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volume of the journal. Photocopies of the supplementary material from this paper only or microfiche (105 X 148 mm, 20X reduction, negatives) containing all of the supplementary material for the papers in this issue may be obtained from the Journals Department,
American Chemical Society, 1155 16th St., N.W., Washington, D. C. 20036. Remit check or money order for $3.00 for photocopy or $2.00 for microfiche, referring to code number JACS-738734.
The Total Synthesis of the Alkaloid Casimiroedine, an Imidazole Nucleoside'" Raymond P. Panzica and Leroy B. Townsend" Contribution from the Department of Chemistry and Department of Biopharmaceutical Sciences, University of Utah, Salt Lake City, Utah 84112. Received August 16,1973 Abstract: The syntheses of the imidazole alkaloid casimiroedine (7), a natural product isolated from the seeds of the Mexican fruit "Zapote blanco," and its hydrolysis product casimidine (6)have been accomplished. The key step in the synthesis of casimiroedine (7) involves the formation of the peptide linkage between trans-cinnamic acid and casimidine. The unambiguous synthesis of 7 established the stereochemistry of the cinnamoyl moiety as trans. This assignment was corroborated by the synthesis of cis-casimiroedine (8) and spectral evidence.
hemical investigations conducted on the seeds of the fruit of the tree Casimiroa e d u h La Llave et Lejarza have shown them t o contain a variety of constituents. 2-4 The principal constituent, the alkaloid casimiroedine (7), was found to be the cinnamic acid amide of casimidine (6).6 Degradation studies6 on casimidine confirmed the presence of N-methylhistamine and a carbohydrate fragment. An X-ray analysis7j8 firmly established the structure of the carbohydrate as P-D-glUCOSe and of casimidine as 4-[2-(methylamino)ethyl]-l-(~-~-glucopyranosyl)imidazole.These studies provided the basic structure of casimiroedine (7) and left one question unanswered, whether casimiroedine was the cis- or trans-cinnamic acid amide of 6 . This final question has now been resolved by the total synthesis of casimiroedine. Ib
C
Results and Discussion Chemical Synthesis. The chloromercury derivativeg (2) of 4-(2-~hloroethyl)imidazolehydrochloridela,ll (1) (Scheme I) was glycosylated with 2,3,4,6-tetra-O-acetyla-D-glucosyl bromide12 (3) to provide 4 as a thick syrup.
Rather than isolate nucleoside material at this point, the syrup was treated with methanolic methylamine in a steel reaction vessel at 100". The purpose of this step 'vas twofold: deacetylation of the glucose moiety and nucleophilic displacement of the chloro group. After removal of the excess methanolic methylamine, the Scheme I
2
I
*,
IY
t A d
OAc 3 4
J
(1) (a) This investigation was supported in part by Research Contract No. C72-3710 with the Division of Cancer Treatment, National
CH,
I
Cancer Institute, National Institutes of Health, Public Health Service. (b) R. P. Panzica and L. B. Townsend, presented in part before the Organic Chemistry Division, 24th Annual Northwest Regional Meeting of the American Chemical Society, University of Utah, Salt Lake City, Utah, June 1969, No. 149. (2) F. B. Power and T. Callan, J. Chem. Soc., 99, 1993 (1911). (3) F. A. IGncl, J. Romo, G. Rosenkranz, and F. Sondheimer, J. Chem. Soc., 4163 (1956). (4) A. Aebi, Hell;. Chim. Acta, 39, 1495 (1956). (5) C. Djerassi, J. Herran, H. N. Khastgir, B. Riniker, and J. Romo, J . Org. Chem., 21, 1510 (1956). (6) C. Djerassi, C. Bankiewicz, A. L. Kapoor, and B. Riniker, Tetrahedron, 2, 168a (1958). (7) S. Raman, J. Reddy, W. N. Lipscomb, A. L. Kapoor, and C. Djerassi, Tetrahedron Lett., 357 (1962). (8) S . Raman, I. Reddy, and W. N. Lipscomb, Acta C r y s t d o g r . , 16, 364 (1963). (9) H. Bauer, J. Org. Chem., 27, 167(1962). (10) T. C. Bruice and J. M. Sturtevant, J. Amer. Chem. Soc., 81, 2860 (1959). (11) R. A. Turner, J. Amer. Chem. Soc., 71, 3476(1949). (12) C. G. Jeremias, G. B. Lucas, and C. A. MacKenzie, J. Amer. Chem. Soc., 70, 2598 (1948).
A
1
HOCHL
5
I
6
syrup (5) was purified on a Dowex 50W-X2 (NH4+) resin column which provided a single product (tlc). This crystalline solid was tentatively identified on the basis of pmr spectroscopy and elemental analysis as 4-[2-(methylamino)ethyl]- 1-(P-D-glucopyranosy1)imidazole ( 6 , casimidine). This assignment was confirmed by a comparison of the ir and mass spectra (EI) of this Panzica, Townsend / Total Synthesis of Casimiroedine
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nucleoside with the ir and mass spectra of an authentic sample of casimidine.13 This preparation of casimidine ( 6 ) provided one of the essential precursors for the total synthesis of casimiroedine (7). However, before we attempted to synthesize 7, several key decisions were required, e.g., a cinnamoyl derivative having the correct stereochemistry had to be selected and the form of this derivative had to be suitable for peptide formation. The route we had envisaged for the synthesis of 7 required coupling of the cinnamoyl derivative directly with casimidine. On this basis, we eliminated the acid chloride method, since it would entail protection of the hydroxyl groups on the glucosyl moiety and necessitate two additional steps, i.e., blocking and deblocking. This decision narrowed our choice to the use of cis- and trans-cinnamic acids as the functional form of the cinnamoyl precursor. At the onset of our synthesis of casimiroedinelb only a limited amount of peptide synthesis had been conducted in the area of n u c l e ~ s i d e s . ~ ~This ~ ’ ~ workI4 dealt mainly with the use of dicyclohexylcarbodiimide (DCC) as the coupling reagent. DCC has been used extensively in the formation of peptide linkages in the syntheses of nucleoside peptides. It has also been used to form ester bonds between amino acids and the free hydroxyl groups of the carbohydrate moiety.Ifi For reasons similar t o those discussed for the acid chloride method (cide supra), we decided against the use of DCC as a coupling agent. This prompted us to examine the use of a new coupling reagent, EEDQ (N-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline). This reagent has been shownl7 to effect peptide coupling in good yield with a minimum of side reactions (Scheme 11). Scheme I1 6
J
\
7
8
When casimidine (6) was reacted with trans-cinnamic acid in the presence of EEDQ, only one nucleoside product was obtained (tlc) in 7 0 z yield. The pmr (60 MHz) spectra of this new nucleoside revealed that (13) The authors wish to thank Professor Carl Djerassi for his generous gift of the authentic samples of casimidine and casimiroedine. (14) E. Schroder and I
