4590
CORlhlUNlC.%TIONST O
THE
EDITOR
Vol. 84
set of data is found, yielding kl = 21.5 M-l, indicated the multicomponent nature of the alkakz = 0.24 and k3 = 0.033 set.-' a t p 1.0 and pH loid extract.1,3--6 Evidence is presented herewith 8.7. These data yield the calculated solid line for assignment of structure I to an alkaloid isolated in Fig. 1, in good agreement with experiment.’ from the acetone-insoluble portion of the strong The calculated and experimental curves for the base fraction, for which we propose the name other data are in reasonable agreement. cyclobuxi?ae.’ Cyclobuxine represents a novel type On the basis of the above evidence mechanism of steroidal alkaloid; i t appears to be the first ( 3 ) for the rnorpholine catalysis can be p o s t ~ l a t e d . ~recognized ~~ to contain a cyclopropane ring and thc first with a substitution pattern a t C-4 and C-14 which is intermediate in the biogenetic scheme, between lanosterol- and cholesterol-type steroids. Cyclobuxine (I), C25H420NZ, m.p. 245-247’ dec., 9S0,’shows Amax 6.00, 11.20 p* (terminal methylene) and n.m.r. peaksY 5.20 and 5.43 (2H, doublets, J < 1 c./s.; terminal inethylene), 5.92 (lH, octuplet, J’s 3, 7 , 9.5 c./s.; CHICHOH-CH), 7.53 and 7.57 (6H, two XCHa), 8.87 and 9.03 (6H, two tertiary CH3);8.92 (3H, doublet, J 6 c./s.; one sec. CH,,) and 9.12 arLd9.95 11 Ii 7 (2H, doublets, J 4 c./s. ; cyclopropyl methylene). Cyclobuxine was converted to several crystalline derivatives: e.g., the diliydrobromide, CZHW ON2Br2, m.p. 288-292’ dec. ; the N.N‘-diniethyl derivative,, CZiH460N2, 1n.p.20-1-205O dec., [cy]% f 99O, n.m.r. peaks a t 5.07, 5,3S, 5.98, 8.87, 9.03, The morpholine catalysis (like the hydroxide ion 9.72, 9.97 (as for cyclobuxine), 5.60 (lH,OH), catalysis) is, on this basis, an example of nucleo- 7.68 and 7.77 ( U H , two x(CH3)Z) and 9.13 r philic catalysis of ester hydrolysis in which the (3H, doublet, J 6.5 c./s.; sec. CH, near N(CH3)d; nucleophile does not react directly with the ester the N,N’-dimethyl-O-a~etate,~C ~ ~ H ~ ~ O Z mN . pZ , linkage to form an unstable intermediate (the usual 173-175’, [ c y ] ? B 69’, A,, 5.81 p , n.m.r. peaks type of nucleophilic catalysis) but rather reacts a t 4.95 (lH, octuplet; CH2-CHOXc--CII), 8.03 with a neighboring group to form an unstable (3H, CH3COO-) ; the triacetate, C ~ I H ~ B O ~ N ~ , intermediate which leads eventually to the hydro- m.p. 256-258’ dec., [ a I z 4 ~- 12’, Amax 5.7% lytic products and the regeneration of the catalyst. 6.14, 11.08,u; the dihydro derivative, C ~ ~ H M O X ~ , -4 similar example in the hydrolysis of a keto-sub- m.p. 208-209’, [ ~ t ] * ~ ~4Bo, , infrared showed 110 stituted phosphoric acid ester is consistent with bands a t 6.08 or 11.20 p , r1.m.r. peaks a t 9.22 1311, this interpretation.10 doublet, J 7 c./s.; new sec. CH,$),9.43 anti 0.73 r (2H, cyclopropyl methylene). (7) T h e theoretical curve was calculated using an Applied Dynamics AD-232PB analog computer by Dr. Kenneth A. Connors of the School The gross skeletal structure was indicated hy the of Pharmacy, University of Wisconsin. I t is assumed in this comstructures suggested for the products of selenium putation t h a t the intermediate has an extinction coe5cient a t 290 mp dehydrogenation : an S-methyl-1,kyclopentenoof approximately two-thirds t h a t of the reactant. phenanthrene (11),C21H2~, n1.p. 145-147’, trinitro(8) T h e constant kl is increased and k: is decreased by increasing p , as predicted b y eq. 3. benzene complex, C27H250,&3, m.p. 165-168’; the (9) Compound I 1 1 is analogous to an intermediate in Schiff base corresponding 5-methyl- 1,2-cyclopentenoant11raformation: E. H. Cordes and W. P. Jencks, J. Am. Chcm. Sac., 84, 832 cene (111), C21HZ2, m.p. 110-112’, trinitrobenzene (1962). complex, C2iH2506N3, m.p. 16s-169’; and two (10) F. Ramirea, B. Hansen and N. B. Dcsai, ibid,. 84, 4588 (1962). (11) Alfred P. Sloan Foundation Research Fellow. naphthalenes, IV, C21H28, m.p. 134-135’, trinitro(12) National Science Foundation Postdoctoral Fellow on leave from benzene complex, C2?H31O6N3, m.p. 143-143° ; and Amherst College. V, C22H28, m.p. 111-117’, trinit,robenzene complex, (13) The authors acknowledge the assistance of Drs. F. 1. Kezdy C28H310&r3, m.p. 139-141 ’. The hydrocarbons and G. E. Clement d t h the morpholine kinetics. were characterized by analysis, infrared, ultraviolet, DEPARTMENT OF CHEMISTRY
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SORTHWESTERN UNIVERSITY MYRONL. BENDER^^ EVANSTON, ILLINOIS MARCS. SILVER^**^^ RECEIVED OCTOBER 6, 1962
THE STRUCTURE OF CYCLOBUXINE
Sir : The medicinal properties of Buxus sempervirens L. have been known since ancient times; extracts of the plant have been used in the treatment of a wide variety of diseases, including malaria and venereal disease. * More recently, an alkaloidal extract of the plant has been reported to possess antitubercular properties. Earlier studies have (1) E. Schlittler, E. Heusler and W. Friedrich, Hclw. Chim. Adas 31, 2209 (1949).
(2) L. E. Weller, C. T.Redemann, R. Y.Gottsball, J. hl. Roberts, E. H. Lucas, and H. M. Sell, Anlibiolics and Chemolheiapy. 3, 603 (1953); Merck 8r Co., Inc., British Patent 782,469 (1957). (3) K. Heusler and E. Schlittler, Helu. Cliim. Acla, 32, 2226 (1949). (4) W. Friedrich and E. Schlittler, i h i d . , 33, 873 (1950). (5) E. Schlittler and W. Friedrich, ibid., 3 3 , 878 (1950). (6) K. S. Brown, Jr., and S. hi. Kupchan, J. Chromulogtuphy, 9, 71 (1962). (7) Cyclobuxine is “111,” t h e alkaloid of Rf0.76 in Fig. 2 uf reference 6. It is most probably the same as “Alkaloid A” of reference 3; although no comparison sample of “A” is available, the phy5ical CUDstants of cyclobuxine and its derivatives correspond clusely tu those of “A” and the respective derivatives. (8) All rotations and infrared spectra are in chloroform. (9) All n.m.r. spectra were determined on a Varian Associates recording spectrometer (A-60) a t 60 hlc. in deuterated chloroform or carbon tetrachloride. Chemical shifts are reported in 7 values (p.p.m.) [G. V. D. Tiers, J. Phys. C h e m . , 62, 1151 (1958)l. We thank Mr. Roy Matsuo and Mr. Arnold Kruhsack for these determinations.
COMMUNICATIONS TO THE EDITOR
Dec. 5, 1962 yNHCH3
I
j'"*
I1
I
IV
I11 -1
459 1
(3H), 9.0s (3H), 9.21 (3H, doublet, J 7 c./s.), and 9.33 and 9.69 7 (2H)14; dihydro-X-benzoyl derivativc, CslII&N, n1.p. W0---52Xo. The ketones still gave positive Zimmermann tests. Hofmann degradation of N,N'-dimethylcyclobuxine monomethiodide, a C~H490N21,m.p. 224227' dec., yielded N,N'-dimethylcyclobuxine (1020%) and VI13 (70%), CZ6HIsON,m.p. 169-170', [CY]'%170'; Xma, 3.00, 6.10, 6.25, 11.15, 11.30 p; 229.5 mp ( E 16,600), shoulders a t 225, 23s mp; n.m.r. peaks a t 3.60-4.60 (2H, complex splitting; vinyl protons), 5.34 (2H, terminal methylene), 6.06 ( l H , octuplet; CHOH), G.8U ( l H , OH), 7.73 (GH, iX(CH,)z), 8.87, 9.03, 9.14 (9H, 3 CH3, as in N,N'-dimethylcyclobuxine), 9.72 and 9.90 r (2H, doublets, J 4 c./s.; cyclopropyl methylene) ; 0-monoacetate, Xmax 5.80 p ; tetrahydro d e r i v a t i ~ e ,C26H430N1 ~ m.p. 161-164', [ a ] z % 36'. VI1 showed no tendency to aromatize upon chloranil dehydrogenation. Base treatment of the ozonolysis product of cyclobuxine12 (dihydrochloride, C24H4002N2.2HCI. HzO, dec. > 225') yielded VIII, a diosphenol showing additional conjugation, Xmax 2.91 (strong), 6.04, 6.18 p ; A"!, 296.5 mp ( E 9,000), Xk!xNsaoH 343.5 mp ( E 6,500) ; triacetate, C Z ~ H ~ I Om.p. ~N, 245-250' dec., Xmax 5.67, 5.78, 5.97, 6.14 p i 277 mp ( E 12,600). The corresponding diosphenol from decyclized cyclobuxine showed Xmax 2.91, 6.00 p; 1 %:" 277 mp (base, 322 mp); triacetate, Xmax 5.68, 5.78, 5.96, 6 . 1 3 X ~E;"~ 247mp ( E 12,500).15~16*17
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m
0
VII
OH VI11
and n.m.r. spectra. Dehydrogenation of decyclized material (in which the cyclopropane had been opened in the usual manner) gave only phenanthrene-related products. Ozonolysis of N, N'-diacyl derivativesIO gave aacylamino-ketones which had lost one carbon atom and which gave negative Zimmermann tests. l 1 Decyclization of cyclobuxine and various derivatives with hydrogen chloride in chloroform gave mixtures showing n.m.r. peaks for a new tertiary methyl group and a new vinyl hydrogen; the new double bonds resisted hydrogenation. Chromic acid or manganese dioxide oxidation of N,N'diacyl derivatives of dihydrocyclobuxine gave cyclopentanones (Amax 5-78 p ) showing positive Zimmermann tests. It was not possible to move the double bonds produced by decyclization into conjugation with the keto-groups produced by manganese dioxide oxidation. The oxidation product of dihydrocyclobuxine12 (N,N'-dibenzoyl derivative, C39H6001N2tm.p. 281-283' dec., 53') rapidly eliminated methylamine in basic solution to give two cisoid cyclopentenones (VIa and VIb): Xmax 5.85, 6.09 p ; A%:" 244 mp ( E 7,700); n.1n.r. peaks for cis13 isomer, VIa, m.p. 149-152', 3.53 ( l H , quadruplet, J 7.5 c./s.; vinyl proton coupled with CH3), 7.60 (3H, NCHs), 8.19 (3H, doublet, J 7.5 c./s.; vinyl CHI), 8.68, 9.05 (6H, 2 tertiary CH3),9.19 (3H, doublet, J 7 c./s. ; secondary CHa), and 9.34 and 9.67 7 (2H, cyclopropyl methylene); n.m.r. peaks for trans isomer, VIb, rn.p. 134-137', 4.35 ( l H , quadruplet, J 7 c./s.), 7.62 (3H), 7.92 (3H, doub!et, J 7 c./s.), 8.77 (10) Non-acylated derivatives were not attacked by ozone or peracid, indicating the close proximity of an amino function to the double bond. (11) W. Zimmermann, Z . phrsiol. Chcm.. 300, 141 (1955). (12) Obtained via the N,N'-di-p-nitrobenzylcarbamate. (13) Cf.L. F. Fieser and M. Fieser, E x p c r i c n l b , 4, 215 (1948).
(14) The conf~gurationsof VIa and VIb were assigned on the basis of the n.m.r. spectra; cf. L. M. Jackman and R. H. Wiley, 3. Chcm. Sac., 2881 (1960). 278 mp; (15) Cf.the analogous diosphenol from cholesterol, acetate, XZ2' 247 ma (L. F. Fieser and R . Stevenson, J . A m . Chem. Soc., 76, 1728 (1954)), and t h a t from cevagenine, 278 ma (base. 320 ma) (E. Sundt, 0. Jeger and V. Prelog, Chem. mrd I n d . , 1365 (1053). (16) Satisfactory analyses have been obtained for products with
cited empirical formulas. We thank Mr. Joseph Alicino, Metuchen, N. J., for the analyses. (17) We gratefully acknowledge the kind assistance of the Ciba Pharmaceutical Company in procurement and large-scale extraction of plant material, and thank especially Drs. Emil Schlittler, Daniel Dickel and Karl Heusler for their kind interest and co-operation. The investigation was supported in part by research grants from the National Institutes of Health (H-2952 and CY-4500). (18) Cooperative National Science Foundation Predoctoral Fellow in Chemistry, 1960-1962.
DEPARTMENT OF PHARMACEUTICAL CHEUISTRY KEITHS. BROWN, J R . ~ ~ UNIVERSITY OF WISCONSIN S. MORRISKUPCHAN MADISON 6, WISCONSIN RECEIVED OCTOBER 26, 1962 r-ALLYL-IRON TRICARBONYL CATIONS
Sir : We wish to report the preparation of a new series of stable salts of n-allyl-iron tricarbonyl cations. The allyl group previously has been found to function as a ?r-type ligand in complexes of Mn, Co, Nil and Pd,l also in the covalent molecule methylallyl-chloro-iron tricarbonylz and in the per(1) W. R.McClellan, H. H. Hoehn, H. N. Cripps. E. L. Muetterties and B. W. Howk, J . A m . Chcm. Soc., 83, l G O l (1961); R. F. Heck and D. S. Breslow, ibid.. 83, 1097 (1961); J. M. Rowe, Proc. Chent. SOL., 66 (1962); G. Wilke and B. Bogdanovic, Angcw. Chcm., 73,756 (1961). and references contained therein. (2) F. J. Impastato and K. G. Ihrman, J . A m Clirm. SOC., 83, 3726 (1961).
