September 1969 STEREOCHEMISTRY OF NETHADOLS 839

in 25 ml of liquid NHI) suspended in 15 ml of PhMe, 1.96 g (0.0084 mole) of 2-chlorophenothiazine was added, the mixture was refluxed for 3 hr, then 1.7 g (0.0084 mole) of XI in 10 ml of PhMe was added, and the whole was refluxed with stirring for 6 hr. After cooling i t was extracted with 30 ml of 10% HCl, the aqueous layer was made alkaline Tvith 50% NaOH, and the oil that separated was extracted (Et20). The extract was dried (Na2S04), the solvent was evaporated, and the oil residue was treated with dry HC1 in ether to give 2.5 g (63%) of II-l.2HC1, mp 189-192" (EtyO-EtOH). 10,ll-Dihydrodibenzocycloheptene Derivatives of 3,S-Diaza-

bicyclo[3.2.1] octanes (111, IV). Synthesis of 8- [5-(10,11-Di- hydrodibenzocycloheptenyl)propylidene] - 3 -methyl - 3,s - diazabi- cyclo[3.2.l]octane (111). (a) Reaction of the Grignard of X with Dibenzosuberone. 8- [5-Hydroxy-5-(10,1 l-dihydrodibenzo- cycloheptenylpropyl)] - 3 - methyl - 3,8 - diazabicyclo[3.2.1] octane (XIV).-To a suspension of 0.9 g (0.037 g-atom) of hlg turnings in 10 ml of anhydrous THF, a crystal of I2 and a few drops of EtBr were added. As the reaction started, a solution of 7.5 g (0.037 mole) of X in 10 ml of T H F was added within 0.5 hr. The mixture was refluxed for 1 hr, then 3.9 g (6.085 mole) of dibenzosuberoiie n-as added portioiiwise, and the whole was refluxed for 16 hr. After cooling the resulting solution was dropped into 200 ml of a stirred 10% solution of xH4Cl a t 0". The oil separated was extracted (CHC13), the extract was dried, and the solvent was evaporated to give 5.6 g (7970 of XIIT, mp 153-155' (EtyO-petroleum ether). Anal. (CZ,H~JY~O) C, H, N.

Dehydration of XIV to 8- [ (10,ll-Dihydrodibenzocyclohep- tenyl)propylidene] -3-methyl-3,s-diazabicyclo [3.2.1] octane(III).-

(b)

,4 mixture of 5.4 g (0.014 mole) of XIV, 3.3 g (0.017 mole) of p-toluenesulfonic acid monohydrate, and 200 ml of PhMe was refluxed 1 hr, then 100 ml of the solvent was slowly distilled. After cooling, the solution was concentrated to a small volume and washed ni th two 20-ml portions of 10% NaOH. The organic layer was dried (Na2S04) and the solvent was evaporated. The residue was chromatographed on silica gel, eluting the impurities with EtOAc-cyclohexane ( 8 : 2), then eluting with MeOH to give 4 g (787,) of I11 as an undistillable oil which exhibited a single spot on tlc.

The dihydrochloride melted a t 271-273". Anal. (C26X&12X2)

3- [5 - (10,ll - Dihydrodibenzocyc1oheptenyl)propylidene - me- thyl-3,8-diazabicyclo [3.2.1] octane (IV) was prepared from X I according to the procedure described for 111. The intermediate 3- [.!%hydroxy- 5 - (10,l l- dihydrodibenzocycloheptenyl)propyl] - 8- methyl-3,8-diazabicyclo[3.2.l]octane (XV), mp 167-169' (ether), was isolated in 42% yield. d n a l . (C2,H,NZO) C, H, N.

Dehydration of 2.1 g of XV led to 1.8 g of an oil which was chromatographed on &03, eluting with EtOAc-cyclohexane (8:2) to give 1.2 g (60%) of pule IV as undistillable oil.

The dihydrochloride melted at 239-242" (EtOH-EtlO).

N, C1.

, I d . (C~SHuC1&;2) N, C1.

Acknowledgment.-The authors wish to thank Dr. A. Vigevani for spectroscopic determinations and ah. A. Campi for chemical analyses.

Stereochemical Studies on Medicinal Agents. V1I.l Absolute Stereochemistry of Methadol Isomers and the

Role of the 6-Methyl Group in Analgetic Activity2l3

P. S. POIZTOGHESE AND D. A. ~ V I L L I A A I S ~

Uepui h e n t of V e d z c c v ~ a l Chenustry, College of Pharmacy, Universzty of Minnesota, Xinneapolis, Mznnesota 56456

Receibed Narch 28, 1969

The stereochemistry of optically act'ive a- and p-methadol has been deduced by the asymmetric synthetic procediire of Prelog. The apparent, dissociation constants of the title compounds, when compared with those of methadone and 3-deoxymethadone, suggest the absence of substantial intramolecular H bonding in aqueous medium. Nmr and ir studies point t'o the presence of strong intramolecular H bonds in nonpolar media, with the p isomer being more strongly internally associated. Possible preferred conformations which are consist,ent with the spectral dat'a are depicted. The (6R) , (6S), and (6R) receptor stereoselect'ivities for methadone, a- methadol, and acetyl-a-methadol, respect'ively, have been rat'ionalized in terms of differing modes of interaction.

I t is generally believed that strong analgetics exert their effect by interacting with specific sites in the CSS, and that these sites possess asymmetric topog- raphies which enable them to distinguish between e1iantiomorphs.j

The more active enantiomers of methadone (1) and certain related analgetics possessing a common asym- metric center have been determined to have the (R) configuration.h It subsequently was pointed out that there itre also :I tiumber of strong :Inalgctics whoic configurations are in the (8) series. and that the reversal

(1) Par t VI of this series: P. S. Portoghese, A. A. Afikhail, and H. J. Kupferberg, J . Med. Chem., 11, 219 (1968).

(2) We gratefully acknowledge support of this work b y Piational In- stitutes of Health Grant N B 05192.

( 3 ) (a) Presented in part a t the 152nd National Meeting of the American Chemical Society, New York, X. Y . , Sept 1966, Abstract P-4. (b) For a preliminary report on this work, see P. S. Portoghese and D. A. Williams. J . Pharm. Sci., 65, 990 (1966).

(4) NIM Predoctoral Fellow 8-E'l-G&I-20515, 1963-1966. (5) P. S. Portoghese. J . Pharm. Sci., 61, 865 (1966), and references cited

therein. (6) A. H. Beckett and A. F. Casy, J . Chem. Soc.. 900 (1955).

of stereoselectivity may be due to differing modes of drug-receptor interaction.'

PhzCCOEt PhzCCH(0R)Et

CH&H(NMe2)CH? I

CH2CH(NMe2)CH3 1 2 , R = H

3, R = Ac

One of the most dramatic and interesting examples of this phenomenon has been in the literature8s9 for some time arid ib illustrated in Table I. The more potent a-methadol enantiomer [( -)-a-21 is derived from (6s)- methadone which has a low order of activity. ?\lore- over, conversion of a-2 to CY-3 again reverses the stereo- selectivity so that the more potent enantiomer, (+)- a-3, now has the (6R) configuration. With the optically active 0 isomers there is no inversion of stereoselec- tivity and, consequently, the activity is found in the (6R) series [( -)-@-2, (-)-p-3] .9

( 7 ) P. S. Portoghese, J. M e d . Chem., 8 , 609 (1965). ( 8 ) A. Pohland, F. J. Marshall, and T. P. Carney, J .4m. Chem. Soc , 71,

(9) N. B. Eddy and E. L. May, J . 078. Chem., 17, 321 (1952). 460 (1949).

111 :in effort t o explain thebe remarkaI)lv c l~inges 111

receptor itereoselectivity. n n investig:ition of the com- plete stereochemistry of the methndol iwmers was uridertakcti.J S m r . ir. :md pKa studies were also cxrricd out i i i order to itivc>.:tig:\te thc conformation:il ltreferericcs of thcw 1nolcc1111~i.

Chemistry.-Application of I ' r e l o g ' ~ ~ ~ procedure f o r determining the absolute configuration of asymmetrir carbinols has been emploj edll ni th great success, arid I\ (3 therefore used thi.: method for our htereochemical studies of the methadol isomers.

ith benzoylformyl rhloride :ifforded henzoylfoi~mate ebter hydrochloride 14.HC1) i n yicltl. Ttic. f i w 1 x 1 ~ (4). upon reaction

Esterification of ( -)-0-mcthadol

I I

with J I e ~ I g I , gave ribe to the atrolactate ester (6, 13 = S.\Ie2) which when wponificd 2 n

S-(+)-ntrolactic acid (7) (T.(i' optic:d purity) in :in

over-all yield of 20c/, (based 011 4). The luw yield of 7 was likely due to tlie formation of

pyrrolidiriium quaternary salt 8 (X = PhCOCOO-) since this compound was isolated when 4 wa5 allowed to stand a t room temperature for 3 days. Presumably, this wa< formed by displaccnient of the benzoyl- i'ormyloxy group in 4 t iu iritraniolecular Sx2 attack by the baqic nitrogen. Treatment of 8 (X = PhCOCOO-) with HC1 gave the quaternary chloride (8, X = C1-) which pobsessed hpectral proprrties identical with thv compound isolated by Perrine arid 1Iay,l2 who had oht:iincd this material in racemic form from reaction of

( I O ) V Prelog, Bull. Soc Cham. France, 987 (1956). (11) (a) V Prelog and H L hleier Hrli Chzm. Acta, 36, 320 (1953),

ib) W. Q Dauben, TI F Ilickel 0 Jeger, and T' Prelog zhzd. , 86, 329 (1954). ( c l 1 J , Hirctl, .I \\ C'laik-Imi\ uiirl i i' lioliertion I C ' h F n i \or 3586 11957)

(12) I 1) Perrinn and t L ;Lla). J O r y L i t e m 19, i i 3 (1954)

H I OH

I

The configurations of the methadols have beeii corroborated by pyrolytic cyclization to isomeric 2- ethyl-3.3-diphenyl-5-niethylfurans"" whose stereochem- istries were elucidated ti)- iimr muly studies. a 8

pKa Studies.-- Dissociat ioii cotistaxits have b ~ i i employed as criteria for assessing the abilit,y of :in

c+ctroneg:ttive group to stabilize the conjugate acid o/' mi amiiie, as thij often gives rise to enhanced basicity due to intraiiiol(.ciil:ir hydrogeli horidirig.l" Pinr(,

(13) P. S. Portogliese and I ) . .\. \Villiams, lS4tli National A,Ieet,inp uf 1 1 1 ~ . American Chemical Society. Chicago, Ill., Sept 1967, Abstracts S-YO; 1'. S . Portoghese antl D. A . Williams. J. Hqterocyc l . Chem.. 6 , 307 (1969).

(14) A . F. Caay and 11. AI. .I. klaasan, Z'elrukedvoi i . 23, 4075 (1967). (15) J . F. king in "Tecl~nic~ue of OrFanic ('hemistry," Part I . Val. XI,

lnterscience Publishers. Inc., New Tork, N . 1.. 1963, Chapter V I , i i 318.

September 1969 STEREOCHEMISTRY OF NETHADOLS 84 1

niethadont: m d the methdols poisess an electronega- tive group a t C-3 which conceivably might stabilize the protonated dimethylamino group, i t was of interest to compare the pKa values of these compounds with :i-deoxymethadonc (Table 11). The substantially greater basicity of methadone when compared to the deoxy analog suggests that the conjugate acid of methadone assumes a cyclic conformation which is stabilized by i ntern:d H bonding. Ifi Two possible i iitertinlly bonded rotamers :we depicted by conforma- tion$ l l a and l l b . It is awtmed that C=O arid the

Ila

Me Ilb

acidic proton are coplanar so as to allow maximum stabilization. If this is the case, the phenyl groups then would be oriented in "quasi-axial" and "quasi-equa- torial" conformations. A4ccordingly, the C-5 and C-6 substituents would be staggered in "axial" and "equa- torial" positions to minimize vicinal nonbonded interactions.

TABLE I1 APPARENT DISSOCIATIOX CONSTANTS FOR METHADONE A N D RELATED COMPOUNDS

llethadone 8 . 6 2

a-JIethadol 7 .86

Compd PKB

3-Ileoxymethadone 7 . 9 3

p-LIethadol 7 . 5 9

The stereospecificity of t'he catalytic r e d u ~ t i o n ~ ~ ~ ~ ' ~ ~ ' ~ of methadone t,o a-methadol may be explained in terms of the cyclic conformat~ions. StuarkBriegleb models indicate the upper face of t'he carbonyl carbon to be less hindered and hence more accessible t'o the hydro- genation catalyst. A similar explanation can be in- voked t'o rationalize the stereospecificity of LAH reduction.18 I n t'his case a cyclic conformation could be maintained by coordination of an alurhinum hydride species between N and 0 functions.

It can be noted (Table 11) that the methadol dia- stereomers are less basic than methadone and its 3- deoxy analog. The decreased dissociation of the methadol diastereomers can be ascribed to one of the

(16) I t has been suggested [A. H. Beckett, J. Pharm. Pharmacol., 8 , 848 (1956)l that intramolecular association of this type could occur with metha- done, although it was found that 3,3-diphenyl-N,N-dimethylpropylamine is a stronger base than 6-desmethylmethadone. A possible explanation for these results might be related to the fact that the former is not a good model compound, since it does not yomess a substituent coniparahle to the size of the propionyl group.

(17) E. L. May and E. hlosettig. J . O w Chem.. 13, 459 (1848). (18) M. E. Speeter, W. M. Byrd, L. C. Cheney. and S. B. Binkley. J . Am.

Chem. Soc., 71, 57 (1948).

following possibilities: (1) tlicrr i5 110 ~uh~t: t r i t ia l intra- molecular H bonding of the type, -(H)O - * * - H-;R; +, or (2) internal 0-He . .N bonding competes with -(H)O- . a .H-S+ and thereby decreases the stability of the

conjugate acid. Factors contributing to 1 might be related to the

lower proton acceptor capacity of the carbinol oxygen (when compared to the carbonyl 0 of methadone) and to greater steric hindrance to intramolecular association when the H-bonding proton acceptor group is attached to a tetrahedral center. In case 2 , OH. . . S bonding might offset stabilization gained from -(H)O. . .H-N+ association.

Of the two possibilities, we presently favor l.19

I n support of this, existing evidencez0 suggests that (H)O. . . H-S+ bonds are stronger than 0-H. . ~3 and hence should substantially increase basicity of tertiary amines by stabilizing the conjugate acid. Since the methadols are less basic than 3-deoxymethadone, it is conceivable that both diastereomers are not internally H bonded in aqueous solution to any great extent. If this is the case, the different pKa values for a- and p- methadol may be due to differences in accessibility of solvent to stabilize the conjugate acid.

Infrared Studies.-Although evidence suggests that the methadol isomers are not substantially internally H bonded in polar solvent\, ir studies indicate the presence of strong iritr:r"ecul:ir associ:ttion in 11011-

polar media. The high-rcsolution ir spectra of 0.4 JI solutions (CC1,) of a- atid p-methadol bases revealed a broad bonded OH absorption overlapping the C H stretching vibrations a t approximately 3000 cm-1.31 Examination of a 0.005 A l l solution of the bases showed no change of the absorption characteristics in the 3000-cm-' region. However, some concentration de- pendence mas observed for the a isomer in that a very weak (e 2.5) free OH absorption appeared at 3580 cm-I. No free OH band could be seen with /3-methadol. The ir data suggest that both a- and p-methadol are strongly internally H bonded in nonpolar solvent and that the former diastereomer forms weaker H bonds. It has been reportedz2 that a chain length of four carbons between electronegative groups gives maximal stability to intramolecular H bonds. The strong internal H bonding observed in the methadol isomers might be due in part to the fact that they possess the optimal number of carbon atoms between the OH and amine functions.

Nmr Studies.-Additional evidence regarding the relative intramolecular H-bonding strengths of a- and p-methadol in nonpolar solvent was obtained by study- ing the temperature dependence of the hydroxylic proton chemical shift. According to H ~ n e , * ~ the dia- stereomer which is intramolecularly H-bonded more strongly should show the OH proton resonance as being less temperature dependent. The results of our variable temperature study (Figure 1) show that the regression corresponding to p-methadol has a lower slope than that of the a isomer. The lower temperature

(19) I n our preliminary reportab we suggested the presence of (H)O. H-N + bonding. Subsequently, however, the apparent pKa value determined for 3-deoxymethadone indicated this to he no longer tenable.

(20 ) H. Rapaport and 9. h,lasamune. .I. Am. Chem. Soc.. 77. 4330 (1955). (21) A similar observation was reported [.I. BI. DeRoos and 0. .I. Bakker.

(22) A. B. Foster, A. H. Haines, and M. Stacep. I'rtrnhedrorr, 16, 177

(23) J. B . Hyne, Can. J . Chem., 38, 125 (1960).

Kec. ?'Tau. Chim.. 81, 219 (1962) ] with several hydroxyyropylaminee.

(1961).

420 K

I I

O C

80 90 100 110 120

Figrii e 1 .--The tenipeiatiire dependelice of the OH iewiiaii((~ foI 0-methadol (0) and d-methadol ( 0 ) 111 C2C1,.

dependelice ioi the OH rcw>ii:iiice of P-meth:idoI -.ug- gryts tha t it i-. moie trongly H bonded

'I'hc cliiditative di m " c ~ 111 H-bond strength ciiii t i c . 1 atiorialized 111 t c ~ t n + of "chair-lihe" cwiforniiitions 12 :tnd 13 for a- :*rid 3-metliadol. respectively. If " d t - :txial" I'h .\re interaction- are important i r i de-tnbiliziiig 12b :mcl 13a. then 12a :irid 13b \hoiild he the primary coiitrihut 011 to thc rot:tmcric populations. Stu:ti-t I3riegleh model^ r w w l tha t 13b i-. less hindered thLm 12a. sirice' thc !jauc.hc iiiteructiori between the two phenyl rings and thc ethyl group 111 the lnttcr is coii4dcwbly greater than the iirigle gaicc4u iriteractiori betweeii t h e v groups iti the former It might he eupected th:it :i

Ph H

13a 13b

tlouhle i/auOre iiiterxction \vould not simply be double t h t of :I hingle intertiction. hiit greater. -.irice otic phenyl group should influelice the oricntLitiori of the second. . \ Io Iec~~ la i~ model< ~ i 1 ~ iiidic:itc' that :I "di:ixi:il" inter- :ictioit hct\veeii the E t :ind the C-5 proton 111 13b pi~olxthly i < much le- than that found iri cyclohesniic I)cv:iiis- of the flexibility of thc, molecule.

Hcticcl, the more stnble "ch:iir-IiL.e" coriforni:itioii of d-methiidol (13b) should be less hiridered than that of cy-rneth:itlol (12a), and this is consi-.tent with the re- y u l t i oht4itcd froin the proton-exchange studies which indicnterl thc 9 isomer t o be more strongly intra- tiiolecularly H bonded.

In CDC13. the OH protons of a- and B-methadol arc seen a t 8.3 (TYH = 30 cps) and 7.9 ( W , = 23 cp5) ppm, rmpectively. Thr appearance of OH ahsorptioii at iiii-

l l ~ l l ~ l ~ ~ ~ lo\$ field hUggt'St5 thP I)IYSf'Ilc(' O f ~ t l ' O l l S 11

September 1969 STEREOCHEUTSTRY OF ~\IETH;\DOT,~ S43

minor role. This is consistent with the stereochemistry of the active isomethadol antipode (15)27 which also possesses thc (:<S) configuration.?v llor’eover, i t re- cently has been reported that the configuration of the more active rnaritiomer of riormethadol (16) also is (3s) . 2o

It has been suggested previously that the constitution and geometric disposition of an H-bonding group on the analgetic molecule has an important bearing on the antipodal discriminatory power of analgetic recep- tors.’ 30 If the reasonable assumption is made that there are several donor and acceptor H-bonding dipoles situated in different locations on the receptor, the vary- ing stereoselectivities of the analgetic-receptor inter- action can be rationalized on this basis. According to this ~ o n c e p t , ~ the steric course of the drug-receptor interaction mould depend upon the particular receptor dipole involved in H bonding, and this would be a func- tion of the constitution of the H bonding group of the analgetic and also upon the over-all conformation of the molecule. This is illustrated schematically in Figure 2. The great difference in C-6 stereoselectivity between methadone and a-methadol could arise from the possibility of the carbonyl oxygen of methadone acting as a proton acceptor (Figure 2-4) and the OH behaving as a proton donor (Figure 2B). This would lead to different modes of interaction of these molecules with analgetic receptors with the result that the C-G asym- metric centers would be located in different steric environments. In this regard, it appears that the receptor environment in the vicinity of the C-6 center of the more active enantiomers of a- and 8-methadol does not have high steric demands, since the configura- tions of the more active enantiomers are (6s) and (GR), respectively. However, with methadone, the mode of binding is such that the configuration a t the C-G asymmetric center is important.

When a-methadol is acetylated, the receptor stereo- selectivity changes from (6s) to (GR) (Table I). This possibly could be related to the fact that such a conver- sion eliminates the H-bonding donating potential of the C-3 group. Thus, the C-3 function can now act only as a proton acceptor, and this alters the mode of interac- tion (Figure 2C). Since the more active enantiomers of both a- and p-methadol acetates possess opposite con- figurations a t C-3, this asymmetric center no longer appears to be of primary importance. This suggests that the steric environment of the receptor in proximity with the C-3 center of the acetate esters is essentially

(27) E L May and N B CddL, J O r g Chem , IT, 1210 (1952) (28) P S. Portoghese and D 4 iVilliams, Tetrahedron Letters, 6299

(29) i F Cask and &I 21 4 Hassan, J Wed C h e m , 11, 601 (1968) ( X I ) 1’ S Purtogliese and L, L Larson J f’huim 6 c r , 63, m? (l‘t6I)

(1966)

A

B

C

Figure 2.-A schematic illustration rationalizing changes ill

the C-6 and C-3 stereoselectivities of analgetic receptors. Hy- drogen-bonding proton donor (H) and acceptor ((2) dipole- located in different positions on the receptor are believed to plaj an important role in the orientation of the analgetic molecule. ( - )-01-2 (R = H, R’ = ?\.le) and ( - )-p-2 (R = Me, R’ = H ) are represented in illustration B. (+)-01-3 (R = H, R’ = E t ) atid (- 1-p-3 (R = Et, R’ = H) are shown in C.

different and less demanding than the highly stereo- selective force field interacting with C-3 of the more active methadol isomers.

Although we have illustrated only one proton donor and one proton acceptor dipole on the receptor, there may be more than one of each type. For instance, it is conceivable that the C-3 proton acceptor function of two analgetics may be involved in H bonding with diff ererit proton donor dipoles located on the receptors. This would also result in a change in the mode of binding. Examples of this type may occur with methadone, its carbethoxy analog, and the basic anilides. All of these analgetics possess a C=O ; however, their modes of interaction have been analyzed as being different from one another.: 7

I t should be emphasized that all of the changes i n stereoselectivity may also be rationalized on the basis of there being more than one receptor species for analgetic activity.jz7 Two receptor species, (Y and 0, may have different steric demands due to differences in the locations of H-bonding dipoles. If analgetic A were bound preferentially by a receptors and B by @ receptors, then :L difference i l l st ereoselectivity also IVOI 1 Id 1 )e ( )hhe rv f ’ t i.