Determination of Enantiomeric Composition of Substituted Tetrahydroisoquinolines Based on Derivatization with Menthyl Chloroformate


A method for the analysis of the optical purity of a series of chiral substituted tetrahydroisoquinolines (THIQs) was developed. The method is based on pre-column derivatization of the analytes with the derivatization reagent (–)-(1R)-menthyl chloroformate. The derivatization reaction selectively gives diastereomeric carbamates that are resolvable on an achiral non-polar GC column. The developed technique covers variously substituted THIQs, which differ significantly in volatility, steric and electronic properties. In all cases, the resolution factors (R) exceeded the value of 1.5. The method represents a robust way of analysis of mixtures of THIQs, which are often present in various matrixes such as body fluids, tissues and reaction mixtures.

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J. Přech, V. Matoušek, J. Václavík, J. Pecháček, K. Syslová, P. Šot, J. Januščák, B. Vilhanová, M. Kuzma and P. Kačer, "Determination of Enantiomeric Composition of Substituted Tetrahydroisoquinolines Based on Derivatization with Menthyl Chloroformate," American Journal of Analytical Chemistry, Vol. 4 No. 3, 2013, pp. 125-133. doi: 10.4236/ajac.2013.43017.

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The authors declare no conflicts of interest.


[1] W. Maruyama, G. Sobue, K. Matsubara, Y. Hashizume, P. Dostert and M. Naoi, “A Dopaminergic Neurotoxin, 1(R), 2(N)-Dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, N-Methyl(R)salsolinol, and Its Oxidation Product, 1, 2(N)-Dimethyl-6,7-dihydroxyisoquinolinium Ion, Accumulate in the Nigro-Striatal System of the Human Brain,” Neuroscience Letters, Vol. 223, No. 1, 1997, pp. 61-64. doi:10.1016/S0304-3940(97)13389-4
[2] W. Zhu, D. Wang, J. Zheng, A. Yarui, Q. Wang, W. Zhang, L. Jin, H. Gao and L. Lin, “Effect of (R)-Salsolinol and N-Methyl-(R)-Salsolinol on the Balance Impairment between Dopamine and Acetylcholine in Rat Brain: Involvement in Pathogenesis of Parkinson Disease,” Clinical Chemistry, Vol. 54, No. 4, 2008, pp. 705-712. doi:10.1373/clinchem.2007.097725
[3] H. Haber, A. Winkler, I. Putscher, P. Henklein, I. Baeger, M. Georgi and M. F. Melzig, “Plasma and Urine Salsolinol in Humans: Effect of Acute Ethanol Intake on the Enantiomeric Composition of Salsolinol,” Alcoholism: Clinical and Experimental Research, Vol. 20, No. 1, 1996, pp. 87-92. doi:10.1111/j.1530-0277.1996.tb01049.x
[4] H. Ihmsen, J. Schmidt, H. Schwilden, H. J. Schmitt and T. Muenster, “Influence of Disease Progression on the Neuromuscular Blocking Effect of Mivacurium in Children and Adolescents with Duchenne Muscular Dystrophy,” Anesthesiology, Vol. 110, No. 5, 2009, pp. 1016-1019. doi:10.1097/ALN.0b013e31819daf31
[5] J. Caldwell, “The Importance of Stereochemistry in Drug Action and Disposition,” Journal of Clinical Pharmacology, Vol. 32, No. 10, 1992, pp. 925-929.
[6] N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya and R. Noyori, “Asymmetric Transfer Hydrogenation of Imines,” Journal of American Chemical Society, Vol. 118, No. 20, 1996, pp. 4916-4917. doi:10.1021/ja960364k
[7] V. Samano, J. A. Ray, J. B. Thompson, R. A. Mook, D. K. Jung, C. S. Koble, M. T. Martin, E. C. Bigham, C. S. Regitz, P. L. Feldman and E. E. Boros, “Synthesis of Ultra-Short-Acting Neuromuscular Blocker GW 0430: A Remarkably Stereoand Regioselective Synthesis of Tetrahydroisoquinolinium Chlorofumarates,” Organic Letters, Vol. 1, No. 12, 1999, pp. 1993-1996. doi:10.1021/ol9911573
[8] M. Ru?i?, A. Pe?avar, D. Prudi?, D. Kralj, C. Scriban and A. Zanotti-Gerosa, “The Development of an Asymmetric Hydrogenation Process for the Preparation of Solifenacin,” Organic Process Research & Development, Vol. 16, No. 7, 2012, pp. 1293-1300. doi:10.1021/op3000543
[9] B. Vilhanová, V. Matou?ek, J. Václavík, K. Syslová, J. P?ech, J. Pechá?ek, P. ?ot, J. Janu??ák, J. Toman, J. Zápal, M. Kuzma and P. Ka?er, “Two Optimized Synthetic Pathways toward a Chiral Precursor of Mivacurium Chloride and Other Skeletal Muscle Relaxants,” Tetrahedron: Asymmetry, Vol. 24, No. 1, 2013, pp. 50-55. doi:10.1016/j.tetasy.2012.11.012
[10] M. Kajita, T. Niwa, M. Fujisaki, M. Ueki, K. Niimura, M. Sato, K. Egami, M. Naoi, M. Yoshida and T. Nagatsu, “Detection of 1-Phenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline and 1-Phenyl-1,2,3,4-tetrahydroisoquinoline in Human Brain by Gas Chromatography-Tandem Mass Spectrometry,” Journal of Chromatography B: Biomedical Sciences and Applications, Vol. 669, No. 2, 1995, pp. 345-351. doi:10.1016/0378-4347(95)00106-S
[11] Y. Makino, Y. Tasaki, S. Ohta and M. Hirobe, “Confirmation of the Enantiomers of 1-Methyl-1,2,3,4-tetrahydroisoquinoline in the Mouse Brain and Foods Applying Gas Chromatography/Mass Spectrometry with Negative Ion Chemical Ionization,” Biological Mass Spectrometry, Vol. 19, No. 7, 1990, pp. 415-419. doi:10.1002/bms.1200190706
[12] H. Ka?oka, O. Rotkaja and L. Vara?eva, “Enantioseparation of 1-Phenyl-1,2,3,4-tetrahydroisoquinoline on Polysaccharide-Based Chiral Stationary Phases,” Chromatographia, Vol. 73, No. 1, 2011, pp. 123-129. doi:10.1007/s10337-011-1991-9
[13] A. Lee, H. J. Choi, K. B. Jin and M. H. Hyun, “Liquid Chromatographic Resolution of 1-Aryl-1,2,3,4-Tetrahydroisoquinolines on a Chiral Stationary Phase Based on (+)-(18-Crown-6)-2,3,11,12-Tetracarboxylic Acid,” Journal of Chromatography A, Vol. 1218, No. 26, 2011, pp. 4071-4076. doi:10.1016/j.chroma.2011.04.088
[14] H. Inoue, D. Matsubara and Y. Tsuruta, “Simultaneous Analysis of 1,2,3,4-Tetrahydroisoquinolines by High-Performance Liquid Chromatography Using 4-(5,6-Dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl Chloride as a Fluorescent Labeling Reagent,” Journal of Chromatography B, Vol. 867, No. 1, 2008, pp. 32-36. doi:10.1016/j.jchromb.2008.03.002
[15] Y. Song, J. Xu, A. Hamme and Y.-M. Liu, “Capillary Liquid Chromatography-Tandem Mass Spectrometry of Tetrahydroisoquinoline Derived Neurotoxins: A Study on the Blood-Brain Barrier of Rat Brain,” Journal of Chromatography A, Vol. 1103, No. 2, 2006, pp. 229-234. doi:10.1016/j.chroma.2005.11.014
[16] M. Cai and Y.-M. Liu, “Quantification of Salsolinol Enantiomers by Stable Isotope Dilution Liquid Chromatography with Tandem Mass Spectrometric Detection,” Rapid Communications in Mass Spectrometry, Vol. 22, No. 24, 2008, pp. 4171-4177. doi:10.1002/rcm.3847
[17] N. R. Srinivas, W. C. Shyu and R. H. Barbhaiya, “Gas Chromatographic Determination of Enantiomers as Diastereomers Following Pre-Column Derivatization and Applications to Pharmacokinetic Studies: A Review,” Biomedical Chromatography, Vol. 9, No. 1, 1995, pp. 1-9. doi:10.1002/bmc.1130090102
[18] E. Gil-Av and D. Nurok, “Resolution of Optical Isomers by Gas Chromatography of Diastereomers,” In: J. C. Giddings and R. A. Keller, Eds., Advances in Chromatography, Marcel Dekker, New York, 1974, pp. 99-172.
[19] J. A. Dale, D. L. Dull and H. S. Mosher, “α-Methoxy-αtrifluoromethylphenylacetic Acid, a Versatile Reagent for the Determination of Enantiomeric Composition of Alcohols and Amines,” Journal of Organic Chemistry, Vol. 34, No. 9, 1969, pp. 2543-2549. doi:10.1021/jo01261a013
[20] F. Shimoma, H. Kusaka, K. Wada, H. Azami, M. Yasunami, T. Suzuki, H. Hagiwara and M. Ando, “A Novel Synthetic Method of the (±)-(3aα,8aα)-Ethyl 8β-Hydroxy6β-methyl-2-oxooctahydro-2H-cyclohepta[b]furan-3α-carboxylate and Its Chemical Transformation to (±)-(3aα, 8aα)-3α,6β-Dimethyl-3,3a,4,5,6,8a-hexahydro-2H-cyclohepta[b]furan-2-one, (+)and (?)-7β-(2-Acetoxy-1α-methylethyl)-4β-methyl-2-cyclohepten-1β-ol, and (+)and (?)-7β-(2-Acetoxy-1α-methylethyl)-4β-methyl-2-cyclohepten-1-one. Possible Common Synthetic Intermediates for Pseudoguaianolides, 4,5-Secopseudoguaianolides, Guaianolides, 4,5-Secoguaianolides, and Octalactins,” Journal of Organic Chemistry, Vol. 63, No. 4, 1998, pp. 920-929. doi:10.1021/jo971529q
[21] D. A. Allen, A. E. Tomaso Jr., O. P. Priest, D. F. Hindson and J. L. Hurlburt, “Mosher Amides: Determining the Absolute Stereochemistry of Optically-Active Amines,” Journal of Chemical Education, Vol. 85, No. 5, 2008, pp. 698-700. doi:10.1021/ed085p698
[22] C. Schotes and A. Mezzetti, “Asymmetric Diels-Alder Reactions of Unsaturated β-Ketoesters Catalyzed by Chiral Ruthenium PNNP Complexes,” Journal of American Chemical Society, Vol. 132, No. 11, 2010, pp. 3652-3653. doi:10.1021/ja910039e
[23] A. M. Gulamhussen, P. Ka?er, J. P?ech, M. Kuzma and L. ?erveny, “Highly Efficient Preparation of (R)-1-Methyltetrahydroisoquinoline Using Chiral Ru(II)-Catalyst,” Reaction Kinetics and Catalysis Letters, Vol. 97, No. 2, 2010, pp. 335-340. doi:10.1007/s11144-009-0036-y
[24] L. Chaoqun and X. Jianliang, “Asymmetric Hydrogenation of Cyclic Imines with an Ionic Cp*Rh(III) Catalyst,” Journal of American Chemical Society, Vol. 130, No. 40, 2008, pp. 13208-13209. doi:10.1021/ja8050958
[25] D. J. Ager, A. H. M. de Vries and J. G. de Vries, “Asymmetric Homogeneous Hydrogenations at Scale,” Chemical Society Reviews, Vol. 41, 2012, pp. 3340-3380. doi:10.1039/C2CS15312B

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