Biological Recognition of Enantiomeric Silanes: Syntheses and

Organometallics , 1995, 14 (1), pp 251–262. DOI: 10.1021/om00001a038. Publication Date: January 1995. ACS Legacy Archive. Cite this:Organometallics ...
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Organometallics 1996, 14, 251-262

251

Biological Recognition of Enantiomeric Silanes: Syntheses and Antimuscarinic Properties of Optically Active (2-Aminoethyl)cyclohexyl( hydroxymethy1)phenylsilanes and Related Quaternary Ammonium Derivatives'' Reinhold Tacke,*'t Dirk Reichel,? Martin Kropfgans,? Peter G. Jones,* Ernst Mutschler,§ J a n Gross,§ Xue H o u , ~Magali Waelbroeck,l and Gunter Lambrecht5 Institut f i r Anorganische Chemie, Universitat Karlsruhe, Engesserstrasse, Geb. 30.45, 0-76128 Karlsruhe, Germany, Znstitut fur Anorganische und Analytische Chemie, Technische Universitat Braunschweig, Postfach 3329, 0-38023 Braunschweig, Germany, Pharmakologisches Znstitut fur Naturwissenschaftler, Biozentrum Niederursel, Universitat Frankfurt, Marie-Curie-Strasse 9, Geb. N 260, 0-60439 Frankfurt, Germany, and Laboratoire de Chimie Biologique et de la Nutrition, Facultd de Mddecine et de Pharmacie, Universitd Libre de Brurelles, Route de Lennik 808, B-1070Bruxelles, Belgium Received August 19, 1994@ The racemic (2-aminoethyl)cyclohexyl(hydroxymethyl)phenylsilanes[rac-Ph(c-Hex)Si(CH~OH)CH2CH2NR21ruc-5a (NR2 = pyrrolidino), ruc-5b (NR2 = piperidino), and r u c d c (NR2 = hexamethylenimino) were synthesized by a five-step synthesis starting from ruc-Ph(c-Hex)Si(CH2Cl)OMe. The (I?)- and (5')-enantiomers of Sa-c were obtained by resolution of ruc5a-c using the antipodes of O,O-di-p-toluoyltartaric acid as resolving agents (resolution by fractional crystallization of diastereomeric salts). The enantiomeric purities of the resolved antipodes of 5a-c were determined to be 298% ee (lH NMR) and 1 9 7 % ee (13C NMR), and respectively (NMR experiments using chiral shift reagents). Reaction of the pure (R)(5')-enantiomers of Sa-c with methyl iodide gave the pure (I?)-and (5')-enantiomers of the respective quaternary ammonium derivatives 6a-c. The absolute configuration of (R)-6b was determined by single-crystal X-ray diffraction. The crystal data for this compound are as follows: C ~ ~ H ~ G I Nspace O S ~group , P212121, u = 890.5(3) pm, b = 916.2(2) pm, c = 2719.4 (7) pm, V = 2.2187(11) nm3, T = -130 "C, 2 = 4, R(F) = 0.0210. On the basis of the experimentally established absolute configuration of (R)-6b,the absolute configurations of all the other aforementioned optically active silicon compounds could be assigned by chemical and optical correlations. The pure (I?)-and (S)-enantiomersof 5 a - c and 6a-c were studied for their affinities for muscarinic M1, M2, M3, and M4 receptors by functional pharmacological experiments (M1, rabbit vas deferens; M2, guinea-pig atria; M3, guinea-pig ileum) and radioligand binding experiments (M1, human NB-OK 1cells; M2, rat heart; M3, rat pancreas; M4, rat striatum). According to these studies, the (I?)-enantiomers of 5a-c and 6a-c exhibited higher affinities for all four muscarinic receptor subtypes than their corresponding (5')-antipodes. The greatest difference (44-fold, M1 receptors) between the enantiomers was observed for l-{2-[cyclohexyl(hydroxymethyl)phenylsilyl]ethyl}-l-methylhexamethyleniminium iodide (6c). The highest receptor selectivity was observed for (R)-6cat MUM2 receptors (20-fold) and at M1M3 receptors (6.9-fold). The potent M1-selective antagonist (I?)-6cis considered to be an interesting lead for the development of new receptor-selective muscarinic antagonists.

Introduction During the past decade, we have a variety of highly potent and selective silicon-based muscarinic antag0nists.l "he racemic silanols, hexahydro-siladifenidollCpf*g,ijJ (HHSiD;rac-1) and p-fluoro-hexahydrosila-difenidollg,i-k(p-F-HHSiD; rac-21, are the most Dedicated to Professor Dr. Klaus Rilhlmann on the occasion of his 65th birthday. * Author to whom correspondence should be addressed. + University of Karlsruhe. Technical University of Braunschweig. P University of Frankfurt. Free University of Brussels. Abstract published in Advance ACS Abstracts, November 1,1994. II

*

@

prominent drugs obtained in these studies. Both compounds are commercially available and are used worldwide as selectivetools for the classificationofmusc.,~c receptor subtypes. The related silanols, sila-procyclidinela~b~d-fJ (3)and sila-tricyclamol iodideleIf(41, are also potent and selective muscarinic antagonists, the (R)enantiomers being more uotent than the corresponding (S)-antipodes.lbIe In the course of our structure-activity relationship studies of silicon-based muscarinic antagonists of this particular formula type, we have synthesized the enantiomers of the related (hydroxymethy1)silanes5a-c and their corresponding quaternary ammonium derivatives

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0276-733319512314-0251$09.00/00 1995 American Chemical Society

Tacke et al.

252 Organometallics, Vol. 14, No. 1, 1995

pharmacological characterization a t muscarinic M1, M2, M3, and M4 receptors. The studies presented here were carried out as part of our systematic investigations in bioorganosilicon ~ h e m i s t r y . ~ 1: R = H . 2: R = F

0,

O ,H

Si

I

n

3

60-6c 4

Results and Discussion 6a-c and have investigated the antimuscarinic properties of these compounds. Instead of the SiOH group of the above-mentioned silanols, compounds 5a-c and 6a-c contain a SiCHzOH unit. The aim of these studies was (i) to contribute to the chemistry of optically active silicon compounds and (ii) to obtain more information about the stereoselectivity of muscarinic receptor binding.2-4 Optically active silanols, such as the enantiomers of 3 and 4, racemize in aqueous solution and are therefore unsuitable for pharmacological stereoselectivity studies.le In contrast, the related (hydroxymethy1)silanes 5a-c and 6a-c were expected to be configurationally stable and therefore to be useful tools for the stereochemical characterization of muscarinic receptor binding. Here we report on the synthesis of the pure enantiomers of Sa-c and 6a-c and their (1)Selected publications on silicon-based muscarinic antagonists: (a) Tacke, R.; Strecker, M.; Lambrecht, G.; Moser, U.; Mutschler, E. Liebigs Ann. Chem. 1983,922-930. (b) Sheldrick, W. S.; Linoh, H.; Tacke, R.; Lambrecht, G.; Moser, U.; Mutschler, E. J. Chem. SOC., Dalton Trans. 1986,1743-1746. (c) Tacke, R.; Linoh, H.; Zilch, H.; Wess, J.; Moser, U.; Mutschler, E.; Lambrecht, G. Liebigs Ann. Chem. 1985,2223-2228. (d) Tacke, R.; Pikies, J.; Linoh, H.; Rohr-Aehle, R.; GiSnne, S. Liebigs Ann. Chem. 1987,51-57. (e) Tacke, R.; Linoh, H.; Emst, L.; Moser, U.; Mutschler, E.; Sarge, S.; Cammenga, H. IC; Lambrecht, G. Chem. Ber. 1987,120,1229-1237.(0 Waelbroeck, M.; Tastenoy, M.; Camus, J.; Christophe, J.; Strohmann, C.; Linoh, H.; Zilch, H.; Tacke, R.; Mutschler, E.; Lambrecht, G. Br. J . Pharmacol. 1989,98,197-205. (g) Lambrecht, G.; Feifel, R.; Wagner-Rtider, M.; Strohmann, C.; Zilch, H.; Tacke, R.; Waelbroeck, M.; Christophe, J.; Boddeke, H.; Mutschler, E. Eur. J . Pharmacol. 1989,168,71-80. (h) Tacke, R.; Linoh, H.; Rafeiner, K.; Lambrecht, G.; Mutschler, E. J . Organomet. Chem. 1989,359,159-168. (i) Waelbroeck, M.; Camus, J.;Tastenoy, M.; Mutschler, E.; Strohmann, C.; Tacke, R.; Lambrecht, G.; Christophe, J. Eur. J . Pharmacol. Mol. Pharmacol. Sect. 1991,206, 93-103. (i)Lambrecht, G.; Feifel, R.; Moser, U.; Wagner-Roder, M.; Choo, L. K.; Camus, J.; Tastenoy, M.; Waelbroeck, M.; Strohmann, C.; Tacke, R.; Rodrigues de Miranda, J. F.; Christophe, J.; Mutschler, E. Trends Pharmacol. Sci. Suppl. 1989,10,60-64.(k) Tacke, R.; Mahner, IC;Strohmann, C.; Forth, B.; Mutschler, E.; Friebe, T.; Lambrecht, G. J . Organomet. Chem. 1991,417,339-353.(1) Waelbroeck, M.; Camus, J.;Tastenoy, M.; Lambrecht, G.; Mutschler, E.; h p f g a n s , M.; Sperlich, J.;Wiesenberger, F.; Tacke, R.; Christophe, J. Br. J . Pharmacol. 1993, 109,360-370. (m) Tacke, R.; Pikies, J.; Wiesenberger, F.; Emst, L.; Schomburg, D.; Waelbroeck, M.; Christophe, J.; Lambrecht, G.; Gross, J.; Mutschler, E. J . Organomet. Chem. 1994,466,15-27. (n) Waelbroeck, M.; Camus, J.; Tastenoy, M.; Feifel, R.; Mutschler, E.; Tacke, R.; Strohmann, C.; Rafeiner, K.; Rodrigues de Miranda, J. F.; Lambrecht, G. Br. J . Pharmacol. 1994, 112, 505-514. (0)Tacke, R.; Kropfgans, M.; Tafel, A.; Wiesenberger, F.; Sheldrick, W. S.; Mutschler, E.; Egerer, H.; Rettenmayr, N.; Gross, J.;Waelbroeck, M.; Lambrecht, G. 2.Nuturforsch., B 1994,49,898-910. (2)Reviews on optically active silicon compounds: (a)Corriu, R. J. P.; Gubrin, C. Adv. Orgunomet. Chem. 1982,20,265-312.(b) Corriu, R.J. P.; Gubrin, C.; Moreau, J. J. E. Top. Stereochem. 1984,15,43198.

Syntheses. The preparation of the (R)- and (S)enantiomers of the title compounds 5a-c and 6a-c is based on the synthesis of the racemic silanes racdac, followed by their resolution into the respective 02)and (,")-enantiomers and subsequent transformation of the latter compounds into the (I?)-and (,")-enantiomers of the ammonium derivatives 6a-c. The racemic compounds rac-5a-c and their quaternary ammonium derivatives rac-6a-c were synthesized according to Scheme 1,starting from rac-(chloromethy1)cyclohexyl(phenyl)methoxysilaneld(ruc-7). In the first step, the methoxysilane rac-7 was transformed into the corresponding vinylsilane r u c d by reaction with vinylmagnesium bromide in THF (yield 91%). Subsequent reaction with sodium acetate in DMF gave the (acetoxymethy1)silane rac-9 (yield 92%),which was converted into the corresponding (hydroxymethy1)silaneruc-10 by reduction with lithium aluminum hydride in diethyl ether followed by hydrolysis with hydrochloric acid (yield 92%). 0-Silylation of rac-10 with chlorotrimethylsilane in n-pentane in the presence of triethylamine (3)Recent publications on optically active silicon compounds (silicon atom as the center of chirality): (a) Terunuma, D.; Kato, M.; Kamei, M.; Uchida, H.; Ueno, S.; Nohira, H. Bull. Chem. SOC.Jpn. 1986,59, 3581-3587. (b) Tacke, R.; Becker, B. Main Group Met. Chem. 1987, 10,169-197. (c) Larson, G. L.; Prieto, J. A.; Ortiz, E. Tetrahedron 1988, 44, 3781-3790. (d) Syldatk, C.; Stoffregen, A.; Brans, A.; Fritsche, K.; Andree, H.; Wagner, F.; Hengelsberg, H.; Tafel, A.; Wuttke, F.; Zilch, H.; Tacke, R. In Enzyme Engineering 9;Blanch, H. W., Klibanov, A. M., Eds.; Ann. N . Y.Acad. Sci., vol. 542;The New York Academy of Sciences: New York, 1988;pp 330-338. (e) Terunuma, D.; Yamamoto, N.; Kizaki, H.; Nohira, H. Nippon Kagaku Kaishi 1990,451-456. (0 Djerourou, A.-H.; Blanco, L. Tetrahedron Lett. 1991,32,6325-6326. (g) Tacke, R.; Brakmann, S.; Wuttke, F.; Fooladi, J.; Syldatk, C.; Schomburg, D. J . Organomet. Chem. 1991, 403,29-41. (h) Tacke, R.; Brakmann, S.; Kropfgans, M.; Strohmann, C.; Wuttke, F.; Lambrecht, G.; Mutschler, E.; Proksch, P.; Schiebel, H.-M.; Witte, L. In Frontiers of Organosilicon Chemistry; Bassindale, A. R., Gaspar, P. P., Eds.; The Royal Society of Chemistry: Cambridge, 1991;pp 218-228. (i) Tacke, R.; Wuttke, F.; Henke, H. J . Organomet. Chem. 1992,424,273-280.(j) Yamamoto, K.;Kawanami, Y.; Miyazawa, M. J. Chem. SOC.,Chem. Commun. 1993,436-437. (k) Tacke, R.; Reichel, D.; Giinther, K.; Merget, S. 2.Naturforsch., B , submitted. (1) See also refs l b and IC. (4)Reviews on stereoselectivity of muscarinic receptor binding: (a) Waelbroeck, M.; Tastenoy, M.; Camus, J.; Feifel, R.; Mutschler, E.; Strohmann, C.; Tacke, R.; Lambrecht, G.; Christophe, J. Trends Pharmacol. Sci. Suppl. 1989,10,65-69. (b) Casy, A. F. The Steric Factor in Medicinal Chemistry: Dissymmetric Probes of Pharmacological Receptors; Plenum Press: New York, London, 1993;pp 287-325. ( 5 ) Review on bioorganosilicon chemistry: Tacke, R.; Linoh, H. In The Chemistry of Organic Silicon Compounds, Part 2; Patai, S., Rappoport, Z., Eds.; Wiley & Sons: Chichester, 1989;pp 1143-1206.

Biological Recognition of Enantiomeric Silanes

Organometallics, Vol. 14, No. 1, 1995 253 Scheme 1

0,

/CHzC’

CHz=CHMgBr

Si

roc-8

roc-7

rac-9

0,

(CH&JCI

/CH20Si(CHS),

N(C2Ha)a

0 Si

roc-5a

roc- 10

HCI

HCI

50,6a

“3

5 b , 6b

“3

Sc, 6c

roc-6a - r o c - 6 c

yielded the corresponding 0-trimethylsilyl derivative rac-11 (yield 84%). Treatment of the vinylsilane rac11 with a mixture of pyrrolidine and its lithium amide in THF, followed by hydrolysis with hydrochloric acid and subsequent workup with aqueous KOH, gave the corresponding (2-pyrrolidinoethy1)silanerac-Sa (82%), which was then transformed into its hydrochloride rac5a HC1 by reaction with hydrogen chloride in diethyl ether (yield 89%). The related (2-piperidinoethy1)silane rue-5b and (2-hexamethyleniminoethy1)silanerac-5c and their corresponding hydrochlorides rac-5b HC1 and rac-5c HC1 were obtained by analogous syntheses ) , (rac-5b HCl), [yields 89% (rac-5b), 85% ( ~ u c - ~ c91% and 90% (rac-5c HCl)]. The quaternary ammonium compounds ruc-6a-c were synthesized in the last step by reaction of the amines rac-Sa-c with methyl iodide in acetone [yields 91% (ruc8a), 91% (rac-6b1, and 90% (rac-6c)l. Compounds ruc-5a and rac-8-11 were isolated as colorless liquids, whereas rac-Sb,c, rac-5a-c HC1, and rac-6a-c were obtained as colorless crystalline solids. The identity of these hitherto unknown compounds was established by elemental analyses (C, H, N), NMRspectroscopic studies (lH, 13C,and 29SiNMR), and massspectrometric investigations (E1 MS and FD MS, respectively). The (R)- and (5’)-enantiomers of 5a-c-HCl were obtained by resolution of rac-Sa-c using the antipodes of 0,O’-di-p-toluoyltartaric acid as resolving agents, followed by reaction of the respective enantiomerically pure (R)- and (5’)-enantiomers of 5a-c with hydrogen chloride in diethyl ether (Scheme 2) (yields 9-12%; for details, see Experimental Section). Reaction of the purified antipodes of 5a-c . HC1 with aqueous NaOH gave the pure (R)- and (S)-enantiomers of 5a-c (yields 84-92%). The pure antipodes of the quaternary ammonium derivatives 6a-c were obtained by reaction of the respective (R)- and (5’)-enantiomers of 5a-c with methyl iodide in acetone (yields 6 7 4 5 % ) . With the exception of (R)-5aand (S)-5a(colorless oily liquids), the aforementioned optically active silicon

-

/CH20H

( J ‘\CH=CH~

roc-1 1

HCI-roc-Sc

-

YO IHCI]

Si

\CH=CH,

1

1 0,

1.) WH,

2.)

“3

compounds were isolated as colorless crystalline solids. The identity of the (R)- and (5’)-enantiomers of 58-c, 5a-c HC1, and 6a-c was established by elemental analyses (C, H, C1, I, N), NMR-spectroscopic studies (lH, 13C,and 29SiNMR), and mass-spectrometric investigations (E1 MS and FD MS, respectively). In addition, (R)-6b was structurally characterized by a single-crystal X-ray diffraction study. The determination of the absolute configurations and enantiomeric purities of the optically active compounds is described in the two following chapters. As the enantiomers of 5a-c and 6a-c were found to be configurationally stable under physiological conditions, they could be used to study the stereoselectivity of muscarinic receptor binding (see Pharmacological Studies). Determination of the Absolute Configurations. The absolute configuration of the levorotatory enantiomer of 6b was determined by single-crystal X-ray diffraction. The crystal data and experimental parameters used for this study are given in Table 1; the structure of the cation of (-)-6b in the crystal is shown in Figure 1. According to this crystal structure analysis, (-)-6b (optical rotation measured for a solution in CHCl3 a t 546 nm) is the (R)-enantiomer. As the N-methylation of 5b with methyl iodide [(-)-5b (-)6b; (+)-5b (+)-6bland the conversion of 5b e HC1 into 5b [(+)-5b HC1- (-)-5b;(-)-5b HC1- (+)-5bldo not affect the configuration at the silicon atom, assignment of the absolute configurations of (-)-5b [- (R)l,(+)-5b [- (571, (+)-5b HC1 [- (R)I, and (-)-5b HC1 [- (5’11 could also be made. Based on the unequivocally established configurations of the (R)- and (5’)-enantiomers of 5b, 5b HC1, and 6b, the absolute configurations of the antipodes of 5a, 5c, 5a HC1,5c HC1,6a, and 6c could be easily assigned by optical correlations (comparison of the signs of the respective optical rotations, measured in CHC13; see Experimental Section). Determination of the Enantiomeric Purities. The enantiomeric purities of the (R)- and (Sbenantiomers of 5a-c were determined by NMR experiments using the chiral shift reagents (-)-2,2,2-trifluoro-1-(9-

-

-

-

Tacke et al.

254 Organometallics, Vol. 14, No. 1, 1995 Scheme 2

roc-Sa-roc-5c

, 1.) fmct. cyst.

1.) fract. cryst.

2.) NoOH

2.) NoOH

5.) HCI

3.) HCI

(R)-5a *HCI-(R)-5c.HCI

1

HOOC,

NoOH

0,. .

,CHzOH

a-

0.0 ’- di - p - t 01 uoy It o rt o r ic ocid (X)

Si

1

,COOH

‘CH2-CH2-NR2

- -

NoOH

0,

a

,CH,OH

Si ‘C H,

- CH, -N R,

-

( S) Sa - ( S) - 5 c

( R) 50 ( R ) 5 c

5a,6a 5b.6b 5c,6c

- -

( R) 6a ( R) - 6 c

I

N 3

N

2

“3

( S) - 60 - ( S) - 6c

anthry1)ethanol [(-)-TFAEI (lH NMR) and (+)-tris[3genic twitch contraction in rabbit vas deferens (M1 (2,2,3,3,4,4,4-heptafluoro-l-hydroxybutylidene)-d-cam-receptors). Furthermore, they inhibited the negative inotropic responses in guinea-pig atria and ileal conphoratoleuropium(III) [(+)-Eu(hfc)31(13C NMR). As shown for 5b in Figure 2, the enantiomers of this silane tractions (M2 and M3 receptors, respectively) mediated and (&enancan be clearly discriminated by NMR spectroscopy and by arecaidine propargyl ester. The (R)tiomers of 5a-c and 6a-c produced parallel shifts of therefore quantitatively determined by integration of the agonist concentration-response curves without their characteristic resonance signals. Analogous NMR changes in basal tension or maximum agonist responses. spectra (not shown) were obtained for 5a and 5c. According to this method, the enantiomeric purities of Arunlakshana-Schild plots were linear over the anthe resolved antipodes of 5a-c were determined t o be tagonist concentration range examined, and the slopes 298% ee (lH NMR) and 297% ee (13C NMR), respecof the regression lines were not significantly different 5a-c HC1 and Sa-c tively. As the reactions 5a-c from unity. In addition, all the competition curves (not 6a-c do not affect the absolute configuration at the shown) obtained in binding studies were compatible silicon atom, the same enantiomeric purities can be with the existence of a single receptor subtype; the Hill assumed for the antipodes of 5a-c.HC1 and 6a-c. coefficients were not different from unity. Thus, all Thus, the (R)and (S)-enantiomers of Sa-c, Sa-c HC1, compounds studied exhibited an apparently competitive and 6a-c prepared in this study were almost enantioantagonism at Ml-M3 receptors in functional studies merically pure. and at Ml-M4 receptors in binding experiments. Pharmacological Studies. The pure (R)and (SIThe pKi values of the (R)and (SI-enantiomers of enantiomers of 5a-C and 6a-C were studied for their 5a-c and 6a-c obtained in binding studies at Ml-M3 affinities for muscarinic M1, M2, M3, and M4 receptors receptors correspond reasonably to the respective antiby functional pharmacological experiments (Ml, M2, muscarinic potencies ( p A z values) determined in funcM3) and radioligand binding experiments (Ml, M2, M3, tional experiments at M1, M2, and M3 receptors (Tables M4). The results of these investigations are sum2 and 3). The binding affinities of the (R)-enantiomers of 5a-c and 6a-c to M4 receptors in rat striatum were marized in Tables 2-4 and Figures 3 and 4. All compounds concentration-dependently antagoalways lower than those found at M1 receptors in NBnized the 4-F-PyMcN+-inducedinhibition of the neuroOK 1 cells, but higher than those obtained at M2 and

-

-

-

Biological Recognition of Enantiomeric Silanes Table 1. Crystal Data and Experimental Parameters for the Crystal Structure Analysis of (R)-6b empirical formula formula mass, g mol-' collection T,"C A(Mo Ka),pm cryst syst space group a, pm b, pm c, pm

v, m3

Z D(calcd), Mg m-3 p(Mo Ka),mm-I

F(OO0) cryst dimens, mm 0 range, deg index ranges no. of coll reflns no. of indep reflns Rim

no. of reflns used no. of params absorption correction SQ R(Ub[Z 2u(Ol

RdF2)C max/min res electron dens, e nm-3

CziH36mOSi 473.5 -130 7 1.073 orthorhombic p212121 890.5(3) 916.2(2) 2719.4(7) 2.2187(11) 4 1.418 1.506 976 0.58 x 0.42 x 0.35 3.16-27.57 -11 5 h 5 11, - 11 5 k 5 0, -35 5 15 35 8210 5129 0.0208 5128 229 $ scans, transmissions 0.67-0.87 1.060 0.0210 0.0468 +447/-385

S = {X[w(Fo2- Fc2)2]/(n- P ) } ' / ~n; = no. of reflections; p = no. of 'RW(P) = {X[w(Foz- F,2)2]/ parameters. R ( R = Z,llFol- lFcll/ZIFol. {Z[w(Fo2)211IiZ.

9

C "C2&

Figure 1. Structure of the cation of (R)-6bin the crystal (ORTEP plot, probability level 50%), showing the atomic numbering scheme. Selected bond distances (pm) and angles (deg): Si-C(l), 188.2(2); Si-C(2), 188.8(2); SiC(10),187.7(2): Si-C(16), 188.5(2);C(l)-O, 142.8(3);C(1)Si-C(2), 109.30(10);C(l)-Si-C(lO), 106.99(11);C(l)-SiC(16), 111.13(10);C(Z)-Si-C(lO), 111.47(10);C(B)-SiC(16),107.40(10);C(lO)-Si-C(lG), 110.57(9);Si-C(1)-0, 110.4(2). The cation and anion of (R)-6bare connected by a hydrogen bond of the type 0-H I [O I, 345.0(2) pml. M3 receptors (except for compounds 5 a and 5 b a t M3 receptors). In general, the (R)-enantiomers (eutomers) exhibited higher affinities at all four muscarinic receptor subtypes than the corresponding (S)-enantiomers (distomers) (Tables 2-4; Figures 3 and 4). In addition, in most cases the (R)-enantiomers showed higher receptor selectivities. The rank order of the functional stereoselectivity ratios (Table 4) of compounds 5 a - c were M3 > M1 2 M2, whereas the quaternary ammonium derivatives 6a-c had the order M1 L M3 > M2 due to the large increase in stereoselectivity at M1 receptors

Organometallics, Vol. 14,No. 1, 1995 255 by N-methylation. The greatest difference between the enantiomers was found for compound 6c (44-fold, M1 receptors). N-Methylation of the (R)-enantiomers of 5 a - c increased the affinity for functional M1, M2, and M3 receptors up to 65-fold [(R)-5c (R)-6c1, the increase being consistently highest a t M1 receptors and lowest at M3 receptors. Thus, N-methylation of (R)-5a-c changed the receptor selectivity pattern from M3 L M1 > M2 to M1 > M3 > M2. The highest receptor ~ Ml/M2 receptors selectivity was observed for ( R 1 - 6 at (20-fold) and a t MUM3 receptors (6.9-fold). This compound represents a potent M1-selective antagonist and is considered to be an interesting lead for the development of new receptor-selective muscarinic antagonists.

-

Conclusions The results described in this paper clearly demonstrate that enantiomeric silanes generally may differ in their biological properties. As shown for the title compounds, biological recognition of chiral silicon compounds (with the silicon atom as the center of chirality) may be reflected, for example, by different pharmacological potencies and selectivities of the respective antipodes. Since biologically active organosilicon compounds have a great potential of application as agrochemicals and for future developments in this field extensive studies of the stereochemistry of chiral silicon compounds are necessary. In particular, the development of new preparative methods for the synthesis of enantiomerically pure chiral silanes is of great importance. In most cases (as in this study), optically active silicon compounds have been obtained by (i) classical resolution of the respective racemic mixtures via fractional crystallization of appropriate diastereomeric derivatives and (ii)stereoselective chemical transformations of the resolved enantiomers. As alternative methods, we have started to investigate (i) stereoselective biotransformations of suitable racemic or prochiral organosilicon substrates (see refs 3b,d,g,h and 5) and (ii) chromatographic racemate resolutions (see ref 3k). The development of efficient asymmetric chemical syntheses of enantiomerically pure chiral silicon compounds represents a further challenge.

Experimental Section General Procedures. All syntheses were carried out under dry nitrogen. The solvents used were dried according to standard procedures and stored under nitrogen. Melting points (uncorrected) were determined with a Leitz Laborlux S microscope, equipped with a heater (Leitz, Model M 350). 'H and 13C NMR spectra were recorded at room temperature on a Bruker AM-400 (IH,400.1 MHz; 13C, 100.6 MHz),Bruker AMX-300 (lH, 300.1 MHz; 13C, 75.5 MHz), or Bruker AC-250 NMR spectrometer (lH, 250.1 MHz; 13C,62.9 MHz). 29SiNMR spectra were recorded on a Bruker AC-250 NMR spectrometer operating at 49.7 MHz. Chemical shifts (ppm) were determined relative to internal CHC13 (lH, 6 7.25), CDC13 (13C, 6 77.051, and TMS P9Si,6 0). Assignment of the 13CNMR data was supported by D E R experiments. Mass spectra were obtained with a Varian MAT-711 mass spectrometer (E1MS, 70 eV, FD MS, 11 kV, CH30H as solvent); the selected mlz values given refer to the isotopes 'H, IZC,14N,I60, 28Si,35Cl, and 1271. Optical rotations were measured with a PerkinElmer polarimeter, Model 241; CHC13 served as solvent

Tacke et al.

256 Organometallics, Vol. 14,No. 1, 1995

- (b)A - (c)klL 3.5

3.4

3.4

3.5

3.3

~ [ P P ~ I

3.5

3.3

3.4

dlppml

3.3

b[ppmI

d (YI(d 137

134

131

128

137

134

b[ppmI

131

128

137

134

d[ppml

131

128

b(ppm1

Figure 2. Quantitative determination of the enantiomeric purities of the antipodes of 5b: Characteristic lH and 13C a n d @)-enantiomers of 5b in t h e presence of (-)-TFAE('H NMR; above) or (f)-Eu(hfc)s NMR partial spectra of the (R)(l3C NMR; below) [(a) racemic mixture; (b) pure @)-enantiomer obtained by preparative resolution; (c) pure (SI-enantiomer obtained by preparative resolution]. For details, see t h e Experimental Section. Table 2. A f f i t i e s (pAz Values) and Slopes of Arunlakshana-Schild Plots (in Parentheses) for the (R)and @)-Enantiomersof 5a-c and 6a-c at Muscarinic M1 Receptors in Rabbit Vas Deferens (RVD), M 2 Receptors in Guinea-Pig Atria (GPA), and M3 Receptors in Guinea-Pig Ileum (GPI) as Well as Receptor Selectivities of These Compounds pA2

compd RVD(M1)

(R)-5a 7.13 f 0.02 (1.00 f 0.04) (R)-5b 7.39 f 0.05 (1.14 i0.12) (R)-5c 7.35 i0.04 (1.01 f 0.07) (R)-6a 8.67 f 0.03 (1.03 f 0.06) (R)-6b 9.09 i0.06 (0.98 i0.10) (R)-6c 9.16 f 0.05 (0.84 f 0.07) (S)-Sa 6.49 f 0.04 (0.91 f 0.08) (S)-5b 6.53 f 0.04 (1.18 f 0.09) ( 3 - 5 c 7.20 i 0.03 (1.04 f 0.05) (S)-6a 7.46 & 0.03 (0.97 f 0.06) (S)-6b 7.74 & 0.04 (1.12 f 0.07) ( 9 - 6 c 7.52 f 0.04 (0.97 i 0.07)

values"

GPA(M2) 6.68 i0.02 (0.99 f 0.04) 6.76 i 0.04 (0.85 5 0.06) 6.74 f 0.03 (0.96 f 0.05) 7.98 f 0.03 (1.05 f 0.05) 8.21 i 0.01 (0.98 f 0.02) 7.86 i 0.05 (0.91 f 0.07) 6.22 f 0.03 (0.90 f 0.05) 6.26 f 0.03 (1.11 f0.06) 6.43 f 0.04 (0.95 f 0.06) 7.44 f 0.03 (0.98 i0.05) 7.57 f 0.05 (1.01 i0.07) 6.98 f 0.04 (0.95 i0.08)

selectivity ratiosb GPI(M3)

MUM2 MUM3 M3lM2 0.3 8.7 2.8 7.62 f 0.04 (1.07 i 0.06) 1.2 3.6 4.3 7.32 i 0.03 (0.91 i 0.08) 6.5 0.6 4.1 7.55 f 0.04 (1.02 f 0.06) 2.5 2.0 4.9 8.38 i0.04 (1.00 f 0.06) 2.8 2.8 7.6 8.65 i0.05 (0.98 i0.07) 2.9 6.9 8.32 i0.04 20 (1.03 i 0.07) 1.5 1.3 1.9 6.32 f 0.04 (1.19 f 0.09) 2.4 0.8 1.9 6.15 f 0.02 (1.03 f 0.06) 1.1 5.6 5.9 7.18 f 0.04 (0.98 f 0.07) 2.4 0.4 1.1 7.08 f 0.03 (1.00 i0.05) 2.4 0.6 1.5 7.36 i0.03 (1.03 & 0.06) 1.1 3.1 3.5 7.03 f 0.03 (0.98 f 0.05)

a The parameters given represent the mean f s e (n = 3-4). KD ratios (pAz = -log KD) are given as a measure of the receptor selectivity; these values were calculated from the antilogs of the differences between the respective pA2 values.

{purified by dynamic drying on a n A1203 column [50 g A1203 (Merck, 1077)/100 mL CHC131 and subsequent distillation}. Preparation of rac-Cyclohexyl(hydroxymethy1)phenyl(2-pyrrolidinoethy1)silane(rac-Sa). A 1.6 M solution of n-butyllithium in n-hexane (20.0 mL, 32.0 mmol of n-BuLi) was added dropwise at 50 "C over 15 min to a stirred solution of pyrrolidine (6.70 g, 94.2 mmol) in THF (100 mL). After stirring at 50 "C for 30 min, a solution of ruc-11 (10.0 g, 31.4 mmol) in THF (100 mL) was added dropwise over 30 min. The resulting mixture was stirred at 50 "C for 3 h, cooled to room temperature, and then cautiously mixed with 2.0 M hydrochloric acid (250 mL). After stirring at room temperature for

Table 3. Affinities (pKi Values) for the (R)-and @)-Enantiomersof 5a-c and 6a-c Obtained in Binding Studies on Homogenates of Human NB-OK1 Cells (M1 Receptors), as Well as Rat Heart (M2 Receptors), Rat Pancreas (M3 Receptors), and Rat Striatum (M4 Receptors)" pKi values

human NB-OK 1 cells compds (MI) 7.816.8 (R)-5a/(S)-5a 7.816.9 (R)-5bl(S)-5b 7.917.4 (R)-5d(S)-5~ (R)-6a/(S)-6a 8.617.5 (R)-6b/(S)-6b 8.917.9 (R)-W(S)-k 8.417.5

rat heart rat pancreas rat striatum 042) 043) 044) 7.316.6 7.316.6 6.516.2 1.416.7 7.216.5 6.616.3 1.417.0 7.717.1 6.816.6 8.017.0 7.416.8 7.716.6 7.9l7.0 8.517.4 7.917.3 7.716.9 8.217.2 7.717.0

"All the experiments were repeated three times in duplicate. The standard deviations of the pKi values were generally close to fO.lO, and always lower than f0.15.

Table 4. Stereoselectivities of the (R)-and @)-Enantiomers of 5a-c and 6a-c at Muscarinic M1 Receptors in Rabbit Vas Deferens (RVD), M 2 Receptors in Guinea-Pig Atria (GPA), and M3 Receptors in Guinea-Pig Ileum (GPI) stereoselectivities" compds

(R)-5a/(S)-5a (R)-Sbl(S)-Sb (R)-5d(S)-5~ (R)-6a/(S)-6a (R)-6bl(S)-6b (R)-6d(S)-6~ a

RVD (Ml)

GPA (M2)

GPI (M3)

4.4 7.2 1.4 16 22 44

2.9 3.2 2.0 3.5 4.4 7.6

20 15 2.3 20 20 20

These values are the antilogs of the differences between the respective

pA2 values.

30 min, diethyl ether (250 mL) and 6.0 M aqueous KOH solution (100 mL) were added. The organic phase was separated and the aqueous layer extracted with diethyl ether (3 x 200 mL). After drying of the combined organic extracts over anhydrous NaZS04, the solvent was removed under reduced pressure and the residue purified by Kugelrohr distillation (170 "C/O.Ol Torr)to give rac-Sa in 82% yield as an oily liquid (8.19 g, 25.8 mmol). lH NMR (300.1 MHz, CDC13): 6 0.85-1.3 and 1.55-1.85 (m, 17 H, SiCHzC, SiCHC2, CCHzC), 2.35-2.7 (m, 6 H, NCHzC), 3.60 (SA)and 3.63 (SB) (ABSystem, JAB= 14.9 Hz, 2 H, SiCHzO), 6.7 (br s, 1 H, OH), 7.45-7.55 (m, 5 H, SiCsHs). 13C NMR (75.5 MHz, CDC13): S 11.5 (SiCHzC), 23.2 (2 C) (CcH2c), 23.4 (c-1, S i C d h ) , 26.7 (CCHzC), 27.50 (CcH2C), 27.54 (CCH2C),27.9 (CCHzC), 28.0

Biological Recognition of Enantiomeric Silanes 10

Organometallics, Vol. 14, No. 1, 1995 257

I

I

9

-0

8

0

a?

= 7

6

5 M i M2 M3

M1 M2 M3

M1 M2 M3

M1 M2 M3

M1 M2 M3

M1 M2 M3

5a 5b 5c 6a 6b 6c Figure 3. Affinity profiles (pA2 values) of the (E)-and (S)-enantiomers of 5a-c and 6a-c at muscarinic M1 receptors in rabbit vas deferens, M2 receptors in guinea-pig atria, a n d M3 receptors in guinea-pig ileum. 10

9

-am

8

.-

y"7

6

5 M1 M2 M3 M4

M1 M2 M3 M4

M1 M2 M3 M4

M1 M2 M3 M4

5a

5b

5c

6a

M1 M2 M3 M4

6b

M1 M2 M3 M4

6c

Figure 4. Affinity profiles (PKi values) of the (E)-and @)-enantiomers of 5a-c and 6a-c at muscarinic M1 receptors in human NB-OK 1 cells, M2 receptors in rat heart, M3 receptors in rat pancreas, and M4 receptors in rat striatum. (CCH2C), 49.2 (SiCHzO), 5.10 (SiCCHzN), 53.7 (2 C) (NCH2C, NC~HS), 127.7 (c-3/c-5, Sic&&), 129.0 (c-4,Sic&&), 134.4 (cI, Sic&&), 134.5 (C-2/C-6, SiCsH5). EI MS: m / 317 ~ (3, M') 84 (100, CH~=NC~HS+). Anal. Calcd for C1gH31NOSi (Mr = 317.5): C, 71.87; H, 9.84; N, 4.41. Found: C, 71.7; H, 10.0; N, 4.3. Preparationof (R)-Cyclohexyl(hydroxymethy1)phenyl(2-pyrrolidinoethy1)silane [(R)-5al. A 2.0 M aqueous NaOH solution (1.0 mL, 2.00 mmol of NaOH) was added to a mixture composed of an aqueous solution (30 mL) of (R)5a HCl(302 mg, 853 pmol) and diethyl ether (30 mL). After stirring for 5 min, the organic phase was separated and the aqueous layer extracted with diethyl ether (3 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04, and the solvent was removed under reduced pressure and the residue dried in vacuo to give (R)-5a in 88%yield as an oily liquid (238 mg, 750 pmol). The NMR and MS data of the product were identical with those obtained for rac-5a. [aI2O546 = -1.7 (CHCl3, c = 1.0). Anal. Calcd for C1gN31NOSi (M, = 317.5): C, 71.87; H, 9.84; N, 4.41. Found: C, 71.8; H, 9.9; N, 4.4. Preparation of (S)-Cyclohexyl(hydroxymethy1)phenyl(2-pyrrolidinoethy1)silane[(S)-5al. This compound was prepared from (S)-5a HCl(312 mg, 881 pmol) analogously to the synthesis of (R)-5a and isolated in 92% yield as an oily

liquid (257 mg, 809 pmol). The NMR and MS data of the product were identical with those obtained for ruc-5a. [aI2O546 = +1.7 (CHCl3, c = 1.0). Anal. Calcd for ClgH31NOSi (Mr = 317.5): C, 71.87; H, 9.84; N, 4.41. Found: C, 71.7; H, 10.0; N, 4.3. Preparation of ruc-Cyclohexyl(hydroxymethy1)phenyl(2-piperidinoethy1)silane (ruc-5b). This compound was prepared analogously to the synthesis of ruc-5a by addition of piperidine to the vinyl group of rac-11 (10.0 g, 31.4 mmol). After Kugelrohr distillation (180 "C/O.Ol Torr) and crystallization of the distillate at room temperature, ruc-5b was isolated in 89%yield as a white crystalline solid (9.29 g, 28.0 mmol); mp 89-90 "C. lH NMR (400.1 MHz, CDCl3): 6 0.91.0,l.O-1.3,1.3-1.5, and 1.5-1.8 (m, 19 H, SiCHzC, SiCHC2, CCH2C), 2.1-2.6 (m, 6H, NCH2C), 3.61 ( 6 ~and ) 3.64 ( 6 ~(AB ) system, JAB= 14.9 Hz, 2 H, SiCH20), 6.5 (br s, 1 H, OH), 7.37.6 (m, 5 H, SiCsHs). 13C NMR (100.6 MHz, CDCl3): 6 9.6 (SiCH&), 23.6 (c-1,SiCsH11), 24.2 (cCH2c), 25.2 (2 c) (CCH2C), 26.8 (CCH2C), 27.59 (CCH2C), 27.63 (CCH&), 28.0 (CCHzC), 28.1 (CCH2C), 49.1 (SiCH20), 54.0 (SiCCHzN), 54.4 (2 C) (NCHzC, NC~HLO), 127.8 (C-3/C-5, Sics&), 129.1 (C-4, SiCsHs), 134.6 (3 C) (C-l/C-2/C-6, Sics&). EI MS: m / ~ 331 (5, M+), 98 (100, CH2=NC5Hlo+). Anal. Calcd for C2oH33NOSi (Mr = 331.6): C, 72.45; H, 10.03; N, 4.22. Found: C, 72.6; H, 10.2; N, 4.2.

258

Organometallics, Vol. 14, No. 1, 1995

Preparation of (R)-Cyclohexyl(hydroxymethy1)phenyl(2-piperidinoethy1)silane [(R)-Sbl. This compound was prepared from (R)-Sb HCl(342 mg, 929 pmol) analogously to the synthesis of (R)-Saand isolated in 87% yield as a white crystalline solid (269 mg, 811 pmol); mp 84-85 "C. The NMR and MS data of the product were identical with those obtained for ruc-Sb. [aIz0546= -4.3 (CHC13, c = 1.0). Anal. Calcd for CzoH33NOSi (M, = 331.6): C, 72.45; H, 10.03; N, 4.22. Found: C, 72.2; H, 10.3; N, 4.2. Preparation of 6)-Cyclohexyl(hydroxymethy1)phenyl(2-piperidinoethy1)silane[(S)-Sbl. This compound was prepared from (S)-Sb* HCl(390 mg, 1.06 mmol) analogously to the synthesis of (&Sa and isolated in 86%yield as a white crystalline solid (302 mg, 911 pmol); mp 84-85 "C. The NMR and MS data of the product were identical with those obtained for ruc-Sb.[aIz0546= +4.3 (CHCl3, c = 1.0). Anal. Calcd for C2oH33NOSi (M, = 331.6): C, 72.45; H, 10.03; N, 4.22. Found: C, 72.4; H, 10.3; N, 4.2. Preparation of ruc-Cyclohexyl(2-hexamethyleniminoethyl)(hydmxymethyl)phenylsilane (rac-Sc). This compound was prepared analogously to the synthesis of rac-Saby addition of hexamethylenimine t o the vinyl group of rac-11 (10.0 g, 31.4 mmol). After Kugelrohr distillation (190 "C/O.Ol Torr) and crystallization of the distillate at room temperature, ruc-Sc was isolated in 85%yield (9.23 g, 26.7 mmol) as a white crystalline solid; mp 54-55 "C. 'H NMR (400.1 MHz, CDC13): 6 0.9-1.0, 1.0-1.3, and 1.5-1.8 (m, 21 H, SiCHzC, ) 3.65 SiCHC2, CCHzC), 2.4-2.7 (m, 6 H, NCHzC), 3.62 ( 6 ~and ( 6 ~(AB ) system, JAB= 14.9 Hz, 2 H, SiCHZO), 6.6 (br s, 1 H, OH), 7.25-7.6 (m, 5 H, Sic&&).13C NMR (100.6 MHz, CDC13): 6 10.4 (SiCHzC), 23.6 (c-1,SiC&1), 26.6 (2 c) (CCHzC), 26.7 (3 C) (CCHzC), 27.60 (CCHzC),27.62 (CCH2C), 28.0 (CCH2C),28.1 (CCH2C),49.1 (SiCH20),53.0 (SiCCHzN), 55.8 (2 c) (NCHzC, NC~HIZ),127.8 (c-3/c-5, SiCsHs), 129.0 (c-4,Sic&), 134.6 (C-2/C-6, SiCeHs), 134.7 (c-1,Sics&). E1 MS: mlz 345 (6, M+), 112 (100, CHZ=NC~HI~+). Anal. Calcd for C Z ~ H ~ ~ N (M, OS =~345.6): C, 72.98; H, 10.21; N, 4.05. Found: C, 73.3; H, 10.2; N, 4.2. Preparation of (R)-Cyclohexyl(2-hexamethyleniminoethyl)(hydroxymethyl)phenylsilane [(R)-Scl. This compound was prepared from (R)-Sca HC1 (306 mg, 801 pmol) analogously to the synthesis of ( R M aand isolated in 84%yield as a white crystalline solid (233 mg, 674pmol); mp 50-51 "C. The NMR and MS data of the product were identical with those obtained for rac-Sc. [aIz0s46= -3.4 (CHCl3, c = 1.0). Anal. Calcd for C21H35NOSi (M, = 345.6): C, 72.98; H, 10.21; N, 4.05. Found: C, 72.8; H, 10.4; N, 4.1. Preparation of (S)-Cyclohexyl(2-hexamethyleniminoethyl)(hydroxymethyl)phenylsilane [(S)-Scl. This compound was prepared from (S)-Sc a HC1 (381 mg, 997 pmol) analogously to the synthesis of (R)-Saand isolated in 86%yield as a white crystalline solid (297 mg, 859 pmol); mp 50-51 "C. The NMR and MS data of the product were identical with those obtained for ruc-Sc. [aIz0s46= +3.4 (CHC13, c = 1.0). Anal. Calcd for C21HasNOSi (Mr = 345.6): C, 72.98; H, 10.21; N, 4.05. Found: C, 72.9; H, 10.4; N, 4.1. Preparation of rac-l-{2-[Cyclohexyl(hydroxymethyl)phenylsilyl]ethyl}pyrrolidinium Chloride (=-Sa HCl). A 3.1 M ethereal HC1 solution (1.0 mL, 3.10 mmol of HC1) was added at room temperature to a stirred solution of rac-Sa(500 mg, 1.57 mmol) in diethyl ether (50 mL). After stirring at room temperature for 15 min, the solvent and excess HC1 were removed under reduced pressure. The solid residue was dried in uucuo and then recrystallized from acetoneldiethyl ether (diffusion of diethyl ether via the gas phase into a solution of the product in acetone at room temperature) to give rucSa HCI in 89%yield as a colorless crystalline solid (495 mg, 1.40 mmol); mp 149-150 "C. 'H NMR (400.1 MHz, CDC13): 6 0.9-1.2, 1.4-1.7, and 1.9-2.1 (m, 17 H, SiCHzC, SiCHC2, CCHzC), 2.7-2.9, 3.0-3.15, 3.2-3.4, and 3.6-3.7 (m, 7 H, NCHzC, OH), 3.78 ( s , 2 H, SiCHZO), 7.3-7.5 (m, 5 H, Sics&,), 11.4 (br s, 1 H, NH). I3C NMR (100.6 MHz, CDC13): 6 7.7

-

Tacke et al. (SiCHZc), 23.28 (c-1,SiCeHii), 23.33 (2 c) (cCH2c), 26.5 (CCH2C), 27.35 (CCH2C1, 27.37 (CCHzC), 27.7 (CCHzC), 27.8 (CCHzC), 50.0 (SiCHzO), 52.4 (NCHzC), 52.5 (NCHZC),52.6 (NCHzC), 128.2 (C-3c-5, Sic&), 129.7 (c-4,SiCaHs), 132.4 (C-1, Sics&), 134.4 (C-2/C-6, Sic&). EI MS: m/z 317 (7, Mime), 84 (100, CH2=NC4Hsf). Anal. Calcd for C19H32ClNOSi (M, = 354.0): C, 64.46; H, 9.11; N, 3.96. Found: C, 64.3; H, 9.0; N, 4.0. Preparation of (R)-l-{2-[Cyclohexyl(hydroxymethyl)phenylsilyllethyl}p~olidiniumChloride [(R)-Sa HCll. The combined mother liquors [enriched with (R)-Sa (S,S)0,O-di-p-toluoyltartaricacid] collected in the several steps of the resolution of rac-Sa[see preparation of (S)-Sa* HC11 were concentrated under reduced pressure, and the solid residue was suspended in water (200 mL). After addition of diethyl ether (200 mL) and 2.0 M aqueous NaOH solution (40 mL), the resulting mixture was stirred at room temperature for 15 min, the organic phase separated, and the aqueous layer extracted with diethyl ether (3 x 150 mL). After drying of the combined organic extracts over anhydrous Na2S04, the solvent was removed under reduced pressure and the residue dried in vacuo to yield a mixture of (R)-Saand (S)-Sa[strongly enriched with (R)-Sal (6.85 g, 21.6 mmol). A boiling solution of this product in acetone (70 mL) was added t o a filtered solution of (R,R)-0,O'-di-p-toluoyltartaricacid (8.33 g, 21.6 mmol) in boiling acetone (330 mL). After cooling of this mixture to room temperature and keeping it undisturbed for 60 h, the crystals that formed (10.1 g) were filtered off and then subjected to a 7-fold fractional crystallization following the procedure described for the preparation of (S)-Sa HC1. The product6 (1.08 g) finally obtained by this method was transand then further formed into crude (R)-Sa(448 mg, 1.41 "01) into (R)-Sa.HCl following the procedure described for the preparation of ( S M a HC1. Compound (R)-Sa HC1 was isolated in 9% yield [related to @)-Sa in the racemic mixture of Sa] as a colorless crystalline solid (503 mg, 1.42 mmol); mp 131-132 "C. The NMR and MS data of the product were identical with those obtained for rac-Sa* HC1. [aIz0546= $0.7 (CHCl3, c = 1.0). Anal. Calcd for Cl~H32ClNOSi(M, = 354.0): C, 64.46; H, 9.11; N, 3.96; C1, 10.01. Found: C, 64.8; H, 9.3; N, 4.1; C1, 10.0. Preparation of (5)-1-{2-[Cyclohexyl(hydroxymethyl)phenylsilyl1ethyl)pyrrolidinium Chloride [@)-Sa HCll. (S,S)-0,O-Di-p-toluoyltartaricacid (11.7 g, 30.3 mmol) was dissolved in boiling acetone (470 mL). The hot solution was filtered and then added to a solution of rue-Sa(9.60 g, 30.2 mmol) in boiling acetone (100 mL). The resulting mixture was cooled to room temperature and then kept undisturbed for 60 h to yield 16.6 g of a crystalline solid. The crystals were isolated by filtration and then subjected to a 7-fold fractional crystallization from acetone. For this purpose, the boiling saturated solution of the crystals in acetone was filtered and then allowed to cool slowly to room temperature over ca. 6 h (slow cooling in a water bath, starting at 55 "C). After keeping the mixture at room temperature for a further 48 h, the crystals formed were isolated by filtration and then subjected to the next crystallization step. In the case of the first three fractional crystallization steps, the crystals of a second precipitate (obtained by removal of the solvent of the filtrate under reduced pressure and crystallization of the resulting residue from boiling acetone in the same manner as described above) were collected as well, whereas in the four following fractional crystallization steps only the primary precipitate was isolated. The product6 (1.29 g) finally obtained by this procedure was suspended in a mixture of water (100 mL) and diethyl ether (100 mL), followed by addition of 2.0 M aqueous NaOH solution (3.0 mL). After stirring at room temperature for 10 min, the organic phase was separated and the aqueous layer extracted with diethyl ether (3 x 100 mL). The combined organic

-

-

-

(6)According to lH and I3C NhfR studies (data not given), this product is the respective 0,O-di-p-toluoylhydrogentartrate containing ca. 1 mol equiv of acetone.

Organometallics, Vol. 14, No. 1, 1995 259

Biological Recognition of Enantiomeric Silanes extracts were dried over anhydrous NazS04, and the solvent was removed under reduced pressure and the residue dried in vacuo to yield crude (S)-5aas an oily liquid (547 mg, 1.72 mmol). M e r dissolving this product in diethyl ether (100 mL), 3.1 M ethereal HCl solution (1.0 mL, 3.10 mmol of HC1) was added at room temperature and the resulting mixture stirred for 10 min. The solvent and excess HC1 were removed under reduced pressure, and the solid residue was dried in vacuo and then recrystallized from acetone/diethyl ether (diffusion of diethyl ether via the gas phase into a solution of the product in acetone at room temperature) t o give (S)-5a* HC1 in 10% yield [related t o (S)-5a in the racemic mixture of Sa] as a colorless crystalline solid (556 mg, 1.57 mmol); mp 131-132 "C. The NMR and MS data of the product were identical with those obtained for rac-5a HC1. [aIz0546 = -0.7 (CHCl3, c = 1.0). Anal. Calcd for C19H32ClNOSi (M, = 354.0): C, 64.46; H, 9.11; N, 3.96; C1, 10.01. Found: C, 64.8; H, 9.4; N, 3.9; C1, 10.0. Preparation of rac-l-{2-[Cyclohexyl(hydroxymethyl)phenylsilyl1ethyl)piperidinium Chloride (ruc-5b HCl). This compound was prepared from rac-5b (500 mg, 1.51 "01) analogously t o the synthesis of rac-5a * HC1 and isolated in 91% yield as a colorless crystalline solid (507 mg, 1.38 mmol); mp 169-170 "C. lH NMR (400.1 MHz, CDC13): 6 0.9-1.25, 1.25-1.3, 1.35-1.9, and 2.0-2.2 (m, 19 H, SiCHzC, SiCHC2, CCHzC), 2.4-2.6, 2.9-3.0, 3.1-3.3, and 3.4-3.6 (m, 6 H, NCHZC),3.1 (br s, 1 H, OH), 3.83 (8, 2 H, SiCHZO), 7.3-7.5 (m, 5 H, Sic,&,), 11.2 (br s, 1 H, NH). I3C NMR (100.6 MHz, CDC13): 6 5.7 (SiCHZC), 22.3 (CCHZC),22.8 (2 C) (CCHzC), 23.3 (c-1,SiCsH11), 26.6 ( C m z c ) , 27.4 (2 c) (CCH2C), 27.77 (CCHZC),27.80 (CCHzC), 50.2 (SiCH20), 51.8 (NCHZC),52.5 (NCHzC), 54.5 (NCHzC), 128.2 (C-3/C-5, Sics&), 129.8 (C-4, Sics&), 132.4 (c-1, Sics&), 134.5 (C-2/C-6, SiC6H5). E1 MS: m/z 331 (4, Mime),98 (100, CHZ=NC~HIO+). Anal. Calcd for CzoH34ClNOSi (M, = 368.0): C, 65.27; H, 9.31; N, 3.81. Found: C, 65.3; H, 9.5; N, 3.8. Preparation of (R)-l-{2-[Cyclohexyl(hydroxymethyl)phenylsilyl]ethyl)piperidinium Chloride [(R)-Sb HCl]. The combined mother liquors [enriched with (R)-Sb (S,S)0,O-di-p-toluoyltartaricacid] collected in the several steps of the resolution of rac-5b [see preparation of (S)-5b* HCl] were concentrated under reduced pressure, and the solid residue was suspended in water (200 mL). After addition of diethyl ether (200 mL) and 2.0 M aqueous NaOH solution (40 mL), the resulting mixture was stirred at room temperature for 15 min, the organic phase separated, and the aqueous layer extracted with diethyl ether (3 x 150 mL). After drying of the combined organic extracts over anhydrous Na2SO4, the solvent was removed under reduced pressure and the residue dried in vucuo to yield a mixture of (R)-5b and (S)-5b[strongly enriched with (R)-5b] (7.32 g, 22.1 mmol). A boiling solution of this product in acetone (75 mL) was added to a filtered solution of (R,R)-0,O-di-p-toluoyltartaric acid (8.53 g, 22.1 mmol) in boiling acetone (1.3 L). After cooling of this mixture t o room temperature and keeping it undisturbed for 60 h, the crystals that formed (12.7 g) were filtered off and then subjected to a 7-fold fractional crystallization following the procedure described for the preparation of (S)-5b HC1. The product6 (1.29 g) finally obtained by this method was transformed into crude (R)-5b (560 mg, 1.69 mmol) and then further into (R)-5b HC1 following the procedure described for the preparation of (S)-5b* HC1. Compound (R)-5b* HC1 was isolated in 10%yield [related t o (R)-5b in the racemic mixture of 5b] as a colorless crystalline solid (567 mg, 1.54 mmol); mp 153-154 "C. The NMR and MS data of the product were = +7.9 identical with those obtained for rac-5b * HC1. [aIz05a (CHC13, c = 1.0). Anal. Calcd for CzoH34ClNOSi (MI = 368.0): C, 65.27; H, 9.31; N, 3.81; C1, 9.63. Found: C, 65.4; H, 9.6; N, 3.8; C1, 9.6. Preparation of (S)-l-{2-[Cyclohexyl(hydroxymethyl)phenylsilyl1ethyl)piperidinium Chloride [(S)-5b HCll. (S,S)-0,O-Di-p-toluoyltartaric acid (11.7 g, 30.3 mmol) was

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dissolved in boiling acetone (1.75 L). The hot solution was filtered and then added to a solution of ruc-Sb (10.0 g, 30.2 mmol) in boiling acetone (100 mL). The resulting mixture was cooled to room temperature and then kept undisturbed for 60 h to yield 19.4 g of a crystalline solid. The crystals were isolated by filtration and then subjected t o a 7-fold fractional crystallization from acetone. For this purpose, the boiling saturated solution of the crystals in acetone was filtered and then allowed to cool slowly to room temperature over ca. 6 h (slow cooling in a water bath, starting at 55 "C). After keeping the mixture at room temperature for a further 48 h, the crystals formed were isolated by filtration and then subjected t o the next crystallization step. In the case of the first three fractional crystallization steps, the crystals of a second precipitate (obtained by removal of the solvent of the filtrate under reduced pressure and crystallization of the resulting residue from boiling acetone in the same manner as described above) were collected as well, whereas in the four following fractional crystallization steps only the primary precipitate was isolated. The product6 (1.52 g) finally obtained by this procedure was suspended in a mixture of water (100 mL) and diethyl ether (100 mL), followed by addition of 2.0 M aqueous NaOH solution (3.0 mL). After stirring at room temperature for 10 min, the organic phase was separated and the aqueous layer extracted with diethyl ether (3 x 100 mL). The combined organic extracts were dried over anhydrous NazS04, and the solvent was removed under reduced pressure and the residue dried in vacuo to yield crude (S)-5bas a white crystalline solid (658 mg, 1.98 mmol). f i r dissolving this product in diethyl ether (100 mL), 3.1 M ethereal HC1 solution (1.0 mL, 3.10 mmol of HC1) was added at room temperature and the resulting mixture stirred for 10 min. The solvent and excess HC1 were removed under reduced pressure, and the solid residue was dried in vacuo and then recrystallized from acetone/diethyl ether (diffusion of diethyl ether via the gas phase into a solution of the product in acetone at room temperature) t o give (S)-5b* HCl in 12% yield [related t o (S)-5bin the racemic mixture of Sb] as a colorless crystalline solid (655 mg, 1.78 "01); mp 153-154 "C. The NMR and MS data ofthe product were identical with those obtained for ruc-5b * HC1. [alZo546 = -7.9 (CHCl3, c = 1.0). Anal. Calcd for CzoH34ClNOSi (MI = 368.0): C, 65.27; H, 9.31; N, 3.81; C1, 9.63. Found: C, 65.4; H, 9.6; N, 3.8; C1, 9.6. Preparation of ruc-l-{2-[Cyclohexyl(hydroxymethyl)phenylsilyl]ethyl}hexamethyleniminium Chloride (rac5c * HC1). This compound was prepared from rac-5c (500 mg, 1.45 mmol) analogously to the synthesis of rac-5a HC1 and isolated in 90% yield as a colorless crystalline solid (498 mg, 1.30 "01); mp 163-164 "C. IH NMR (300.1 MHz, CDCl3): 6 0.8-1.2, 1.3-1.8, and 1.9-2.2 (m, 21 H, SiCHzC, SiCHCz, CCHzC),2.7-3.1 and 3.1-3.5 (m, 7H, NCHzC, OH), 3.82 (s, 2 H, SiCHzO), 7.25-7.6 (m, 5 H, Sic&,), 11.1 (br s, 1 H, NH). 13C NMR (62.9 MHz, CDC13): 6 6.2 (SiCHzC), 23.3 (C-1, SiCsH11), 23.6 (2 c) (CCH&), 26.5 (3 c) (cCH2c), 27.4 (2 c) (CCHzC), 27.7 (2 C) (CCHzC), 49.9 (SiCHzO), 53.0 (NCHzC), 53.7 (NCHzC), 54.9 (NCHzC), 128.1 (C-3/C-5, Sics&), 129.7 (C-4, Sic&), 132.5 (C-I, Sic,&), 134.4 (C-2/C-6, Sic,&). EI MS: m/z 345 (5, Miase), 112 (100, CHZ=NC~H~Z+). Anal. Calcd for C21H36ClNOSi (M, = 382.1): C, 66.02; H, 9.50; N, 3.67. Found: C, 66.2; H, 9.8; N, 3.7. Preparation of (R)-l-{2-[Cyclohexyl(hydroxymethyl)phenylsilyl]ethyl)hexamethyleniminium Chloride [(R)5c HCl]. The combined mother liquors [enriched with (R)5c (S,S)-0,O-di-p-toluoyltartaricacid] collected in the several steps of the resolution of rac-5c [see preparation of (S)5c * HCl] were concentrated under reduced pressure, and the solid residue was suspended in water (200 mL). After addition of diethyl ether (200 mL) and 2.0 M aqueous NaOH solution (40 mL), the resulting mixture was stirred at room temperature for 15 min, the organic phase separated, and the aqueous layer extracted with diethyl ether (3 x 150 mL). After drying of the combined organic extracts over anhydrous NazS04, the

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260 Organometallics, Vol. 14,No. 1, 1995 solvent was removed under reduced pressure and the residue dried in vacuo to yield a mixture of (R)-Scand (S)-Sc [strongly enriched with (R)-Sc] (7.21 g, 20.9 mmol). A boiling solution of this product in acetone (75 mL) was added to a filtered solution of (RP)-O,O-di-p-toluoyltartaric acid (8.06 g, 20.9 mmol) in boiling acetone (1.2 L). After cooling of this mixture to room temperature and keeping it undisturbed for 60 h, the crystals formed (13.1 g) were filtered off and then subjected t o a 7-fold fractional crystallization following the procedure described for the preparation of (S)-Sc * HC1. The product6 (1.20 g) finally obtained by this method was transformed into crude (R)-Sc(532 mg, 1.54 mmol) and then further into (R)Sc HC1 following the procedure described for the preparation of (S)-Sc HCl. Compound (R)-Sc* HC1 was isolated in 9% yield [related to (R)-Sc in the racemic mixture of Scl as a colorless crystalline solid (512 mg, 1.34 mmol); mp 133-134 "C. The NMR and MS data of the product were identical with those obtained for ruc-Sc HC1. [aI2O546 = +7.0 (CHCb, c = 1.0). Anal. Calcd for C21H36ClNOSi (M, = 382.1): C, 66.02; H, 9.50; N, 3.67; C1, 9.28. Found: C, 66.0; H, 9.7; N, 3.7; C1, 9.3. Preparation of ( S ) -1-{24Cyclohexyl(hydroxymethy1)phenylsilyl]ethyl}hexamethyleniminium Chloride [(S)Sc HCl]. (S,S)-0,O-Di-p-toluoyltartaric acid (11.6 g, 30.0 mmol) was dissolved in boiling acetone (1.75 L). The hot solution was filtered and then added to a solution of rac-Sc (10.4 g, 30.1 mmol) in boiling acetone (100 mL). The resulting mixture was cooled to room temperature and then kept undisturbed for 60 h t o yield 20.6 g of a crystalline solid. The crystals were isolated by filtration and then subjected to a 7-fold fractional crystallization from acetone. For this purpose, the boiling saturated solution of the crystals in acetone was filtered and then allowed to cool slowly to room temperature over ca. 6 h (slow cooling in a water bath, starting at 55 "C). After keeping the mixture at room temperature for a further 48 h, the crystals that formed were isolated by filtration and then subjected t o the next crystallization step. In the case of the first three fractional crystallization steps, the crystals of a second precipitate (obtained by removal of the solvent of the filtrate under reduced pressure and crystallization of the resulting residue from boiling acetone in the same manner as described above) were collected as well, whereas in the four following fractional crystallization steps only the primary precipitate was isolated. The product6 (1.35 g) finally obtained by this procedure was suspended in a mixture of water (100 mL) and diethyl ether (100 mL), followed by addition of 2.0 M aqueous NaOH solution (3.0 mL). After stirring at room temperature for 10 min, the organic phase was separated and the aqueous layer extracted with diethyl ether (3 x 100 mL). The combined organic extracts were dried over anhydrous NazSO4,and the solvent was removed under reduced pressure and the residue dried in vacuo t o yield crude (S)-Sc as a white crystalline solid (591 mg, 1.71 mmol). After dissolving of this product in diethyl ether (100 mL), 3.1 M ethereal HC1 solution (1.0 mL, 3.10 mmol of HC1) was added at room temperature and the resulting mixture stirred for 10 min. The solvent and excess HC1 were removed under reduced pressure, and the solid residue was dried in vacuo and then recrystallized from acetone/diethyl ether (diffusion of diethyl ether via the gas phase into a solution of the product in acetone at room temperature) to give (S)-Sc HC1 in 10%yield [related to (S)5c in the racemic mixture of SC] as a colorless crystalline solid (601 mg, 1.57 mmol); mp 133-134 "C. The NMR and MS data of the product were identical with those obtained for rac5c * HC1. [alZo546 = -7.0 (CHC13, c = 1.0). Anal. Calcd for CZ~H~&MO (M, S ~= 382.1): C, 66.02; H, 9.50; N, 3.67; C1,9.28. Found: C, 66.1; H, 9.7; N, 3.7; C1, 9.3. Preparation of rac-1-{2-[Cyclohexyl(hydroxymethyl)phenylsilyllethyl}-1-methylpyrrolidiniumIodide (ruc6a). Methyl iodide (2.23 g, 15.7 mmol) was added to a solution of rac-Sa (500 mg, 1.57 mmol) in acetone (50 mL) and the resulting mixture stirred at room temperature for 21 h. After

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Tacke et al. removal of the solvent and excess methyl iodide under reduced pressure, the solid residue was dried in vacuo and then recrystallized from acetone/diethyl ether (diffusion of diethyl ether via the gas phase into a solution of the product in acetone at room temperature) to give rac-6ain 91%yield as a colorless crystalline solid (660 mg, 1.44 mmol); mp 142-143 "C. lH NMR (250.1 MHz, CDC13): 6 1.0-1.8 and 2.1-2.3 (m, 17 H, SiCHZC, SiCHC2, CCHzC), 3.1 (br s, 1 H, OH), 3.15 (s, 3 H, NCHs), 3.35-3.55, 3.55-3.75, and 3.8-4.0 (m, 6 H, NCHzC), 3.86 (s, 2 H, SiCH20), 7.3-7.55 (m, 5 H, SiCsHd. 13C NMR (62.9 MHz, CDC13): 6 6.1 (SiCH2C), 21.8 (2 C) (CCHzC),23.3 (c-1,SiCeH11), 26.5 (CCHZC), 27.4 (2 c) (CCHzC), 27.70 (CCHzC), 27.73 (CCHzC), 48.3 (NCHs), 48.7 (SiCHZO), 62.2 (NCH2C), 63.3 (NCHzC),63.7 (NCH2C), 128.3 (C-3/C-5, Sic&), 129.8 (c-4,Sics&), 132.5 (c-1, Sic&), 134.4 (C-2/C-6, Sic&). FD MS: m/z 332 (100, M:ation). Anal. Calcd for C2oH34INOSi (M, = 459.5): C, 52.28; H, 7.46; N, 3.05. Found: C, 52.7; H, 7.8; N, 3.1. Preparation of (R)-l-{2-[Cyclohexyl(hydroxymethyl)phenylsilyl]ethyl}-1-methylpyrrolidiniumIodide [(R)6a]. This compound was prepared analogously to the synthesis of ruc-6aby addition of methyl iodide (184 mg, 1.30 mmol) to a solution of (R)-Sa(210 mg, 661 pmol) in acetone (40 mL). (R)-6awas isolated in 71%yield as a colorless crystalline solid (216 mg, 470 pmol); mp 135-136 "C [recrystallization by diffusion of diethyl ether via the gas phase into a solution of the product in ethyl acetate/acetone (1/5, v/v) at room temperature]. The NMR and MS data of the product were identical with those obtained for ruc-6a. [aIz0546 = -5.6 (CHCl3, c = 1.0). Anal. Calcd for C2oH34INOSi (M, = 459.5): C, 52.28; H, 7.46; N, 3.05; I, 27.62. Found: C, 52.4; H, 7.5; N, 3.0; I, 27.8. Preparation of ( S )- 1- {2-[Cyclohexyl(hydroxymethy1)phenylsilyllethyl}-1-methylpyrrolidiniumIodide [(S)6a]. This compound was prepared analogously to the synthesis of rac-6aby addition of methyl iodide (207 mg, 1.46 mmol) to a solution of (S)-Sa(231 mg, 728 pmol) in acetone (40 mL). (S)-6awas isolated in 67%yield as a colorless crystalline solid (225 mg, 490 pmol); mp 135-136 "C [recrystallization by diffusion of diethyl ether via the gas phase into a solution of the product in ethyl acetate/acetone (1/5, v/v) at room temperature]. The NMR and MS data of the product were identical with those obtained for rac-6a. [aIz0546 = +5.6 (CHCl3, c = 1.0). Anal. Calcd for C2oH34INOSi (M, = 459.5): C, 52.28; H, 7.46; N, 3.05; I, 27.62. Found: C, 52.6; H, 7.7; N, 3.0; I, 27.7. Preparation of rac-1-{2-[Cyclohexyl(hydroroxymethyl)phenylsilyl]ethyl}-1-methylpiperidiniumIodide (ruc6b). This compound was prepared analogously to the synthesis of rac6a by addition of methyl iodide (860 mg, 6.06 mmol) to a solution of rac-Sb(1.00 g, 3.02 mmol) in acetone (100 mL). rac-6bwas isolated in 91%yield as a colorless crystalline solid (1.30 g, 2.75 mmol); mp 141-142 "C. IH NMR (250.1 MHz, CDCl3): 6 0.95-1.5 and 1.5-2.0 (m, 19 H, SiCHZC, SiCHCZ, CCHzC), 3.1 (br s, 1 H, OH), 3.14 (s, 3 H, NCHs), 3.35-3.65 and 3.85-4.05 (m, 6 H, NCHzC), 3.87 (s, 2 H, SiCHZO), 7.37.55 (m, 5 H, Sics&). 13C NMR (62.9 MHz, CDC13): 6 4.1 (SiCH2C), 20.1 (2 C) (CCHzC), 20.8 (CCHzC), 23.4 (C-1, SiCeHll),26.5 (CCHZC),27.5 (2 c)(CCHzC),27.7 (CCHzC), 27.8 (CCH2C), 47.2 (NCHs), 48.7 (SiCH20), 59.8 (NCH2C), 60.3 (NCHZC),61.9 (NCHZC),128.3 (C-3/C-5, Sics&), 129.9 (C-4, FD SiC,jHs), 132.5 (C-1, Sics&), 134.4 (C-2/C-6, S & c,i& MS: m/z 346 (100, MZation).Anal. Calcd for C Z I H ~ ~ I N (M, OS~ = 473.5): C, 53.27; H, 7.66; N, 2.96. Found: C, 53.3; H, 7.7; N, 3.0. Preparation of (R)-l-{2-[Cyclohexyl(hydroxymethyl)phenylsilyllethyl}-1-methylpiperidiniumIodide [(R)-6bl. This compound was prepared analogously t o the synthesis of ruc-6aby addition of methyl iodide (177 mg, 1.25 mmol) to a solution of (R)-Sb(205 mg, 618 pmol) in acetone (40 mL). (R)6b was isolated in 82% yield as a colorless crystalline solid (239 mg, 505 pmol); mp 164-165 "C. The NMR and MS data

Biological Recognition of Enantiomeric Silanes

Organometallics, Vol. 14,No. 1, 1995 261

of the product were identical with those obtained for rac-6b. g, 146 mmol); bp 101 "C/O.Ol Torr. 'H NMR (400.1 MHz, [aIz0546= -5.9 (CHCl3, c = 1.0). Anal. Calcd for C Z ~ H ~ ~ I N O SCDCld: ~ 6 1.2-1.4 and 1.7-1.9 (m, 11H, SiCsH11), 3.17 (s, 2 (M, = 473.5): C, 53.27; H, 7.66; N, 2.96; I, 26.80. Found: C, H, SiCHzCl), 5.95 (dd, Jgem = 5.9 Hz, Jtrans = 18.2 Hz, 1 H, 53.3; H, 7.7; N, 3.0; I, 26.7. SiCH=CHH), 6.29 (dd, Jgem = 5.9 Hz, Jcis= 14.9 Hz, 1 H, Preparation of (S)-l-{2-[Cyclohexyl(hydroxymethyl)- SiCH=CHH), 6.34 (dd, Jcis= 14.9 Hz, Jk,,, = 18.2 Hz, 1 H, 13CNMR (100.6 MHz, SiCH=CHZ), 7.4-7.7 (m, 5 H, Sic,&). phenylsilyllethy1)-1-methylpiperidiniumIodide [(S)-6b]. CDC13): 6 22.9 (c-1, SiC6Hi1), 26.7, 26.8, 27.3 (2 c ) , 27.91, This compound was prepared analogously to the synthesis of and 27.94 (CCHZC,SiCHzCl), 127.9 (c-3/c-5, SiC6H5), 129.7 ruc-6aby addition of methyl iodide (184 mg, 1.30 mmol) to a (c-4, Sics&), 131.5 (SiCH=CHZ), 132.7 (c-1,SiCsHs), 135.0 solution of (S)-Sb(215 mg, 648 pmol) in acetone (40 mL). (5')(C-WC-6,Sic&), 136.4 (SiCH=CHZ). E1 MS: m/z 264 (5, M+), 6b was isolated in 82% yield as a colorless crystalline solid 215 (67, M+ - CHzCl), 181 (18, M+ - CsH11),133 (100, CsHg(252 mg, 532 pmol); mp 164-165 "C. The NMR and MS data Si+). Anal. Calcd for C15Hz1ClSi (M, = 264.9): C, 68.02; H, of the product were identical with those obtained for rac-6b. 7.99. Found: C, 68.1; H, 8.1. [alZ05a= +5.9 (CHC13, c = 1.0). Anal. Calcd for C21H36INOSi (M, = 473.5): C, 53.27; H, 7.66; N, 2.96; I, 26.80. Found: C, Preparationof ruc-(Acetoxymethyl)cyclohexyl(phen53.4; H, 7.8; N, 2.9; I, 26.8. y1)Vinylsilane (rac-9). A mixture of rac-8(15.0 g, 56.7 mmol) Preparationof rac-l-{2-[Cyclohexyl(hydroxymethyl)and sodium acetate (4.65 g, 56.7 mmol) in DMF (65 mL) was phenylsilyllethy 1) - 1-methylhexamethyleniminium Iostirred under reflux for 5 h. The mixture was cooled t o room dide (mc-6c). This compound was prepared analogously to temperature, the precipitate filtered off, and the solvent the synthesis of rac-6aby addition of methyl iodide (830 mg, removed under reduced pressure. The residue was distilled 5.85 mmol) to a solution of rac-Sc (1.00 g, 2.89 mmol) in in uucuo (Vigreux column) to give rac-9 in 92% yield as a acetone (100 mL). rac-6c was isolated in 90% yield as a colorless liquid (15.1 g, 52.3 mmol); bp 110 "C/O.Ol Torr. lH colorless crystalline solid (1.27 g, 2.60 mmol); mp 149-150 "C. NMR (400.1 MHz, CDCl3): 6 1.1-1.3 and 1.7-1.9 (m, 11 H, lH NMR (250.1 MHz, CDC13): 6 1.0-2.0 (m, 21 H, SiCHzC, SiC&1), 2.02 (s, 3 H, CCHs), 4.17 ( 6 ~and ) 4.19 ( 6 ~ (AB ) SiCHC2, CCHzC), 3.1 (br s, 1 H, OH), 3.15 (s, 3 H, NCHs), system, JAB = 14.5 Hz, 2 H, SiCHZO), 5.88 (dd, Jgem = 5.3 Hz, 3.25-3.6 and 3.85-4.0 (m, 6 H, NCHzC), 3.88 (s, 2 H, SiCHZO), Jtrans = 18.6 Hz, 1 H, SiCH=CHH), 6.21 (dd, J,,, = 5.3 Hz, 7.3-7.55 (m, 5 H, SiCsH5). l3C NMR (62.9 MHz, CDC13): 6 Jd, = 14.7 Hz, 1H, SiCH=CHH), 6.28 (dd, J,,, = 14.7 Hz, Jt,,, 5.1 (SiCHzC), 22.0 (CCHzC), 22.1 (CCHzC), 23.4 (c-1, Sics&), = 18.6 Hz, 1H, SiCH=CHZ), 7.35-7.65 (m, 5 H, Sics&). I3C 26.5 (CCHzC), 27.3 (2 C) (CCHzC), 27.5 (2 C) (CCHzC), 27.7 NMR (100.6 MHz, CDC13): 6 20.8 (CCH3),23.3 (C-1, SiC&11), (CCHzC), 27.8 (CCHzC), 48.7 (SiCHZO), 50.0 (NCH3), 63.3 26.7 (CCHzC), 27.4 (2 C) (CCHzC), 27.9 (2 C) (CCHzC), 53.3 (NCHzC),63.5 (NCH2C),64.1 (NCHzC), 128.3(C-3/C-5, SiC6H5), (SiCH20), 127.8 (C-3c-5, Sic&), 129.5 ((2-4, Sic,&), 131.6 129.9 (C-4, Sics&), 132.5 (C-I, SiCsHs), 134.4 (C-2/C-6, (SiCH=CHZ), 132.8 (c-1,Sic&), 134.8 (C-2/C-6, Sic&&), 136.0 (SiCH=CHZ), 171.7 (CO). E1 MS: m/z 261 (8, M+ Sic&&). FD MS: m/z 360 (100, M;ation). Anal. Calcd for CH=CHz), 211 (12, M+ - CsH51, 205 (100, M+ - CsH11), 133 CzzH38INOSi (M, = 487.5): C, 54.20; H, 7.86; N, 2.87. Found: (60, CaHeSi+). Anal. Calcd for C17H2402Si (M, = 288.5): C, C, 53.7; H, 7.7; N, 3.0. Preparation of (R)-l-{2-[Cyclohexyl(hydroxymethyl)- 70.78; H, 8.39. Found: C, 70.7; H, 8.3. phenylsilyl]ethyl}-1-methylhexamethyleniminiumIoPreparationof ruc-Cyclohexyl(hydroxymethy1)phendide [(R)-6cl. This compound was prepared analogously t o yl(viny1)silane (ruc-10). A solution of ruc-9 (36.4 g, 126 the synthesis of rac-6aby addition of methyl iodide (164 mg, mmol) in diethyl ether (300 mL) was added dropwise at -30 1.16 mmol) t o a solution of (E)& (200 mg, 579 pmol) in "C over 2 h to a stirred suspension of lithium aluminum ~ isolated in 85%yield as a colorless acetone (40 mL). ( R 1 - 6was hydride (9.57 g, 252 mmol) in diethyl ether (500 mL). The crystalline solid (239 mg, 490 pmol); mp 176-177 "C. The mixture was stirred at -30 "C for 30 min and then added in NMR and MS data of the product were identical with those 20-mL portions (-30 "C) to ice-cold 18% hydrochloric acid (1.0 obtained for rac-6c. [aIz0546 = -1.7 (CHCl3, c = 1.0). Anal. L). The organic phase was separated and the aqueous layer Calcd for C22H3sINOSi (M, = 487.5): C, 54.20; H, 7.86; N, 2.87; extracted with diethyl ether (4 x 500 mL). After drying of I, 26.03. Found: C, 54.3; H, 8.0; N, 2.9; I, 26.2. the combined organic extracts over anhydrous NazS04 and removal of the solvent under reduced pressure, the residue Preparation of (S)-l-{ 2-[Cyclohexyl(hydroxymethyl)was distilled in uacuo (Vigreux column) to give rac-10in 92% phenylsilyl]ethyl}-1-methylhexamethyleniminium Ioyield as a colorless liquid (28.7 g, 116 mmol); bp 105 "C/O.Ol dide [(S)-6c]. This compound was prepared analogously to the synthesis of rac-6aby addition of methyl iodide (204 mg, Torr. 'H NMR (400.1 MHz, CDC13): 6 1.1(br s, 1 H, OH), 1.1-1.4 and 1.6-1.9 (m, 11H, SiCsH11), 3.79 (s, 2 H, SiCHZO), (250 mg, 723 pmol) in acetone 1.44 mmol) to a solution of (S1-5~ (40 mL). (S)-6bwas isolated in 83% yield as a colorless 5.93 (dd, Jgem = 5.4 Hz, J,,, = 18.7 Hz, 1 H, SiCH=CHH), crystalline solid (294 mg, 603 pmol); mp 176-177 "C. The 6.25 (dd, Jgem = 5.4 Hz, Jcis= 14.9 Hz, 1H, SiCH=CHH), 6.32 NMR and MS data of the product were identical with those (dd, JdB= 14.9 Hz, Jt,.,, = 18.7 Hz, 1 H, SiCH=CHz), 7.3513CNMR (100.6 MHz, CDC13): 6 23.1 7.65 (m, 5 H, Sci&&)., obtained for rac-6c. [aIz0546= +1.7 (CHCl3, c = 1.0). Anal. (C-1, SiCsH11), 26.8 (CCH2C), 27.6 (2 C) (CCHzC), 27.9 Calcd for C22H3sINOSi (M, = 487.5): C, 54.20; H, 7.86; N, 2.87; (CCHzC),28.0 (cCH&), 51.7 (SiCHzO), 127.9 (c-3/c-5, Sic&&), I, 26.03. Found: C, 54.6; H, 8.0; N, 3.0; I, 26.0. 129.5 (C-4, SiCeH5), 132.2 (SiCH=CHz), 133.4 (C-1, Sic&), Preparation of rac-(Chloromethyl)cyclohexyl(meth135.0 (C-2/C-6,Sic&&,), 136.1 (SiCH=CH2). E1 MS: m/z 246 0xy)phenylsilane (ruc-7).Synthesis was as described in ref (2, M+), 215 (52, M+ - CHzOH), 163 (74, M+ - CsHii), 133 Id. (100, CsHgSi+). Anal. Calcd for ClsHzzOSi (M, = 246.4): C, Preparation of ruc-(Chloromethyl)cyclohexyl(phen73.11; H, 9.00. Found: C, 73.1; H, 9.0. y1)vinylsilane (ruc-8).A 1.0 M solution of vinylmagnesium Preparation of rac-Cyclohexyl(pheny1)[(trimethylsibromide in THF (200 mL, 200 mmol of CHZ=CHMgBr) was lyloxy)methyl]vinylsilane (rac-11).A solution of chlorotriadded dropwise at room temperature over 70 min t o a stirred solution of ruc-7 (43.0 g, 160 mmol) in THF (200 mL). After methylsilane (52.2 g, 480 mmol) in n-pentane (270 mL) was heating under reflux for 6 h and stirring at room temperature added dropwise at -30 "C over 100 min t o a stirred solution for 14 h, a saturated aqueous NH4C1 solution (300 mL) was of ruc-10(29.6 g, 120 mmol) and triethylamine (13.0 g, 128 mmol) in n-pentane (430 mL). The solution was allowed to added to the reaction mixture at 0 "C. The organic phase was warm up to room temperature and then stirred for 19 h. The separated and the aqueous layer extracted with diethyl ether precipitate was filtered off, the solvent removed under reduced (4 x 200 mL). After drying of the combined organic extracts pressure, and the residue distilled in vacuo (Vigreux column) over anhydrous NazS04 and removal of the solvent under to give rac-11in 84% yield as a colorless liquid (32.3 g, 101 reduced pressure, the residue was distilled in uucuo (Vigreux mmol); bp 86 "C/O.Ol Torr. lH NMR (400.1 MHz, CDC13): 6 column) t o give ruc-8 in 91% yield as a colorless liquid (38.6

Tacke et al.

262 Organometallics, Vol. 14, No. 1, 1995 Table 5. Atomic Coordinates ( x 104) and Equivalent Isotropic Displacement Parameters (pmz x 1O-I) for (R)-6b atom X Y Z 9270.0(2) 4778.5( 1) 31.6(1) 2892.4(2) 5109.1(6) 3853.7(2) 19.7(1) 2224.9(7) 5079(2) 4049.7(7) 45.1(5) -783(2) 6094(3) 394539) 31.8(5) 391(3) 4790(2) 4470.6(7) 22.7(4) 3139(2) 403l(2) 4836.2(6) 19.5(3) 2122(2) 5369.3(6) 16.1(3) 2666(2) 4032(2) 5394.8(8) 25.3(5) 4187(2) 3347(3) 5560.1(7) 24.4(4) 5586(2) 2695(3) 6105.6(7) 32.3(5) 5653(3) 3013(3) 6396.6(8) 34.4(6) 4763(3) 1876(3) 6214.1(8) 28.0(5) 3199(3) 1836(3) 5661.7(8) 22.2(4) 3145(2) 1553(2) 3535.9(7) 22.1(4) 1782(2) 3342(2) 33 16(3) 3143.6(9) 31.6(5) 765(3) 2898.0(10) 40.3(6) 437(3) 2034(3) 733(3) 3042.0(9) 36.2(5) 1085(3) 718(3) 3434.3(8) 31.1(4) 2068(3) 2012(2) 24.4(5) 2417(2) 3675.8(8) 20.9(4) 3565(2) 6232(2) 3473.4(7) 26.3(4) 2858(3) 6710(2) 2985.9(7) 30.4(5) 7625(3) 2675.9(8) 3922(3) 6817(3) 2578.6(9) 33.7(6) 5378(3) 32.7(5) 6114(3) 6348(3) 3058.5(9) 25.8(5) 5057(2) 5451(2) 3378.6(8) The equivalent isotropic displacement parameter U(eq) is defined as one-third of the trace of the orthogonalized Uij tensor.

0.10 (9, 9 H, SiCH3), 1.1-1.4 and 1.7-1.9 (m, 11H, SiC&1), 3.69 (6, 2 H, SiCHZO), 5.58 (dd, J,,, = 5.1 Hz, Jk,. = 19.2 Hz, 1H, SiCH=CKH), 6.20 (dd, J,,, = 5.1 Hz, Jd8 = 14.9 Hz, 1H, SiCH=CHH), 6.32 (dd, J e = 14.9 Hz, Jt,,, = 19.2 Hz, 1 H, SiCH=CHZ), 7.35-7.7 (m, 5 H, Sic&). 13C N M R (100.6 MHz, CDC13): 6 -0.8 (SiCHs), 23.3 ((2-1, SiCsH11), 27.0 (CCHzC), 27.6 (2 C) (CCHzC), 28.1 (CCHzC), 28.2 (CCHzC), 51.5 (SiCHZO), 127.6 (C-3/C-5, SiCsHs), 129.2 (C-4, SiCsHs), 133.0 (SiCH=CHZ), 134.6 (C-1, Sic&), 135.1(C-WC-6, Sic&), 135.3 (SiCH=CHZ). E1 MS: mlz 318 (1,M+), 235 (99, M+ CeH11), 133 (100, CsHQSi+). Anal. Calcd for C18H300Siz (M, = 318.6): C, 67.86; H, 9.49. Found: C, 67.8; H, 9.5. Crystal Structure Analysis of (R)-6b. Intensities were measured with monochromatized Mo Ka radiation on a Stoe STADI-4 diffractometer equipped with a Siemens LT-2 lowtemperature attachment. The structure was solved by the heavy-atom method and refined anisotropically on F (program SHELXL-93, G. M. Sheldrick, University of Gottingen). Hydrogen atoms were included with a riding model except for methyl or hydroxyl H (rigid groups). The absolute configuration was determined by an x refinement;I x refined to -0.028(12). For further details, see Table 1. The atomic coordinates and equivalent isotropic displacement parameters for (R)-6b are listed in Table 5 ; the atomic numbering scheme is given in Figure 1. Tables of anisotropic thermal parameters, atomic coordinates for the hydrogen atoms, and complete lists of bond distances and angles are provided as supplementary material. NMR-Spectroscopic Determination of the Enantiomeric Purities of the Antipodes of Sa-c. The enantiomeric purities of the (R)- and (5')-enantiomers of Sa-c were determined by NMR experiments using the chiral shift re[(-)-TFAE] (lH agents (-)-2,2,2-trifluoro-1-(9-anthryl)ethanol (7) Flack, H. D. Acta Crystallogr. Ser. A 1983, 39, 876-881.

NMR) and (+)-tris[3-(2,2,3,3,4,4,4-heptafluoro-l-hydroxybutylidene)d-camphorato]europium(III)[(+)-Eu(hfc)s] NMR). (-)-TFAE and (+)-Eu(hfc)~were purchased from Sigma and Aldrich, respectively. The NMR spectra were recorded at room temperature on a Bruker AM-400 NMR spectrometer operating at 400.1 MHz ('H) and 100.6 MHz (W),respectively. The composition of the samples used for the lH NMR experiments was as follows: 30.2 pmol of Sa-c, 152 pmol of (-)-TFAE, 0.5 mL of CDC13. The composition of the samples used for the 13CN M R experiments was as follows: 90.5 pmol of Sa-c, 45.2 pmol of (+)-Eu(hfc)a, 0.5 mL of CDCl3. Functional PharmacologicalStudies. As a measure of affinity, p A 2 values of the pure (R)and (5')-enantiomers of Sa-c and 6a-c were determined at muscarinic M1 receptors in rabbit vas deferens [l-[4-[[(4-fluorophenyl)carbamoylloxyl2-butyn-1-yll-1-methylpyrrolidinium tosylate (4-F-PyMcN+)as agonist], M2 receptors in guinea-pig atria, and M3 receptors in guinea-pig ileum (arecaidine propargyl ester as agonist) according to published procedures.lg Concentration-response curves of the agonists were constructed in the absence and in the presence of the antagonists [(R)and (5')-enantiomers of Sa-c and 6a-c]. Dose ratios calculated from the respective ECso values of the agonists were used t o perform a Schild analysis.8 Since the Arunlakshana-Schild plots of all the compounds investigated were linear and the slopes of the regression lines were not significantly different from unity, p A 2 values were estimated as the intercept on the abscissa scale by fitting to the data the best straight line with a slope of unity (constrained plot).9 The p A 2 values given in Table 2 correspond to -log KDvalues (KD= dissociation constant of the antagonist-receptor complex). Radioligand Binding Studies. Radioligand binding studand (5')-enantiomers of Sa-c and 6a-c ies of the pure (R)were carried out with homogenates of human NB-OK 1 neuroblastoma cells (M1 receptors), as well as with homogenates of rat heart (M2 receptors), rat pancreas (M3 receptors), and rat striatum (M4 receptors). The radioligand was [3H]N-methylscopolamine (0.24-1.0 nM). Data of the binding experiments were analyzed by an iterative curve fitting procedure. Dissociation constants (Ki values) of the (R)and (S)-enantiomers of Sa-c and 6a-c were determined from IC50 values obtained from competition curves. The pKi values given in Table 3 correspond to -log Ki values. For more experimental details, see ref lf,i.

Acknowledgment. This work was supported by the Volkswagen-Stiftung (R.T.),the Fonds der Chemischen Industrie (G.L., R.T.), the Fonds de la Recherche Scientifique MBdical (M.W.), and the Bayer AG, Germany (R.T.). Supplementary Material Available: Tables of anisotropic thermal parameters, atomic coordinates for the hydrogen atoms, and complete lists of bond distances and angles for (R)6b (6 pages). Ordering information is given on any current masthead page. OM940667S (8)Arunlakshana, 0.;Schild, H. 0.Br. J.Pharmacol. 1969,14,48-

85.

(9)Tallarida, R. J.; Murray, R. B. Manual of Pharmacologic Calculations with Computer Programs; Springer: Berlin, 1986.