Abstract

Rishitin, systematically named (1''S'',2''R'',3''R'',7''R'')-1-methyl-7-(prop-1-en-2-yl)-1,2,3,4,5,6,7,8-octahydronaphthalene-2,3-diol, is a sesquiterpenoid compound with molecular formula C₁₄H₂₂O₂ and molar mass 222.328 g·mol^-1. This bicyclic diterpenoid derivative exhibits characteristic structural features including two hydroxyl groups at positions C-2 and C-3 and an isopropenyl substituent at C-7. The compound demonstrates moderate polarity with calculated logP values ranging from 2.1 to 2.8, indicating balanced hydrophobic-hydrophilic character. Rishitin displays typical sesquiterpenoid reactivity patterns, undergoing dehydration, oxidation, and electrophilic addition reactions. Its crystalline form melts within the range of 145-148°C, with decomposition observed above 200°C. The compound's stereochemical complexity, featuring four chiral centers in specific absolute configurations, contributes to its distinctive chemical behavior and makes it a subject of ongoing synthetic and structural investigations.

Introduction

Rishitin represents a structurally complex sesquiterpenoid compound belonging to the eremophilane class of natural products. First isolated in 1968 from the potato cultivar 'Rishiri' (Solanum tuberosum L.), this compound derives its name from its botanical source. As a member of the oxygenated sesquiterpene family, rishitin exemplifies the structural diversity achieved through terpenoid biosynthesis. The compound's molecular framework consists of a decalin core system functionalized with two secondary alcohol groups and an unsaturated isopropenyl side chain. This structural arrangement places rishitin among the more complex monocyclic and bicyclic sesquiterpenoids found in plant species, particularly within the Solanaceae family. The compound's discovery contributed significantly to understanding plant chemical defense mechanisms and expanded the known structural diversity of terpenoid natural products.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

Rishitin possesses the molecular formula C₁₄H₂₂O₂ with exact mass 222.1619 g·mol^-1. The compound features a fused bicyclic system comprising a cyclohexane ring fused to a cyclopentane ring, creating a trans-decalin framework characteristic of eremophilane sesquiterpenoids. X-ray crystallographic analysis reveals that the molecule adopts a chair-chair conformation for the decalin system with the cyclohexane ring in chair conformation and the cyclopentane ring adopting an envelope conformation. The four chiral centers exhibit absolute configurations established as 1S, 2R, 3R, and 7R, creating a specific stereochemical environment that influences the molecule's physical properties and chemical reactivity.

Bond length analysis shows typical carbon-carbon single bonds ranging from 1.52-1.55 Å and carbon-oxygen bonds measuring approximately 1.42 Å for the hydroxyl groups. The isopropenyl group features a carbon-carbon double bond length of 1.34 Å, consistent with typical alkene character. Molecular orbital calculations indicate highest occupied molecular orbital (HOMO) energy of -8.7 eV and lowest unoccupied molecular orbital (LUMO) energy of -0.3 eV, resulting in a HOMO-LUMO gap of 8.4 eV. This electronic configuration suggests moderate stability toward electrophilic attack while maintaining reactivity toward strong electrophiles and oxidizing agents.

Chemical Bonding and Intermolecular Forces

The molecular structure of rishitin features predominantly covalent bonding with sp³ hybridization at most carbon centers. The two hydroxyl groups at C-2 and C-3 create localized regions of polarity within the otherwise hydrophobic molecular framework. Dipole moment calculations yield values of 2.8-3.2 D, indicating moderate molecular polarity. The compound exhibits intramolecular hydrogen bonding between the C-2 and C-3 hydroxyl groups with an O···O distance of 2.78 Å and O-H···O angle of 155°, creating a stable six-membered hydrogen-bonded ring.

Intermolecular forces in crystalline rishitin include conventional hydrogen bonding with O-H···O distances of 2.82 Å, van der Waals interactions, and London dispersion forces. The crystal packing demonstrates a herringbone arrangement with molecules organized in layers separated by 4.2 Å. The presence of two hydroxyl groups enables extensive hydrogen bonding network formation, contributing to the compound's relatively high melting point and crystalline stability. The hydrophobic isopropenyl group and methyl substituents create regions of lipophilicity, while the hydroxyl groups provide hydrophilic character, resulting in amphiphilic properties.

Physical Properties

Phase Behavior and Thermodynamic Properties

Rishitin typically crystallizes as colorless needles or plates from appropriate solvents. The compound exhibits a sharp melting point range of 145-148°C with decomposition beginning above 200°C. Differential scanning calorimetry shows an endothermic peak at 147°C corresponding to melting, with enthalpy of fusion measured at 28.5 kJ·mol^-1. The crystalline density determined by X-ray diffraction is 1.15 g·cm^-3 at 25°C.

Thermodynamic parameters include heat capacity C_p of 312 J·mol^-1·K^-1 at 25°C and entropy S° of 398 J·mol^-1·K^-1. The compound demonstrates limited volatility with vapor pressure of 2.3 × 10^-5 mmHg at 25°C. Solubility characteristics show moderate dissolution in polar organic solvents including methanol (85 g·L^-1), ethanol (72 g·L^-1), and acetone (110 g·L^-1), with lower solubility in water (1.2 g·L^-1) and non-polar solvents such as hexane (8.5 g·L^-1).

Spectroscopic Characteristics

Infrared spectroscopy of rishitin reveals characteristic absorption bands at 3350 cm^-1 (broad, O-H stretch), 2925 cm^-1 and 2850 cm^-1 (C-H stretch), 1645 cm^-1 (C=C stretch), 1450 cm^-1 (C-H bend), and 1050 cm^-1 (C-O stretch). The absence of carbonyl stretching vibrations confirms the alcoholic nature of the oxygen functions.

Proton nuclear magnetic resonance (¹H NMR, 400 MHz, CDCl₃) displays characteristic signals at δ 5.35 (1H, br s, H-13a), 4.95 (1H, br s, H-13b), 4.25 (1H, m, H-2), 3.85 (1H, m, H-3), 2.85 (1H, m, H-7), 2.15 (3H, s, H-15), 1.75 (3H, s, H-14), and multiple signals between 0.8-2.4 ppm for the remaining aliphatic protons. Carbon-13 NMR (100 MHz, CDCl₃) shows signals at δ 148.5 (C-11), 110.5 (C-13), 75.8 (C-2), 72.4 (C-3), 45.8 (C-1), 42.5 (C-7), 40.2 (C-10), 39.5 (C-4), 35.8 (C-8), 32.4 (C-6), 28.5 (C-5), 27.8 (C-9), 22.5 (C-12), 20.8 (C-15), and 18.5 (C-14).

Mass spectrometric analysis exhibits a molecular ion peak at m/z 222.1619 (calculated for C₁₄H₂₂O₂⁺, 222.1619) with major fragment ions at m/z 204 (M-H₂O)⁺, 189 (M-H₂O-CH₃)⁺, 161, 147, and 135, corresponding to characteristic dehydration and retro-Diels-Alder fragmentation patterns.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Rishitin demonstrates reactivity typical of secondary alcohols and trisubstituted alkenes. The hydroxyl groups undergo standard alcohol transformations including esterification with acetic anhydride (yield 85% after 2 hours at 25°C), oxidation with Jones reagent to the corresponding diketone (yield 78%), and ether formation with alkyl halides under basic conditions. Dehydration reactions occur under acidic conditions, primarily yielding the Δ^2,3 unsaturated derivative with minor formation of the Δ^1,2 isomer.

The isopropenyl group participates in electrophilic addition reactions with bromine (yielding the dibromide derivative) and undergoes ozonolysis to produce acetone and the corresponding aldehyde. Hydrogenation over palladium catalyst reduces the double bond, yielding dihydrorishitin. Reaction rates for acetylation follow second-order kinetics with rate constant k₂ = 1.8 × 10^-3 L·mol^-1·s^-1 at 25°C. The compound demonstrates stability in neutral and acidic conditions but undergoes gradual decomposition in strong alkaline media above pH 10.

Acid-Base and Redox Properties

The hydroxyl groups in rishitin exhibit typical alcohol acidity with estimated pK_a values of 15.2-15.8, similar to secondary aliphatic alcohols. The compound shows no significant basic character and remains stable across pH range 3-9. Oxidation potential measurements using cyclic voltammetry reveal an irreversible oxidation wave at +1.25 V vs. SCE, corresponding to oxidation of the alcohol functions.

Reductive processes include catalytic hydrogenation of the isopropenyl group with uptake of 1 equivalent of hydrogen. The compound demonstrates resistance to reduction by sodium borohydride and other mild reducing agents. Electrochemical reduction occurs at -2.1 V vs. SCE, associated with reduction of the alkene functionality. The redox stability spans from -1.5 V to +1.0 V, indicating moderate electrochemical stability under typical conditions.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

Total synthesis of rishitin represents a significant challenge due to its four chiral centers and specific stereochemical requirements. The most efficient reported synthesis begins with commercially available (+)-carvone as chiral starting material. Key steps include regioselective epoxidation of the isopropenyl group, followed by Lewis acid-mediated rearrangement to establish the eremophilane skeleton. Stereoselective dihydroxylation using osmium tetroxide with N-methylmorpholine N-oxide establishes the C-2 and C-3 stereocenters with 85% diastereoselectivity.

Alternative synthetic approaches utilize intramolecular Diels-Alder reactions to construct the decalin system or enzymatic resolution to obtain enantiomerically pure intermediates. The longest linear sequence requires 18 steps with overall yield of 7.3%. Purification typically involves column chromatography on silica gel followed by recrystallization from ethyl acetate/hexane mixtures. The synthetic material exhibits identical spectroscopic properties and melting behavior to natural rishitin, confirming structural identity.

Analytical Methods and Characterization

Identification and Quantification

Chromatographic analysis of rishitin employs reverse-phase high performance liquid chromatography with C18 columns using acetonitrile/water mobile phases. Retention time typically ranges from 12.5-13.8 minutes under gradient conditions (40-80% acetonitrile over 20 minutes). Detection utilizes ultraviolet absorption at 210 nm with molar absorptivity ε = 4200 L·mol^-1·cm^-1. Gas chromatographic analysis requires derivatization by silylation to improve volatility, with retention indices of 1850-1870 on methylsilicone stationary phases.

Quantitative analysis achieves detection limits of 0.5 μg·mL^-1 by HPLC with UV detection and 0.1 μg·mL^-1 using GC-MS with selected ion monitoring of m/z 222. Method validation demonstrates accuracy of 98.5% and precision of 2.3% RSD at concentration levels from 1-100 μg·mL^-1. Calibration curves show linearity (r² > 0.999) across the analytical range.

Purity Assessment and Quality Control

Purity assessment of rishitin utilizes differential scanning calorimetry to determine crystalline purity (>98% by DSC) and chromatographic methods to detect organic impurities. Common impurities include dehydration products (Δ^2,3-anhydrorishitin) and oxidation derivatives. Spectroscopic purity determination employs quantitative ¹H NMR with internal standards, typically achieving uncertainty of ±1.5%.

Quality control specifications for research-grade rishitin require minimum purity of 97% by HPLC, water content below 0.5% by Karl Fischer titration, and residual solvent limits conforming to ICH guidelines. Storage recommendations include protection from light at -20°C under inert atmosphere to prevent oxidation and dehydration. Under these conditions, rishitin demonstrates stability for at least 24 months with purity degradation less than 1% per year.

Applications and Uses

Research Applications and Emerging Uses

Rishitin serves primarily as a reference compound in phytochemical research and as a model system for studying sesquiterpenoid chemistry. The compound's complex stereochemistry and functional group arrangement make it valuable for methodological development in asymmetric synthesis and stereochemical analysis. Research applications include investigations of hydrogen bonding effects on molecular conformation and studies of solvent effects on hydroxyl group reactivity.

Emerging applications explore rishitin as a chiral building block for the synthesis of more complex terpenoid structures and as a template for molecular recognition studies. The compound's amphiphilic character suggests potential as a molecular scaffold for supramolecular chemistry applications. Patent literature indicates interest in rishitin derivatives as intermediates for fragrance compounds and specialty chemicals, though industrial applications remain limited due to synthetic challenges and availability constraints.

Historical Development and Discovery

The isolation and characterization of rishitin in 1968 marked a significant advancement in understanding plant chemical defense mechanisms. Initial structural elucidation relied on classical chemical degradation methods including ozonolysis, hydrogenation, and functional group interconversions. The absolute configuration determination required X-ray crystallographic analysis of heavy atom derivatives and later verification by total synthesis.

Early synthetic efforts in the 1970s focused on biomimetic approaches attempting to replicate the proposed biosynthetic pathway. The first total synthesis, completed in 1983, established the complete stereochemistry and confirmed the structural assignment. Subsequent methodological improvements in the 1990s and 2000s enabled more efficient syntheses with better stereocontrol and higher yields. The compound's historical significance lies in its role as one of the first fully characterized sesquiterpenoid phytoalexins, providing a structural prototype for related natural products.

Conclusion

Rishitin represents a structurally complex sesquiterpenoid with distinctive chemical and physical properties derived from its specific molecular architecture. The compound's four chiral centers arranged in 1S, 2R, 3R, 7R configuration create a unique three-dimensional structure that influences its reactivity, spectroscopic characteristics, and crystalline properties. The presence of two hydroxyl groups and an isopropenyl functionality provides multiple sites for chemical modification while maintaining overall molecular stability.

Ongoing research challenges include development of more efficient synthetic routes, exploration of novel derivatives with modified properties, and investigation of potential applications in materials science and chiral synthesis. The compound continues to serve as valuable model system for methodological development in natural product chemistry and stereochemical analysis. Future investigations will likely focus on catalytic asymmetric synthesis approaches and exploration of structure-property relationships within the eremophilane sesquiterpenoid family.