Cephalotaxine yields

Harringtonine (107) has been synthesized 170) by the method shown in Scheme 59. Claisen condensation between 283 and ethyl oxalate in the presence of NaH gave 284 which, when heated under reflux with aqueous HC1, was converted to a mixture from which the oxide (285) was isolated. Without purification, 285 was treated with HCl/MeOH to yield 286, saponification of which yielded the unsaturated acid as its sodium salt 287. After conversion to the acid chloride, reaction with cephalotaxine yielded 288. 

In the follow-up detailed report, Hudlicky s group (53) also described the synthesis of homoharringtonine from the unsaturated keto acid 151 (Scheme 23). Acid 151 was treated with formic acid in the presence of perchloric acid to provide the intermediate formylated derivative 163, which, on treatment with aqueous sodium hydroxide, produced hydroxy acid 164. Esterification of 164 with cephalotaxine yielded the cephalotaxyl ester 165, which underwent the Reformatsky reaction with methyl bro-... 

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]. 

Sha et al. (45) reported an intramolecular cycloaddition of an alkyl azide with an enone in an approach to a cephalotaxine analogue (Scheme 9.45). Treatment of the bromide 205 with NaN3 in refluxing methanol enabled the isolation of compounds 213 and 214 in 24 and 63% yields, respectively. The azide intermediate 206 underwent 1,3-dipolar cycloaddition to produce the unstable triazoline 207. On thermolysis of 207 coupled with rearrangement and extrusion of nitrogen, compounds 213 and 214 were formed. The lactam 214 was subsequently converted to the tert-butoxycarbonyl (t-Boc)-protected sprrocyclic amine 215. The exocyclic double bond in compound 215 was cleaved by ozonolysis to give the spirocyclic ketone 216, which was used for the synthesis of the cephalotaxine analogue 217. 

Molander and Hiersemann (60) reported the preparation of the spirocyclic keto aziridine intermediate 302 in an approach to the total synthesis of (zb)-cephalotax-ine (304) via an intramolecular 1,3-dipolar cycloaddition of an azide with an electron-deficient alkene (Scheme 9.60). The required azide 301 was prepared by coupling the vinyl iodide 299 and the aryl zinc chloride 300 using a Pd(0) catalyst in the presence of fni-2-furylphosphine. Intramolecular 1,3-dipolar cycloaddition of the azido enone 301 in boiling xylene afforded the desired keto aziridine 302 in 76% yield. Hydroxylation of 302 according to Davis s procedure followed by oxidation with Dess-Martin periodinane delivered the compound 303, which was converted to the target molecule (i)-cephalotaxine (304). 

Figure 13. Relative extraction yields (%) of cephalotaxine (7) from C. wilsoniana leaves by SC-C02 by added modifiers when compared with methanol extraction [45], Reproduced with permission from the Pharmaceutical Society of Korea 1999.

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,... 

The second total synthesis of cephalotaxine (157-159) was very different conceptually since it was a convergent synthesis involving the two intermediates 248 and 249. The azabicyclic intermediate (248) was prepared from pyrrolidone (250) (Scheme 52), which with the Meerwein reagent gave 251. The latter was treated with an excess of allyl Grignard reagent to yield 252. 

An approach to the cephalotaxine skeleton, based upon the presumed biogenetic route, has been reported (164) and involves the oxidation of the 1-phenethylisoquinoline derivative (260) with VOF3 (Scheme 54). Alkaline cleavage of the dienone (261) gave 262 which, as the hydrochloride salt, was reduced 263. A-trifluoroacetylation followed by O-methylation yielded 264 which, after hydrogenolysis to 265, was oxidized with potassium ferricyanide to give the dienone (266). 

Treatment of perhydro-4-azaazulene (3) with mercuric acetate produces a mixture of dehydro derivatives 31a and 31b, which, with acids, yields homogeneous salts of structure 32 (56JOC344). The enamine 34, which was obtained by the same route from 33, served as a model compound in a study of the synthesis of cephalotaxine (72JOC3691). A reaction with ethyl y-bromo-acetoacetate surprisingly yielded the quinolizidine 36, which was formed by rearrangement of the intermediate annellation product 35 (Scheme 3) Phthalimides 38 were obtained from a Baeyer-Villiger oxidation of 4-azaazulen-3-ones 37 (77JOC1093). 

Cephalotaxine. Later, Tse and Snieckus (759) also carried out the same cyclization on the iodoenamide 344 and obtained the tricyclic compound 345 in 46% yield. This lactam 345 was then reduced first with platinum... 

The intramolecular azide cycloaddition has also been used in approaches to the aspidosperma alkaloids <2004TL919, 20050BC213>. The cycloaddition of 123 proceeds directly to aziridine 124 in 80% yield (Equation 28) <2004TL919>. This is an interesting transformation in that none of the initially formed triazoline is observed and because of the high regioselectivity of the addition. A conceptually related approach to the synthesis of cephalotaxine has also been reported <1997TL4347>. 

In the final stages of the total synthesis of (+)-cephalotaxine by M.E. Kuehne et al., a tetracyclic c/s-vicinal diol was oxidized to the a-diketone. Using PCC, pyridine/SOs or the Swem protocol did not yield the desired product. However, by applying the Corey-Kim protocol, NCS-DMS in dichloromethane at -42 °C, afforded the diketone in 89% yield. 

The second synthesis of cephalotaxine was reported by Semmelhack and co-workers (24), also in 1972. Their convergent strategy involved the alkylation of spirocycle 49, prepared in several steps from p)nTolidone 45, with p-nitrobenzenesulfonate ester 50, prepared from piperonal in 45-55% overall yield as shown in Scheme 2. The resulting key intermediate, 51a (X = Cl), was converted to ( )-cephalotaxinone (22), initially through an aryne intermediate. Route I, Scheme 3, in 15% yield. Cephalotaxinone was then converted to ( )-cephalotaxine (1) upon reduction with diisobutyl-aluminum hydride. The Semmelhack group expended considerable effort studying the conditions of the nucleophilic aromatic substitution (i.e., 51a-c... 

The Semmelhack synthesis provided racemic cephalotaxine in 12-13% yield from pyrrolidone 45 in 11 steps (25,26). The SrnI reaction employed in the second-generation approach to the key aryl bond formation added novelty as well as efficiency to the overall design. The overall sequence is longer than Weinreb s most likely because of the effort expended in the construction of spirocycle 49. 

These two milestone syntheses were soon followed by others, and activity in this field continued to be driven by interest in the biologically active esters of cephalotaxine. In 1986, Hanaoka et al. (27) reported the stereoselective synthesis of ( )-cephalotaxine and its analog, as shown in Scheme 4. The amide acid 52, prepared by condensation of ethyl prolinate with 3,4-dimethoxyphenylacetyl chloride, followed by hydrolysis of the ethyl ester, was cyclized to the pyrrolobenzazepine 53 by treatment with polyphos-phoric acid, followed by selective O-alkylation with 2,3-dichloropropene (54) in the presence of sodium hydride. The resulting enol ether 55 underwent Claisen rearrangement on heating to provide C-allylated compound 56, whose reduction with sodium borohydride yielded the alcohol, which on treatment with 90% sulfuric acid underwent cationic cyclization to give the tetracyclic ketone 57. Presumably, this sequence represents the intramolecular version of the Wichterle reaction. On treatment with boron tribromide, ketone 57 afforded the free catechol, which was reacted with dibromometh-ane and potassium fluoride to give methylenedioxy derivative 58, suited for the final transformations to cephalotaxine. Oxidation of ketone 58... 

In addition, compound 76 was reduced with aluminum hydride to give amine 62, the penultimate compound in Hanaoka s earlier cephalotaxine synthesis (27). The attainment of this material constituted a formal synthesis of ( )-cephalotaxine (1) in a 2% overall yield, but without improvement of the earlier strategy. 

L-(+)-glutamic acid and piperonal by Weinreb s method (22,23) and then resolved into its enantiomers by means of L-(+)-tartaric acid. Treatment of (-)-cephalotaxine with sodium borohydride yielded (-)-cephalotaxine (1) of the same absolute configuration as natural cephalotaxine. 

In 1975, the Tumor Research Group of the Chinese Academy of Medical Science (47) reported a short synthesis of harringtonine (2) as shown in Scheme 19. Treatment of the olefinic pyruvate 148, obtained from the reaction of cephalotaxine and the corresponding acid, with mercuric tri-fluoroactate, followed by reduction with sodium borohydride yielded the known hemiketal 140. Reformatsky reaction of 140 with methyl bromo-acetate yielded harringtonine (2). 

Zhao and co-workers 48) reported the first synthesis of homoharringtonine (3) in 1980 (Scheme 20). Unsaturated keto acid 151, prepared either from 5,5-dimethyl-5-valeroIactone 150, or by chain extension from the commercially available bromide 149, was esterified with cephalotaxine to give the cephalotaxyl derivative 152, which reacted with methyl bromoacetate under Reformatsky conditions to yield a mixture of epimers of dehydro-homoharringtonine 153. This mixture was converted to homoharringtonine and its epimer by means of oxymercuration, as well as by acid catalysis. As in the aforementioned syntheses of harringtonine, the Reformatsky reaction proceeded with no stereoselectivity, and diastereomeric mixtures resulted from all of these approaches. 

Another synthesis of homoharringtonine was reported by Wang et al. 49-51) in 1980 (Scheme 21). Treatment of the sodium salt 154 of the protected keto acid with oxalyl chloride, followed by cephalotaxine, gave the cephalotaxyl ester 155, which, under Reformatsky conditions, reacted with methyl bromoacetate to furnish the expected diastereomeric mixture of ketals 156. Hydrolysis of 156 yielded an equilibrium mixture of ketone 157 and its cychc hemiketal 158. Treatment of this mixture with methyl-magnesium iodide yielded homoharringtonine (3) and its epimer. 

Two new cephalotaxine esters having significant antileukemic activity, neoharringtonine (11) and anhydroharringtonine (12), were isolated in 1992 by Wang and co-workers (9) from C. fortunei Hook f. These authors also reported their semisynthesis from cephalotaxine and harringtonine, respectively (Scheme 31). On treatment with phenyl pyruvyl chloride in the presence of pyridine, cephalotaxine (1) produced an intermediate a-keto ester. Reformatsky reaction of this cephalotaxyl phenyl pyruvate with methyl bromoacetate yielded a mixture of neoharringtonine (11) and its epimer. 

An early approach to the synthesis of cephalotaxine (Scheme 32) was reported by Dolby et al. (64) in 1972, shortly before Auerbach s and Wein-reb s report (22). The Vilsmeier-Haack condensation of piperonylamide 187 with pyrrole yielded ketone 188, which was successively reduced with sodium borohydride, hydrogenated, and acylated to give the precursory chloro amide 189. The photocyclization of 189 produced lactam 190, which, after reduction of the carbonyl with lithium aluminum hydride and subsequent oxidation with mercuric acetate, yielded the enamine 43. This mate-... 

Another approach to cephalotaxine intermediate 43 was reported by Weinstein and Craig (65) in 1976 (Scheme 33). The reaction of 3,4-(methy-lenedioxy)-iS-phenethyl tosylate (191), a derivative of the previously used nosylate 117, and sodium 2-carboethoxypyrrole (192), followed by hydrolysis, produced the carboxylic add 193. Intramolecular Friedel-Crafts acylation of 193 with stannic chloride and trifluoroacetic anhydride yielded the benzazepine 194, which was reduced, hydrogenated, and finally oxidized to produce the tricyclic Dolby-Weinreb enamine 43. 

Several other biomimetic approaches to the synthesis of cephalotaxine have also been reported. In 1977, Kupchan etal. (72,73) prepared tetrahy-droisoquinoline 214, which underwent intramolecular oxidative coupling to 215 by means of vanadium(V) oxytrifluoride and trifluoroacetic acid/ trifluoroacetic anhydride (Scheme 38). Treatment of 215 with 1 N sodium hydroxide in methanol yielded the ring-expanded product, imine 216, which was converted in five steps to amine 217. Transannular cyclization of 217... 

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