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1. Synthesis of model bacteriochlorophylls containing substituents of native rings A, C and E

   https://doi.org/10.1039/d1nj02469h  

   Chung, Duy T. ; Tran, Phuong Vy ; Chau Nguyen, Khiem ; Wang, Pengzhi ; Lindsey, Jonathan S. ( August 2021 , New Journal of Chemistry)

   null (Ed.)

   A route under development for the synthesis of bacteriochlorophyll a and analogues relies on joining an AD-dihydrodipyrrin (bearing a D-ring carboxaldehyde) and a BC-dihydrodipyrrin (bearing a C-ring β-ketoester group and a B-ring dimethoxymethyl group) via Knoevenagel condensation followed by double-ring closure (Nazarov cyclization, electrophilic aromatic substitution, and elimination of methanol). Prior synthetic studies afforded the bacteriochlorophyll skeleton containing a gem-dimethyl group in ring B, a trans -dialkyl group in ring D, and a carboethoxy group at the 3-position of ring A. To explore the incorporation of native substituents, the synthesis of two bacteriochlorophyll analogues thereof was pursued, one with 12-methyl and 3-carboethoxy groups and the other with 2,12-dimethyl and 3-acetyl groups. The 12-methyl group resulted in half the yield ( versus the unsubstituted analogue) in the Knoevenagel reaction, but insignificant effects in all other steps including the rate and yield of double-ring closure despite the known effects of alkyl groups to facilitate electrophilic substitution of pyrroles. The 2-methyl-3-acetyl group, however, resulted in diminished yields in several steps, including the Knoevenagel reaction, but not the double-ring closure. The results point to obstacles and openings on the path to total syntheses of the native pigments. 

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2. Synthesis of AD-Dihydrodipyrrins Equipped with Latent Substituents of Native Chlorophylls and Bacteriochlorophylls

   https://doi.org/10.1021/acs.joc.1c01239  

   Wang, Pengzhi ; Lindsey, Jonathan S. ( July 2021 , The Journal of Organic Chemistry)

   null (Ed.)

   Native chlorophylls and bacteriochlorophylls share a common trans-substituted pyrroline ring D (17-propionic acid, 18-methyl), whereas diversity occurs in ring A particularly at the 3-position. Two dihydrodipyrrins equipped with native-like D-ring substituents and tailorable A-ring substituents have been synthesized. The synthesis relies on a Schreiber-modified Nicholas reaction to construct the stereochemically defined precursor to ring D, a dialkyl-substituted pent-4-ynoic acid. The carboxylic acid group of the intact propionic acid proved unworkable, whereupon protected propionate (−CO2tBu) and several latent propyl ethers were examined. The tert-butyldiphenylsilyl-protected propanol substituent proved satisfactory for reaction of the chiral N-acylated oxazolidinone, affording (2S,3S)-2-(3-((tert-butyldiphenylsilyl)-oxy)propyl)-3-methylpent-4-ynoic acid in ∼30% yield over 8 steps. Two variants for ring A, 2-tert-butoxycarbonyl-3-Br/H-5-iodo-4- methylpyrrole, were prepared via the Barton−Zard route. Dihydrodipyrrin formation from the pyrrole and pentynoic acid entailed Jacobi Pd-mediated lactone formation, Petasis methenylation, and Paal−Knorr-type pyrroline formation. The two AD- dihydrodipyrrins bear the D-ring methyl and protected propanol groups with a stereochemical configuration identical to that of native (bacterio)chlorophylls, and a bromine or no substitution in ring A corresponding to the 3-position of (bacterio)chlorophylls. The analogous β-position of a lactone−pyrrole intermediate on the path to the dihydrodipyrrin also was successfully brominated, opening opportunities for late-stage diversification in the synthesis of (bacterio)chlorophylls. 

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3. Catalytic intramolecular hydroamination of aminoallenes using titanium complexes of chiral, tridentate, dianionic imine-diol ligands

   https://doi.org/10.1039/C8DT05156A  

   Sha, Fanrui ; Mitchell, Benjamin S. ; Ye, Christopher Z. ; Abelson, Chase S. ; Reinheimer, Eric W. ; LeMagueres, Pierre ; Ferrara, Joseph D. ; Takase, Michael K. ; Johnson, Adam R. ( January 2019 , Dalton Transactions)

   Alkylation of d - or l -phenylalanine or valine alkyl esters was carried out using methyl or phenyl Grignard reagents. Subsequent condensation with salicylaldehyde, 3,5-di- tert -butylsalicylaldehyde, or 5-fluorosalicylaldehyde formed tridentate, X 2 L type, Schiff base ligands. Chiral shift NMR confirmed retention of stereochemistry during synthesis. X-ray crystal structures of four of the ligands show either inter- or intramolecular hydrogen bonding interactions. The ligands coordinate to the titanium reagents Ti(NMe 2 ) 4 or TiCl(NMe 2 ) 3 by protonolysis and displacement of two equivalents of HNMe 2 . The crystal structure of one example of Ti(X 2 L)Cl(NMe 2 ) was determined and the complex has a distorted square pyramidal geometry with an axial NMe 2 ligand. The bis-dimethylamide complexes are active catalysts for the ring closing hydroamination of di- and trisubstituted aminoallenes. The reaction of hepta-4,5-dienylamine at 135 °C with 5 mol% catalyst gives a mixture of 6-ethyl-2,3,4,5-tetrahydropyridine (40–72%) and both Z - and E -2-propenyl-pyrrolidine (25–52%). The ring closing reaction of 6-methyl-hepta-4,5-dienylamine at 135 °C with 5 mol% catalyst gives exclusively 2-(2-methyl-propenyl)-pyrrolidine. The pyrrolidine products are obtained with enantiomeric excesses up to 17%. 

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4. Enzymatic Knoevenagel condensation in dual‐functionalized water‐mimicking ionic liquids and tertiary amide solvents

   https://doi.org/10.1002/jctb.7603  

   Zhao, Hua ; Campbell, Chante' D. ( February 2024 , Journal of Chemical Technology & Biotechnology)

   Knoevenagel condensation is an important tool for building carbon–carbon (CC) bonds, especially when catalyzed by enzymes to enable a potentially high chemo‐, regio‐ and/or stereoselectivity. Although many Knoevenagel condensation reactions are carried out in aqueous solutions, insoluble hydrophobic substrates often lead to poor catalytic efficiencies. The use of water‐miscible organic solvents improves the substrate solubilization, but usually induces activity suppression or inactivation of enzymes. There is a great need to develop alternative solvents for both substrate dissolution and enzyme compatibility in CC bond formation reactions.

   Our group previously developed dual‐functionalized water‐mimicking ionic liquids (ILs) for the activation and stabilization of hydrolases (e.g. lipase and protease). In the present study, we evaluated the Knoevenagel condensation of 4‐chlorobenzaldehyde with acetylacetone, and found that porcine pancreas lipase in water‐mimicking ILs carrying ammonium, imidazolium and benzimidazolium cations enabled higher reaction rates (up to 3.22 μmol min⁻¹ g⁻¹lipase) and better yields thantert‐butanol, glymes and [BMIM][Tf₂N]. Interestingly, tertiary amide solvents such asN‐methyl‐2‐pyrrolidone (NMP),N,N‐dimethylformamide (DMF) andN,N‐dimethylacetamide (DMAc) led to 8.2‐ to 11.1‐fold increases in the initial rate (up to 35.66 μmol min⁻¹ g⁻¹lipase) when compared with dual‐functionalized ILs, which is likely due to some synergistic effect of these tertiary amides with the lipase.

   Dual‐functionalized ILs based on ammonium, imidazolium and benzimidazolium cations improved Knoevenagel condensation reaction rates and yields when compared withtert‐butanol and glymes. Tertiary amides (NMP, DMF and DMAc) significantly increased the reaction rate. © 2024 The Authors.Journal of Chemical Technology and Biotechnologypublished by John Wiley & Sons Ltd on behalf of Society of Chemical Industry (SCI).

    

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5. A Validated UHPLC–MS/MS Method for Determination of Nalbuphine in Human Plasma and Application for Pharmacokinetic Study of Patients Undergoing General Anesthesia

   https://doi.org/10.1093/chromsci/bmac094  

   Gao, Xiaonan ; Nie, Xuyang ; Gao, Jinglin ; Heng, Tianfang ; Zhang, Yuqi ; Hua, Li ; Sun, Yaqi ; Feng, Zhangying ; Jia, Li ; Wang, Mingxia ( December 2022 , Journal of Chromatographic Science)

   Nalbuphine was a semisynthetic opioid analgesic widely used in the treatment of both acute and chronic pain. We developed and validated a rapid, simple and sensitive method by ultra-performance liquid chromatography–tandem mass spectrometry (MS/MS) for the simultaneous quantitation of nalbuphine in human plasma, and we reported the pharmacokinetic features of patients during general anesthesia for abdominal surgery. Sample separation was achieved on a Kinetex Phenyl-Hexyl column (50 × 2.1 mm, 1.7 μm) after simple protein precipitation with acetonitrile. The mobile phase was composed of acetonitrile and 3 mM of ammonium acetate aqueous solution with 0.1% formic acid. Gradient elution was used in 4.5 min with a flow rate of 0.5 mL/min at 40°C. MS detection using AB Sciex QTRAP 5500 mass spectrometer was characterized by electrospray ionization for positive ions in multiple reaction monitoring mode. Quantitative ion pairs were m/z 358.4 → 340.1 for nalbuphine and m/z 340.0 → 268.3 for nalmefene, which were used as the internal standard (IS). The calibration curves showed good linearity (r2>0.99) over concentration range of 0.1–500 ng/mL. The intra-and inter-batch precisions were within 10.67%, and accuracy ranged from 94.07 to 105.34%. The IS–normalized matrix factors were 1.02–1.03 with RSD% (≤5.82%). The recoveries ranged from 101.09 to 106.30%. In conclusion, a rapid, simple, sensitive and economical analytical method was developed and validated to detect the concentration in plasma samples obtained from patients receiving nalbuphine intravenous injection and was successfully applicated to human pharmacokinetic studies of nalbuphine.

    

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