules bearing ester moieties, which were successfully chemoselectively reduced to the corresponding aldehydes. This journal is
Synthesis of Functionalized Aliphatic Acid Esters via the Generation of Alkyl Radicals from Silylperoxyacetals
Matsumoto, Akira,Shiozaki, Yoko,Sakurai, Shunya,Maruoka, Keiji
, p. 2431 - 2434 (2021/08/07)
We describe a catalytic method for the synthesis of a variety of functionalized aliphatic acid esters using silylperoxyacetals, which are versatile alkyl radical precursors with a terminal ester moiety. In the presence of an appropriate transition-metal catalyst, the in situ generation of alkyl radicals and the subsequent bond-forming process proceeds smoothly to afford synthetically valuable aliphatic acid derivatives. The present method can be applied to the efficient synthesis of a pharmaceutically important 1,1-diarylalkane motif. In addition, a novel strategy for the synthesis of structurally diverse hydroxy acid derivatives via a C?O bond formation process that utilizes TEMPO has been developed.
Directing Selectivity to Aldehydes, Alcohols, or Esters with Diphobane Ligands in Pd-Catalyzed Alkene Carbonylations
Aitipamula, Srinivasulu,Britovsek, George J. P.,Nobbs, James D.,Tay, Dillon W. P.,Van Meurs, Martin
, p. 1914 - 1925 (2021/06/28)
Phenylene-bridged diphobane ligands with different substituents (CF3, H, OMe, (OMe)2, tBu) have been synthesized and applied as ligands in palladium-catalyzed carbonylation reactions of various alkenes. The performance of these ligands in terms of selectivity in hydroformylation versus alkoxycarbonylation has been studied using 1-hexene, 1-octene, and methyl pentenoates as substrates, and the results have been compared with the ethylene-bridged diphobane ligand (BCOPE). Hydroformylation of 1-octene in the protic solvent 2-ethyl hexanol results in a competition between hydroformylation and alkoxycarbonylation, whereby the phenylene-bridged ligands, in particular, the trifluoromethylphenylene-bridged diphobane L1 with an electron-withdrawing substituent, lead to ester products via alkoxycarbonylation, whereas BCOPE gives predominantly alcohol products (n-nonanol and isomers) via reductive hydroformylation. The preference of BCOPE for reductive hydroformylation is also seen in the hydroformylation of 1-hexene in diglyme as the solvent, producing heptanol as the major product, whereas phenylene-bridged ligands show much lower activities in this case. The phenylene-bridged ligands show excellent performance in the methoxycarbonylation of 1-octene to methyl nonanoate, significantly better than BCOPE, the opposite trend seen in hydroformylation activity with these ligands. Studies on the hydroformylation of functionalized alkenes such as 4-methyl pentenoate with phenylene-bridged ligands versus BCOPE showed that also in this case, BCOPE directs product selectivity toward alcohols, while phenylene-bridge diphobane L2 favors aldehyde formation. In addition to ligand effects, product selectivities are also determined by the nature and the amount of the acid cocatalyst used, which can affect substrate and aldehyde hydrogenation as well as double bond isomerization.
Method for reducing carboxylic acid into aldehyde compounds
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Paragraph 0035-0038, (2020/02/27)
The invention discloses a method for reducing carboxylic acid into aldehyde compounds, and belongs to the field of organic chemical synthesis. Specifically, in an argon atmosphere, a carboxylic acid compound, a transition metal nickel compound, an anhydride compound, a ligand and a reducing agent are dissolved in an organic solvent, the mixture is heated and subjected to stirring reaction, after the reaction is finished, the pressure is reduced to remove the organic solvent, column chromatography separation is performed, and various aldehyde compounds are obtained. The method has the advantages of simple synthesis steps, mild reaction conditions, simplicity and easiness in operation, realization of successful reduction of the carboxylic acid compound into the aldehyde organic compounds, small use amount of the reaction catalyst, high product yield, and provision of a new approach for reduction of the carboxylic acid compound into the aldehyde compounds. Compared with a conventional method, the method has the advantages that raw materials are cheap, easy to obtain and environmentally friendly, substrate universality and functional group compatibility are improved, and the method hascertain innovativeness and unique research significance in organic synthesis methodology.
IONIZABLE AMINE LIPIDS AND LIPID NANOPARTICLES
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Page/Page column 126; 127, (2020/11/04)
The disclosure provides ionizable amine lipids and salts thereof (e.g., pharmaceutically acceptable salts thereof) useful for the delivery of biologically active agents, for example delivering biologically active agents to cells to prepare engineered cells. The ionizable amine lipids disclosed herein are useful as ionizable lipids in the formulation of lipid nanoparticle-based compositions.
Site-Selective 1,1-Difunctionalization of Unactivated Alkenes Enabled by Cationic Palladium Catalysis
Jeon, Jinwon,Ryu, Ho,Lee, Changseok,Cho, Dasol,Baik, Mu-Hyun,Hong, Sungwoo
supporting information, (2019/07/03)
A palladium(II)-catalyzed 1,1-difunctionalization of unactivated terminal and internal alkenes via addition of two nucleophiles was developed using a cationic palladium(II) complex. The palladacycle generated in situ as a result of a regioselective addition of a nucleophile to the alkene can readily undergo regioselective β-hydride elimination and migratory insertion with a cationic palladium catalyst. The resulting η3-π-allyl palladium(II) complex is the key intermediate that reacts with a second nucleophile to furnish the desired 1,1-difunctionalization of the alkene. Under the optimized reaction conditions, a wide range of indoles and anilines add to alkene units of 3-butenoic or 4-pentenoic acid derivatives to afford the synthetically useful γ,γ- or δ,δ-difunctionalized products with excellent regiocontrol. Furthermore, by employing internal hydroxyl or acid groups and external carbon nucleophiles, this transformation enables unsymmetric 1,1-difunctionalization to forge challenging and important oxo quaternary carbon centers. Combining experiments and DFT calculations on the mechanism of the reaction is investigated in detail.
Site-Selective 1,1-Difunctionalization of Unactivated Alkenes Enabled by Cationic Palladium Catalysis
Jeon, Jinwon,Ryu, Ho,Lee, Changseok,Cho, Dasol,Baik, Mu-Hyun,Hong, Sungwoo
supporting information, p. 10048 - 10059 (2019/07/04)
A palladium(II)-catalyzed 1,1-difunctionalization of unactivated terminal and internal alkenes via addition of two nucleophiles was developed using a cationic palladium(II) complex. The palladacycle generated in situ as a result of a regioselective addition of a nucleophile to the alkene can readily undergo regioselective β-hydride elimination and migratory insertion with a cationic palladium catalyst. The resulting η 3-π-allyl palladium(II) complex is the key intermediate that reacts with a second nucleophile to furnish the desired 1,1-difunctionalization of the alkene. Under the optimized reaction conditions, a wide range of indoles and anilines add to alkene units of 3-butenoic or 4-pentenoic acid derivatives to afford the synthetically useful γ,γ-or ?,?-difunctionalized products with excellent regiocontrol. Furthermore, by employing internal hydroxyl or acid groups and external carbon nucleophiles, this transformation enables unsymmetric 1,1-difunctionalization to forge challenging and important oxo quaternary carbon centers. Combining experiments and DFT calculations on the mechanism of the reaction is investigated in detail.
Iron-Catalyzed Aerobic Oxidation of Alcohols: Lower Cost and Improved Selectivity
Jiang, Xingguo,Liu, Jinxian,Ma, Shengming
, p. 825 - 835 (2019/05/02)
An aerobic oxidation reaction of alcohols toward aldehydes or ketones using catalytic amounts of Fe(NO3)3·9H2O, 4-OH-TEMPO, and NaCl has been developed. Compared with the former catalytic system with TEMPO developed in this group, the new protocol using 4-OH-TEMPO, which is much cheaper on an industrial scale, accomplished the transformation with a higher selectivity, especially for aliphatic alcohols toward aldehydes. α,β-Unsaturated alkynals or alkynones can be efficiently synthesized from propargyl alcohols, which has been much less studied in the literature.
Nylon Intermediates from Bio-Based Levulinic Acid
Marckwordt, Annemarie,El Ouahabi, Fatima,Amani, Hadis,Tin, Sergey,Kalevaru, Narayana V.,Kamer, Paul C. J.,Wohlrab, Sebastian,de Vries, Johannes G.
supporting information, p. 3486 - 3490 (2019/02/13)
Use of ZrO2/SiO2 as a solid acid catalyst in the ring-opening of biobased γ-valerolactone with methanol in the gas phase leads to mixtures of methyl 2-, 3-, and 4-pentenoate (MP) in over 95 % selectivity, containing a surprising 81 % of M4P. This process allows the application of a selective hydroformylation to this mixture to convert M4P into methyl 5-formyl-valerate (M5FV) with 90 % selectivity. The other isomers remain unreacted. Reductive amination of M5FV and ring-closure to ?-caprolactam in excellent yield had been reported before. The remaining mixture of 2- and 3-MP was subjected to an isomerising methoxycarbonylation to dimethyl adipate in 91 % yield.
