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Determination of Absolute Configurations and Predominant Conformations of General Inhalation Anesthetics: Desflurane
Determination of Absolute Configurations and Predominant Conformations of General Inhalation Anesthetics: Desflurane P. L. POLAVARAPU'~, A. L. CHOLLI,* AND G. VERNICE' Received September 8, 1992, from the *Departmentof Chemist Vanderbilt University, Nashville, TN 37235, the *BOC Group, Inc., Technical Accepted for publication Center, Murray Hill, NJ 07974, and *Anaquest, Inc., Division of ZOC Health Care, Murray Hfll, NJ 07974. December 7 , 1992. Abstract 0 Although the mechanism of anesthetic action is not yet
clearly understood, it was recently shown that the pure enantiomers of chiral inhalation anesthetic agents interact differentially with the ion channels in the central nervous system. This differential interaction was suggested to arise from stereospecific binding of chiral enantiomers to proteins. To understand and model the differential nature of binding of enantiomers it is necessary to determine their absolute configurations and the number of predominant conformers. From studies on circular dichroism in the vibrational transitions of desflurane (CF,HOCHFCF,), we found that (+)-desflurane has the (R)-configuration and (-)desflurane has the (9-configuration. In addition, each enantiomer existed in two distinct conformations at room temperature.
Desflurane (CF2HOCHFCF3) is currently in the final stages of clinical trials as a next generation inhalation anesthetic agent. Recent studies1 indicate that desflurane is less toxic than commonly used isoflurane(CF2HOCHCICF3) and has low blood-gas solubility. The molecular basis for anesthetic action is not clearly understood. Because achiral molecules such as diethyl ether have long been used as successful anesthetic agents, the possibility for stereospecific interactions between the anesthetic agents and biological systems has not been addressed. However, recently developed anesthetic agents,2 including desflurane, have chiral structures. At present, the most commonly used inhalation anesthetics are administered as racemic mixtures (equal amounts of mirror image isomers or enantiomers). Recent development3.4 of separation schemes for obtaining the pure enantiomers has permitted investigations on the anesthetic effectof individual enantiomers of isoflurane, which is similar to desflurane (the difference being the chlorine atom in isoflurane is replaced by fluorine). The (+I- and (-1-enantiomers of isoflurane have nearly a twofold difference in their effectiveness on the anesthetic-activated potassium current and in their inhibition of current mediated by acetylcholine receptors.6 These differences were attributed to the stereospecific binding between the chiral enantiomers and the anestheticsensitive proteins in the brain.6.6 To understand these stereospecific interactions at the molecular level it is necessary to know the absolute configurations of the chiral enantiomers and the conformations in which they exist. This information is not available for desflurane. The absolute configuration of desflurane cannot be determined from the commonly used techniques of X-ray diffraction and electronic circular dichroism. This is because desflurane does not crystallize and does not have electronic transitions in the accessible visible range. However, optical activity is also supported by the molecular vibrational transitions, and the informational content in such a spectrum is the complete stereochemistry of a molecule in the solution phase. The optical activity in vibrational transitions can be measured in the IR spectrum as vibrational circular dichroism7 and in the b a n spectrum as b a n 0022-3~9/93/osoO-0791$02.50/0 0 1993. American Pharmaceutical Association
optical activity.8 We present here vibrational circular dichroism studies on desflurane and the absolute configurations and predominant conformations determined from these data. This structural information is expected to pave the way for madeling and understanding the stereospecific interactions between desflurane and the chiral environment in biological systems.
Experimental Section The experimentalabsorption and circulardichroism spectra in the 1600-700 cm-' region were measured on a Fourier transform IR instrument (Cygnus 100, Mattson Instruments Inc.) modified9 to enable circular dichroism measurements.A ZnSe photoelastic modulator (HindsInternational)and a KRS-5 polarizer (Molectron) were used to generate left and right circular polarizations at 37 kHz. A high sensitivity HgCdTe detector with D* = 4 x 1 0 ' was used for the light detection.A lock-in- amplifier (PAR 124A) tuned to the modulator frequency was used for demodulating the circular dichroism signal. The minimize the baseline artifacts, the circular dichroism spectra for (+)-enantiomerwere obtained in the commonly practiced way as one-halfof the differencebetween the raw spectra for (+)- and (-)-enantiomers. The spectra were obtained at 4 cm-' resolution for desflurane dissolved in CDC1, (1500-900 cm-l region) at a concentration of -0.2 M. The sampleswere held in a cell equipped with KBr windows at room temperature (20 "C).The data collection time wae 1 h per sample. Typical absorption and circular dichroiem spectra are displayed in Figures 1 and 2.
-
Theoretical Section For the theoretical predictions, the sequential steps involved are full geometry optimization (where all bond lengths and angles were optimized for minimum energy), vibrational frequencies, and circular dichroism intensity calculations. Ab intio quantum theoretical predictions of optimized structures and vibrational absorption spectra were obtained with the GAUSSIAN 9010 and CADPAC" program packages with the M l G * basis set.12 Corresponding circular dichroism spectra were obtained with the localized molecular orbital theory13 with the ab intio LMOVCD program, which has correctly predicted14 the absolute configurations of other molecules. This program used the localized orbital centroids obtained from the GAMESS program package16 with the Boys' localization scheme.16 The same theoretical model and the experimental method were used for determining the absolute configuration of isoflurane..17 A Cray Y-MP supercomputer at North Carolina Supercomputing Center and a mini supercomputer (SCS-40) at Vanderbilt University were used for the above-mentioned calculations. The theoretical spectrawere simulated with Lorentzian band shapes. The theoretical spectra for the two lowest energy conformers are compared with the experimental spectra in Figures 1and 2. Journal of Pharmaceutical SciencesI 791 Vol. 82, No. 8, August 1993
1
Desfiurane
Conformer
2
(R)-Desflurane 6-31G'
Conformer
2
A L Conformer
1
6-310'
-
Conformer
1
A
6-310'
Conformers 1 + 2
M
Experiment in CDC13
(+)-Desflurane
900
I
I
I
I
I
1600
11'00
1ioo
t
I300
1400
1500
1 900
1 1000
1100
1200
1300
1400
1500
wavenumbers Figure 24xperimental (bottomtrace) and theoretical (top three traces) vibrational circular dichroism spectra for desflurane. The experimental spectrum was obtained for 0.2 M solution in CDCI,. The theoretical frequencies obtained with the 6-31G* basis set were multiplied by 0.87 to bring them closer to the experimental frequencies. Experimental spectra are for the (+)-enantiornerand theoretical spectra are for the R-configuration. All spectra are presented on arbitrary intensity scales. Equal populationsare assumed in simulatingthe theoretical spectrum for the mixture of conformers 1 and 2.
Results and Discussion Nine different conformations are possible for desflurane. Rotations around the 0-C* bond (* representing the chiral center) and the C-0 bond give rise to nine plausible conformations. However, steric interactions limit rotations around the 0-C* bond that lead to gauche orientations of the CF, and CF,H groups. The two lowest energy conformers, which differ in energy by -1 k d m o l are shown in Figure 3. The next lower energy conformer is -3 k d m o l higher in energy than the lowest energy conformer shown in Figure 3. From a comparison of the experimental and theoretical absorption spectra (Figure 1) it becomes clear that in the region around 1100 cm-' the experimental absorption spectrum contains more bands than can be accounted for by only one conformer. The theoretical energy difference between conformers 1 and 2 leads to their relative populations being 80%and 20%,respectively. However, considering the uncertainty in the energy difference predicted at the 6-31G* level and because a better comparison between the experimental and theoretical relative intensities is obtained with equal populations, it is assumed that the two conformers have equal populations. The theoretical absorption spectra for the two lowest energy conformers are combined, assuming equal 792 I Journal of Pharmaceutical Sciences Vol. 82, No. 8, August 7993
populations, and compared with the experimental absorption spectrum in Figure 1. The theoretical circular dichroism obtained as a sum of those for the two lowest energy conformers with (R)configurations is found to match with the experimental circular dichroism obtained for the (+)-enantiomer (Figure 2). The theoretical circular dichroism spectrum of any one of the two conformers alone does not satisfactorily reproduce the experimental spectrum, and the presence of both conformers is required to match the experimental spectrum. Most significantly, conformer 2 is required to satisfactorily reproduce the negative-positive-negative triplet found in the experimental circular dichroism spectrum at -1100 cm-'. To reproduce the negative circular dichroism band at 1210 cm-l of the experimental spectrum, the presence of conformer 1is required. Contributions from both conformers are reinforced to generate the strong positive band at -1188 cm-l that matches the strong positive band found in the experimental circular dichroism spectrum. The satisfactory agreement for the overall sign pattern in the experimental and theoretical circular dichroism spectra permits reliable conclusions on the absolute configurations of desflurane enantiomers.
References and Notes 1. Weiskopf, R. B.; Eger, E. I., 11.; Ionescu, P.; Yasuda, N.; Cahalan, M. K.;Freire, B.; Peterson, N.; Lockhart, S. H.; Rampil, I. J.; Laster M. Anesth. Analg. 1992,74,570. 2. Terrell, R. C. ;Speers, L.; Szur,A. J.;Treadwell, J.;Ucciardi, T. R. J. Med. Chem. 1971,14,517--519. 3. Meinwald, J.; Thom son, W. R.; Pearson, D. L.; Konig, W. A.; Runge, T.; Francke, Science 1991,251,560-561. 4. Huang, C. G.,et al., paper presented at the 203rd National American Chemical Society meeting, San Francisco, CA; April 4-10,1992. 5. Franks, N. P.; Lieb, W. R. Science 1991,254,427-430. 6. Matthews, R. Science 1992,255,156157. 7. Holzwarth,G.;Hsu,E.C.;Mosher,H.S.;Faulkner,T.R.;M~tz, A. J. Am. Chem. &. 1974,96,251.Chabay,I.; Holzwarth, G. Appl. Opt. 1975,14,454-459.Nafie, L. A; bidc~ling,T. A; Stephens, P. J. J. Am. Chem. SOC. 1976,98,2715-2723. d, M. P.; Buckingham, A. D. J. Am. Chem. 8. Barron, L.D.;Bo Soc. 1973,95,60E5. 9. Polavarapu, P. L. Appl. Spectrosc. 1989,43,1295-1297. 10. Frisch, M. J.;Head-Gordon, M.; Trucks, G. W.; Foresman, J. B.; Schlegel, H. B.; Raghavachari, K.; Robb, M. A.; Binkley, J. S.; Gonzalez, C.; Defrees, D. J.; Fox,D. J.; Whiteside, R.A.;Seeger, R.; Melius, C.F.; Baker, J.; Martin, R. L.; Kahn, L. R.; Stewart, J. J. P.; Topiol, S.; Pople, J. A. GAUSSIAN 90,Gaussian Inc., Pittsburgh, PA, 1990. 11. Amos, R. D.;Rice, J. E. CADPAC: The Cambridge Analytical Derivative Package, Issue 4.0,Cambridge, U.K., 1987. 12. Hariharan, P. C.; Pople, J.A. Chem. Phys. Lett.1972,6,217-219. Francl, M. M.; Pietro, W.J.;Hehre, W. J.;Binkley, J. S.; Gordon, M. S.; Defreee, D. J.; Pople, J. A. J. Chem. Phys. 1982, 77, 3654-3665. 13. Walnut, T. H.;Nafie, L. A. J. Chem, Phys. 1977, 67, 1501-1509. Nafie, L.A; Walnut, T. H. Chem. Phys. L.ett. 1977,49,441-446. Nafie, L. A; Polavarapu, P. L. J. Chem. Phys. 1981,75,2935-2944. 14. Polavara u, P. L. C L m . Phys. Lett. 1*0, 171, 271-276. Polavarapu, L.; Bose, P. K. J. Chem. Phys. 1990,93,7624.Polavarapu, P. L.; Bose, P. K. J. Phys. Chem. 1991,95,1606.PolavaraDu. P. L.: Bose. P. K.: Pickard. S. T. J.Am. Chem. Soc. 1991, 113,-43.Polavara u, P. L.; Pickaid, S. T.; Smith, H. E.; Black, T. M.; Rauk, A.; $ang, D. J. Am. Chem. Soc. 1991,113,9747. Pickard, S. T.; Smith, H. E.; Polavarapu, P. L.; Black, T. M.; Rauk, A.; Yan D J. Am. Chem. Soc. 1992,114,6850.Polavarapu, P. L.; P i c h , S. T.; Smith, H. E.; Pandurangi, R. S. Talan&, in ress. Pickard, S. T., Smith, H. E., Polavarapu, P. L., UnDublieied results. 15. &dt,,M. W.;Boatz, J. A;Baldridge, 5 K.; K m k i , S.; Gordon, M. S.; Elbert, S. T.; Lam, B. QCPE Bulletzn 1987,7,115. 16. Foster, J. M:;Boys, S. F. Re;. Mod. Phys. 1960,32,300-302. 17. Polavarapu, P. L.;Cholli, A. L.; Vemice, G. J. Am. Chem. Soc., 1992,10953-10955.
b.
8.
Conformer 1 Figure =Three dimensional structures of the two lowest energy conformations for (4-desflurane. The electronic energy of conformer 1 (bottom structure) is -1 kcallmol less than that of conformer 2 (top structure).
Conclusions Circular dichroism in the vibrational transitions provides a unique method for determining the absolute configurations of chiral inhalation anesthetics. These studies suggest that (+)-desflurane has the (R)-configuration [hence, (-1desflurane has the tS)-configuration] and that desflurane exists in two conformations (Figure 3) at room temperature.
Acknowledgments The experimental spectra were obtained on an instrument that was funded by NIH (GM29375).Some of the quantum theoretical calculations were done on a SCS-40 mini su computer that was funded by NSF (CHE8808018).We thank Drs. C G .Huang, L. A. Rozov, and D. F. Halpern forprwidingthe desflurane enantiomem d i n this study, R Pand for some of the experimental measurements, and A. J. E & e n z . A d elstein for their support and encouragement.
Journal of Pharmaceutical Sciences I 793 Vol. 82, No. 8, August 1993
clearly understood, it was recently shown that the pure enantiomers of chiral inhalation anesthetic agents interact differentially with the ion channels in the central nervous system. This differential interaction was suggested to arise from stereospecific binding of chiral enantiomers to proteins. To understand and model the differential nature of binding of enantiomers it is necessary to determine their absolute configurations and the number of predominant conformers. From studies on circular dichroism in the vibrational transitions of desflurane (CF,HOCHFCF,), we found that (+)-desflurane has the (R)-configuration and (-)desflurane has the (9-configuration. In addition, each enantiomer existed in two distinct conformations at room temperature.
Desflurane (CF2HOCHFCF3) is currently in the final stages of clinical trials as a next generation inhalation anesthetic agent. Recent studies1 indicate that desflurane is less toxic than commonly used isoflurane(CF2HOCHCICF3) and has low blood-gas solubility. The molecular basis for anesthetic action is not clearly understood. Because achiral molecules such as diethyl ether have long been used as successful anesthetic agents, the possibility for stereospecific interactions between the anesthetic agents and biological systems has not been addressed. However, recently developed anesthetic agents,2 including desflurane, have chiral structures. At present, the most commonly used inhalation anesthetics are administered as racemic mixtures (equal amounts of mirror image isomers or enantiomers). Recent development3.4 of separation schemes for obtaining the pure enantiomers has permitted investigations on the anesthetic effectof individual enantiomers of isoflurane, which is similar to desflurane (the difference being the chlorine atom in isoflurane is replaced by fluorine). The (+I- and (-1-enantiomers of isoflurane have nearly a twofold difference in their effectiveness on the anesthetic-activated potassium current and in their inhibition of current mediated by acetylcholine receptors.6 These differences were attributed to the stereospecific binding between the chiral enantiomers and the anestheticsensitive proteins in the brain.6.6 To understand these stereospecific interactions at the molecular level it is necessary to know the absolute configurations of the chiral enantiomers and the conformations in which they exist. This information is not available for desflurane. The absolute configuration of desflurane cannot be determined from the commonly used techniques of X-ray diffraction and electronic circular dichroism. This is because desflurane does not crystallize and does not have electronic transitions in the accessible visible range. However, optical activity is also supported by the molecular vibrational transitions, and the informational content in such a spectrum is the complete stereochemistry of a molecule in the solution phase. The optical activity in vibrational transitions can be measured in the IR spectrum as vibrational circular dichroism7 and in the b a n spectrum as b a n 0022-3~9/93/osoO-0791$02.50/0 0 1993. American Pharmaceutical Association
optical activity.8 We present here vibrational circular dichroism studies on desflurane and the absolute configurations and predominant conformations determined from these data. This structural information is expected to pave the way for madeling and understanding the stereospecific interactions between desflurane and the chiral environment in biological systems.
Experimental Section The experimentalabsorption and circulardichroism spectra in the 1600-700 cm-' region were measured on a Fourier transform IR instrument (Cygnus 100, Mattson Instruments Inc.) modified9 to enable circular dichroism measurements.A ZnSe photoelastic modulator (HindsInternational)and a KRS-5 polarizer (Molectron) were used to generate left and right circular polarizations at 37 kHz. A high sensitivity HgCdTe detector with D* = 4 x 1 0 ' was used for the light detection.A lock-in- amplifier (PAR 124A) tuned to the modulator frequency was used for demodulating the circular dichroism signal. The minimize the baseline artifacts, the circular dichroism spectra for (+)-enantiomerwere obtained in the commonly practiced way as one-halfof the differencebetween the raw spectra for (+)- and (-)-enantiomers. The spectra were obtained at 4 cm-' resolution for desflurane dissolved in CDC1, (1500-900 cm-l region) at a concentration of -0.2 M. The sampleswere held in a cell equipped with KBr windows at room temperature (20 "C).The data collection time wae 1 h per sample. Typical absorption and circular dichroiem spectra are displayed in Figures 1 and 2.
-
Theoretical Section For the theoretical predictions, the sequential steps involved are full geometry optimization (where all bond lengths and angles were optimized for minimum energy), vibrational frequencies, and circular dichroism intensity calculations. Ab intio quantum theoretical predictions of optimized structures and vibrational absorption spectra were obtained with the GAUSSIAN 9010 and CADPAC" program packages with the M l G * basis set.12 Corresponding circular dichroism spectra were obtained with the localized molecular orbital theory13 with the ab intio LMOVCD program, which has correctly predicted14 the absolute configurations of other molecules. This program used the localized orbital centroids obtained from the GAMESS program package16 with the Boys' localization scheme.16 The same theoretical model and the experimental method were used for determining the absolute configuration of isoflurane..17 A Cray Y-MP supercomputer at North Carolina Supercomputing Center and a mini supercomputer (SCS-40) at Vanderbilt University were used for the above-mentioned calculations. The theoretical spectrawere simulated with Lorentzian band shapes. The theoretical spectra for the two lowest energy conformers are compared with the experimental spectra in Figures 1and 2. Journal of Pharmaceutical SciencesI 791 Vol. 82, No. 8, August 1993
1
Desfiurane
Conformer
2
(R)-Desflurane 6-31G'
Conformer
2
A L Conformer
1
6-310'
-
Conformer
1
A
6-310'
Conformers 1 + 2
M
Experiment in CDC13
(+)-Desflurane
900
I
I
I
I
I
1600
11'00
1ioo
t
I300
1400
1500
1 900
1 1000
1100
1200
1300
1400
1500
wavenumbers Figure 24xperimental (bottomtrace) and theoretical (top three traces) vibrational circular dichroism spectra for desflurane. The experimental spectrum was obtained for 0.2 M solution in CDCI,. The theoretical frequencies obtained with the 6-31G* basis set were multiplied by 0.87 to bring them closer to the experimental frequencies. Experimental spectra are for the (+)-enantiornerand theoretical spectra are for the R-configuration. All spectra are presented on arbitrary intensity scales. Equal populationsare assumed in simulatingthe theoretical spectrum for the mixture of conformers 1 and 2.
Results and Discussion Nine different conformations are possible for desflurane. Rotations around the 0-C* bond (* representing the chiral center) and the C-0 bond give rise to nine plausible conformations. However, steric interactions limit rotations around the 0-C* bond that lead to gauche orientations of the CF, and CF,H groups. The two lowest energy conformers, which differ in energy by -1 k d m o l are shown in Figure 3. The next lower energy conformer is -3 k d m o l higher in energy than the lowest energy conformer shown in Figure 3. From a comparison of the experimental and theoretical absorption spectra (Figure 1) it becomes clear that in the region around 1100 cm-' the experimental absorption spectrum contains more bands than can be accounted for by only one conformer. The theoretical energy difference between conformers 1 and 2 leads to their relative populations being 80%and 20%,respectively. However, considering the uncertainty in the energy difference predicted at the 6-31G* level and because a better comparison between the experimental and theoretical relative intensities is obtained with equal populations, it is assumed that the two conformers have equal populations. The theoretical absorption spectra for the two lowest energy conformers are combined, assuming equal 792 I Journal of Pharmaceutical Sciences Vol. 82, No. 8, August 7993
populations, and compared with the experimental absorption spectrum in Figure 1. The theoretical circular dichroism obtained as a sum of those for the two lowest energy conformers with (R)configurations is found to match with the experimental circular dichroism obtained for the (+)-enantiomer (Figure 2). The theoretical circular dichroism spectrum of any one of the two conformers alone does not satisfactorily reproduce the experimental spectrum, and the presence of both conformers is required to match the experimental spectrum. Most significantly, conformer 2 is required to satisfactorily reproduce the negative-positive-negative triplet found in the experimental circular dichroism spectrum at -1100 cm-'. To reproduce the negative circular dichroism band at 1210 cm-l of the experimental spectrum, the presence of conformer 1is required. Contributions from both conformers are reinforced to generate the strong positive band at -1188 cm-l that matches the strong positive band found in the experimental circular dichroism spectrum. The satisfactory agreement for the overall sign pattern in the experimental and theoretical circular dichroism spectra permits reliable conclusions on the absolute configurations of desflurane enantiomers.
References and Notes 1. Weiskopf, R. B.; Eger, E. I., 11.; Ionescu, P.; Yasuda, N.; Cahalan, M. K.;Freire, B.; Peterson, N.; Lockhart, S. H.; Rampil, I. J.; Laster M. Anesth. Analg. 1992,74,570. 2. Terrell, R. C. ;Speers, L.; Szur,A. J.;Treadwell, J.;Ucciardi, T. R. J. Med. Chem. 1971,14,517--519. 3. Meinwald, J.; Thom son, W. R.; Pearson, D. L.; Konig, W. A.; Runge, T.; Francke, Science 1991,251,560-561. 4. Huang, C. G.,et al., paper presented at the 203rd National American Chemical Society meeting, San Francisco, CA; April 4-10,1992. 5. Franks, N. P.; Lieb, W. R. Science 1991,254,427-430. 6. Matthews, R. Science 1992,255,156157. 7. Holzwarth,G.;Hsu,E.C.;Mosher,H.S.;Faulkner,T.R.;M~tz, A. J. Am. Chem. &. 1974,96,251.Chabay,I.; Holzwarth, G. Appl. Opt. 1975,14,454-459.Nafie, L. A; bidc~ling,T. A; Stephens, P. J. J. Am. Chem. SOC. 1976,98,2715-2723. d, M. P.; Buckingham, A. D. J. Am. Chem. 8. Barron, L.D.;Bo Soc. 1973,95,60E5. 9. Polavarapu, P. L. Appl. Spectrosc. 1989,43,1295-1297. 10. Frisch, M. J.;Head-Gordon, M.; Trucks, G. W.; Foresman, J. B.; Schlegel, H. B.; Raghavachari, K.; Robb, M. A.; Binkley, J. S.; Gonzalez, C.; Defrees, D. J.; Fox,D. J.; Whiteside, R.A.;Seeger, R.; Melius, C.F.; Baker, J.; Martin, R. L.; Kahn, L. R.; Stewart, J. J. P.; Topiol, S.; Pople, J. A. GAUSSIAN 90,Gaussian Inc., Pittsburgh, PA, 1990. 11. Amos, R. D.;Rice, J. E. CADPAC: The Cambridge Analytical Derivative Package, Issue 4.0,Cambridge, U.K., 1987. 12. Hariharan, P. C.; Pople, J.A. Chem. Phys. Lett.1972,6,217-219. Francl, M. M.; Pietro, W.J.;Hehre, W. J.;Binkley, J. S.; Gordon, M. S.; Defreee, D. J.; Pople, J. A. J. Chem. Phys. 1982, 77, 3654-3665. 13. Walnut, T. H.;Nafie, L. A. J. Chem, Phys. 1977, 67, 1501-1509. Nafie, L.A; Walnut, T. H. Chem. Phys. L.ett. 1977,49,441-446. Nafie, L. A; Polavarapu, P. L. J. Chem. Phys. 1981,75,2935-2944. 14. Polavara u, P. L. C L m . Phys. Lett. 1*0, 171, 271-276. Polavarapu, L.; Bose, P. K. J. Chem. Phys. 1990,93,7624.Polavarapu, P. L.; Bose, P. K. J. Phys. Chem. 1991,95,1606.PolavaraDu. P. L.: Bose. P. K.: Pickard. S. T. J.Am. Chem. Soc. 1991, 113,-43.Polavara u, P. L.; Pickaid, S. T.; Smith, H. E.; Black, T. M.; Rauk, A.; $ang, D. J. Am. Chem. Soc. 1991,113,9747. Pickard, S. T.; Smith, H. E.; Polavarapu, P. L.; Black, T. M.; Rauk, A.; Yan D J. Am. Chem. Soc. 1992,114,6850.Polavarapu, P. L.; P i c h , S. T.; Smith, H. E.; Pandurangi, R. S. Talan&, in ress. Pickard, S. T., Smith, H. E., Polavarapu, P. L., UnDublieied results. 15. &dt,,M. W.;Boatz, J. A;Baldridge, 5 K.; K m k i , S.; Gordon, M. S.; Elbert, S. T.; Lam, B. QCPE Bulletzn 1987,7,115. 16. Foster, J. M:;Boys, S. F. Re;. Mod. Phys. 1960,32,300-302. 17. Polavarapu, P. L.;Cholli, A. L.; Vemice, G. J. Am. Chem. Soc., 1992,10953-10955.
b.
8.
Conformer 1 Figure =Three dimensional structures of the two lowest energy conformations for (4-desflurane. The electronic energy of conformer 1 (bottom structure) is -1 kcallmol less than that of conformer 2 (top structure).
Conclusions Circular dichroism in the vibrational transitions provides a unique method for determining the absolute configurations of chiral inhalation anesthetics. These studies suggest that (+)-desflurane has the (R)-configuration [hence, (-1desflurane has the tS)-configuration] and that desflurane exists in two conformations (Figure 3) at room temperature.
Acknowledgments The experimental spectra were obtained on an instrument that was funded by NIH (GM29375).Some of the quantum theoretical calculations were done on a SCS-40 mini su computer that was funded by NSF (CHE8808018).We thank Drs. C G .Huang, L. A. Rozov, and D. F. Halpern forprwidingthe desflurane enantiomem d i n this study, R Pand for some of the experimental measurements, and A. J. E & e n z . A d elstein for their support and encouragement.
Journal of Pharmaceutical Sciences I 793 Vol. 82, No. 8, August 1993