Stereoselective Synthesis and Catalytical Application of Perillaldehyde-Based 3-Amino-1,2-diol Regioisomers.

A library of regioisomeric monoterpene-based aminodiols was synthesised and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The synthesis of the first type of aminodiols was achieved starting from (-)-8,9-dihydroperillaldehyde via reductive amination, followed by Boc protection and dihydroxylation with the OsO4/NMO system. Separation of formed stereoisomers resulted in a library of aminodiol diastereoisomers. The library of regioisomeric analogues was obtained starting from (-)-8,9-dihydroperillic alcohol, which was transformed into a mixture of allylic trichloroacetamides via Overman rearrangement. Changing the protecting group to a Boc function, the protected enamines were subjected to dihydroxylation with the OsO4/NMO system, leading to a 71:16:13 mixture of diastereoisomers, which were separated, affording the three isomers in isolated form. The obtained primary aminodiols were transformed into secondary derivatives. The regioselectivity of the ring closure of the N-benzyl-substituted aminodiols with formaldehyde was also investigated, resulting in 1,3-oxazines in an exclusive manner. To explain the stability difference between diastereoisomeric 1,3-oxazines, a series of comparative theoretical modelling studies was carried out. The obtained potential catalysts were applied in the reaction of aromatic aldehydes and diethylzinc with moderate to good enantioselectivities (up to 94% ee), whereas the opposite chiral selectivity was observed between secondary aminodiols and their ring-closed 1,3-oxazine analogues.

Synthesis of Chiral 1,2-Amino Alcohol-Containing Compounds Utilizing Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Unprotected α-Ketoamines.

Herein, we disclose a facile synthetic strategy to access an important class of drug molecules that contain chiral 1,2-amino alcohol functionality utilizing highly effective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-ketoamines. Recently, the COVID-19 pandemic has caused a crisis of shortage of many important drugs, especially norepinephrine and epinephrine, for the treatment of anaphylaxis and hypotension because of the increased demand. Unfortunately, the existing technologies are not fulfilling the worldwide requirement due to the existing lengthy synthetic protocols that require additional protection and deprotection steps. We identified a facile synthetic protocol via a highly enantioselective one-step process for epinephrine and a two-step process for norepinephrine starting from unprotected α-ketoamines 1b and 1a, respectively. This newly developed enantioselective ruthenium-catalyzed asymmetric transfer hydrogenation was extended to the synthesis of many 1,2-amino alcohol-containing drug molecules such as phenylephrine, denopamine, norbudrine, and levisoprenaline, with enantioselectivities of >99% ee and high isolated yields.

Unexpectedly stable homopurine parallel triplex of SNA:RNA*SNA and L-aTNA:RNA*L-aTNA.

Homopurine strands are known to form antiparallel triplexes stabilized by G*G and A*A Hoogsteen pairs, which have two hydrogen bonds. But there has been no report on the parallel triplex formation of homopurine involving both adenosine and guanosine to the duplex. In this paper, we first report parallel triplex formation between a homopurine serinol nucleic acid (SNA) strand and an RNA/SNA duplex. Melting profiles revealed that the parallel SNA:RNA*SNA triplex was remarkably stable, even though the A*A pair has a single hydrogen bond. An L-acyclic threoninol nucleic acid (L-aTNA) homopurine strand also formed a stable parallel triplex with an L-aTNA/RNA duplex.

A H2O2-specific fluorescent probe for evaluating oxidative stress in pesticides-treated cells, rice roots and zebrafish.

Hydrogen peroxide (H2O2) plays an irreplaceable role in the evaluation of the redox status in versatile circumstances. The levels of H2O2 can be affected by both internal and external stimuli, including environmental hazards. Abnormal production of H2O2 is a common characteristic of pesticide-caused damage. Therefore, H2O2 levels can intuitively and conveniently reflect the oxidative stress caused by various pesticides in cells and organisms. However, reliable and convenient monitoring of H2O2 in living cells is still limited by the lack of specific imaging probes. In this study, a fluorescent probe (HBTM-HP) was developed for in situ observation of H2O2 fluctuations caused by pesticide treatment over time in mammalian cells, rice roots and zebrafish. HBTM-HP showed high sensitivity and selectivity for H2O2. Fluorescence imaging results confirmed that HBTM-HP could be applied to reveal H2O2 production induced by multiple pesticides. This study revealed that HBTM-HP could serves as a versatile tool to monitor the redox status related to H2O2 both in vitro and in vivo upon exposure to pesticides, and also provides a basis for clarifying the mechanisms of pesticides in physiological and pathological processes.

Expectations related to home-based telemonitoring of high-risk pregnancies: A qualitative study addressing healthcare providers' and users' views in Norway.

INTRODUCTION: A pregnancy can be evaluated as high-risk for the woman and/or the fetus based on medical history and on previous or ongoing pregnancy characteristics. Monitoring high-risk pregnancies is crucial for early detection of alarming features, enabling timely intervention to ensure optimal maternal and fetal health outcomes. Home-based telemonitoring (HBTM) is a marginally exploited opportunity in antenatal care. The aim of this study was to illuminate healthcare providers' and users' expectations and views about HBTM of maternal and fetal health in high-risk pregnancies before implementation. MATERIAL AND METHODS: To address diverse perspectives regarding HBTM of high-risk pregnancies, four different groups of experienced healthcare providers or users were interviewed (n = 21). Focus group interviews were conducted separately with midwives, obstetricians, and women who had previously experienced stillbirth. Six individual interviews were conducted with hospitalized women with ongoing high-risk pregnancies, representing potential candidates for HBTM. None of the participants had any previous experience with HBTM of pregnancies. The study is embedded in a social constructivist research paradigm. Interviews were analyzed using a thematic approach. RESULTS: The participants acknowledged the benefits and potentials of more active roles for both care recipients and providers in HBTM. Concerns were clearly addressed and articulated in the following themes: eligibility and ability of women, availability of midwives and obstetricians, empowerment and patient safety, and shared responsibility. All groups problematized issues crucial to maintaining a sense of safety for care recipients, and healthcare providers also addressed issues related to maintaining a sense of safety also for the care providers. Conditions for HBTM were understood in terms of optimal personalized training, individual assessment of eligibility, and empowerment of an active patient role. These conditions were linked to the importance of competent and experienced midwives and obstetricians operating the monitoring, as well as the availability and continuity of care provision. Maintenance of safety in HBTM in high-risk pregnancies was crucial, particularly so in situations involving emerging acute health issues. CONCLUSIONS: HBTM requires new, proactive roles among midwives, obstetricians, and monitored women, introducing a fine-tuned balance between personalized and standardized care to provide safe, optimal monitoring of high-risk pregnancies.

Facile Synthesis of Some New Peptidomimetic ß3 -and ß2,3 -Amino Alcohols Possessing Pyridyl Moiety via Reductive Ring Opening of Pyridyl-isoxazolidines.

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(3-pyridyl)-N-phenylnitrone (2) with variedly substituted dipolarophiles (3, 4) were carried out to obtain substituted pyridyl-isoxazolidines (5-8). Reductive cleavage of pyridyl-isoxazolidines (5-8) with ammonium formate, methanol-THF solvents, at ambient temperature, in the presence of Pd/C provided a facile route for the synthesis of ß3 -and ß2,3 -amino alcohols (9-12), with a substitution pattern having pronounced influence on torsional angles. The obtained compounds (9-12) are valuable scaffolds which can be utilized for peptidomimetics. Thus, the present methodology for reductive opening of isoxazolidine ring avoids the disadvantages of using expensive apparatus and hazards involved in the use of hydrogen gas. The preferential formation of amino-alcohols in case of bicyclic isoxazolidines (8a-c), which precludes any recyclization is rationalized by DFT calculations.

Chemoselective Esterification of Natural and Prebiotic 1,2-Amino Alcohol Amphiphiles in Water.

In cells, a vast number of membrane lipids are formed by the enzymatic O-acylation of polar head groups with acylating agents such as fatty acyl-CoAs. Although such ester-containing lipids appear to be a requirement for life on earth, it is unclear if similar types of lipids could have spontaneously formed in the absence of enzymatic machinery at the origin of life. There are few examples of enzyme-free esterification of amphiphiles in water and none that can occur in water at physiological pH using biochemically relevant acylating agents. Here we report the unexpected chemoselective O-acylation of 1,2-amino alcohol amphiphiles in water directed by Cu(II) and several other transition metal ions. In buffers containing Cu(II) ions, mixing biological 1,2-amino alcohol amphiphiles such as sphingosylphosphorylcholine with biochemically relevant acylating agents, namely, acyl adenylates and acyl-CoAs, leads to the formation of the O-acylation product with high selectivity. The resulting O-acylated sphingolipids self-assemble into vesicles with markedly different biophysical properties than those formed from their N-acyl counterparts. We also demonstrate that Cu(II) can direct the O-acylation of alternative 1,2-amino alcohols, including prebiotically relevant 1,2-amino alcohol amphiphiles, suggesting that simple mechanisms for aqueous esterification may have been prevalent on earth before the evolution of enzymes.

Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpene 1,3-Aminoalcohol Regioisomers.

A series of novel diterpene-type 1,3-aminoalcohols and their regioisomers have been synthesised from natural stevioside in a stereoselective manner. The key intermediate ß-keto alcohol was prepared using Wagner-Meerwein rearrangement of the epoxide derived from steviol methyl ester. The primary aminoalcohol was formed via Raney-nickel-catalysed hydrogenation of an oxime, and a versatile library of aminoalcohols was synthesised using a Schiff base with the primary amines. The aminoalcohol regioisomers were prepared from the mesylate of the ß-keto alcohols. The corresponding primary aminoalcohol was formed via the palladium-catalysed hydrogenation of hydroxyl-azide, and click reactions of the latter were also carried out. The new compounds were characterised using 1D- and 2D-NMR techniques and HRMS measurements. The in vitro investigations showed high inhibition of cell growth in human cancer cell lines (HeLa, SiHa, A2780, MCF-7 and MDA-MB-231) in the case of naphthalic N-substituted derivatives. The antiproliferative effects were assayed using the MTT method.

Ring Opening of Glycerol Cyclic Phosphates Leads to a Diverse Array of Potentially Prebiotic Phospholipids.

Phospholipids are the primary constituents of cell membranes across all domains of life, but how and when phospholipids appeared on early Earth remains unknown. Pressingly, most prebiotic syntheses of complex phospholipids rely upon substrates not yet shown to have been available on early Earth. Here, we describe potentially prebiotic syntheses of a diverse array of complex phospholipids and their building blocks. First, we show that choline could have been produced on early Earth by stepwise N-methylation of ethanolamine. Second, taking a systems chemistry approach, we demonstrate that the intrinsically activated glycerol-2,3-cyclic phosphate undergoes ring opening with combinations of prebiotic amino alcohols to yield complex phospholipid headgroups. Importantly, this pathway selects for the formation of 2-amino alcohol-bearing phospholipid headgroups and enables the accumulation of their natural regioisomers. Finally, we show that the dry-state ring opening of cyclic lysophosphatidic acids leads to a range of self-assembling lysophospholipids. Our results provide new prebiotic routes to key intermediates on the way toward modern phospholipids and illuminate the potential origin and evolution of cell membranes.

De Novo Synthetic Approach to 2,4-Diamino-2,4,6-trideoxyhexoses (DATDH): Bacterial and Rare Deoxy-Amino Sugars.

A synthetic route to 2,4-diamino-2,4,6-trideoxysugar stereoisomers in 6-7 steps and 22-33% overall yield is described. A key step in this pathway is the carbonyl coupling of d- and l-threoninol or d- and l-allo-threoninol to a phthalimido-allene mediated by chiral iridium-H8-BINAP, which allows for installation of two new chiral centers in one, highly diastereoselective (>20:1 dr) step. This approach provides a more concise, diastereoselective, and versatile method to access these deoxy-amino sugars than is currently available.

[Construction of multi-enzyme cascade reactions and its application in the synthesis of bifunctional chemicals].

The synthesis of fine chemicals using multi-enzyme cascade reactions is a recent hot research topic in the field of biocatalysis. The traditional chemical synthesis methods were replaced by constructing in vitro multi-enzyme cascades, then the green synthesis of a variety of bifunctional chemicals can be achieved. This article summarizes the construction strategies of different types of multi-enzyme cascade reactions and their characteristics. In addition, the general methods for recruiting enzymes used in cascade reactions, as well as the regeneration of coenzyme such as NAD(P)H or ATP and their application in multi-enzyme cascade reactions are summarized. Finally, we illustrate the application of multi-enzyme cascades in the synthesis of six bifunctional chemicals, including ω-amino fatty acids, alkyl lactams, α, ω-dicarboxylic acids, α, ω-diamines, α, ω-diols, and ω-amino alcohols.

Rapid Chemical Ligation of DNA and Acyclic Threoninol Nucleic Acid (aTNA) for Effective Nonenzymatic Primer Extension.

Previously, nonenzymatic primer extension reaction of acyclic l-threoninol nucleic acid (L-aTNA) was achieved in the presence of N-cyanoimidazole (CNIm) and Mn2+; however, the reaction conditions were not optimized and a mechanistic insight was not sufficient. Herein, we report investigation of the kinetics and reaction mechanism of the chemical ligation of L-aTNA to L-aTNA and of DNA to DNA. We found that Cd2+, Ni2+, and Co2+ accelerated ligation of both L-aTNA and DNA and that the rate-determining step was activation of the phosphate group. The activation was enhanced by duplex formation between a phosphorylated L-aTNA fragment and template, resulting in unexpectedly more effective L-aTNA ligation than DNA ligation. Under optimized conditions, an 8-mer L-aTNA primer could be elongated by ligation to L-aTNA trimers to produce a 29-mer full-length oligomer with 60% yield within 2 h at 4 °C. This highly effective chemical ligation system will allow construction of artificial genomes, robust DNA nanostructures, and xeno nucleic acids for use in selection methods. Our findings also shed light on the possible pre-RNA world.

Asymmetric Access to Boryl-Substituted Vicinal Aminoalcohols through Cu-Catalyzed Reductive Coupling.

Herein, we report the development of a Cu-catalyzed enantioselective borylative aminoallylation of aldehydes using a N-substituted allene to access boryl-substituted 1,2-aminoalcohol synthons for diversification to chiral heteroatom-rich organic compounds. The reported reaction provides access to several different substitution patterns of chiral 1,2-aminoalcohol products from the same readily available starting materials with high diastereo- and enantioselectivity.

Aminoalcohol Synthesis through Nonprecious Metal Catalysis: Enantioselective Cu-Catalyzed Reductive Coupling of Aldehydes and Allenamides.

Herein, we report the development of a Cu-catalyzed aminoallylation of aldehyde electrophiles through reductive coupling by circumventing the problematic competitive reduction of the aldehyde electrophile by a CuH catalyst. This leads to a highly diastereo- and enantioselective process for the synthesis of chiral 1,2-aminoalcohols containing secondary alcohol substitution. Cleavage of the N substituents on the reaction products was performed, allowing access to the other diastereomer of the aminoalcohol, which was investigated in the context of a synthesis of eligulstat.

5-Chloro-8-nitro-1-naphthoyl (NNap): A Selective Protective Group for Amines and Amino Acids.

The synthesis of 5-chloro-8-nitro-1-naphthoyl chloride and its use as a protective group for amines is described. Protection is carried out with an auxiliary amine or under mild Schotten-Baumann conditions in high yield (>86%), while deprotection can be achieved easily under gentle reducing conditions due to the large steric tension between C-1 and C-8 naphthalene substituents. The reaction has been successfully tested in dipeptide synthesis and amino alcohols protection, and it has proved selective for the ε-amine group of lysine.

Multicomponent Domino Cyclization of Ethyl Trifluoropyruvate with Methyl Ketones and Amino Alcohols as A New Way to γ-Lactam Annulated Oxazacycles.

A new route to bicyclic γ-lactams was found, which was proposed as a three-component cyclization of ethyl trifluoropyruvate with methyl ketones and 1,2-, 1,3-amino alcohols. As a result, a series of trifluoromethyl-substituted tetrahydropyrrolo [2,1-b]oxazol-5-ones and tetrahydropyrrolo[2,1-b][1,3]oxazine-6-ones was synthesized, in which the substituent at the nodal carbon atom was varied. The introduction of a twofold excess of ethyl trifluoropyruvate in reactions with amino alcohols and acetone made it possible to obtain the same bicycles, but functionalized with a hydroxyester fragment, which are formed due to four-component interactions of the reagents. Transformations with 2-butanone and aminoethanol lead predominantly to similar bicycles, while an analogous reaction with aminopropanol gives N-hydroxypropyl-2,3-dihydropyrrol-5-one. Almost all bicycles are formed as two diastereomers, the structure of which was determined using 1H, 19F, 13C NMR spectroscopy, including two-dimensional experiments and XRD analysis. A domino mechanism for the formation of tetrahydropyrrolo[2,1-b]oxazacycles was proposed, which was confirmed by their stepwise synthesis through the preliminary preparation of the aldol and bis-aldol from ethyl trifluoropyruvate and methyl ketones.

Comparative Pharmacokinetic Investigation on Multiple Active Aminoalcohol-Diterpenoid Alkaloids after Single Oral Administrations of Monomers and Aqueous Extract of Fuzi (Aconiti Lateralis Radix Praeparata) by UFLC-MS/MS.

To further study the aminoalcohol-diterpenoid alkaloids (ADAs) in Fuzi (Aconiti Lateralis Radix Praeparata), a simple and sensitive UFLC-MS/MS method was established and validated for the determination of five ADAs, aconine, mesaconine, hypaconine, deoxyaconine and fuziline, in rat plasma to compare the pharmacokinetic characteristics of pure ADAs and Fuzi decoction. After precipitating protein with methanol, plasma samples were isolated at 0.5 mL/min flow rate on Waters Acquity UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 µm). The mobile phase was composed of 0.1% formic acid-water and methanol with gradient elution. Mass spectrometric inspection was conducted on a 5500 UFLC-MS/MS system with an electrospray ionization source in patterns of positive ion and multiple reaction-monitoring (MRM). All calibration curves were proved to have acceptable linearity (r2 > 0.99) in linear ranges. Intra-day and inter-day precision and the accuracy met the requirements. The matrix effects of all analytes were between 85% and 115% of three concentration levels. This method has been under verification for comparative pharmacokinetic research after oral administration between aqueous extract of Fuzi and single pure ADAs. The results demonstrated that there are evident pharmacokinetic discrepancies between them, and administration in the extract form instead of pure form may contribute to higher absorption.

New isoxazolidinyl-based N-alkylethanolamines as new activators of human brain carbonic anhydrases.

Carbonic anhydrases (CAs) are widespread metalloenzymes which catalyse the reversible hydration of carbon dioxide (CO2) to bicarbonate (HCO3-) and a proton, relevant in many physiological processes. In the last few years, the involvement of CA activation in different metabolic pathways in the human brain addressed the research to the discovery of novel CA activators. Here, a new series of isoxazoline-based amino alcohols as CA activators was investigated. The synthesis and the CA activating effects towards four human CA isoforms expressed in the human brain, that are hCAs I, II, IV and VII, were reported. The best results were obtained for the (methyl)-isoxazoline-amino alcohols 3 and 5 with KA values in the submicromolar range (0.52-0.86 µM) towards hCA VII, and a good selectivity over hCA I. Being hCA VII involved in brain function and metabolism, the newly identified CA activators might be promising hit compounds with potential therapeutic applications in ageing, epilepsy or neurodegeneration.

Additive-free synthesis of fused tricyclic cyanoisoxazolidines using in situ formed cyanonitrones.

Herein, we disclose the first report on the generation of cyanonitrone in situ from diazoacetonitrile and nitrosoarene, and its subsequent [3+2] cycloaddition with oxabicyclic alkenes to access fused tricyclic cyanoisoxazolidines. Further, this methodology could be extended to access fused tricyclic trifluoromethylated and phosphonylated isoxazolidines. Surprisingly, the reductive ring-opening of cyanoisoxazolidines was followed by a spontaneous lactonization to produce fused tricyclic amino lactones. Moreover, the N-O bond of the obtained tricyclic trifluoromethylated isoxazolidines could be cleaved to obtain 1,3-amino alcohols.

A Facile Synthesis of 2-Oxazolines via Dehydrative Cyclization Promoted by Triflic Acid.

2-oxazolines are common moieties in numerous natural products, pharmaceuticals, and functional copolymers. Current methods for synthesizing 2-oxazolines mainly rely on stoichiometric dehydration agents or catalytic dehydration promoted by specific catalysts. These conditions either generate stoichiometric amounts of waste or require forcing azeotropic reflux conditions. As such, a practical and robust method that promotes dehydrative cyclization while generating no byproducts would be attractive to oxazoline production. Herein, we report a triflic acid (TfOH)-promoted dehydrative cyclization of N-(2-hydroxyethyl)amides for synthesizing 2-oxazolines. This reaction tolerates various functional groups and generates water as the only byproduct. This method affords oxazoline with inversion of α-hydroxyl stereochemistry, suggesting that alcohol is activated as a leaving group under these conditions. Furthermore, the one-pot synthesis protocol of 2-oxazolines directly from carboxylic acids and amino alcohols is also provided.