Stereoselective Formation Research Articles

Chemical Synthesis of β‐(1,4)‐d‐Oligomannurarates with Purported Anti‐Alzheimer Activity

Sodium oligomannate, a sophisticated mixture of acidic linear β‐(1,4)‐d‐oligomannurarate ranging from dimers to decamers with an average molecular weight of 670∼880 Da, has gained conditional approval for the treatment of Alzheimer's disease. Herein, we develop an efficient approach to the chemical synthesis of well‐defined β‐(1,4)‐d‐mannurarate di‐, tetra‐, hexa‐ and octasaccharides (1‐4), utilizing N‐phenyl trifluoroacetimidate donors and thioglycoside acceptors for the stereoselective assembly of the desired β‐(1,4)‐d‐mannuronate linkages. This approach features a straightforward protecting group strategy with only two types of protecting groups: tert‐butyldimethylsilyl (TBS) for the 4‐OH at the non‐reducing end and benzyl (Bn) for free hydroxyl and carboxylic acid moieties, thereby ensuring the stereoselective formation of the β‐mannosyl bonds and facilitating sequential transformation into the target β‐(1,4)‐d‐mannurarate oligosaccharides. The scalability of the present synthesis of these oligosaccharides paves the way for in‐depth structure‐activity relationship studies and pharmacological investigations of sodium oligomannates.

Chemical synthesis of a trisaccharide fragment of a fucosylated glucuronomannan isolated from brown algae

Fucose is abundant in marine organisms, primarily as fucoidan and fucosylated chondroitin sulfate. Our previous study characterized a sulfated and fucosylated glucuronomannan (SFGM) isolated from marine brown algae, exhibiting notable antiviral activity and potential for drug development. Herein, a trisaccharide fragment of this SFGM in the form of [α-L-Fuc(2, 4-diS)]-(1→3)-α-D-Man-(1→4)-α-D-GlcA-OMP was synthesized for the first time. Stereoselective formation of the α-1,2-cis-fucosidic bond was achieved by leveraging solvent effects. The sulfated trisaccharide as the final product, featuring a 2,4-diS-fucose unit and the p-methoxyphenyl group as a pendant at the anomeric position, was successfully accomplished. The synthetic strategy developed in this study offers a foundation for the pharmaceutical development of these SFGM oligosaccharides.

Synthesis of exocyclic enaminone-based thiohydantoins as potent antifungal agents

A highly efficient and stereoselective synthesis of (E)-5-(dimethylamino)methylene thiohydantoins is herein reported. It was carried out through a one-pot, two-step reaction between methyl N-arylglycinates, isothiocyanates, and DMFDMA under microwave irradiation. The thermal and catalyst-free reaction of the (dimethylamino)methylene thiohydantoins with anilines led to the stereoselective formation of (E)-(anilinomethylene) thiohydantoins. The antifungal activity of the products was evaluated with a series of five Candida spp., finding a potent effect, even against a fluconazole-resistant C. glabrata strain. The docking studies suggest that this inhibitory effect is due to the binding of the compounds to the active site of fungal HMGR.

Stereoselective Synthesis of Spirolactone Analogues of Pyrrolomorpholine Alkaloids.

The synthesis of a spirolactone analogue of xylapyrraside B1, a potent antioxidant agent, is described. The key step is the stereoselective formation of the spirolactone skeleton via the formal [3+2] annulation of the isopropylidene-protected glyceraldehyde and δ-methylene lactone, mediated by trifluoroborane etherate. This study addresses the stereoselective synthesis of pyrrolomorpholine spiroketal alkaloids, enabling the production of these bioactive compounds and their analogues.

Synthesis of 2-Amino-2-deoxy Sugars via Boron-Catalyzed Coupling of Glycosyl Fluorides and Silyl Ether Acceptors.

Although aminosugars are important components in a variety of bioactive molecules, their stereoselective formation is made challenging by the Lewis basic nature of amino substituents. Additionally, the use of N-acyl protecting groups is often problematic due to the competing formation of oxazolines during the glycosylation of 2-aminosugar derivatives. Herein, we report a boron-catalyzed strategy utilizing silyl ether glycosyl acceptors and 2-aminosugar donors that employs the 2,2,2-trichloroethoxycarbonyl (Troc) protecting group for the C2 amino functionality in glycosyl fluorides. This modification allows for operationally simple room-temperature glycosylations and features a rapid reaction profile that addresses some of the limitations in the synthesis of 2-amino-2-deoxy sugar-containing glycosides. Tailoring the order of reactivity of the silyl acceptors enables one-pot iterative glycosylations, thus streamlining the synthesis of complex oligosaccharides while allowing fewer intermediates and purification steps.

Harnessing a Pd4 Water-Soluble Molecular Capsule as a Size-Selective Catalyst for Targeted Oxidation of Alkyl Aromatics.

Molecular hosts with functional cavities can emulate enzymatic behavior through selective encapsulation of substrates, resulting in high chemo-, regio-, and stereoselective product formation. It is still challenging to synthesize enzyme-mimicking hosts that exhibit a narrow substrate scope that relies upon the recognition of substrates based on the molecular size. Herein, we introduce a Pd4 self-assembled water-soluble molecular capsule [M 4 L 2] (MC) that was formed through the self-assembly of a ligand L (4',4‴'-(1,4-phenylene)bis(1',4'-dihydro-[4,2':6',4″-terpyridine]-3',5'-dicarbonitrile)) with the acceptor cis-[(en)Pd(NO3)2] [en = ethane-1,2-diamine] (M). The molecular capsule MC showed size-selective recognition towards xylene isomers. The redox property of MC was explored for efficient and selective oxidation of one of the alkyl groups of m-xylene and p-xylene to their corresponding toluic acids using molecular O2 as an oxidant upon photoirradiation. Employing host-guest chemistry, we demonstrate the homogeneous catalysis of alkyl aromatics to the corresponding monocarboxylic acids in water under mild conditions. Despite homogeneous catalysis, the products were separated from the reaction mixtures by simple filtration/extraction, and the catalyst was reused. The larger analogues of the alkyl aromatics failed to bind within the MC's hydrophobic cavity, resulting in a lower/negligible reaction outcome. The present study represents a facile approach for selective photo-oxidation of xylene isomers to their corresponding toluic acids in an aqueous medium under mild conditions.

Mild and Stereoselective Synthesis of (1E,3E)-Dienes through Silver(I)-Catalyzed β-Hydride Migration from Allylic α-Diazo Esters

AbstractA mild procedure for the diastereoselective preparation of functionalized 1,3-dienes and their synthetic versatility are described herein. The silver-catalyzed decomposition of α-diazo-γ,δ-unsaturated esters through β-hydride migration at room temperature resulted in the stereoselective formation of 12 conjugated (1E,3E)-dienes. Further synthetic post-modifications included intramolecular Heck reaction and hydrogenation, leading to a novel substituted indene and an aliphatic diester, respectively. To rationalize the observed reaction outcome, a computational investigation of the mechanisms was conducted, emphasizing the importance of factors such as metallocarbenoid stability, substituent effects, and microkinetics simulations to better understand the reaction intricacies.

Visible-Light-Induced Dearomative Annulation of Indoles toward Stereoselective Formation of Fused- and Spiro Indolines.

Dearomatization approaches are attractive for their abilities to transform simple, planar arenes into complex, three-dimensional architectures. In particular, visible-light driven dearomatization strategies are significant because of their mild, green, and sustainable nature, enabling the fabrication of new chemical bonds via an electron transfer or energy transfer process. Indole compounds, being potentially bioactive and readily accessible, can be employed efficiently as building blocks for constructing diverse annulated frameworks under photocatalysis. Highly stereoselective radical cascade reactions of appropriate indole systems can provide complex cyclic scaffolds bearing multiple stereocenters. In fact, the past few years have witnessed the renaissance of dearomative cycloadditions of indoles via visible-light-induced photocatalysis. The present review highlights recent advances (2019-mid 2024) in visible-light-driven dearomative annulation of indoles leading to formation of polycyclic indolines, including angularly fused and spiro indolines. Most of the reactions described in this review are simple, providing quick access to the desired products. Additionally, characteristic reaction mechanisms are offered to provide an understand of how indole scaffolds show distinctive reactivity under photocatalytic conditions.

Et3Al/Light-Promoted Radical-Polar Crossover Reactions of α-Alkoxyacyl Tellurides.

Here, we report new radical-polar crossover reactions of α-alkoxy carbon radicals for constructing highly oxygenated molecules with contiguous stereocenters. The method employs a 370 nm UV light-emitting diode (LED) for the photoexcitation of α-alkoxyacyl telluride, and Et3Al as the radical initiator and terminator. First, Et3Al and UV LED promoted radical coupling between the α-alkoxyacyl telluride and cyclopentenone via C-Te bond homolysis, CO expulsion, and C-C bond formation. Second, Et3Al converted the radical species to the corresponding aluminum enolate. Third, the second C-C bond formation occurred via a polar mechanism: intermolecularly with aldehydes/ketones and intramolecularly with epoxide, producing aldol and SN2 adducts, respectively. The present coupling reactions increase the molecular complexity in a single step by stereoselective formation of the two hindered C-C bonds. The devised method is expected to be useful for the expeditious assembly of densely oxygenated natural products.

Mechanistic insight into benzylidene-directed glycosylation reactions using cryogenic infrared spectroscopy

The stereoselective formation of 1,2-cis glycosidic linkages is challenging. The currently most widely used strategy for their installation uses 4,6-O-benzylidene-protected building blocks. The stereoselectivity of this reaction is thought to be driven by a covalent intermediate, which reacts via an SN2 mechanism. However, the role of cationic SN1-type intermediates in this reaction is unclear. Here we elucidate the structure of glycosyl cations carrying 4,6-O-benzylidene groups using cryogenic infrared ion spectroscopy and computational methods. The data reveal that the intermediates form anhydro cations, which correlates well with the stereoselective outcome of SN1-type glycosylations. The study highlights how cryogenic infrared spectroscopy can elucidate the role of intermediates in sugar chemistry and how these structural data can be linked to reactions in solution.

Selective Synthesis of Deuterated cis- and trans-Isohumulones and trans-Isohumulinones

AbstractDeuterated isohumulones can be prepared directly from humulones by an acyloin ring contraction under either magnesium-catalyzed basic conditions or by photochemical-induced reactions in deuterated solvents. Reactions of humulones with biphasic methylene chloride/aqueous NaOD and MgSO4 in D2O leads to stereoselective formation of cis-d 3-isohumulones (cis/trans ratio of 82:18) as the magnesium salts in yields of 71–83%. Greater than 95% incorporation of three deuterons is observed at the C5 position of the pentenone ring and the methylene position of the C4 acyl group. Photochemical isomerization with a 400 nm blue LED source enables stereospecific formation of deuterated trans-isohumulones in 36–82% yield with greater than 95% incorporation of deuterium at the C5 ring position. Oxidation of humulones with cumene hydroperoxide in basic D2O gives isohumulinones with partial 55–73% incorporation of deuterium due to keto–enol isomerization of the methylene substituent of the C4 acyl group. The structural identities of the deuterated products are determined by a combination of negative-mode electrospray mass spectrometry (MS-ESI–) and 2D heteronuclear proton–carbon HMQC NMR analysis.

Optimization for the Preparation of Procyanidin B3: Strategy for Gram-Scale and Stereoselective Formation of 4,8-Interflavan Bonds

Optimization for the Preparation of Procyanidin B3: Strategy for Gram-Scale and Stereoselective Formation of 4,8-Interflavan Bonds

Construction of the Akuammiline Alkaloid Core Structure via Stereoselective E-Ring Formation.

Construction of the core structure of akuammiline alkaloids with three-dimensional cage-like structures for their diversity-oriented synthesis was investigated. Extensive exploration centered around the introduction of nitrogen functional groups and construction of the E-ring in an intramolecular or intermolecular manner revealed that a Claisen rearrangement approach involving intramolecular amination provided a common precursor, potentially facilitating divergent access to various types of akuammiline alkaloids.

Chemical Synthesis and Antigenicity Evaluation of an Aminoglycoside Trisaccharide Repeating Unit of Pseudomonas aeruginosa Serotype O5 O-Antigen Containing a Rare Dimeric-ManpN3NA.

Pseudomonas aeruginosa bacteria are becoming increasingly resistant against multiple antibiotics. Therefore, the development of vaccines to prevent infections with these bacteria is an urgent medical need. While the immunological activity of lipopolysaccharide O-antigens in P. aeruginosa is well-known, the specific protective epitopes remain unidentified. Herein, we present the first chemical synthesis of highly functionalized aminoglycoside trisaccharide 1 and its acetamido derivative 2 found in the P. aeruginosa serotype O5 O-antigen. The synthesis of the trisaccharide targets is based on balancing the reactivity of disaccharide acceptors and monosaccharide donors. Glycosylations were analyzed by quantifying the reactivity of the hydroxyl group of the disaccharide acceptor using the orbital-weighted Fukui function and dual descriptor. The stereoselective formation of 1,2-cis-α-fucosylamine linkages was achieved through a combination of remote acyl participation and reagent modulation. The simultaneous SN2 substitution of azide groups at C2' and C2″ enabled the efficient synthesis of 1,2-cis-β-linkages for both 2,3-diamino-D-mannuronic acids. Through a strategic orthogonal modification, the five amino groups on target trisaccharide 1 were equipped with a rare acetamidino (Am) and four acetyl (Ac) groups. Glycan microarray analyses of sera from patients infected with P. aeruginosa indicated that trisaccharides 1 and 2 are key antigenic epitopes of the serotype O5 O-antigen. The acetamidino group is not an essential determinant of antibody binding. The β-D-ManpNAc3NAcA residue is a key motif for the antigenicity of serotype O5 O-antigen. These findings serve as a foundation for the development of glycoconjugate vaccines targeting P. aeruginosa serotype O5.

Insights into stereoselective ring formation in canonical strigolactone: Identification of a dirigent domain-containing enzyme catalyzing orobanchol synthesis

Strigolactones (SLs) are plant apocarotenoids with diverse roles and structures. Canonical SLs, widespread and characterized by structural variations in their tricyclic lactone (ABC-ring), are classified into two types based on C-ring configurations. The steric C-ring configuration emerges during the BC-ring closure, downstream of the biosynthetic intermediate, carlactonoic acid (CLA). Most plants produce either type of canonical SLs stereoselectively, e.g., tomato (Solanum lycopersicum) yields orobanchol with an α-oriented C-ring. The mechanisms driving SL structural diversification are partially understood, with limited insight into functional implications. Furthermore, the exact molecular mechanism for the stereoselective BC-ring closure reaction is yet to be known. We identified an enzyme, the stereoselective BC-ring-forming factor (SRF), from the dirigent protein (DIR) family, specifically the DIR-f subfamily, whose biochemical function had not been characterized, making it a key enzyme in stereoselective canonical SL biosynthesis with the α-oriented C-ring. We first confirm the precise catalytic function of the tomato cytochrome P450 SlCYP722C, previously shown to be involved in orobanchol biosynthesis [T. Wakabayashi et al., Sci. Adv. 5, eaax9067 (2019)], to convert CLA to 18-oxocarlactonoic acid. We then show that SRF catalyzes the stereoselective BC-ring closure reaction of 18-oxocarlactonoic acid, forming orobanchol. Our methodology combines experimental and computational techniques, including SRF structure prediction and conducting molecular dynamics simulations, suggesting a catalytic mechanism based on the conrotatory 4π-electrocyclic reaction for the stereoselective BC-ring formation in orobanchol. This study sheds light on the molecular basis of how plants produce SLs with specific stereochemistry in a controlled manner.

Asymmetric Total Synthesis of (+)-Lemnardosinane A.

The asymmetric total synthesis of (+)-lemnardosinane A, a rare rearranged sesquiterpenoid, has been accomplished from (S)-carvone. Key features of the synthesis are the formation of a bicyclo[3.3.1]nonane skeleton using the intramolecular aldol reaction, the stereoselective introduction of an alkyne group, and the stereoselective formation of a tricyclic skeleton via intramolecular pinacol coupling.

Reaction Rate and Stereoselectivity Enhancement in Glycosidations with O-Glycosyl Trihaloacetimidate Donors due to Catalysis by a Lewis Acid-Nitrile Cooperative Effect.

Activation of O-glycosyl trihaloacetimidate glycosyl donors with AuCl3 as a catalyst and pivalonitrile (tBuCN) as a ligand led to excellent glycosidation results in terms of yield and anomeric selectivity. In this way, various β-d-gluco- and β-d-galactopyranosides were obtained conveniently and efficiently. Experimental studies and density functional theory (DFT) calculations, in order to elucidate the reaction course, support formation of the tBuCN-AuCl2-OR(H)+ AuCl4- complex as a decisive intermediate in the glycosidation event. Proton transfer from this acceptor complex to the imidate nitrogen leads to donor activation. In this way, guided by the C-2 configuration of the glycosyl donor, the alignment of the acceptor complex enforces the stereoselective β-glycoside formation in an intramolecular fashion, thus promoting also a fast reaction course. The high stereocontrol of this novel 'Lewis acid-nitrile cooperative effect' is independent of the glycosyl donor anomeric configuration and without the support of neighboring group or remote group participation. The power of the methodology is shown by a successful glycoalkaloid solamargine synthesis.

Phospholanes via Twofold C‐H‐Addition to Phospholes

AbstractA synthetic route towards phospholanes via twofold C−H‐addition of a DMSO molecule to β‐H substituted phospholes is described. The resulting fused phospholane oxothiolane system in case of symmetric α‐substitution possesses four stereogenic centers or rather six in case of asymmetric α‐substitution. The reaction conditions are shown to be applicable for a variety of phospholes with different P‐ or α‐substituents always leading to stereoselective formation of the fused heterocyclic ring system. All phospholane derivatives with one exception are sufficiently air stable for purification with column chromatography and are fully characterized by NMR and elemental analysis and mass spectrometry. With the help of X‐ray crystallography, the different configurations of the isomers could be demonstrated. For one model system derivatization reactions are presented. When oxidizing or reducing the sulfoxide group only a single diastereomer is observed.

Use of Novel Homochiral Thioureas Camphor Derived as Asymmetric Organocatalysts in the Stereoselective Formation of Glycosidic Bonds.

We synthesized six new camphor-derived homochiral thioureas 1-6, from commercially available (1R)-(-)-camphorquinone. These new compounds 1-6 were evaluated as asymmetric organocatalysts in the stereoselective formation of glycosidic bonds, with 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl and 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates as donors, and several alcohols as glycosyl acceptors, such as methanol, ethanol, 1-propanol, 1-butanol, 1-octanol, iso-propanol, tert-butanol, cyclohexanol, phenol, 1-naphtol, and 2-naphtol. Optimization of the asymmetric glycosylation reaction was achieved by modifying reaction conditions such as solvent, additive, loading of catalyst, temperature, and time of reaction. The best result was obtained with 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates, using 15 mol% of organocatalyst 1, in the presence of 2 equiv of MeOH in solvent-free conditions at room temperature for 1.5 h, affording the glycosidic compound in a 99% yield and 1:73 α:β stereoselectivity; under the same reaction conditions, without using a catalyst, the obtained stereoselectivity was 1:35 α:β. Computational calculations prior to the formation of the products were modeled, using density functional theory, M06-2X/6-31G(d,p) and M06-2X/6-311++G(2d,2p) methods. We observed that the preference for β glycoside formation, through a stereoselective inverted substitution, relies on steric effects and the formation of hydrogen bonds between thiourea 1 and methanol in the complex formed.

Highly Stereoselective Synthesis of Branched Fructooligosaccharides ABW90-1 and ABW50-1 from Achyranthes bidentata with Potent Antiosteoporosis Activities.

The branched fructooligosaccharides ABW90-1 and ABW50-1 from Achyranthes bidentata with potent antiosteoporosis activities have been synthesized for the first time. The synthetic approach highlights the following features: (1) 6-O-picoloyl-directed β-d-fructofuranosylation via a hydrogen-bond-mediated aglycone delivery strategy for the highly stereoselective constructions of β-(2 → 6)-d-fructofuranosidic linkages and β-(2 → 1)-d-fructofuranosidic linkages in the internal positions under the reaction conditions (DBDMH, -20 °C, CH2Cl2) and (2) the reaction conditions (DBDMH, -78 °C to -35 °C, toluene) for highly stereoselective formations of β-(2 → 1)-d-fructofuranosidic linkages in the terminal positions.