Cathedulin

As a result of a detailed collaborative investigation between the Chemistry Department of the University of Nottingham (Crombie, Whiting) and the U.N. Narcotics Laboratory (Szendrei), at least 14 cathedulin alkaloids have been isolated and formulated (46,47). Plant material collected in Kenya, Ethiopia, and the Yemen Arab Republic was extracted as fresh material, as freeze-dried material, and as sun-dried material. A number of extraction procedures were also employed, with methods directed toward the isolation of weak bases. In one procedure fresh material was extracted with ethanol in the presence of sodium bicarbonate, and the diluted extract was adjusted to pH 5.5 and extracted with... 

Two groups of the cathedulin alkaloids, E3, E4, E5, and E6 and Kl, K2, K6, and K15, form subsets which differ within each other only in the acetylated or nonacetylated state of certain hydroxyl groups. In consequence, certain alkaloids could be artifacts caused by deacetylation induced by isolation or chromatography, or acetyl migration might have unexpectedly occurred. This cannot be ruled out with certainty in all cases, but there is evidence which indicates in general... 

Little is known about the pharmacological activity of the cathedulin alkaloids. However, Kubo et al. (49) have reisolated cathedulins E3, E4, and E5 by HPLC and report that all three compounds are potent growth inhibitors for the pink bollworm at approximately 1 ppm. This is nearly as strong as azadirachtin, one of the strongest known natural growth inhibitors. 

The cathedulin alkaloids of medium molecular weight (750-9(K)) comprise four members, cathedulins Kl, K2, K6, and K15 with K2 (42) being the most intensively studied. It was shown by mass spectral and H- and C-NMR... 

Cathedulin K17 (C59H62N2O23) (62), isolated as crystalline but only as a 2.5-mg sample, revealed in its H-NMR spectrum an euonyminol core carrying eight ester groups, with the usual free tertiary 4-hydroxyl. The same 3,13-bridging edulinic residue was present as was found in K19. Two acetate units, a benzoate. 

The roots of Ethiopian khat contain cathedulins E2, E3, E4, E5, and E6. The root bark itself is orange-red, and this was found to be caused by the presence of triterpenoid quinones (48). Those identified were celastrol (64), pristimerin (65),... 

VIII. Synthetic Work Relevant to Cathedulin Alkaloids... 

Although none of the known triterpene cores of the cathedulin group of alkaloids has been synthesized, progress has been made in the broader area of synthesis of Celastraceae sesquiterpenes, which is relevant to this problem. Thus, a completely stereoselective synthesis of the trihydroxylated dihydroagar-ofuran isocelorbicol (70) has been reported by Huffman and Raveendranath (60,61), which improves upon an earlier synthesis (62). The synthesis (Scheme 6) starts from the ketoagarofuran 71, which is available in six steps and 10% overall yield from carvone and methyl vinyl ketone. 

Khat, a drug produced from leaves and shoots of Catha edulis, is used as a stimulant, primarily in East Africa and Southern Arabia [167]. Interest in this drug led to investigation of the components of C. edulis, which included a number of macrocyclic sesquiterpene pyridine alkaloids, the cathedulins. 

Cathedulins -K17, -K19, and -K20 have been isolated from C. edulis, and their structures determined using FABMS, and one- and two-dimensional and NMR [169]. Cathedulins -K17 and -K19 each contain edulinic acid (B) as the acid component of the macrocyclic dilactone. The absolute configuration of B derived from cathedulin -K19 was established by synthesis of the (5)-dialcohol C from methyl (R)-3-hydroxy-2-methylpropionate. The product (C) was identical to the compound produced by UAIH4 reduction of cathedulin -K19, in sign of optical rotation, IR, H and NMR spectra [170]. 

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