Cephalotaxine alkaloids

Azaspirocyclic ketoaziridines 304 (X = Cl or OTBS), potential intermediates for the total synthesis of antitumor alkaloid cephalotaxine 305, have been prepared in 26% (X = Cl) and 76% (X = OTBS) yields, respectively, via an lAOC reaction of azide 303 (Eq. 34) [80]. 

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... 

In 1988 and 1990, Fuchs reported a new approach to the synthesis of the Cephalotaxus alkaloids ( )-cephalotaxine (1) (30,31), ( )-ll-hydroxyceph-alotaxine (26) (31), and ( )-drupacine (28) (31), which was based on the exploitation of vinyl sulfones as convenient multifunctional synthons (Schemes 7 and 8). The synthesis of cephalotaxine (Scheme 7) began with the ortho ester 77, obtained from piperonyl alcohol in five steps, which was... 

Erythrina Alkaloids Homoerythrina Alkaloids Cephalotaxine Alkaloids... 

Homoharringtonine (HHT) (19) is an ester derivative of the parent alkaloid cephalotaxine (20), which has an unusual tetracyclic ring system. Cephalotaxine was isolated from two Cephalotaxus species" and its final structure was assigned by X-ray crystallography." HHT was isolated in 1970 by workers at the USDA laboratories in Peoria" but its anticancer activity was first recognized by Chinese investigators. 

In their enantioselective total synthesis of the alkaloid cephalotaxine (246), Tietze and Schirok [127] used a combination of a Tsuji-Trost and a Mizoroki-Heck reaction (Scheme 8.62). It was necessary to adjust the reactivity of the two palladium-catalysed transformations to allow a controlled process. Reaction of 243a using Pd(PPh3)4 as catalyst led to 244, which furnished 245 in a second palladium-catalysed reaction. In this process, the nucleophilic substitution of the allylic acetate is faster than the oxidative addition of the arylbromide moiety in 243a however, if one uses the iodide 243b, then the yield drops dramatically due to an increased rate of the oxidative addition. 

Some of the most synthetically useful reactions are intramolecular cycloadditions. An intramolecular cyclopentenone cycloaddition led to the formation of the tricyclic aziridine 54, an intermediate for the preparation of the alkaloid ( )-cephalotaxine, in good yield (Scheme 6.25). The intermediate triazoline was not detected. A related synthesis of the aziridine 55 was used as a step in a synthesis of the alkaloid ( )-aspidospermidine. °... 

Palladium-mediated methylencyclopentane annelation of nitrostyrene is used for a total synthesis of cephalotaxine, which is the predominant alkaloid of the cephalataxus species (Scheme 10.25).133... 

Parry conducted experiments that demonstrated the biosynthetic origin of cephalotaxin (1) from one molecule each of tyrosine and phenylalanine, indicating that the compound should be regarded as a modified 1-phenethyltetrahydroisoquinoline alkaloid.s... 

The alkaloids dealt with in this section of the chapter are hyoscyamine (1), scopolamine (2), methylephedrine (3), norephedrine (4), ephedrine (5), pseudoephedrine (6), and cephalotaxine (7). 

Another example for SFE of alkaloids using basified modifiers was reported for cephalotaxine (7) from Cephalotaxus wilsoniana leaves [45]. In this report, basified methanol was found to greatly enhance the extraction efficiency relative to any other modifiers (Figure 13). 

The biosynthetic pathway suggested for cephalotoxine (Scheme 8) includes intermediates whch are homologous with those for Erythrina alkaloids (see above). It depends in part on the fact that homo-Erythrina alkaloids co-occur naturally with those having the cephalotaxine skeleton. 

Alkaloid distribution in C. harringtonia in relation to age has been noted. Physiological stress (pruning) was found to cause hydrolysis of cephalotaxine esters. Environmental factors also caused hydrolysis and, in addition, oxidation of cephalotaxine (85) to 11-hydroxycephalotaxine and of two other alkaloids to epoxy-derivatives.24... 

Harringtonine (9a), an anti-tumour alkaloid ester from Cephalotaxus harring-tonia, referred to above, has now been synthesized23 from cephalotaxine (9b)... 

Recently, Weisleder etal.26 have reported the carbon-13 chemical-shift assignments for cephalotaxine and related alkaloids. 

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,... 

A minor alkaloid from C. fortunei (98) showed an IR spectrum identical to that of cephalotaxine, but its melting point was depressed by it. The physical properties of this alkaloid were found to be identical to the minor product obtained by reduction of cephalotaxinone (112) using LAH (102). The alkaloid was therefore 3-epicephalotaxine (105b). Although a small amount of 105b was produced on reduction of cephalotaxinone with LAH, the use of borohydride or DIBAL-H gave only cephalotaxine (98). 

During the structure elucidation work, cephalotaxine was shown to form a mono-O-acetate (106) (102), and this compound was later found as a minor alkaloid in C. fortunei (98). An impure sample of acetylcephalotaxine was also obtained from C. wilsoniana Hay. (90). 

When the alkaloidal extracts of C. harringtonia var. harringtonia were found to possess antileukemia properties, a search for the responsible alkaloids was initiated, since the major component, cephalotaxine, was inactive. Four alkaloids (the harringtonines) that exhibited anticancer properties were isolated. The structures of harringtonine, isoharringtonine, and homo-harringtonine were reported in 1970 (107), and that of deoxyharringtonine was reported in 1972 (108). 

Two minor alkaloids (C18H21N05), obtained from C. harringtonia var. drupacea (Sieb and Zucc) Koidz.,were deduced to be 11-hydroxycephalo-taxine (114) and its related ketal drupacine (115) (101, 104). The NMR spectrum of the former exhibited features similar to that of cephalotaxine, with the addition of a triplet at S 4.78 ppm, which was part of an ABX system. The alkaloid formed a diacetate wherein the position of the methine... 

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... 

The total synthesis of alkaloids of the cephalotaxine type has attracted considerable attention (75) because of the anticancer activity reported for certain derivatives (100) (see Section IV,A). The first synthesis of cephalotaxine (105a) was reported by Auerbach and Weinreb (155, 156), closely... 

Although cephalotaxine itself exhibits no significant antileukemic activity, a number of naturally occurring esters of the alkaloid, the harringtonines (107-110), are active against LI 210 and P388 leukemias in mice (89,100, 108), and so some attention has been devoted to the synthesis of the dicar-boxylic acid side chains (see also Section IV,A). 

The group of activated olefins, which has so far probably received most attention in radical cyclizations, are enamides. Syntheses of various natural products, especially alkaloids, have been successfully completed using this strategy. Cyclizations onto enamides of the 6-endo type led to erysotrine [76] and lycorine alkaloids [77-79]. The skeleton of hydroapoerysopines [80] was successfully constructed by a 1-endo cyclization. Two new examples of radical tandem reactions, which commence with a 1-endo type cyclization, have appeared in recent literature. Construction of the cephalotaxine core structure 29 was achieved from enamide 30 in only one step (Scheme 11) [81]. 

Chinese workers have continued their pharmacological exploration of esters of cephalotaxine (3a) and have reported the transformation of this alkaloid into harringtonine (26a)12 and 0-(2-oxo-5-methylhexanoyl)cephalotaxine (26b).13 The latter compound is an intermediate in the synthesis of the antineoplastic alkaloid deoxyharringtonine (26c). The overall conversion of cephalotaxine into deoxyhar-ringtonine (26c) via (26b) has been patented.14 Of twenty-two esters of (-)-... 

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. 

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