The Structure, Configuration and Synthesis of Thalicarpine, a Novel

APORPHINE-BENZYLISOQUINOLINE ALKALOID1. Sir: Thalicarpine is a hypotensive alkaloid from Thalic- trum dasycarpum Fisch. and Fall, and its isolation ...
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1Iay 3 , 1963

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reversion in the presence of maleic a n h ~ d r i d e - 2 ~ 3 - C ~and ~ ; n.m.r. peaks4 7.55, 7.52 (6H, two NCH3), 6.40, (3.29, 6.21, 6.19, 6.17, 6.09, 6.05 (21H, seven OCH3,, and ( 2 ) by determining an approximate equil. brium 3.79, 3.47, 3.40, 3.37, 3.32, 1.77 r ( i H , aromatic;. constant [K = 1.7 If = (maleic anhyd ide)(2Hofmann degradation2 yielded a methine which was methylfuran)/(adduct) ] from the intc grated n.m.r. characterized as the dimethiodide, C ~ ~ H & E N ~ ~ Z . H ~ O , spectra of reactants and product in CC14. Column 4 of m.p. 275-276". A second Hofmann degradation Table I1 gives the % remaining adduct :esulti g from yielded the des-N-rnethine,2 C39H3808, m.p. 1'70-172". readdition as calculated from the equilibrium c nstant. Sodi im in liquid ammonia reduction of I a f f x 12 1 Column 6, alternatively, gives the yo reformel adduct (-)XI -hydroxylaudanosine (11) and (+)-3,G-5 neth as determined by C14-incorporation, Here, one asoxyapirphine (111), both in amorphous form. I1 was sumes that return only occurs during vvork up (;.e., chara-terized as the hydriodide, C21H2705N.HI.H20, concentration after decomposition has been quenched). -71" (methanol), and the 0m.p. 184-186', The specific activity of added maleic anhydride-c'? methylmethiodide, C Z ~ H ~ Z O Sm.p. N I , 223-224", [ C X ] , ~ ~ D decreases as adduct-decomposition prc gresses There109". Hofmann degradation of the methiodide fore return of a maleic anhydride-C14-molecule after gave a methyl methine (IVa), C;3H3lOjN, m.p. 12580% reaction is accompanied with more return of 127", [c\1I2*Df O o , 282 mp ( E 19,000), 343 mp (E 30,50:)), natural anhydride than one returning after 30y0 reacmass spectral peaks at m/e 401, m/e 58.5 To locate tion. Hence the figures in column 6, Table 11,represent the phenolic hydroxyl group, I1 was converted to the the maximum possible return; the true dezree of re0-ethylethiodide, which upon Hofmanii degradation versibility is somewhere between the values given in yielded IVb, C Z ~ H ~ ~ O m.p. ~ N 88-89', , columns 4 and 6. Since there was no ini ial maleic [ c x ] ~ ' D =too; anhydride present, the amount of return, in the runs of Amax 290 mp ( e 12,000), 336 mp ( E 12,600). The Table I, is less than the figures of Table 11. methiodide of IVb (C&3805NI, m.p. 201-202") was For a two-step adduct-decomposition, kv/kIv was treated with methanolic alkali t o yield the des-Nmethine, C22H26051 m.p. 129-130'. Oxidation of the assumed t o be 1.15. One might expect the reciprocal, 0.87, for the isotope effect of the reverse reaction. des-N-methine with potassium permanganate gave 2The ratio, [IV]/ [VI, from return should be independent ethoxy-4,5-dimethoxybenzoic acid.6 of extent of return and equal t o 1.15. If 15% of the 111was characterized as the methiodide,' CzoH2402N1, isolated adduct comes via return then the observed D (methanol), and the Hofm.p. 164-16G0, [ c x ] ~ ~4-66' effect would have led t o O . l 5 [ ( I V / V ) r e t u r n e d = 1.151 0.85 [ ( I V / V ) u n r e a c t e d L 2 1.31 = 1.28. Therefore, the C H 3H,' -NT:Ei: ::1:V;CH3 small amount of adduct that comes from readdition during decomposition of the adduct does not affect the conclusion that both a and b are breaking simultaneously in the slow step. From the principle of / / OCH3 CH3O microscopic reversibility, the formation of this DielsOCH3 Alder adduct involves forming bonds a and b simulI t aneousl y .E Acknowledgment.-We acknowledge, with appreciation, the discussions with and help given by Dr. Gerald Dudek, Harvard University, in the n.m.r. studies.

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(8) For a discussion of this problem see: A. Wasserman, J. Chem. SOL., GI2 (1912); C. Walling and J. Peisach, J . A m . Chem. SOL.,80, 5819 (1958); R . B. Woodward and T. J. Katz, Tetrahedron, 6, 70 (1959); J. A. Berson, A . Remanick and W. A. Mueller, J. A m . ChemSoc., 82, 5501 (1960); J. A. Berson and W. A . Mueller, ibid., 83, 1940 (19611, 83, 4947 (1961); M. S. Newman, J . Org. C h e w . , 26, 2030 (1901); M. G. Ettlinger and E. S. Lewis, 7'rxas J . Sci . , 14, 58 (1902); J. Sauer, D. Lang and A. Mielert, Angew. Chem. I w l e n z . E d . E d . , 1, 268 (1962); R . P. Lutz and J , D. Roberts, J . A m . Chem. Soc., 83, 2198 (1961).

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CHEMISTRY DEPARTMENT STANLEY SELTZER BROOKHAVEN SATIONAL LABORATORY VPTON,LOSC ISLASD,NEW YORK RECEIVED JASUARY 17, 1963

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THE STRUCTURE, CONFIGURATION AND SYNTHESIS OF THALICARPINE, A NOVEL DIMERIC APORPHINE-BENZYLISOQUINOLINE ALKALOID'

OCH3

Sir: Thalicarpine is a hypotensive alkaloid from Thalictrum dasycarpum Fisch. and Lall, and its isolation and preliminary characterization have recently been reported.? The elucidation of structure and absolute configuration I and the total synthesis of thalicarpine are reported herewith. Thalicarpine represents a novel type of alkaloid; i t appears to be the first recognized dimeric alkaloid which contains an aporphine moiety, Thalicarpine (I)>C41H4808N~, m.p. 160-161", [ a I z 5 ~ +S9°,3 shows Xmax 282 mp ( E 17,000), 302 mp ( E 13,000) ( 1 ) This is part I 1 of a series entitled "Thalictrum Alkaloids"; part I is ref. 2. ( 2 ) S. M Kupchan, K . K . Chakravarti and S . Yokoyama, J. Pharm. Sci., in press. ( 3 ) Rotations and infrared spectra are in chloroform unless otherwise noted. All ultraviolet spectra are in methanol.

OCH3

V (4) N.m.r. spectra were determined on a Varian Associates recording spectrometer (A-60) a t 60 Mc. in deuterated chloroform. Chemical shifts are reported in r values (p.p.m.) [G. V. D . Tiers, J . P h y s . Chem., 62, 1161 (1958) 1. ( 5 ) We thank Professor K. Biemann and D r . B . C. Das, Massachusetts Institute of Technology, for t h e mass spectral d a t a . ( 6 ) J. B. D . Mackenzie and A. Robertson, J . Chem. Soc., 497 (1949). We thank Professor W. B.Whalley, School of Pharmacy, University of London, for an authentic sample of Z-ethoxy-4,5-dimethoxybenzoicacid. ( 7 ) '1'. Kitamura, J . Pharm. SOL.Japan, 80, 1104 (1960).

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mann m e t h i r ~ e ,C20H2302Nj ~ m.p. 102-103", mass spectral peaks a t m/e 309, mle 251, m/e 58. Positive identification was achieved via the hydriodide, C19H210sN.HI,m.p. 238-240°, which was directly compared with 3,G-dimethoxyaporphine hydriodide prepared from an authentic sample of (+)-3-hydroxy-6metho~yaporphine.~,~ Synthesis of thalicarpine was accomplished by modified Ullmann condensation of (-)-6'-bromolaudanosine (V) with isocorydine (VI).Io Since practical total syntheses of laudanosine" and of isocorydine12 had previously been accomplished, the condensation reaction constituted a total synthesis 'of thalicarpine. Furthermore, since the absolute configurations of ( - ) l a ~ d a n o s i n e 'and ~ of i s ~ c o r y d i n e ' ~ had - ~ ~ been elucidated earlier, the synthesis served also to establish the absolute configuration of thalicarpine. 17,l8

recrystallization from methanol and sublimation a t reduced pressure. The molecular formula of tetrahymanol was established unambiguously as C30H520 by mass spectral studies7 of the parent alcohol and also of its derivatives, tetrahymanyl acetate, m.p. 303-305" (ilnal. Calcd. for C32H5402: C, 81.64; H, 11.56. Found: C, 81.66, 81.43; H, 11.46, 11.27)) and tetrahymanone,a m.p. 289-290' (Anal. Calcd. for C30H600 : C, 84.44; H, 11.81. Found: C, 84.39, 84.25; H, 11.83, 11.62). The GO-hlc. proton n.m.r. spectrag of tetrahymanol and tetrahymanyl acetate each show four sharp peaks characteristic of triterpenoid methyl groups'" a t 7 > 9.03 with area corresponding to eight methyls (tetrahymanol: 46, 49, 51 and 58 C.P.S. with relative areas 1: 3 : 1:3 ; tetrahymanyl acetate: 47.5, 49, 50.5 and 58 C.P.S. with relative areas 1: 1 : 4 : 2 ) . The methyl peaks in the 100-Mc. spectrumg of the acetate are observed ( 8 ) We thank Professor XI. Tomita, Kyoto University, for a n authentic a t 79, 81.5, 84 and 96.5 c.P.s.; the increase by the facsample uf .'~-hydr~ixy-0-methoxyaporphine hydrochloride. tor 100/60 in all these peak separations in the 100-Mc. (9) T h e hydrogennlysis of t h e methoxy group a t C-5 of the aporphine residue of thalicarpine finds clnse analogy in a similar cleavage of O-methylspectrum compared with those in the 60-Mc. spectrum domesticine described in ref. 7 . indicates the absence of strong spin-spin coupling of ( I O ) We thank I l r . R . H. 1'. XIanske, Dominion Ruhber C o . I,td., Guelph, any methyl protons with other protons in the molecule Ontario, for a generous gift of isocorydine. (11) A . Pictet and S I . Finkelstein, B e y . , 42, 1979 (1909). and thus demonstrates that no methyl group is at( 1 2 ) I . Kikkawa, J . P h a i i n . SOL.Japaiz, 78, 1000 (1958). tached to a carbon which also bears a hydrogen. Of ( 1 3 ) I1 C(irrodi and E . Hardegger, Hela. Chilit. Acta, 39, 880 ( I M > ( i ) . the various triterpenoid skeletons known to occur ( 1 4 ) I