Acetal Substitution Reactions: Stereoelectronic Effects, Conformational Analysis, Reactivity vs Selectivity, and Neighboring-Group Participation

Synlett, Journal Year: 2024, Volume and Issue: 35(15), P. 1763 - 1787

Published: Jan. 16, 2024

Abstract Acetal substitution reactions can proceed by a number of mechanisms, but oxocarbenium ion intermediates are involved in many these reactions. Our research has focused on understanding the conformational preferences, structures, and intermediates. This account summarizes our observations that electrostatic effects play significant role defining preferred conformations, torsional determine how those react. Neighboring-group not as straightforward they might seem, considering equilibrium with structures involve stabilization nearby substituent.1 Introduction 2 Unexpected Stereoselectivities 3 Determining Conformational Preferences Oxocarbenium Ions 4 Structures Carbocations NMR Spectroscopy X-ray Crystallography 5 Stereoelectronic Models for Reactions Involving Other 6 Stereoselectivity Reactivity: When They Correlate, Do Not 7 Neighboring–Group Participation Is Simple It Seems 8 What True Carbonyl Compounds 9 Torsional Effects Enolates 10 Summary Expected Selectivities Cyclic Acetals 11 Conclusion

Language: Английский

---

Cooperative Catalysis in Stereoselective O- and N-Glycosylations with Glycosyl Trichloroacetimidates Mediated by Singly Protonated Phenanthrolinium Salt and Trichloroacetamide

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 4, 2024

The development of small-molecule catalysts that can effectively activate both reacting partners simultaneously represents a pivotal pursuit in advancing the field stereoselective glycosylation reactions. We report herein singly protonated form readily available phenanthroline as an effective cooperative catalyst facilitates coupling wide variety aliphatic alcohols, phenols, and aromatic amines with α-glycosyl trichloroacetimidate donors. reaction likely proceeds via SN2-like mechanism, generating β-selective glycoside products. developed protocol provides access to O- N-glycosides good yields excellent levels β-selectivity enables late-stage functionalization cross-coupling Importantly, this method exhibits is unattainable through C2-O-acyl neighboring group participation strategy, especially case glycosyl donors already containing C2 heteroatom or sugar unit. Kinetic studies demonstrate byproduct trichloroacetamide plays previously undiscovered role influencing reactivity selectivity reaction. A proposed mechanism involving simultaneous activation donor acceptor by phenanthrolinium salt assistance supported kinetic analysis preliminary computational studies. This catalysis process involves four consecutive hydrogen bond interactions. first interaction occurs between carbonyl oxygen hydroxyl alcohol nucleophile (C═O···HO). second trichloroacetamide-NH2 forming nitrogen atom (NH···N). third (═NH) engaging phenanthrolinium-NH (NH···N═H). Lastly, trichloroacetimidate-NH2 forms fluorine tetrafluoroborate ion.

Language: Английский

---

Stabilization of Glucosyl Dioxolenium Ions by “Dual Participation” of the 2,2-Dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) Protection Group for 1,2-cis-Glucosylation

The Journal of Organic Chemistry, Journal Year: 2022, Volume and Issue: 87(14), P. 9139 - 9147

Published: June 24, 2022

The stereoselective introduction of glycosidic bonds is paramount importance to oligosaccharide synthesis. Among the various chemical strategies steer stereoselectivity, participation by either neighboring or distal acyl groups used particularly often. Recently, use 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) protection group was shown offer enhanced steering compared other groups. Here, we investigate origin stereoselectivity induced DMNPA through systematic glycosylation reactions and infrared ion spectroscopy (IRIS) combined with techniques such as isotopic labeling anomeric center isomer population analysis. Our study indicates that does not lie in direct nitro moiety but formation a dioxolenium strongly stabilized group.

Language: Английский

---

Phase-Transfer Catalyzed Microfluidic Glycosylation: A Small Change in Concentration Results in a Dramatic Increase in Stereoselectivity

Catalysts, Journal Year: 2023, Volume and Issue: 13(2), P. 313 - 313

Published: Feb. 1, 2023

Phase-transfer catalysis (PTC) is widely used in glycochemistry for the preparation of aryl glycosides by glycosylation reaction. While investigating possibility synthesis 4-(3-chloropropoxy)phenyl sialoside (Neu5Ac-OCPP) from N-acetylsialyl chloride with O-acetyl groups (1), we have recently discovered a strong dependence PTC outcome on mixing mode: under batch conditions, only α-anomer Neu5Ac-OCPP was obtained, albeit low yield (13%), while microfluidic conditions increased to 36%, although stereoselectivity decreased (α/β ≤ 6.2). Here, report that this reaction, performed using Comet X-01 micromixer (at 2 μL/min flow rate), non-linearly depends concentration 1 (5–200 mmol/L). The target obtained noticeably higher (up 66%) accompanied enhanced = 17:1–32:1) high range (C > 50 mmol/L), whereas (10–36%) and especially, 0.9:1–6.2:1) were lower This dramatic stepwise increase above critical (50 mmol/L) apparently related changes presentation molecules surface supramers glycosyl donor, which exist different ranges.

Language: Английский

---

Mixer Design and Flow Rate as Critical Variables in Flow Chemistry Affecting the Outcome of a Chemical Reaction: A Review

Inventions, Journal Year: 2023, Volume and Issue: 8(5), P. 128 - 128

Published: Oct. 16, 2023

Flow chemistry offers several advantages for performing chemical reactions and has become an important area of research. It may seem that sufficient knowledge already been acquired on this topic to understand how choose the design microreactor/micromixer flow rate in order achieve desired outcome a reaction. However, some experimental data are difficult explain based commonly accepted concepts reactivity performance microfluidic systems. In mini review, we attempt identify such offer rational explanation unusual results supramer approach. We demonstrate variation regime (determined by mixer rate) can either improve or worsen lead completely different products, including stereoisomers. is not necessary mix reagents with maximum efficiency. The real challenge right way since at too high low (in particular mixer), molecules incorrectly presented surface supramers, leading altered stereoselectivity, form tight which most located inside core inaccessible attack, yields.

Language: Английский

---

Stereoelectronic Effect of Protecting Groups on the Stability of Galactosyl Donor Intermediates

Molecules, Journal Year: 2025, Volume and Issue: 30(2), P. 218 - 218

Published: Jan. 7, 2025

Using methods of DFT, we investigated the effect electron withdrawing and donating groups on relative stability tentative glycosyl donor reaction intermediates. The calculation shows that by changing stereoelectronic properties protecting group, can influence dioxolenium type intermediates up to 10 kcal mol−1, increasing nucleophillicity 4-O-Bz intermediate becomes more stable than a triflate–donor pair. We exploited this mechanism design galactosyl donors with custom O2 O4, outcome cyclohexanol. showed no change in product distribution, which suggests neighboring group participation takes precedence over remote due kinetic barriers.

Language: Английский

---

Stereoselective 1,1´-glycosylation via reactivity tuning with protecting groups

Organic & Biomolecular Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Chemical 1,1'-glycosylation for the synthesis of non-reducing disaccharides is complicated by need to simultaneously control stereochemistry at two anomeric centers. While considerable progress has been made in α,α-disaccharides, assembly 1,1'-β,β- and 1,1'-β,α-linked sugars received comparatively less attention. Many naturally occurring their biologically active mimetics feature asymmetrically located functional groups different positions on pyranose rings, highlighting demand reliable stereoselective methods synthesize fully orthogonally protected 1,1'-conjugated suitable targeted functionalisation create important biomolecules. By exploiting specific electronic torsional effects imposed protecting both glycosyl donor lactol acceptor molecules, we achieved highly β,β- β,α-1,1'-glycosylation successfully synthesised a library β,α-linked diglucosamines. Our approach based premise that reactivity can greatly influence stereochemical outcome glycosylation reaction. We show tailored choice orthogonal alter preferences acceptors, stabilising conformations, group-driven modulation nucleophilicity useful tool achieve 1,1'-glycosidic bond formation. Structure-activity relationships have established number donor-lactol pairs, with focus optimizing facilitate 1,1'-β,α-glycosylation side enhance neighboring stereoselectivity side.

Language: Английский

---

Why Are 5-Thioglycopyranosyl Donors More Axially Selective than their Glycopyranosyl Counterparts? A Low and Variable Temperature NMR Spectroscopy and Computational Study

JACS Au, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

5-Thioglycopyranosyl donors differ in reactivity and selectivity from simple glycopyranosyl donors. An extensive study has been conducted on the nature stability of reactive intermediates generated activation per-O-acetyl per-O-methyl 5-thioglucopyranosyl corresponding glucopyranosyl Variable temperature nuclear magnetic resonance (NMR) studies with per-O-methylated or glycosyl sulfoxides trichloroacetimidates trifluoromethanesulfonic anhydride trimethylsilyl triflate are reported. These show that following initial adduct formation promoter conversion to triflates requires higher temperatures than triflates. It is demonstrated neighboring group participation a less important phenomenon for peracetylated thioglucosyl glucosyl A thiocarbenium ion was by protonation 2,3-dihydro-4H-thiopyran at low characterized NMR spectroscopy. However, thenium ions were not observed any 5-thiopyranosyl donors: electron-withdrawing C–O bonds around thiopyranoside core discourage formation, just as they oxocarbenium formation. Density functional theory (DFT) calculations reveal tetrahydrothiopyranyl be approximately 2.5 kcal/mol lower energy tetrahydropyranyl relative covalent computations 5.8 barrier ion, while ion–triflate pair only 2.6 kcal·mol–1. Overall, greater axial 5-thioglycopyranosyl compared analogous derives (i) kinetic necessitating reaction temperatures, (ii) over facilitating equilibration under thermodynamic conditions, (iii) magnitude anomeric effect 5-thiosugars, (iv) decreased per-esterified 5-thiosugars.

Language: Английский

---

Isothiourea – catalyzed α-selective glycosylations

Chemical Communications, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Here, we disclose the discovery that isothioureas efficiently catalyze formation of both α-1,2- cis and trans glycosyl linkages from either bromide or chloride donors, furnishing glycosides in good to complete selectivities.

Language: Английский

---

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

Beilstein Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: 21, P. 369 - 406

Published: Feb. 17, 2025

Stereoselective glycosylations are one of the most challenging tasks synthetic glycochemists. The protecting building blocks on glycosides contribute significantly in attaining required stereochemistry resulting glycosides. Strategic installation suitable groups C-2 position, vicinal to anomeric carbon, renders neighbouring group participation, whereas distal C-3, C-4, and C-6 positions often claimed exhibit remote participation with carbon. Neighbouring being widely studied help glycochemists design protocols for multistep synthesis complex oligosaccharides turn, standardise process glycosylation towards a particular stereochemical output. While has been quite effective achieving produced glycosides, exhibits comparatively less efficacy complete stereoselectivity reactions. Remote is still highly debated topic scientific community. However, implementing participating role reactions practised achieve better stereocontrol facilitate formation synthetically glycosidic linkages.

Language: Английский

---