Absolute Configurations of the Inhalation Anesthetics Isoflurane and ...

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Anesthetics Isoflurane and Desflurane. Volker Schurig,* Markus Juza, Bernard S. Green,. Jorg Horakh, and Arndt Simon *. The chiral inhalation anestheticsĀ ...
COMMUNICATlONS can assume that the ee value is very high in this reaction, since the 100MHz 13C NMR spectrum of (S,S,R)-8(R = Ph) shows signals from only one diastereoisomer. We can therefore access interesting synthetic building blocks in high optical yield using this new method of asymmetric C-C bond formation. In this way the principle of diastereoselective complexation of a temporarily chirally modified ligand"] is used for enantioselective preparation of the chiral q2-enonemanganese complex 5, from which, after diastereoselective conversion and decomplexation, chiral, nonracemic, synthetically useful products can be obtained. Further investigations are currently underway, which focus predominantly on the use of functionalized alkylating reagents, as well as reactions at the carbony1 group of the planar-chiral enone-metal complex.

5.8 Hz;H2).5.16(dd. 1 H , J = 8.3,3.9 Hz;H6),3.52(d.3H.J = 1 . 2 Hz;H13).

2.81-2.77(m,lH;H5),274-2.66(dm,IH, J = 1 9 . 1 Hz;H4),2.42-2.33(m,

[12]

Experimental Procedure (R)-7 (R = alIy1)- n-Butyllithiuin (515 pL, 0.77 mmol, 1 . 5 ~in hexane) was added dropwise to a solution of diisopropylamine (101 pL. 0 77 mmol) in T H F ( 5 mL) at 0 -C. The resulting solution was stirred for 30 min at 0 C This LDA solution was then added dropwise over a period of IOmin to a solution of (S)-5 (150mg. 0.55 mmol) in T H F ( 5 mL), precooled to -78 C. After addition, the solution was stirred for 2 h at -78 ' C . Finally allyl bromide (67 pL, 0.77 mmolj was added, and the solution allowed to warm to 0 C over a period of about 12 h. The reaction mixture was concentrated on a rotary evaporator, and the components separated by flash chromatography with diethyl ether as eluent. Yield- 70mg of (S,R)-6, yellow powder (41 YO).[TI;' = -103 (c = 1 0 in benzene); 'H NMR (400 MHz, C,D,): 6 = 5.65 (br., 1 H). 4.93 (ZH), 3.91 (1 H), 3.73-3.67 (4H), 3.30 ( 1 H), 2.66-2.52 (2H). 2.21 ( I H ) , 1.98 ( 1 H), 1.78 (1 H), 1.24 (s. 3H); I3C NMR (lOOMHz,C,D,:* = quatenaryc. = CH,, - = CH,CH,j:d = 233.6(*),232 7 ( + ) . 2 1 4 7 ( * ) , 1 3 6 6 ( - ) , 116.2(+), 101.2(*).85.3(-).85.2(-).84.5(-).842 ( - ) , 67.3 ( - ) , 53.9 ( - ) . 4 0 8 (-), 34.8 ( + I . 33.7 ( + I , 12.1 ( - ) . IR (KBr)i. = 1965 (s). 1904(s), 1699(s), 1457 (w). 1175 (w),917(w), 601 (m), 573(m)cm-l: MS (CI, NH,): mi: (%): 313 (9) [M' + HI. 256 (4). 140 (44) [NH: + enone], 123 (100) [enone' HI. (S,R)-6( R = allyl) (62 mg. 0.198 mmol) was dissolved in acetonitrile (5 mL), and the yellow solution heated under reflux for 1 h. It was then allowed t o cool, and air was introduced into the flask through a needle for 20 min at room temperature. The brown precipitate that formed was separated by filtration, and the solvent removed on a rotary evaporator. After flash chromatography with pentaneldiethy1 ether (1:l) as eluent, 16 mg (R)-7 (R = allyl) was obtained in the form of a colorless oil (66% yield). [z];" = + 67.5 (c = 0.8 in CHCI,); 8 5 % er (GC, LipodexE), 'H N M R (400 MHz, CDCI,) : 6 =7.69 (dt, 1 H, J = 2.6, 5.7 Hz), 6.18 (m, 1 H), 5.75 (m. 1 H). 5.06 (2H), 2.83 (dm. 1 H, J = 19.3 Hz), 2.55 (m. 1 H). 245-2.38 (2H),2.19-2.11 (1H); I 3 C N M R (100MHz. CDCI,): d = 2 1 1 . 6 (*), 163 (-j. 135.2 ( - ) , 133.8 ( - ) . 116.8 ( + ) . 43 9 ( - ) , 35.2 ( +) , 34.8 ( + ) .

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Received: February 26, 1996 [28870IE] German version' Angeii.. Cliem. 1996, 108. 1825- 1827

Keywords: aldol reactions . alkylations . asymmetric syntheses . manganese compounds [l] Examples of planar-chiral v6-, q4-. and q'-complexes: H. G Schmalz. B. Millies, l W. Bats, G Durner, Angrii. Chem. 1992,104,640. Af7gPil'. Cliem Inr. M . Engl. 1992.31.631 ; H -J. Knolker, H. Herrmann, ;hid. 1996, 108,363 and 1996. 35, 341: D. Enders. S. von Berg, B. Jandeleit, Synletr 1996, 18. [2] D. Schinzer, T. Blume, R U. Rojas-Wahl, Svzlrrt, 1994, 297. [3] D. Schinzer, T. Blume. M. Woltering, Synletr 1994, 1045. 141 C. J. Kowalski, A. E. Weber. A W. Fields. J. Org. chm7. 1982, 47. 5089. [5] F. E. Ziegler, A. Nangia, G. Schulte, J A m . Cl7etn. Soc. 1987, 109. 3987. [6] C. R Johnson, H. Sakaguchi, Synlerr 1992. 813. [7] A. Wahhab, D. F. Tovares, A. Rauk. Cun J Chrm. 1990. 68, 1559. [XI X . Zhou, P J. De Clercq, Terruherlron- A . \ ~ w i z r r r j1995, ~ 6, 1551 [9] A. M. Rosan. J Clirm. Suc Cliem. Commun. 1981, 31 1 [lo] W. G. Griffith, S. V. Ley, G. P. Withcombe. A. D. White. J. Chrn.nl.Soc. Chetn. Commun. 1987, 1625. 11 11 The absolute configuration of (S)-5was determined by conversion of the aldol product ( S 3 9 to the diastereomeric Mosher esters a und band determination of the 'H N M R shift differences in the spectra of these compounds (I. Ohtain, Kusumi, Y. Kashman, H. Kakisawa. J. Am Chem. So ( R ) ,Table6 in Ref. [ l l ] ) . The pure enantiomers of 1 and 2 can be isolated by preparative gas chromatography on two 7-cyclodextrin derivatives;[I2,1 3 ] the dextrorotatory enantiomers are always eluted first arid the levorotatory enantiomers second." From thermodynamic measurements it was concluded that the enantiomers of 1 and 2 with identical absolute configuration and differing only in the haloatom at the stereogenic center, possess the same sign of optical rotation and the same elution order in contrast to the chiroptical assignment (VCD) . [ l Z 1 Determining the absolute configuration of 2 by anomalous dispersion of X-rays was considered impossible because the highly volatile ether was suspected to be n~ncrystallizable,['~ and indeed, it failed for the less volatile 1.['] In the present work the dextrorotatory (sodium D line) enantiomers of isoflurane, ( + ) - 1 , and desflurane, ( + ) - 2 , each obtained by preparative gas chromatography as the first fraction,["] were investigated with X-ray crystallography. From both compounds single crystals could be grown, which were suitable for the crystal structure analysis (CSA) at - 180 "C. As seen in Figure 1 both dextrorotatory enantiomers possess the (S)-configuration.['61 Thus, the chiroptical assignment of dextrorotatory isoflurane as (+)-(S)-l(VCD) is confirmed,

~

BrF3 (+)-(S)-2

(-)-(@-1

(according to VCD)

(according to CSA)

Moreover. the experimental spectra were not recorded in the gas phase but in solution (1 in CS,, 2 in CDCI,). Isomer ( + ) - 2 was synthesized from (-)-I with the expected inversion of configuration (Walden inversion) on substituting chlorine with fluorine by using BrF, in the solvent Br,.15] In light of the absolute configuration assignment by VCD, this substitution was later reinterpreted as proceeding with retention of configuration.['] In this journal, the decarboxylation of (+)-(R)-1-methoxytetrafluoropropanoic acid [( +)-(R)-31 to (-)-(S)-l,2,2,2,-tetrafluoroethyl methyl ether [( -)-(s)-4] was proposed to proceed 3

F A" A~"CH3

3

x0/cH3

retention F P O H inversion KOH, KOH, triethylene l y ~ o l , ~ ~ ~ triethylene lycol, 2054 2052

Fig. 1. molecular structureof(+)-(S)-l (top)and(+)-(S)-Z(boctom)at -180 C , displacement ellipsoids for 50% probability; the size of the hydrogen atoms is arbitrary. (according to CSA)

(according to VCD)

with compleie inversion of configuration. The surprising stereochemical course of this reaction was based exclusively on the VCD assignment of the subsequent product desflurane as (-)-(.S)-2 (VCD).["''O1 Based on the absolute configuration assigned by VCD, the gas chromatographic elution order of the enantiomers of 1 (and two congeners) on several cyclodextrin derivatives was given as

while the chiroptical assignment of dextrorotatory desflurane as ( + ) - ( R ) - 2(VCD) must be Irevised as (+)-(S)-2(CSA). Due to the absence of heavy atoms and the low anomalous diffraction difference of the atoms hydrogen and fluorine at the stereogenic center, the determination of the absolute configuration for 2 is somewhat ambiguous. Yet, the Flack-parameter" '1 of 2[161supports the ( + ) - ( S )Configuration. This result is in agreement with the following conclusions:

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Enantiomers of 1 and 2 with the same sign of optical rotation possess identical absolute configurations. Enantiomers of 1 and 2 with identical absolute configurations exhibit the same gas-chromatographic elution order ( S ) before ( R ) on y-cyclodextrin derivatives (derived from D-glUcose) .["I Enantiomers of 1 and 2 with identical absolute configurations exhibit the same NMR-spectroscopic, low-field shift of the proton resonances [ ( R ) >( S ) ] on y-cyclodextrin derivatives (derived from D-glUCOSe)."81 Enantiomers of 1 and 2 are transformed into each other with inversion of configuration (Walden inversion) by halogen exchange (e.g., BrF, in the solvent BI-,).[~] (+)-(R)-1-Methoxytetrafluoropropanoic acid (3) is transformed into ( -)-1,2,2,2,-tetrafluoroethyl methyl ether (4) with retention of configuration, and the ether possesses the ( R ) and not the ( S ) c o n f i g ~ r a t i o n . [ ~ . ' * ~

The revised assignment of the absolute configuration of 2 (and of congeners[' 'I) has consequences for the CAS-numbering, patent literature, and the stereochemical course of reactions.I8- "1

Esper imen tnl Proceciure The sign of the optical rotation of 1 and 2 is based on the sodium D line ;it 20 C (at other wavelengths no change of the sign of optical rotation was observed) a ) Pri>p.prira/iicriimi/iiinier ,sqxir-n/iim. ( + ) - I (er > 99.9 'XI j and ( + )-2 (iv=80.8 %) were obtained by preparative gas chromatography on octakis (3-0-butanoyl-2.6-diO-ji-pentyl)-;-cyclodextrin [I 51 dissolved in the polysiloxane SE-54 [I 21. The enantiomers were checked before crystal sample preparation by analytical enantioselective gas chromatography for enantiomeric purity and elution order to preclude fortuitous errors. h j Cr) .\td .smnp/e prqxir-[irion An X-ray-capillary (0.2 mm diameter) was filled to a length of 1 cm by dipping its open end into the liquid. The sample was kept cold on a dry-ice block, and the capillary was sealed on both sides. Investigations with the modified Guinier technique [I41 did not show any evidence o f a phase transition. in the case of ( + ) - 2 between -185 C and the melting point at -126 C.( + ) - I could not be investigated with the Guinier camera because ofdelayed crystdllization accompanied by the destruction of the capillary c) Cri..strilgi-oii~rhSingle crystals of ( + ) - I and ( +)-2 were grown in situ on a Syntex P 2 , four-circlediffrdctometer. Aftercoolingroa temperature below - 110 C(+)-I crystallized as a colorless powder. Annealing for several hours 1 2 C below the melting point at -98 C resulted in larger crystallites While the temperature was carefully increased in steps o f 0 1 - 0 2 C. the extensive meltins o f a crystallite could be monitored by the decrease of a strong reflection t o 1 '20 of the original value of its intensity After repeated cycles of partial melting and slow cooling. rotation and oscillation photographs showed the formation of a suitable single crystal. which could be cooled for X-ray analysis down to - 180 C without undergoing 21 phase traiisilion The growth of a single crystal of ( + ) - 2 was succesful by the method described above for ( + ) - l at a correspondingly lower temperature The melting point of a ( + ) - 2 sample, considered to be enantiomerically pure. was - 126 C

(81 a ) "Organolluorine compounds i n Medical Chemistry and Bioinedicai Applications": D. F Halpern. Stin/.Orx. C h i . ( A i m f w d r i m ) 1993. 4R. 125: h) Criiif. Piip F/iiiir-fiw Mrd. 21,r C ' w r i q (Manchester) 1994. No. 15 [Y] K Raniig. L. Hrockunier. P. W. Rnhlko. L. A Rozov. A i i ~ r e i i .C 7 i w 1995. 1117. 254 255. AJiRivR2 = 0.159 and RI = 0.049 for all 2732 data with 4 $ 2 0 C 54 and 100 refined parameters: Flack-parameter [ I 71: .v = 0.04(10) for the conformation described above and 0.96(10) for the inverted configuration i i i the enantiomorphous space group P6,. b) Crystal data for ( + ) - 2 : apace group P l , (No.4): ( I = 454.97(8), h = 7Y3.68(18). c = 762.75(1 I ) pm. /{ = 92.510(13) . phr, = 2.028 g c m - ' at the recording temperature at - 180 C;Z = 2. Mo,, irradiation. structure solution with direct methods [19]. refinement with SHELXL-93 [20]. wR2 = 0 112 and R1 = 0 045 for all 2621 data with 4 $ 7 0 C72 and 100 refined parameters: Flack-parameter [17]: Y = - 0.24(4X) for the confizuration described above and I .24(48) for the inberted configuration. c ) Crystallographic data (excluding structure factors) for the structure(s) reported in this paper have been deposited with the Cambridge Ci-ystallographic Data Centre iis supplementary publication no. CCDC-179-65. Copies of the data can be obtained free of charge on application to The Director. CCDC. 12 Union Road, Cambridge CB2 IEZ. UK (Fax: int. code (1223)336-033. e-mail. techedw chemcrys.cam ;ic.ukj [17] = 0 for the correct configuration. .v = 0.5 for both configurations (racemic mixture). and .A = I fortheiiivertedconfiguration: G. Bernadelli. H. D. Flack. A(./ri C r ~ ~ d / ( ~ , S q rN- .~A. 1985. 500-51 I . [lX] Our investigations showed that both enantiomei-s ( - j-1 and (-)-2, eluted as the second peak in GC. exhibited it stonger down-field shift in the ' H NMR spektrum i n the presence of octakis(3-O-hutanoyl-2.~-di-O-il-pentyl)-~-cyclodextrin. [I91 G M , Sheldrick. SHELXTL-PLUS. S/riii./iir-c Drrrr-iiiirrririoji .So//ii.cir-i,, Nicolet Instruments. Madison. WI (USA). 1990. [20]G. M. Sheldrick. SHELXL-93, Gottingen. 1993.

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Received: March 1. 1996 [Z 8890 IE] German version. Aiigiw. Chiwi. 1996. ION. 1814 1816

Keywords: configuration determination * inhalation anesthetics [ l ] a) N. P. Franks. W. R. Lieb. Scitwce 1991. 254,4277430: b) R. Matthews. ihid. 1992. 255. 156- 157: c) N. P. Franks. R. Dickerson. W. R. Lieb, Con/: P[ip. F/uorini, Med. 21sr Ci,ntirr-i'(Manchester) 1994. No. 16; d ) N. P. Franks. W. R. Lieb. N f i r i i r e 1994. 367, 6077614; e) E. J Moody. B. D. Harris. P. Skolnick, T,.cnr/.\ Phrrr-nirico/ SCJ.1994. 15, 387-39 I [2] C. G. Huang. L. A. Rozov. D . F. Halpern. G. G Vernice. J. Or-x.C / i m . 1993. 58, 7382-7387. [3] J. W. Young. S. Brandt (Sepracor. Inc.). US-A 5114714, 1992 [C/wiii. Ahsrr. 1992. 117. 834581. [4] J. W Young, S Brandt (Sepracor, Inc ). US-A 5114715. 1992 [C/icwi. Ah.s/i-. 1992, l I 7 . 834591. [ 5 ] L. A. Rozov. C Huang, D F.Halpern. G G. Vernice (Anaquest. Inc.). US-A 5283372. 1994 [Chrni. Ahsrr. 1994, 120. 3227401 [6] P L. Polavarspu, A. L. Cholli. G Vernice. J. A m C/ioii. Snc. 1992. 114. 10953-10955. [7] P. L Polavarapu. A. L. Cholli. G . Vernicc. J. Plior-. S i . 1993. N2. 791 -~793.

Influence of Anchor Lipids on the Homogeneity and Mobility of Lipid Bilayers on Thin Polymer Films Dierk Beyer, Gunther Elender, Wolfgang Knoll, Martin Kiihner, Steffen Maus, Helmut Ringsdorf,* and Erich Sackmann Supported phospholipid bilayers were first described by McConnell et al."] and are supposed to be ideal systems for investigations on incorporated membrane proteins and are expected to form the basis for future biosensors.['I They allow application of a variety of methods for the investigation of biomembranes that are restricted to planar surfaces,[31which are generally not applicable for known model membranes. [*I Prof. Dr. H. Ringsdorf. Dip1.-Chem. D. Beyer Institut fur Organische Chemie der Universitit J.-J.-Becher Weg 18 22. D-55099 Mainz (Germany) Fax' Int. code +(6131)393145 Prof. Dr. W Knoll. Dipl.-Cheni. S. Maus Max-Planck-liistitut fur Polymerforschung. Mainz (Germany) Dip1 -Phys. G. Elender, DipLPhys M. Kiihner. Prof. Dr. E. Sackmann Institut fur Biophysik der Technische Universitit Miinchen (Germany)