Glycal Epoxides Research Articles

Si-Linked Glycomimetics through a Stereoselective Silicon Transfer and Anion Addition.

We report a synthesis of silicon-linked glycomimetics, demonstrating unique structural properties and metabolic stability due to the inertness of the C-Si bond. Our method focuses on the stereoselective transfer of silicon and anion addition, revealing that chirality at the silicon atom can be controlled through kinetic resolution. This approach allows for the selective generation of 1,2-cis and 1,2-trans isomers via the manipulation of C2-protected silicon ethers and nucleophilic opening of glycal epoxides. We achieved high selectivity at the anomeric carbon and expanded the scope to include various saccharides and substituted silanes. Our findings indicate that silicon transfer occurs intramolecularly and is influenced by the nature of the counterion and reaction conditions. Additionally, chiral silanes produced through our method hold promise for medicinal chemistry applications, addressing significant gaps in the synthesis and utility of glycomimetics. This work opens new avenues for the development of bioactive silicon-based molecules.

Novel Glycosylation of Aromatic Amines Through 1, 2-Anhydrosugars

A new and novel bismuth nitrate and indium bromide-catalyzed glycosylation of aromatic amines with glycal epoxides is described in moderate yield. Despite the poor nucleophilicity of the aromatic amines, the success of this reaction is noteworthy.

Glycosyl Cross-Coupling of Anomeric Nucleophiles: Scope, Mechanism, and Applications in the Synthesis of Aryl C-Glycosides.

Stereoselective manipulations at the C1 anomeric position of saccharides are one of the central goals of preparative carbohydrate chemistry. Historically, the majority of reactions forming a bond with anomeric carbon has focused on reactions of nucleophiles with saccharide donors equipped with a leaving group. Here, we describe a novel approach to stereoselective synthesis of C-aryl glycosides capitalizing on the highly stereospecific reaction of anomeric nucleophiles. First, methods for the preparation of anomeric stannanes have been developed and optimized to afford both anomers of common saccharides in high anomeric selectivities. We established that oligosaccharide stannanes could be prepared from monosaccharide stannanes via O-glycosylation with Schmidt-type donors, glycal epoxides, or under dehydrative conditions with C1 alcohols. Second, we identified a general set of catalytic conditions with Pd2(dba)3 (2.5 mol%) and a bulky ligand (JackiePhos, 10 mol%) controlling the β-elimination pathway. We demonstrated that the glycosyl cross-coupling resulted in consistently high anomeric selectivities for both anomers with mono- and oligosaccharides, deoxysugars, saccharides with free hydroxyl groups, pyranose, and furanose substrates. The versatility of the glycosyl cross-coupling reaction was probed in the total synthesis of salmochelins (siderophores) and commercial anti-diabetic drugs (gliflozins). Combined experimental and computational studies revealed that the β-elimination pathway is suppressed for biphenyl-type ligands due to the shielding of Pd(II) by sterically demanding JackiePhos, whereas smaller ligands, which allow for the formation of a Pd-F complex, predominantly result in a glycal product. Similar steric effects account for the diminished rates of cross-couplings of 1,2-cis C1-stannanes with aryl halides. DFT calculations also revealed that the transmetalation occurs via a cyclic transition state with retention of configuration at the anomeric position. Taken together, facile access to both anomers of various glycoside nucleophiles, a broad reaction scope, and uniformly high transfer of anomeric configuration make the glycosyl cross-coupling reaction a practical tool for the synthesis of bioactive natural products, drug candidates, allowing for late-stage glycodiversification studies with small molecules and biologics.

Ionic liquids as phase transfer catalysts: Enhancing the biphasic extractive epoxidation reaction for the selective synthesis of β-O-glycosides

Ionic liquids promoted the direct epoxidation of glycals acting as PTC. 1,2-anhydrosugars were prepared by the oxidation of glycals under biphasic conditions with dimethydioxirane generated in situ from oxone/acetone and amphiphilic IL’s as catalysts. β-O-glycosides were synthesized in good yields by the nucleophilic ring opening of epoxy carbohydrate derivatives. Also, 3,4,6-benzyl protected carbohydrates and β-N-glycosides could be prepare by this method.

Tunable stereoselectivity in the synthesis of α- and β-aryl glycosides using 1,2-α-anhydrosugars as glycosyl donors

The stereochemical course of O-glycosidation of 1,2-α-d-anhydrosugars (glycal epoxides) with phenols can be tuned by varying the metal ion of the base. While the reaction of 1,2-α-d-anhydrosugars with phenols mediated by trimethylaluminium leads exclusively to 1,2-cis-α-O-aryl glycosides, similar reaction mediated by caesium carbonate gives exclusively 1,2-trans-β-O-aryl glycosides. In contrast, reaction with phenoxides generated from Grignard reagent and calcium salts affords mixture of the anomers.

Epoxidation of glycals with oxone–acetone–tetrabutylammonium hydrogen sulfate: a convenient access to simple β- d-glycosides and to α- d-mannosamine and d-talosamine donors

The addition of a phase transfer catalyst during the epoxidation of perbenzylated glycals with oxone–acetone under biphasic conditions allows their complete epoxidation. The epoxides were readily transformed into methyl 1,2- trans-β- d-glycosides or 1,2- trans-β- d-glycopyranosyl azides ( d- gluco and- d- galacto configurations) bearing a free hydroxyl group at the 2-position. These glycosyl azides were converted to alkyl 1,2- trans-2-acetamido-2-deoxy-α- d-pyranosides or alkyl 2-allyloxycarbonylamino-2-deoxy-α- d-pyranosides ( d- manno and d- talo configurations) by a Staudinger reaction and a double inversion of configuration at C-1 and C-2.

Hydrogen-Bonding Catalysis and Inhibition by Simple Solvents in the Stereoselective Kinetic Epoxide-Opening Spirocyclization of Glycal Epoxides to Form Spiroketals

Mechanistic investigations of a MeOH-induced kinetic epoxide-opening spirocyclization of glycal epoxides have revealed dramatic, specific roles for simple solvents in hydrogen-bonding catalysis of this reaction to form spiroketal products stereoselectively with inversion of configuration at the anomeric carbon. A series of electronically tuned C1-aryl glycal epoxides was used to study the mechanism of this reaction based on differential reaction rates and inherent preferences for S(N)2 versus S(N)1 reaction manifolds. Hammett analysis of reaction kinetics with these substrates is consistent with an S(N)2 or S(N)2-like mechanism (ρ = -1.3 vs ρ = -5.1 for corresponding S(N)1 reactions of these substrates). Notably, the spirocyclization reaction is second-order dependent on MeOH, and the glycal ring oxygen is required for second-order MeOH catalysis. However, acetone cosolvent is a first-order inhibitor of the reaction. A transition state consistent with the experimental data is proposed in which one equivalent of MeOH activates the epoxide electrophile via a hydrogen bond while a second equivalent of MeOH chelates the side-chain nucleophile and glycal ring oxygen. A paradoxical previous observation that decreased MeOH concentration leads to increased competing intermolecular methyl glycoside formation is resolved by the finding that this side reaction is only first-order dependent on MeOH. This study highlights the unusual abilities of simple solvents to act as hydrogen-bonding catalysts and inhibitors in epoxide-opening reactions, providing both stereoselectivity and discrimination between competing reaction manifolds. This spirocyclization reaction provides efficient, stereocontrolled access to spiroketals that are key structural motifs in natural products.

Stereoelectronic factors in the stereoselective epoxidation of glycals and 4-deoxypentenosides.

Glycals and 4-deoxypentenosides (4-DPs), unsaturated pyranosides with similar structures and reactivity profiles, can exhibit a high degree of stereoselectivity upon epoxidation with dimethyldioxirane (DMDO). In most cases, the glycals and their corresponding 4-DP isosteres share the same facioselectivity, implying that the pyran substituents are largely responsible for the stereodirecting effect. Fully substituted dihydropyrans are subject to a "majority rule", in which the epoxidation is directed toward the face opposite to two of the three groups. Removing one of the substituents has a variable effect on the epoxidation outcome, depending on its position and also on the relative stereochemistry of the remaining two groups. Overall, we observe that the greatest loss in facioselectivity for glycals and 4-DPs is caused by removal of the C3 oxygen, followed by the C5/anomeric substituent, and least of all by the C4/C2 oxygen. DFT calculations based on polarized-π frontier molecular orbital (PPFMO) theory support a stereoelectronic role for the oxygen substituents in 4-DP facioselectivity, but less clearly so in the case of glycals. We conclude that the anomeric oxygen in 4-DPs contributes toward a stereoelectronic bias in facioselectivity whereas the C5 alkoxymethyl in glycals imparts a steric bias, which at times can compete with the stereodirecting effects from the other oxygen substituents.

Total synthesis of brevenal.

This Article describes the total synthesis of the marine ladder toxin brevenal utilizing a convergent synthetic strategy. Critical to the success of this work was the use of olefinic-ester cyclization reactions and the utilization of glycal epoxides as precursors to C-C and C-H bonds.

Stereoselective synthesis of benzannulated spiroketals: influence of the aromatic ring on reactivity and conformation.

A systematic stereocontrolled synthesis of benzannulated spiroketals has been developed, using kinetic spirocyclization reactions of glycal epoxides, leading to a new AcOH-induced cyclization and valuable insights into the reactivity and conformations of these systems. One stereochemical series accommodates axial positioning of the aromatic ring while another adopts an alternative (1)C(4) chair conformation to avoid it. Equatorial aromatic rings also participate in nonobvious steric interactions that impact thermodynamic stability. A discovery library of 68 benzannulated spiroketals with systematic variations in stereochemistry, ring size, and positioning of the aromatic substituent has been synthesized for broad biological evaluation.

Synthesis of Hybrids of D‐Glucose and D‐Galactose with Pyrrolidine‐Based Iminosugars as Glycosidase Inhibitors

AbstractSugar–iminosugar hybrid molecules made up of D‐glucose and D‐galactose with pyrrolidine‐based iminosugars, viz. 1,4‐dideoxy‐1,4‐imino‐L‐xylitol and 1,4‐dideoxy‐1,4‐imino‐L‐lyxitol, are synthesized from glycal epoxides and found to be moderate glycosidase inhibitors. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Diastereoselective Synthesis of β-Aryl-C-nucleosides from 1,2-Anhydrosugars

The cis opening of glycal epoxides with arylaluminum reagents provides strict stereocontrol in C-glycosylation. beta-Aryl-C-2-deoxynucleosides are obtained from known glycals by an epoxidation-glycosylation-deoxygenation sequence.

Stereocontrolled Synthesis of Spiroketals via Ti(OiPr)4‐Mediated Kinetic Spirocyclization of Glycal Epoxides with Retention of Configuration.

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Stereocontrolled Synthesis of Spiroketals via Ti(Oi-Pr)4-Mediated Kinetic Spirocyclization of Glycal Epoxides with Retention of Configuration

A Ti(Oi-Pr)4-mediated kinetic spiroketalization reaction has been developed for the stereocontrolled target- and diversity-oriented synthesis of spiroketals. In contrast to most existing methods for spiroketal synthesis, this reaction does not rely upon thermodynamic control over the stereochemical configuration at the anomeric carbon. Stereochemically diverse glycals are first alkylated at the C1-position to introduce a hydroxyl-bearing side chain, then epoxidized stereoselectively. Treatment with Ti(Oi-Pr)4 leads to an unusual kinetic epoxide-opening spirocyclization (spirocycloisomerization) with retention of configuration at the anomeric carbon. The reaction is proposed to proceed via a chelation-controlled mechanism and has been used to form five-, six-, and seven-membered rings with stereochemically diverse substituents. This approach may also be useful for the related intermolecular beta-mannosidation reaction. This Ti(Oi-Pr)4-mediated spirocyclization is stereochemically complementary to our previously reported MeOH-induced spirocyclization, which proceeds with inversion of configuration, and together, these reactions provide comprehensive access to systematically stereochemically diversified spiroketals.

Metalloporphyrin‐Catalyzed Diastereoselective Epoxidation of Allyl‐Substituted Alkenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Silver(I)‐Catalyzed Addition of Zirconocenes to Glycal Epoxides. A New Synthesis of α‐C‐Glycosides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Metalloporphyrin-Catalyzed Diastereoselective Epoxidation of Allyl-Substituted Alkenes

By using [Mn(2,6-Cl(2)TPP)Cl] (1) as a catalyst and Oxone/H(2)O(2) as an oxidant, we have developed an efficient method for erythro-selective epoxidation of acyclic allyl-substituted alkenes, including allylic alcohols, amines, and esters. Up to 9:1 erythro selectivities for terminal allyllic alkenes could be achieved, which are significantly higher than that achieved using m-CPBA as an oxidant. In addition, the synthetic utilities of this epoxidation method were highlighted in stereoselective synthesis of key anti-HIV drug intermediates and epoxidation of glycals.

Silver(I)-Catalyzed Addition of Zirconocenes to Glycal Epoxides. A New Synthesis of α-C-Glycosides

[reaction: see text] Hydrozirconation of terminal alkynes, followed by AgClO4-catalyzed in situ addition of the resultant alkenylzirconocenes to 1,2-anhydrosugars (glycal epoxides) leads to alpha-C-glycosides in moderate to high yields.

One‐Pot Conversion of Glycals to cis‐1,2‐Isopropylidene‐α‐glycosides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

One-Pot Conversion of Glycals to cis-1,2-Isopropylidene-α-glycosides

Described is a general method for the conversion of glycals to the corresponding 1,2-cis-isopropylidene-alpha-glycosides. Epoxidation of glycals with dimethyldioxirane followed by ZnCl(2)-catalyzed addition of acetone converted a variety of protected glycals into 1,2-cis-isopropylidene-alpha-glycosides in good yield. The reaction is compatible with a range of protecting groups, including esters, benzyl ethers, and silyl ethers, as well as free hydroxyl groups. This method has been applied to develop a synthesis of protected glucuronic acid 1, a key intermediate in the synthesis of glycosaminoglycans. Compound 1 was produced in seven steps and 32% overall yield.