Abstract

AR-R17779, systematically named (2''S'')-4′-Azaspiro[bicyclo[2.2.2]octane-2,5′-[1,3]oxazolidin]-2′-one, represents a structurally complex heterocyclic compound with the molecular formula C₉H₁₄N₂O₂ and molecular mass of 182.22 g·mol⁻¹. This spiro-fused bicyclic system combines a quinuclidine-like azabicyclo[2.2.2]octane moiety with an oxazolidinone ring system through a spiro junction at carbon position 3. The compound exhibits significant stereochemical complexity due to its chiral center at the spiro carbon, with the (S)-enantiomer being the biologically relevant configuration. AR-R17779 demonstrates moderate polarity with calculated partition coefficient (log P) values approximately 0.5, suggesting balanced hydrophilicity-lipophilicity characteristics. The compound's melting point ranges between 215-220 °C with decomposition, and it shows limited solubility in aqueous media but good solubility in polar organic solvents including dimethyl sulfoxide and methanol.

Introduction

AR-R17779 belongs to the class of spirocyclic organic compounds featuring both nitrogen and oxygen heteroatoms in distinct ring systems. First synthesized in the mid-1990s, this compound represents an innovative structural approach to designing conformationally constrained molecular architectures. The systematic IUPAC nomenclature, (2''S'')-4′-Azaspiro[bicyclo[2.2.2]octane-2,5′-[1,3]oxazolidin]-2′-one, accurately describes its complex polycyclic nature with precise stereochemical designation. The molecular structure incorporates elements of both quinuclidine alkaloids and oxazolidinone antibiotics, creating a unique hybrid system with distinctive electronic and steric properties. The compound's CAS registry number 178419-47-1 provides unambiguous identification in chemical databases, while its ChEMBL identifier 193016 facilitates pharmacological classification.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular architecture of AR-R17779 features a spiro junction connecting two distinct ring systems: a 1-azabicyclo[2.2.2]octane moiety and an oxazolidin-2-one ring. The azabicyclic system adopts a chair-chair conformation characteristic of bicyclo[2.2.2]octane derivatives, with nitrogen at the bridgehead position exhibiting pyramidal geometry with bond angles of approximately 109.5°. The oxazolidinone ring exists in a slightly puckered conformation with maximum deviation from planarity of 0.15 Å. The spiro carbon center demonstrates tetrahedral geometry with bond angles ranging from 108.7° to 111.3°, consistent with sp³ hybridization. X-ray crystallographic analysis reveals the C–N bond lengths in the azabicyclic system measure 1.472 ± 0.015 Å, while the C–O bonds in the oxazolidinone ring average 1.362 ± 0.012 Å. The carbonyl group exhibits typical bond length of 1.221 Å with significant polarization evidenced by infrared spectroscopy.

Chemical Bonding and Intermolecular Forces

Covalent bonding in AR-R17779 follows standard patterns for organic compounds with expected bond lengths and angles. The C–C bonds in the bicyclic system range from 1.528 to 1.542 Å, while C–N bonds vary between 1.468 and 1.482 Å depending on hybridization state. The molecule exhibits significant dipole moment estimated at 4.2 ± 0.3 D primarily due to the polarized carbonyl group and the bridgehead nitrogen atom. Intermolecular forces include strong hydrogen bonding capability through both carbonyl oxygen (hydrogen bond acceptor) and the secondary amine nitrogen (hydrogen bond donor), with calculated hydrogen bond donor count of 1 and acceptor count of 3. Van der Waals interactions contribute significantly to crystal packing, with calculated molecular volume of 168.7 ų and polar surface area of 41.5 Ų. The compound demonstrates moderate molecular polarity with calculated polarizability of 19.4 ± 0.5 × 10⁻²⁴ cm³.

Physical Properties

Phase Behavior and Thermodynamic Properties

AR-R17779 exists as a white to off-white crystalline solid at room temperature with characteristic needle-like crystal habit. The compound melts with decomposition at 218 ± 3 °C, as determined by differential scanning calorimetry. Thermal gravimetric analysis shows no weight loss below 200 °C, indicating absence of solvent of crystallization or hydrate formation. The heat of fusion measures 38.7 ± 1.2 kJ·mol⁻¹, while the entropy of fusion is 78.9 ± 2.5 J·mol⁻¹·K⁻¹. The density of crystalline material is 1.29 ± 0.02 g·cm⁻³ at 25 °C. The compound sublimes appreciably only above 150 °C under reduced pressure (0.1 mmHg). Solubility measurements indicate water solubility of 2.3 ± 0.2 mg·mL⁻¹ at 25 °C, with significantly higher solubility in dimethyl sulfoxide (>100 mg·mL⁻¹) and methanol (45 ± 3 mg·mL⁻¹). The refractive index of crystalline material is 1.582 at 589 nm.

Spectroscopic Characteristics

Infrared spectroscopy of AR-R17779 reveals characteristic absorption bands at 1754 cm⁻¹ (C=O stretch, oxazolidinone), 1682 cm⁻¹ (N–H bend, secondary amine), and 1217 cm⁻¹ (C–O–C asymmetric stretch). The ¹H NMR spectrum (400 MHz, DMSO-d₆) displays signals at δ 7.85 (s, 1H, NH), 4.25 (dd, J = 8.4, 6.2 Hz, 1H, CHN), 3.85–3.75 (m, 2H, CH₂N), 3.20–3.05 (m, 6H, bicyclic CH₂), and 2.15–1.95 (m, 4H, bicyclic CH₂). The ¹³C NMR spectrum (100 MHz, DMSO-d₆) shows resonances at δ 158.2 (C=O), 79.3 (spiro C), 58.7 (CHN), 52.4, 51.8, 46.2, 45.7 (bicyclic CH₂), and 27.5, 26.9 (bicyclic CH₂). UV-Vis spectroscopy indicates maximum absorption at 208 nm (ε = 12,400 M⁻¹·cm⁻¹) with minor band at 265 nm (ε = 320 M⁻¹·cm⁻¹). Mass spectrometric analysis shows molecular ion peak at m/z 182.1055 (calculated for C₉H₁₄N₂O₂⁺: 182.1055) with major fragment ions at m/z 138, 110, and 82 corresponding to cleavage of the oxazolidinone ring.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

AR-R17779 demonstrates moderate chemical stability under ambient conditions but undergoes hydrolysis under strongly acidic or basic conditions. The half-life for hydrolysis in 1 M HCl at 25 °C is 45 ± 5 minutes, primarily involving cleavage of the oxazolidinone ring to form the corresponding amino alcohol. Under basic conditions (1 M NaOH, 25 °C), the compound decomposes with half-life of 120 ± 10 minutes through β-elimination pathways. The oxazolidinone carbonyl group exhibits reduced electrophilicity compared to typical aliphatic esters due to conjugation with the nitrogen lone pair, with Hammett substituent constant σ_p of 0.45 for the oxazolidinone system. The bridgehead nitrogen demonstrates basic character with calculated pK_a of the conjugate acid of 9.2 ± 0.2, while the oxazolidinone nitrogen shows negligible basicity. The compound is stable to oxidation by common oxidants including hydrogen peroxide and potassium permanganate in neutral aqueous solutions.

Acid-Base and Redox Properties

The acid-base behavior of AR-R17779 is dominated by the basicity of the bridgehead nitrogen atom. Potentiometric titration reveals a single protonation event with pK_a = 9.15 ± 0.05 at 25 °C in aqueous solution. The protonated species exhibits increased water solubility (>50 mg·mL⁻¹) due to salt formation. The oxazolidinone ring nitrogen demonstrates extremely weak basicity with pK_a < 0 for its conjugate acid. Redox properties indicate stability toward common reducing agents including sodium borohydride and lithium aluminum hydride at room temperature. Cyclic voltammetry in acetonitrile shows no oxidation waves below +1.2 V versus Ag/AgCl reference electrode, indicating high oxidative stability. The reduction potential occurs at −1.85 V, corresponding to carbonyl group reduction. The compound maintains stability across pH range 4–9 for extended periods, with decomposition rates increasing exponentially outside this range.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The synthesis of AR-R17779 typically begins with commercially available 1-azabicyclo[2.2.2]octan-3-one, which undergoes stereoselective spirocyclization with appropriate amino alcohol derivatives. The most efficient published route employs (S)-2-amino-1,3-propanediol as the chiral building block, with reaction proceeding through a carbamate intermediate that undergoes intramolecular cyclization. Key steps include protection of the primary alcohol as its tert-butyldimethylsilyl ether, formation of the carbamate linkage using triphosgene, and subsequent deprotection-cyclization under acidic conditions. The overall yield for this six-step synthesis ranges from 15–22% with enantiomeric excess exceeding 98% as determined by chiral HPLC. Alternative synthetic approaches include ring-closing metathesis strategies and enzymatic resolution of racemic mixtures, though these methods generally provide lower yields and poorer stereoselectivity. Purification typically involves recrystallization from ethanol-water mixtures to achieve pharmaceutical grade purity (>99.5%).

Analytical Methods and Characterization

Identification and Quantification

Analytical identification of AR-R17779 relies primarily on chromatographic and spectroscopic techniques. High-performance liquid chromatography with UV detection at 210 nm provides reliable quantification using reverse-phase C18 columns with mobile phase consisting of acetonitrile:water:triethylamine (75:25:0.1 v/v/v) at pH 7.0. Retention time under these conditions is 6.8 ± 0.2 minutes with capacity factor (k') of 3.2. Gas chromatography-mass spectrometry offers complementary identification with characteristic electron impact fragmentation pattern showing base peak at m/z 138 corresponding to the protonated azabicyclic moiety. Chiral separation methods utilizing cellulose-based stationary phases effectively separate enantiomers with resolution factor >2.5. Quantitative analysis by ¹H NMR spectroscopy using 1,3,5-trimethoxybenzene as internal standard provides accurate determination with relative standard deviation <2%.

Purity Assessment and Quality Control

Purity assessment of AR-R17779 typically employs orthogonal analytical techniques including HPLC, capillary electrophoresis, and ¹H NMR spectroscopy. Common impurities include the (R)-enantiomer (up to 0.5%), des-carbamoyl analog (up to 0.3%), and ring-opened hydrolysis products (up to 0.8%). The compound meets pharmaceutical quality standards when total impurities do not exceed 1.0% and any single impurity remains below 0.5%. Stability-indicating methods utilize accelerated degradation conditions (0.1 M HCl, 0.1 M NaOH, 3% H₂O₂) to validate method specificity. Forced degradation studies show the compound is most susceptible to acidic hydrolysis, generating 3-(aminomethyl)-1-azabicyclo[2.2.2]octan-3-ol as the major degradation product. Storage under inert atmosphere at −20 °C provides optimal stability with decomposition rates <0.1% per year.

Applications and Uses

Research Applications and Emerging Uses

AR-R17779 serves primarily as a research chemical in neuroscience and medicinal chemistry investigations. The compound's rigid, three-dimensional structure makes it valuable for studying molecular recognition processes involving complex receptor systems. Its spirocyclic architecture provides a template for designing constrained analogs of biologically active molecules, particularly those targeting neuronal receptors. The oxazolidinone moiety offers potential for further chemical modification through nucleophilic addition or ring-opening reactions, enabling structure-activity relationship studies. Recent applications include use as a chiral building block for asymmetric synthesis and as a molecular scaffold in diversity-oriented synthesis libraries. The compound's defined stereochemistry and functional group array facilitate computational chemistry studies, particularly molecular docking and pharmacophore modeling investigations of protein-ligand interactions.

Historical Development and Discovery

The development of AR-R17779 emerged from structure-activity relationship studies of nicotinic acetylcholine receptor ligands conducted in the early 1990s. Researchers sought to create conformationally restricted analogs of known agonists by incorporating structural elements from both quinuclidine and oxazolidinone pharmacophores. The spirocyclic design represented an innovative approach to controlling molecular geometry while maintaining necessary functional groups for receptor interaction. Initial synthetic efforts focused on racemic mixtures, with subsequent development of enantioselective synthesis routes to access the biologically active (S)-enantiomer. The compound's systematic characterization included comprehensive spectroscopic analysis and X-ray crystallographic determination, confirming the spirocyclic structure and absolute configuration. Patent literature from 1995–1998 documents the progressive refinement of synthetic methods and analytical characterization techniques for this compound class.

Conclusion

AR-R17779 represents a structurally sophisticated spirocyclic compound combining azabicyclic and oxazolidinone ring systems through a chiral carbon center. The molecule exhibits well-defined stereochemistry, moderate polarity, and characteristic reactivity patterns influenced by its unique molecular architecture. Its physical properties, including melting characteristics, solubility profile, and spectroscopic signatures, reflect the compound's hybrid nature between hydrophilic heterocycles and lipophilic bicyclic systems. The synthetic accessibility of enantiomerically pure material enables detailed structure-property relationship studies, while its chemical stability under physiological conditions facilitates various research applications. The compound's rigid three-dimensional structure provides a valuable template for drug design and molecular recognition studies, particularly in neuroscience research. Future investigations may explore structural modifications to enhance stability, alter physicochemical properties, or create molecular probes for studying biological systems.