Total synthesis of the alkaloid casimiroedine, an imidazole nucleoside

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 irans-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. Chemical investigations conducted on the seeds of the fruit of the tree Casimiroa edulis La Llave et Lejarza have shown them to 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 A-methylhistamine and a carbohydrate fragment. An X-ray analysis7•8 firmly established the structure of the carbohydrate as /S-D-glucose and of casimidine as 4-[2-(methylamino)ethyl]-l-(/3-D-glucopyranosyl)imidazole. These studies provided the basic structure of casimiroedine (7) and left one question unanswered, whether casimiroedine was the cisor trans-cinnamic acid amide of 6. This final question has now been resolved by the total synthesis of casimiroedine.113 Results and DiscussionChemical Synthesis. The chloromercury derivative9 (2) of 4-(2-chloroethyl)imidazole hydrochloride10•11 (1) (Scheme I) was glycosylated with 2,3,4,6-tetra-O-acetyl--D-glucosyl bromide12 (3) to provide 4 as a thick syrup.(1) (a) This investigation was supported in part by Research Contract No. C72-3710 with the

Antimutagenic Constituents of Casimiroa edulis with Potential Cancer Chemopreventive Activity

“…Imidazole alkaloid derivatives have been isolated from the leaves of C. edulis (Romero et al, 1983). There have been a number of synthetic studies published on the various constituents of C. edulis (Meisels and Sondheimer, 1957;Weinstein and Hylton, 1964;Dreyer and Bertelli, 1967;Panzica and Townsend, 1973).…”

Total assignment of the1H and13C NMR spectra of casimiroedine and its peracetylated derivative

“…A 1 H spectrum of 1 was originally run in DMSO-d 6 since it had earlier been reported that 1 was only significantly soluble in that solvent. 6 However, the spectrum for the glucose region in particular was extremely complex owing to a combination of the presence of two isomers and slow OH exchange in DMSO-d 6 , resulting in 1 H-C-O-1 H coupling. Subsequently, it was determined that 1 was sufficiently soluble in CD 3 OD to obtain spectra with adequate signal-to-noise ratio and greatly improved 1 H resolution.…”

“…Spectra were obtained for 3 mg of 1 dissolved in CD 3 OD or an 80 : 20 (v/v) mixture of CD 3 OD and DMSO-d 6 . Spectra for 2 were obtained using 6 mg dissolved in CDCl 3 .…”

“…2 The structure of 1 was established in a series of investigations 2 -6 and it has been reported that it has significant anti-tumor activity against lymphoid leukemia. 6 However, almost no NMR data have been reported for 1, other than a poorly resolved 220 MHz 1 H spectrum for the aromatic/olefinic region, 6 and there apparently has been only one brief report of the further isolation of 1 since 1973. 7 During the course of an ongoing phytochemical and pharmacological investigation of Zapote Blanco, 8 we reisolated 1 in an impure form, with the major impurity being sucrose.…”

“…13 C and 1 H chemical shift assignments for major and minor isomers of 1 in CD 3 OD and (in parentheses) in an 80 : 20 (v/v) mixture of CD 3 OD and DMSO-d6 …”