Cu-Catalyzed Amination of Base-Sensitive Aryl Bromides and the Chemoselective N- and O-Arylation of Amino Alcohols.

We report a general and functional-group-tolerant method for the Cu-catalyzed amination of base-sensitive aryl bromides including substrates possessing acidic functional groups and small five-membered heteroarenes. The results presented herein substantially expand the scope of Cu-catalyzed C-N coupling reactions. The combination of L8, an anionic N1,N2-diarylbenzene-1,2-diamine ligand, along with the mild base NaOTMS leads to the formation of a stable yet reactive catalyst that resists deactivation from coordination to heterocycles or charged intermediates. This system enables the use of low catalyst and ligand loadings. Exploiting the differences in nucleophile deprotonation in C-O and C-N coupling reactions catalyzed by Cu·L8 we developed a method to chemoselectively N- and O-arylate a variety of amino alcohol substrates. Employing NaOt-Bu as the base resulted exclusively in C-O coupling when the amino alcohols featured primary alcohols and more hindered amines or aniline groups. Utilizing NaOTMS enabled the ability to override the steric-based selectivity of these reactions completely and exclusively promoted C-N coupling regardless of the structure of the amino alcohol. The ability to invert the observed chemoselectivity is distinct from previously described methods that require protecting group manipulations or rely entirely on steric effects to control reactivity. These results substantially improve the scope of Cu-catalyzed C-N coupling reactions using N1,N2-diarylbenzene-1,2-diamine ligands and introduce a new chemoselective method to arylate amino alcohols.

The Intramolecular Charge Transfer Mechanism by Which Chiral Self-Assembled H8-BINOL Vesicles Enantioselectively Recognize Amino Alcohols.

The chiral H8-BINOL derivatives R-1 and R-2 were efficiently synthesized via a Suzuki coupling reaction, and they can be used as novel dialdehyde fluorescent probes for the enantioselective recognition of R/S-2-amino-1-phenylethanol. In addition, R-1 is much more effective than R-2. Scanning electron microscope images and X-ray analyses show that R-1 can form supramolecular vesicles through the self-assembly effect of the π-π force and strong hydrogen bonding. As determined via analysis, the fluorescence of the probe was significantly enhanced by mixing a small amount of S-2-amino-1-phenylethanol into R-1, with a redshift of 38 nm, whereas no significant fluorescence response was observed in R-2-amino-1-phenylethanol. The enantioselective identification of S-2-amino-1-phenylethanol by the probe R-1 was further investigated through nuclear magnetic titration and fluorescence kinetic experiments and DFT calculations. The results showed that this mechanism was not only a simple reactive probe but also realized object recognition through an ICT mechanism. As the intramolecular hydrogen bond activated the carbonyl group on the probe R-1, the carbonyl carbon atom became positively charged. As a strong nucleophile, the amino group of S-2-amino-1-phenylethanol first transferred the amino electrons to a carbonyl carbocation, resulting in a significantly enhanced fluorescence of the probe R-1 and a 38 nm redshift. Similarly, S-2-amino-1-phenylethanol alone caused severe damage to the self-assembled vesicle structure of the probe molecule itself due to its spatial structure, which made R-1 highly enantioselective towards it.

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.

Beyond the ß-amino alcohols framework: identification of novel ß-hydroxy pyridinium salt-decorated pterostilbene derivatives as bacterial virulence factor inhibitors.

BACKGROUND: Bacterial virulence factors are involved in various biological processes and mediate persistent bacterial infections. Focusing on virulence factors of phytopathogenic bacteria is an attractive strategy and crucial direction in pesticide discovery to prevent invasive and persistent bacterial infection. Hence, discovery and development of novel agrochemicals with high activity, low-risk, and potent anti-virulence is urgently needed to control plant bacterial diseases. RESULTS: A series of novel ß-hydroxy pyridinium cation decorated pterostilbene derivatives were prepared and their antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) were systematacially assessed. Among these pterostilbene derivatives, compound 4S exhibited the best antibacterial activity against Xoo in vitro, with an half maximal effective concentration (EC50) value of 0.28 µg mL-1. A series of biochemical assays including scanning electron microscopy, crystal violet staining, and analysis of biofilm formation, swimming motility, and related virulence factor gene expression levels demonstrated that compound 4S could function as a new anti-virulence factor inhibitor by interfering with the bacterial infection process. Furthermore, the pot experiments provided convinced evidence that compound 4S had the high control efficacy (curative activity: 71.4%, protective activity: 72.6%), and could be used to effectively manage rice bacterial leaf blight in vivo. CONCLUSION: Compounds 4S is an attractive virulence factor inhibitor with potential for application in treating plant bacterial diseases by suppressing production of several virulence factors. © 2024 Society of Chemical Industry.

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.

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.

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.

Synthesis of Trifluoromethylated Monoterpene Amino Alcohols.

For the first time, monoterpene trifluoromethylated ß-hydroxy-benzyl-O-oximes were synthesized in 81-95% yields by nucleophilic addition of the Ruppert-Prakash reagent (TMSCF3) to the corresponding ß-keto-benzyl-O-oximes based on (+)-nopinone, (-)-verbanone and (+)-camphoroquinone. Trifluoromethylation has been determined to entirely proceed chemo- and stereoselective at the C=O rather than C=N bond. Trifluoromethylated benzyl-O-oximes were reduced to the corresponding α-trifluoromethyl-ß-amino alcohols in 82-88% yields. The structure and configuration of the compounds obtained have been established.

Engineering Enzyme Substrate Scope Complementarity for Promiscuous Cascade Synthesis of 1,2-Amino Alcohols.

Biocatalytic cascades are uniquely powerful for the efficient, asymmetric synthesis of bioactive compounds. However, high substrate specificity can hinder the scope of biocatalytic cascades because the constituent enzymes may have non-complementary activity. In this study, we implemented a substrate multiplexed screening (SUMS) based directed evolution approach to improve the substrate scope overlap between a transaldolase (ObiH) and a decarboxylase for the production of chiral 1,2-amino alcohols. To generate a promiscuous cascade, we engineered a tryptophan decarboxylase to act efficiently on ß-OH amino acids while avoiding activity on l-threonine, which is needed for ObiH activity. We leveraged this exquisite selectivity with matched substrate scope to produce a variety of enantiopure 1,2-amino alcohols in a one-pot cascade from aldehydes or styrene oxides. This demonstration shows how SUMS can be used to guide the development of promiscuous, C-C bond forming cascades.

Induction and rationalization of supramolecular chirality in a highly flexible Zn(II)porphyrin dimer: structural, spectroscopic and theoretical investigations.

A highly flexible pyrrole-bridged Zn(II)porphyrin dimer has been successfully utilized as an efficient host which enables an accurate determination of the absolute configuration directly for a large number of chiral amino alcohols and 1,2-diols. The addition of substrates resulted in the formation of 1 : 1 sandwich complexes which, after the addition of excess substrates, produced 1 : 2 host-guest complexes. In principle, the 1 : 2 host-guest complexes can be stabilized in three possible conformations, viz. exo-exo, exo-endo, and endo-endo based on how a substrate binds to the metal. The endo-endo conformation is stabilized by two strong interligand H-bonds [O-H⋯O(H)] between encapsulated diols which thereby interlock the stereochemistry. In the absence of such interligand H-bonding interactions, exo-endo binding is preferred as it is indeed observed for amino alcohols which show weaker CD couplets due to the free movement of substrates. The sandwich complexes with amino alcohols show a more intense CD couplet compared to the diols due to the stronger binding of the amine functionality (-NH2) towards a Zn-atom over an alcoholic moiety (-OH). The CD amplitude showed linear dependence with a binding constant for the 1 : 1 sandwich complex upon varying the substrates. Spectroscopic investigations, single crystal X-ray structure determination of four such host-guest complexes and DFT studies have enabled us to rationalize systematically the origin of optical activity unambiguously in the 1 : 1 and 1 : 2 host-guest complexes, which lead to an absolute stereochemical determination of a large number of chiral substrates. The larger vertical and horizontal flexibility of a diethyl pyrrole spacer induces stronger binding of the substrates to form the 1 : 1 complex with a much larger torsional angle along with intense CD couplets. In contrast, a rigid dibenzothiophene-bridged tweezer, due to its limited horizontal and vertical flexibility, facilitates 1 : 2 complexation more as compared to the highly flexible pyrrole-bridged host which results in stronger binding of the substrate with the intense CD couplet for the former.

Dynamic Covalent Optical Chirality Sensing with a Sterically Encumbered Aminoborane.

A sterically encumbered aminoborane sensor is introduced and used for quantitative stereochemical analysis of monoalcohols, diols and amino alcohols. The small-molecule probe exhibits a rigid ortho-substituted arene scaffold with a proximate boron binding site and a triarylamine circular dichroism (CD) reporter unit which proved to be crucial for the observed chiroptical signal induction. Coordination of the chiral target molecule produces strong Cotton effects and UV changes that are readily correlated to its absolute configuration, enantiomeric composition and concentration to achieve comprehensive stereochemical analysis within a 5 % absolute error margin. The sensing method was successfully applied in the chromatography-free analysis of less than one milligram of a crude asymmetric reaction mixture and the advantages of this chiroptical sensing approach, which is amenable to high-throughput experimentation equipment and automation, over traditional methods is discussed.

Application of pyrrolo-protected amino aldehydes in the stereoselective synthesis of anti-1,2-amino alcohols.

Herein, we demonstrate the applicability of the 2,5-dimethylpyrrolo unit as a complementary N-protecting group in the highly diastereoselective synthesis of more than 20 different anti-amino alcohols (63-90% yields with up to 20 : 1 dr). Cleavage of the pyrrolo-N-protecting group was accomplished, e.g. in the presence of NH2OH under microwave conditions with yields exceeding 80%. The applicability of the protecting groups was further demonstrated by a short total synthesis of the sphinganine-like natural product clavaminol A. The introduction of the N-pyrrolo protecting group also offers the possibility to analyse product mixtures by NMR measurements due to the absence of conformational isomers, which are otherwise common for N-protecting groups.

A Racemic Naphthyl-Coumarin-Based Probe for Quantitative Enantiomeric Excess Analysis of Amino Acids and Enantioselective Sensing of Amines and Amino Alcohols.

A new racemic naphthyl-coumarin-based probe was found to bind covalently with amino acids in MeOH-KOH system and thereby generates distinct CD responses. The induced strong CD signals allowed quantitative enantiomeric excess analysis of amino acids and enantioselective sensing of amines and amino alcohols. The mechanism for the reaction of the coumarin-aldehyde probe with an amino acid was investigated by CD, UV-Vis, NMR, ESI-MS analyses and ECD calculation.

Methyl group configuration on acyclic threoninol nucleic acids (aTNAs) impacts supramolecular properties.

We have synthesized acyclic allo-threoninol nucleic acids (allo-aTNAs), artificial xeno-nucleic acids (XNAs) that are diastereomers of acyclic threoninol nucleic acids (aTNAs), and have investigated their supramolecular properties. The allo-aTNAs formed homo-duplexes in an antiparallel manner but with lower thermal stability than DNA, whereas aTNAs formed extremely stable homo-duplexes. The allo-aTNAs formed duplexes with complementary aTNAs and serinol nucleic acid (SNA). The affinities of L-allo-aTNA were the highest for L-aTNA and the lowest for D-aTNA, with SNA being intermediate. The affinities of D-allo-aTNA were the reverse. Circular dichroism measurements revealed that L- and D-allo-aTNAs had weak right-handed and left-handed helicities, respectively. The weak helicity of allo-aTNAs likely explains the poor chiral discrimination of these XNAs, which is in contrast to aTNAs that have strong helical orthogonality. Energy-minimized structures of L-allo-aTNA/RNA and L-allo-aTNA/L-allo-aTNA indicated that the methyl group on the allo-aTNA strand is unfavourable for duplex formation. In contrast, the methyl group on L-aTNA likely stabilizes the duplex structure via hydrophobic effects and van der Waals interactions. Thus, the configuration of the methyl group on the XNA scaffold had an unexpectedly large impact on the hybridization ability and structure.

Functionalized Acyclic (l)-Threoninol Nucleic Acid Four-Way Junction with High Stability In Vitro and In Vivo.

Oligonucleotides are increasingly being used as a programmable connection material to assemble molecules and proteins in well-defined structures. For the application of such assemblies for in vivo diagnostics or therapeutics it is crucial that the oligonucleotides form highly stable, non-toxic, and non-immunogenic structures. Only few oligonucleotide derivatives fulfil all of these requirements. Here we report on the application of acyclic l-threoninol nucleic acid (aTNA) to form a four-way junction (4WJ) that is highly stable and enables facile assembly of components for in vivo treatment and imaging. The aTNA 4WJ is serum-stable, shows no non-targeted uptake or cytotoxicity, and invokes no innate immune response. As a proof of concept, we modify the 4WJ with a cancer-targeting and a serum half-life extension moiety and show the effect of these functionalized 4WJs in vitro and in vivo, respectively.

Thiol-based chemical probes exhibit antiviral activity against SARS-CoV-2 via allosteric disulfide disruption in the spike glycoprotein.

The development of small-molecules targeting different components of SARS-CoV-2 is a key strategy to complement antibody-based treatments and vaccination campaigns in managing the COVID-19 pandemic. Here, we show that two thiol-based chemical probes that act as reducing agents, P2119 and P2165, inhibit infection by human coronaviruses, including SARS-CoV-2, and decrease the binding of spike glycoprotein to its receptor, the angiotensin-converting enzyme 2 (ACE2). Proteomics and reactive cysteine profiling link the antiviral activity to the reduction of key disulfides, specifically by disruption of the Cys379-Cys432 and Cys391-Cys525 pairs distal to the receptor binding motif in the receptor binding domain (RBD) of the spike glycoprotein. Computational analyses provide insight into conformation changes that occur when these disulfides break or form, consistent with an allosteric role, and indicate that P2119/P2165 target a conserved hydrophobic binding pocket in the RBD with the benzyl thiol-reducing moiety pointed directly toward Cys432. These collective findings establish the vulnerability of human coronaviruses to thiol-based chemical probes and lay the groundwork for developing compounds of this class, as a strategy to inhibit the SARS-CoV-2 infection by shifting the spike glycoprotein redox scaffold.

Ruthenium-catalyzed acceptorless dehydrogenative coupling of amino alcohols and ynones to access 3-acylpyrroles.

Herein, a new strategy for the direct synthesis of functionalized pyrroles from ß-amino alcohols and ynones via ruthenium-catalyzed acceptorless dehydrogenative coupling has been demonstrated. This developed methodology proceeds in an atom- and step-economic fashion together with the merits of broad substrate scope, operational simplicity, and water and hydrogen gas as the sole by-products, which provides an alternative and sustainable way to access functionalized pyrroles. Further, this method was applied to the rapid synthesis of the COX-1/COX-2 inhibitor and boron dipyrromethene derivative successfully.

Pre-Clinical Activity of Amino-Alcohol Dimeric Naphthoquinones as Potential Therapeutics for Acute Myeloid Leukemia.

BACKGROUND: The clinical outcomes of patients with Acute Myeloid Leukemia (AML) remain unsatisfactory. Therefore the development of more efficacious and better-tolerated therapy for AML is critical. We have previously reported anti-leukemic activity of synthetic halohydroxyl dimeric naphthoquinones (BiQ) and aziridinyl BiQ. OBJECTIVE: This study aimed to improve the potency and bioavailability of BiQ compounds and investigate antileukemic activity of the lead compound in vitro and a human AML xenograft mouse model. METHODS: We designed, synthesized, and performed structure-activity relationships of several rationally designed BiQ analogues with amino alcohol functional groups on the naphthoquinone core rings. The compounds were screened for anti-leukemic activity and the mechanism as well as in vivo tolerability and efficacy of our lead compound was investigated. RESULTS: We report that a dimeric naphthoquinone (designated BaltBiQ) demonstrated potent nanomolar anti-leukemic activity in AML cell lines. BaltBiQ treatment resulted in the generation of reactive oxygen species, induction of DNA damage, and inhibition of indoleamine dioxygenase 1. Although BaltBiQ was tolerated well in vivo, it did not significantly improve survival as a single agent, but in combination with the specific Bcl-2 inhibitor, Venetoclax, tumor growth was significantly inhibited compared to untreated mice. CONCLUSION: We synthesized a novel amino alcohol dimeric naphthoquinone, investigated its main mechanisms of action, reported its in vitro anti-AML cytotoxic activity, and showed its in vivo promising activity combined with a clinically available Bcl-2 inhibitor in a patient-derived xenograft model of AML.

Efficient preparation of stereopure amphiphilic 1,2-amino alcohols by using preparative enantioselective HPLC.

Chiral amphiphiles are useful for controlling the structures and properties of supramolecular assemblies, but their stereocontrolled synthesis is generally difficult, because their long alkyl chains tend to bring unfavorable effects on the solubility, reactivity, and crystallinity of molecules. Typical examples are amphiphilic 1,2-amino alcohols (S)-1 and (1S,2S)-2 developed by our group, which were known to serve as chiral reaction media for controlling the stereochemistry of asymmetric photoreactions. We previously developed synthetic schemes for these 1,2-amino alcohols, but their synthetic efficiencies were unsatisfactory (13 steps with 2% overall yield for (S)-1; eight steps with 8% yield for (1S,2S)-2). As the main reason of such low efficiencies, the stereocontrolling methods we previously employed (diastereomer-salt crystallization for (S)-1; stereoselective reactions for (1S,2S)-2) were not ideal. Here, we report highly improved synthetic schemes for (S)-1 and (1S,2S)-2 based on the enantioselective high performance liquid chromatography (HPLC) separation of intermediates in preparative scales. Compared with the previous schemes, the new schemes are advantageous in fewer number of steps, higher overall yield, and lower risk of racemization (seven steps with 15% overall yield for (S)-1; seven steps with 26% overall yield for (1S,2S)-2).