STUDIESIN
JUNE,1964
THE
1299
SYNTHESIS OF ATISINE
Studies in the Synthesis of Atisine. Terpenes. X L. H. ZALKOWAND N. N. GIROTRA Department of Chemistry, Oklahoma Slate University, Stillwater, Oklahoma Received December 19, 1963 The carbon skeleton of atisine, a diterpenoid alkaloid, has been synthesized from maleopimaric acid. The latter compound has been prepared from abietic acid, which has been totally synthesized. The compound synthesized is enantiomeric with the isoprenoid portion of the naturally occurring alkaloid.
The synthesis of the diterpenoid alkaloid, atisine (I), has provided a challenge for many workers all over the world. During the past year approximately a dozen
I
publicationsl-ll have appeared dealing with various aspects of the synthesis of this interesting compound ; Japanese workers2 have recently reported the first total synthesis of the alkaloid in its racemic form. The problem involves two distinct phases. One, synthesis of the nitrogen-containing E ring and its subsequent conversion to the oxazolidine F ring, and second, construction of the C-D bicyclo [2.2.2]octane ring system with means of introducing the desired substituents a t C-15 and C-16. A number of ingenuous methods have been utilized in the synthetic approaches to the nitrogen-containing E ring, involving classical reactions2~10~11 and the more modern method of phoa number of pathways have been t o l y s i ~ . ~Likewise, ,~ offered for the synthesis of the bicyclic C-D ring system. Pelletier and P a r t h a ~ a r a t h yused ~ the Dieckniann reaction, Bell and Irelanda utilized an aldol type condensation, Nagata, et a1.,2 used a displacement reaction, and other workers1g6have approached the problem via the Diels-Alder reaction. We have previously prepared? hydrocarbon (+)-V from maleopimaric acid (111) which in turn has been made by a Diels-Alder reaction between abietic acid (11) and maleic anhydride; abietic acid itself has been totally synthesized. l 2 , l 3 Ayer, McDonald, and Iverach6 likewise synthesized (+)-V by a similar sequence of reactions and, in addition, found that it was, as predicted, enantiomeric with the product obtained by Wolf-Kishner reduction of VI, which had been previously obtained from atisine by Ap Simon, Edwards, and Howe.14 We now wish to report the (1) A. A. Othrnan and N. A . J. Rogers, Tetrahedron Letters, 1339 (1963). (2) W . Nagata, T. Sugasawa, M. Narisada, T . Wakabayashi, and Y. Hayase, J . A.m. Chem. Soc.. 86, 2342 (1963). (3) R . A . Bell and R . E. Ireland, Tetrahedron Letter#. 269 (1963). (4) W . L. Meyer and A . S. Levinson. Proc. Chem. SOC., 15 (1963). ( 5 ) S. W. Pelletier and P. C. Parthasarathy, Tetrahedron Letter8. 205 (1963). (6) W. A. Ayer, C. E. McDonald, and G. G . Iverach, ihid., 1095 (1963). (7) L. H. Zalkow and N . N . Girotra, J. Org. Chem., 28, 2037 (1963). (8) I. Iwai and A. Ogiao, Chem. Ind. (London), 1084 (1963). (9) J. W . Ap Simon and 0. E. Edwarde, Can. J. Chem., 40, 896 (1962). (10) J. A . Findlay, W . A . Henry, T. C. Jain, Z. Valenta, K . Wieaner. and C . M. W o n g , Tetrahedron Lettare, 869 (1962) (11) I. Iwai, A. Ogiao, and B. Shimizu, Chem. I n d . (London), 1288 (1962). (12) G . Stork and J. W. Schulenberg, J . A m . Chem. Soc., 84, 284 (1962). (13) A. W. Burgstahlei and L. R . Worden, ihid., 89, 2587 (1961). (14) J. W. Ap Simon, 0. E. Edwards, and R. Howe, Can. J. Chem., 40, 630 (1962).
conversion of IV, an intermediate obtained in the preparation of V, into XXI, which possesses the entire diterpenoid skeleton of atisine in its correct relative configuration. Reduction of keto ester IV with lithium aluminum hydride gave a mixture of alcohols (VIIa and b) which was oxidized directly to give the keto aldehyde VIII. Huang-Minlon168l6 reduction of VI11 gave crystalline alkene IX. The n.m.r. spectrum of I X showed the three methyl-group protons at C-4 and C-10 as sharp
I
I steps
VI
singlets a t 6 0.82, 0.87, and 0.96. This is to be contrasted with compounds of this type which contain a double bond a t C-13. In such cases the C-10 methylgroup protons appear at 6 0.50.'? The vinylic protons in I X appeared as three sharp lines a t 6 5.92, 5.95, and 6.02. The double bond in I X was hydrated by the Brown hydroboration procedure'8 to yield a mixture of alcohols XVI (a, b) and XVII (a, b) which was treated with chromic anhydride in pyridine. Chromatography of the oxidation product on alumina gave two ketones, A (m.p. 145-146', Amax 5.78 p ) and B (m.p. 146-148', Amax 5.81 p ) in a ratio of approximately 4:1, the less abundant isomer B being eluted first. That no skeletal rearrangement had occurred in these transformations was shown by the facile conversion of both ketones A and B to the previously reported hydrocarbon (+)-V by the H~ang-Minlon'~*'~ procedure. The n.m.r. spectra of ketones A and B were very similar except that in A the methylene protons adjacent to the carbonyl group gave a signal a t 6 1.82, whereas in ketone B these protons appeared a t 6 2.17. Ketone A gave a positive Cotton effect in its optical rotatory dispersion curve whereas ketone B showed a negative Cotton effect. Although the above information did not allow an unambiguous decision to be made as to (15) (16) (17) (18)
Huang-Minlon, J. A m . Chem. Soc.. 68, 2487 (1946). Huang-Minlon, ihid., 71, 3301 (1949). L. H. Zalkow and N . N . Girotra, J . Org. Chem., 28, 2033 (1963). H. C. Brown, et al., J . A m . Chem. Soc., 82, 4233 (1980).
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ZALKOWAND GIROTRA
VOL. 29
SCHEME I n
IV(R=CHs)
-
& 3
-,@3 -*&TI xx
$ HiX, R = COzCH, I
XI, XII, XIII,
I @
I
H
I@-
VIIa, R = VIIb, R =
