April 5, 1062
ROTATORY DISPERSION OF EQUATORIAL METHYL GRUCPS
[CONTRIBUTION FROM
THE
1249
DEPARTMENT OF CHEMISTRY O F STANFORD UNIVERSITY, STANFORD, CALIF.]
Optical Rotatory Dispersion Studies. LXIV. Detection of Conformational Changes Caused by Equatorial Methyl Groups2 B Y CARLDJERASSI, E.
LUNDAND A. A. AKHREM'
RECEIVED OCTOBER 28, 1961 By using the molecular amplitude of the Cotton effect of ( +)-3-methylcyclohexanone as a standard value for a n equatorial methyl group p to the carbonyl group in a cyclohexane ring and combining this value with the molecular amplitude of a 3-keto-&-steroid (111) or its bicyclic analog V, a calculated Cotton effect amplitude is obtained which differs considerably from the experimentally observed value for I1 or IV. This difference is ascribed to conformational distortion of the Cyclohexanone ring caused by steric interaction between the newly introduced equatorial methyl group (in I1 or I V ) and a suitably located hydrogen atom (C-11 in 3-keto steroids; peri-hydrogen atom in the decalone) in another ring. Confirmation of these views could be provided by the synthesis of ( - )-3,9-dimethyl-trans-l-decalone (XII), where the equatorial group is not disturbed by any such hydrogen interactions and where the calculated and observed rotatory dispersion amplitudes coincide. A similar observation was also made with the corresponding ( - )-3-t-butyl-9-methyl-trens-l-decalone (XIII).
One of the most important applications of our rotatory dispersion measurements of cycloh e x a n o n e ~has ~ been in the field of conformational analysis, because of the peculiar sensitivity of this method to very subtle conformational alterations. Frequently gross changes (e.g., inversion of sign of Cotton effect) in the rotatory dispersion curve can be used to good advantage, as has for instance been done recently in the assignment of boat-like conformations to ring A of various steroid ketones6 A different rotatory dispersion approach involves the collection of standard values6 of rotatory contributions (in terms of molecular amplitudes) of various substituents (e.,q., halogens, methyl, etc.) to the Cotton effect of a cyclohexanone. Comparison of calculated and observed values can lead to very instructive conclusions, as has been shown recently7 in the recognition of a twist conformation in cis-2-t-butyl-5-methylcyclohexanone.We should now like to record another instance where this rotatory dispersion approach has led to the detection of a subtle conformational change. The rotatory dispersion curve of (+)-3methylcyclohexanone (I) in methanol solution has been measured several times in our laboratory8 and an acceptable average value for the molecular amplitude a (molecular rotation of peak minus molecular rotation of trough divided by 100) is (4-23). This becomes the standard value for the rotatory contribution of an equatorial methyl group /3 to the carbonyl group of a chairg cyclohexane (1) Paper LXIII, C. S. Barnes and C. Djerassi, Chemistry & Indus' t r y , 177 (1962). (2) Supported b y grant No. CRTY-5061 from the National Cancer Institute of the National Institutes of Health, U. S. Public Health Service. (3) Visiting investigator from the N. D. Zelinski Institute of Organic Chemistry, Soviet Academy of Sciences, Moscow, USSR, under the Bronk-Nesmeyanov exchange agreement of the U. S. National Academy of Sciences and the USSR Academy of Sciences. (4) C. Djerassi, "Optical Rotatory Dispersion: Applications t o Organic Chemistry," McGraw-Hill Book Co., Inc., New York, N. Y., 1960, chapters 4-9. (b) Inter al., (a) C. Djerassi, N. Finch, R. C. Cookson and C. W. Bird, J . A m . Chem. Soc., 82, 5488 (1960), (b) F. Sondheimer, Y. Klibansky, Y. M . Y. Haddad, G. H . R . Summers and W. Klyne, J . Chem. Soc., 767 (1961); (c) D. T. Cropp, B. B. Dewhurst and J. S. E. Holker, Chemistry & Industry, 209 (1961). (6) See for instance C. Djerassi and W. Klyne, J . Chcm. SOC.,in press (1962). and references cited therein. (7) C. Djerassi, E. J. Warawa, J. M. Berdahl and E. J. Eisenhraun, J . A m . Chem. Soc., 83, 3334 (19G1). ( 8 ) E.g., C. Djerassi a n d G. W. Krakower, ibid., 81, 237 (1858).
ring. The recent availability'o of 16- and lamethyl-3-keto steroids made possible the experimental measurement of the Cotton effect of such substances and as an example we may cite the molecular amplitude a (+72) for lp-methyldihydrotestosterone acetate (11). In order to obtain a calculated value for the molecular amplitude of 11, all that is necessary is to subtract" (+as), the contribution of an equatorial methyl group (see I ) , from a (+54), which represents the experimentally observed molecular amplitude of the Cotton effect of dihydrotestosterone acetate (111) itself. Provided that such additivity of rotatory contributions is permissible-a point which will be proved below-then the gross divergence between the observed value (+72) and the calculated one (+29) must indicate some type of conformational distortion of ring A in I1 presumably due to the steric interference between the equatorial 16-methyl and the 1la-hydrogen atom. Inspection of Dreiding models12shows immediately that such non-bonded interaction is readily relieved by converting ring A from a perfect chair toward a twist13 conformation. Such an intermediate form would be expectedg to show a strong positive Cotton effect and while it is impossible a t this stage to indicate quantitatively the extent of this conformational change, there is little doubt that its existence is herewith demonstrated for the first time. A second example where this type of analysis seems applicable is ( - ) -4,lO-dimethyl-trans-2decalone (IV)I4 with a negative Cotton effect of molecular amplitude (- 49). The rotatory dispersion curve of the corresponding analog V with(9) This is only an approximation, because in solution probably 1020% of the substance exists in a conformation other than the chair form I. However, for the type of calculations performed a t present, this is satisfactcry (see for instance ref. 7). (10) For starting materials see A. Popper, German Patent 1,023,764 (to Schering, A. GJ, and R. Wiechert and E. Kaspar, Ber., 93, 1710 (1960). We are indebted to Dr. Horst Witzel of Schering, A. G., Berlin for a gift of 11. (11) Subtraction, rather than addition, is required because the lamethyl group lies in a negative octant in the perfect chair conformation of 11; for details of the octant rule, see W. Moffitt, R . B. Woodward, A. Moscowitz, W. Klyne and C. Djerassi, J . A m . Chem. SOC., 8 3 , 4013 (1961). (12) A. Dreiding, Helo. Chim. Acta, 4 2 , 1339 (1959). (13) For definition see W.S. Johnson, V. J. Bauer, J. L. Margrave, hl. A . Frisch, L. H. Drieger and W. N. Hubbard, J . A m . Chem. Soc., 83, 606 (1961). (14) L. H. Zalkow, F. X. Markley and C . Djerassi, ibid., 82, 6354 (1960).
1250
CARL DJERASSI,
E,L U N U A N D A. A . AKHREM
VOl. 84
VI1 and then methylated with diazomethane. l 8 The resulting mixture of enol ethers VI and VII119 was separated readily and the new enol ether VI11 was treated successively with methyllithiumzO and sulfuric acid to afford (+)-3,9-dimethyltrans-AzZ6-hexalone-1 (IX) , the rotatory dispersion curve of which is reproduced in Fig. 1. The ultraviolet, infrared and n.m.r. spectral properties of this a$-unsaturated ketone were fully consistent with the formulation I X and the homogeneity of the liquid ketone was established by gas phase chromatography, thin-layer chromatography*l and preparation of a sharp-melting 2,4-dinitrophenylhydrazone with the expectedz2ultraviolet absorption maximum a t 387 mp. Just as was observed14 earlier with trans-4,lO-dimethyl-A3r6-hexalone-2 (XV), catalytic hydrogenation of IX with a palladium-calcium carbonate catalyst in the presence of alkali reduced only the conjugated double bond of I X to afford ( -)-3,9-dimethyl-trans-A6octalone-1 (XI). This ketone also proved to be homogeneous by the above-mentioned criteria and i t s e e m safe to assume-as had been establishedlJ -. L--1-.--1in the hydrogenation of the isomer XV-that hy330 400 500 600 700 Xlm,u). drogenation occurred from the opposite side of Fig. 1.-Optical rotatory dispersion curves (dioxane solu- the angular methyl group to generate an equation of ( +)-4-methoxy-lO-methyl-tuens- A3v6-hexalone-3 torially oriented C-3 methyl group. Complete ( V I I I ) , ( +)-3,9-dimethyl-lrans-A~~~-hexaloiie-l (IX) and hydrogenation of the isolated double bond in the octalone X I was effected with palladized charcoal ( + )-3-t-b~ty1-9-methyl-lrans-A~~~-hexalone-l (X). catalyst giving the desired (- ) -3,9-dimethylout the equatorial methyl group had been deter- trans-1-decalone (XII). Its negative Cotton effect mined earlier15 in dioxane solution and repeat (methanol solution) was characterized by a measurements in methanol now gave a (-51). molecular amplitude of a ( - 32), while trans-9Introduction of the extra equatorial methyl group methyl-1-decalone (XIV) exhibited a (-27) . z 3 ( a = 25) into a positive octant leads to a predicted Addition of (- 2 5 ) , the rotatory contribution of amplitude (-26) for the ketone IV, which again the equatorial methyl group (see I) in a negative differs from the observed one (-42), although the octant, leads to a predicted amplitude (-52) discrepancy is not as large as in the steroid 11. for XIV, which is in exact agreement with the We believe that the simplest explanation for this experimentally observed one. These results condifference is to assume a deformation from the firm the validity of our earlier discussed conclusions ideal all-chair conformation, most likely caused by and support the assumption that an equatorial the equatorial hydrogen atom situated in the per; methyl group in the C-3 position of a trans-lposition a t C-5, although possible interference with decalone is not subject to any steric interaction. some of the hydrogens of the angular methyl group Alternatively, one can state that the difference between the molecular amplitudes of XI1 and XIV cannot be excluded a t this time. If discrepancies between observed and calculated offers another means of arriving a t the standard rotatory dispersion amplitudes are to be used as value of (23) for the rotatory contribution of an criteria of conformational alterations, then i t is equatorial methyl group located @ to the ketone necessary to demonstrate good agreement between function in a cyclohexane chair. these values in a substance where no conformaThe above reaction sequence opened the way tionally disturbing factors enter into play. For to determine the effect of a very bulky substituent, this purpose, we have selected 3,9-dimethyl- the t-butyl moiety, and for that purpose the trans-1-decalone (XII), where the equatorial methyl enol ether VI11 was treated with t-butylmagnesium group in the C-3 position should be completely chloride followed by acid cleavage to yield (+)-34undisturbed, and its synthesis is described below. (18) See C. T a m m , Helv. Chim.A c t o , 43, 1700 (1960), for the diazoSince optically active material was required, methane methylation of cholestane-1,3-dione. we started with the ( +)-antipodeI6 of 3-methoxy-9(19) T h e rotatory dispersion curves of the two isomeric enol ethers ~~iethyl-trans-~?~~-hexalone-l (VI) l7 of knownI6 proved t o be very distinct; see Fig. 1 of present paper (R. D. curve of absolute configuration. This was cleaved with \-I11 in dioxane) and Fig. 5 in C. Djerassi, R . Riniker and B. Riniker, A m . Chc?n.Soc., 7 8 , 6377 (1956). sulfuric acid to the previously describedI6 diketone J.(20) A similar conversion of the enol ether VI to X V has already been -I_
1
I
(15) C . Djerassi, R. Riniker and R . Riniker, J. A m . Circm. SOL.,7 8 , ti382 (1966). (18) A . J . Speziale, J. A. Stephens and Q. E. Thompson, J . A m . C ' h e ~ n .Soc., 76, 5011 (1954). We are deeply indebted t o Dr. 'Xilliam S. Knowles of the Monsanto Chemical Co. for a generous gift of this material. (17) R . B. Woodward, F. Sondheimer, D. T a u b , K. Heusler and U'. 11. WcLamore, J . A i n . C h e m . S o c . , 74, 4223 (1952).
reported in an earlier paper from this Laboratory (ref 14) in connection with synthetic work in the eremophilone series. (21) T h e isomeric enol ethers V I and VI11 as well as IX and its position isomer XV (ref. 14) are readily separable on silica gel plates with the system hexane (or benzene)-lO% ethyl acetate. (22) C. Djerassi and E. Ryan, J . A m . Chem. SOC.,'71, 1000 (1949). (23) This value is based on new measurements conducted in methanol solution since the earlier data (ref. 15) pertained to dioxane.
April 5, 1962
ROTATORY DISPERSION OF EQUATORIAL METHYL GROUPS
butyl-9-methyl-trans-Az~6-hexalone-l (X).24
1251
Experimentalz6
Hy-
drogenation of both double bonds was achieved ( +)-4-Methoxy-lO-rnethyl-tr~ns-A~~~-hexalone-3 (VIII) .with palladized charcoal catalyst leading to the A mixture of 11.6 g. of the enol ether V116 (m.p. 91-93', [ a ]+58.6"), ~ 6.7 cc. of sulfuric acid, 42 cc. of water and required ( - ) -3-t-butyl-9-methyl-trans-1-decalone 57 cc. of dioxane was permitted to stand a t room tempera(XIII) with a negative Cotton effect (a = -66). ture overnight and was then processed as described16 Since the rotatory dispersion curve of (+)-34- for its antipode. The resulting diketone VI1 (yield 9.2 ~ in methanol) was suspended butylcyclohexanone (XVI) has already been meas- g., m.p. 184-189', [ a ]$151' red^^ in methanol solution, its U-value (37) need in 100 cc. of ether and stirred overnight a t room temperature a solution of 4 g. of distilled diazomethane in 200 cc. only be added to that ( - 2 7 ) of trans-9-methyl-l- with of ether. Evaporation of the solvent in uacuo and crystaldecalone (XIV) to arrive a t a calculated molecular lization of the residue from petroleum ether (b.p. 60-68") afforded 2.9 g. of the enol ether VI, m.p. 91-94'. Evapoamplitude of (-64) for (-)-3-t-butyl-9-methyltrans-1-decalone (XIII), which is in very reason- ration of the filtrate left 6.9 g. of yellow oil, which was chromatographed on 900 g. of Merck neutral alumina (acable agreement with the observed one (-66). tivity 1-11), the composition of the eluates being monitored I t follows, therefore, that there does not seem to by thin-layer chromatography,21 VI being more mobile exist any conformational distortion in the decalone than VIII. Elution was accomplished with benzene conX I I I , a conclusion which was not necessarily taining 16% of ether. The first fractions provided an 1.8 g. of the enol ether V I (m.p. 91-94'), while self-evident because of possible interaction between additional the later eluates gave 4.0 g. of the desired enol ether VI11 one of the t-butyl methyl groups and the axial as a yellowish thick oil. Distillation a t 160" (0.5 mm.) afforded a distillate which crystallized immediately, m.p. hydrogen atoms a t positions 2 and 4.
c:
0
I
b *
1
C H,>
XVI
I
OAc
8. . H.
II,R=CH, III,R=H
IV, R - CHI V,R=H
0
VI1 I
c I
J.
.
a
CH30 0
O
H
xv
49-50',
[ a ] 3 O+313" ~
249 mp, log
e
4.17,
(c 5.0 in chloroform);
XEf:3 '
6.10 and 6.28
p,
R.Db(c 0.11 in dioxane)
reproduced in Fig. 1: [a1569 $290 , [ a 1 3 3 2 $2980D, [alzss f33g0, [a1270 f2940". The n.m.r. spectrum (deuteriochloroform) showed signalP a t 1.12 (angular methyl group), 3.70 (methoxyl), 5.30 (C-3 hydrogen) and 5 . i O p.p.m. (C-6 and C-7 hydrogens). Anal. Calcd. for C12H1602: C, 74.97; H , 8.39; 0, 16.65; OCHa, 16.12. Found: C, 74.87; H, 8.22; 0, 16.70; OCHz, 15.82. ( +)-3,9-Dimethyl-tran~-Az~~-hexalone-l (IX).28--h solution of the enol ether VI11 in 6 cc. of anhydrous ether was added slowly in an atmosphere of nitrogen to methyllithium prepared from 0.16 g. of lithium, 1.3 cc. of methyl iodide and 6 cc. of ether. After stirring a t room temperature for 20 hr., the mixture was poured into ice-water, extracted with ether and the solvent evaporated. The oily residue, dissolved in 20 cc. of dioxane, 12 cc. of water and 2.2 cc. of sulfuric acid, was stirred for 3 hr. a t room temperature, the product was isolated with ether and purified by chromatography on 10 g. of neutral alumina (activity 11). Elution with benzene and distillation a t a bath temperature of 110-130" (0.1 mm.) furnished 0.30 g. of hexalone IX as a colorless oil, which gave a single peak on gas phase chromatography a t 190" using a 15yo phenyldiethanolamine succinate on Chromosorb column; thinlayer chromatography on silica gelz1 showed a single spot with I Z t 0.4. The ketone exhibited 234 mp, log E 4.11, X$F3:' 6.05 p, (strong peaks a t 7.60, 9.05, 9.90 and 11.85 p serve to distinguish it from the isomer X Y ) and its R.D. curve i c 0.14 in dioxane) is shown in Fig. 1: i a l ; ~ ~
H
VI11
b H
XIV
.b H
SI (24) The rotatory dispersion curve of X closely resembles that of its lower homolog IX as illustrated in Fig. 1 . (2.7) C. Djerassi, E. Warawa, K. E. TYolff and E. J Eisenhraiin, J . O r p . CheJJI,, 25, 917 (1960).
contained signalsz7 a t 1.00 (angular methyl group), 1.95 (methyl group attached to double bond), 5.63 (C-6 and C-iprotons) and 5.80p.p.m. (C-2 proton). Anal. Calcd. for C12H160: C, 81.77; H , 9.15. Found: C, 81.38; H, 9.18. The red 2,4-dinitrophenylhydrazone of IX was recrystallized from ethanol, whereupon it showed m.p. 186187', X:yF13 387 mp, log 64.45. Anal. Calcd. for Cl&oT\T404: C, 60.66; H , 5.66; S , 15.72. Found: C, 60.62; H, 5.77; N, 15.96. ( - )-3,9-Dimethyl-trans-A~-octalone-l (XI).-A 210-mg. sample of the above hexalone IX was hydrogenated with (26) All melting points were determined on the Kofler block. We are indebted to h h . R u t h Records for the rotatory dispersion measurements, t o Dr. Lois Durham for the n.m.r. spectra and to Mr. E. Meier for the microanalyses. (27) Reported in p.p.m. as 8-values (c.P.s. (relative to tetramethylsilane)/60); see C. Djerassi, T.Nakano, A. S. James, L. H. Zalkoiv, E. J. Eisenbraun and J. N. Shoolery, J . O i g . Chem., 16, 1192 (1961). (28) Attempts to synthesize this ketone by 1,4-addition of methylmagnesium iodide (in the presence of cuprous chloride) to the enol ether V I were abortive, the products being unreacted V I , c l e a v a j e i,r
