Cephalotaxus alkaloid

The presence of alkaloids in the plants of Cephalotaxus was known for a long time but it was not until 1963 that pure alkaloids were isolated from the stems and leaves of C. harringtonia van drupacae (121). 

There are two groups of Cephalotaxus alkaloids the cephalotaxine - har-ringtonine group and the group represented by alkaloids II and III. The latter are often called homoerythrinan alkaloids. 

A possible pathway of the biosynthesis of Cephalotaxus alkaloids is shown in Fig. 5.2.13 (120). A similarity has been pointed out between this scheme and that of Erythrina alkaloids (Sect. 5.2.2.5.T). The starting open-ring intermediate in the present case is phenethylisoquinoline, instead of benzylisoquinoline for the Erythrina alkaloids. On this basis, homoerythrinan-type alkaloids are also called phenethylisoquinoline-type alkaloids. 

A study of the constituents of Cephalotaxus plants was made by using a young plant grown in a controlled environment (33). The concentration of free alkaloids (homoerythrinan-type alkaloids and cephalotaxine) did not increase with age, but that of cephalotaxine esters did. Total alkaloid concentrations increased in the older leaves and decreased in the older stems. Hydrolytic cleavage 

Much attention has been paid to the Cephalotaxus alkaloids, particularly in China, because of their antitumor activity. 

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Because of the postulated biosynthetic derivation of the Cephalotaxus alkaloids from the Homoerythrina bases, the former, relatively new group is included in this chapter. Anticancer activity has been found in certain members of the Cephalotaxus group, so the subject has already been reviewed several times (7-9). Annual coverage is given to the Erythrina, Homoerythrina, and Cephalotaxus alkaloids in the Specialist Periodical Reports of the Chemical Society (10-1 la). 

The Homoerythrina alkaloids have not been reviewed before, except briefly in conjunction with Cephalotaxus alkaloids, with which they occur in Cephalotaxus species (9). 

Cephalotaxus is a genus of plum yew natural to Eastern Asia, although it is now cultivated in many parts of the world (94). There are about seven species and most have been examined for alkaloids, which have been obtained from all parts of the plants. Since the alkaloidal extracts were reported in 1969 to exhibit antitumor activity (95), an intense investigation of the Cephalotaxus alkaloids has followed (8, 9). Most of the isolation work, structural elucidation, and pharmacological assay has come from the Northern Regional Research Laboratory in Illinois (5). 

The alkaloids were best isolated from the ethanol extract of the plant material, partially fractionated by counter-current distribution, and subsequently purified by preparative chromatography. Of the 11 known Cephalotaxus alkaloids (105-115 in Figs. 8 and 9), cephalotaxine (105a) is ubiquitous and the most abundant (up to 64% of the total alkaloid extract) in all species examined. C. wilsoniana Hay., which yields only minor quantities of cephalotaxine, is the exception, however it is rich in Homoerythrina alkaloids,... 

In a very recent examination of C. manii Hook., a new antitumor alkaloid was isolated but found to be structurally unrelated to the usual Cephalotaxus alkaloids. In view of the chemical results the botanical classification of the plant is being reexamined (96). 

It was noted that chromatography of Cephalotaxus alkaloid fractions over neutral alumina resulted in considerable losses (111). Further elution with dilute aqueous acetic acid resulted in the isolation of a new alkaloid, desmethylcephalotaxinone ([a]D +2.3°). The IR spectrum of this alkaloid was consistent with the presence of a vinylic hydroxyl group (3520 cm-1) and a conjugated carbonyl group (1690 cm 1). The NMR spectrum obtained in deuterochloroform contained features of the cephalotaxine structure, but included a singlet attributable to an isolated methylene (<5 2.54 ppm). In DMSO-c/6 this resonance appeared as an AB quartet. Acetylation... 

Arguing from structural similarities, it was originally suggested (10) that the Cephalotaxus alkaloids could be derived in vivo from the same precursor as the aromatic erythrina bases, but since Cephalotaxus and homoerythrina alkaloids have been isolated (90) from E. wilsoniana, it has been postulated (10b, 89) that both groups have a 1-phenethyltetrahydroisoquinoline as a common precursor (Scheme 36). Tyrosine is incorporated (122) into cepha-lotaxine, but the labeling pattern did not seem to be consistent with a... 

Scheme 36. Possible biosynthetic route to the Cephalotaxus alkaloids.

Cephalotaxus Alkaloids.—Preliminary results indicate that the homo-Erythrina alkaloid schelhammeridine (52) derives from phenylalanine and tyrosine by way of a phenethylisoquinoline precursor [as (53)].52 Previous evidence for the biosynthesis of the related alkaloid cephalotaxine (54), obtained with tyrosine labelled in the side-chain, has indicated a different pathway which involves two molecules of this amino-acid.53 Recently, however, tyrosine labelled in the aromatic ring was examined as a cephalotaxine precursor and was found54 to label ring A of (54) almost exclusively, i.e. only one unit of tyrosine is used for biosynthesis. This is obviously inconsistent with the previous evidence and the early incorporations are... 

A photochemical preparation of a Cephalotaxus alkaloid synthon (20) has been reported (Scheme 2).10 The readily accessible maleimide (17) was iodinated with iodine and silver trifluoroacetate, in 71% yield, and the resulting compound was transformed in two steps (70% overall yield) into the methylene-pyrrolone (18) by the action of methylmagnesium iodide followed by dehydration. Irradiation of (18) afforded (19) (46% yield), which, by successive hydrogenation and reduction with lithium aluminium hydride, gave the dihydro-pyrrolo[2,l-b][3]benzazepine (20). This derivative has served as a key intermediate in the total synthesis of cephalo-taxine described previously (see Vol. 7 of these Reports). 

Inhibition of protein synthesis in eukaryotic cells by the Cephalotaxus alkaloids harringtonine, homoharringtonine, and isoharringtonine has been studied.16 In model systems, these alkaloids were found not to inhibit any of the initiation steps but to block certain parts of the elongation phase of translation. 

Moreover, the 4-azaazulene skeleton has been found in natural products, such as Cephalotaxus alkaloids and Erythrina alkaloids (78MI1) (Section V,B). 

Photochemical formation of a biphenyl linkage in 119 to give the tetracyclic compound 120 could be achieved in 4.4% yield (72TL5031). A photocyclization of the phthalimidine 121 to 122, which subsequently transformed into Schopf s base IV (71) (R = H), proceeded in 21.5% yield (71TL4867). Similarly, 123 reacted to give the Cephalotaxus alkaloid synthon (124) (76CC505). 

Cephalotaxine (189) is a representative Cephalotaxus alkaloid several ester derivatives, both natural products and semisynthetic ones, were found to exhibit significant antitumor activity (85MI3). Syntheses of cephalotaxinones 44 (Section III,D) and 109 (Section IV,A,4) have been mentioned. 

Alder reaction [524, 525]. Danishefsky et al. have used nitroso dienophiles for the synthesis of mitomycin K and antibiotics of the FR 900482 family, the latter ones are structurally unique aziridino-l,2-oxazine derivatives [526-529]. An approach directed to the cephalotaxus alkaloids has been worked out by Fuchs et al. [530], and several indolizidine alkaloids have been prepared by Keck s [531] and Kibayashi s groups [532,533]. Kibayashi et al. also synthesised Nuphar piperidine alkaloids in enantiomerically pure form by means of an asymmetric nitroso Diels-Alder reaction [534]. 

Spencer GF, Plattner RD, Powell RG. Quantitative gas chromatography and gas chromatography-mass spectrometry of Cephalotaxus alkaloids. J. Chromatogr. 1976 120 335-341. Grem JL, Cheson BD, King SA, Leyland-Jones B, Suffness M. Cephalotaxine esters antileukemic advance or therapeutic failure J. Natl. Cancer Inst. 1988 80 1095-1103. 

Cephalotaxus alkaloids Cephalotaxus fortunei CHCI3-O.O7 M sodium phosphate-0.04 M citric acid (pH 5.0) (1 1) HSCCC... 

A comprehensive review concerning the synthesis of the Cephalotaxus alkaloids has appeared/ Another review incorporates this subject in the context of the synthesis of alkaloids which embody in part a benzazepine framework/... 

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