Cephalotaxine synthesis

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. 

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]. 

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... 

A combination of two palladium catalyzed reactions has also been used for the synthesis of estra-dioll75al 144 and cephalotaxine 145 by us I75b,cl however, here the step-wise procedures give better yidds. Reaction of 140 and enantiopure 141 leads via 142 to 143 in 55% yidd which can be transformed into estradiol in three steps (scheme 29). For the transformation of 142 into 143 the palladacene 146 was used. 

Scheme 29. Synthesis of estradiol and cephalotaxine by two subsequent palladium-catalyzed domino reactions...

Finally, the Nazarov reaction was used to build a quaternary center in a study aimed at the synthesis of a potential precursor of cephalotaxine <2000S2113>. 

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). 

Padwa etal. utilized the ammonium ylide [1,2]-shift in the synthesis of tetrahydroisoquinoline and benzazepine fused with a five-membered ring, a structure found in a cephalotaxine family. When diazo ester 172 is treated with a catalytic amount of Cu(acac)2 in refluxing toluene, 5,7-fused compound 174 is isolated in 73% (Equation (25)). Again, use of Rh2(OAc)4 results in slow reaction and eventually gives a complex mixture of the products after a prolonged reaction time. 

The synthesis of a mixture of two diastereoisomers of harringtonine has also been reported24 by esterifying cephalotaxine (9b) with the acid chloride (33) of racemic 4-benzyloxy-7,7-dimethyl-2-oxo-l-oxacycloheptane-4-carboxylic acid and converting the functionality of the acyl moiety into that of harringtonine. Isomerically pure harringtonine (9a) was made formally accessible by optical resolution of a hydroxy-acid precursor. 

In addition to the regiocontrol, the use of SMA carbamates provides activation to the reaction through overlapping of the lone-pair electrons on the nitrogen with the s-orbital of the C-Si bond.96 In this process, the trimethylsilyl group is replaced by a methoxy group. In fact any nucleophile can be used. Thus, various carbanions were utilized for the synthesis of spiro compounds that are synthons, for example, in an excellent route to cephalotaxine.354... 

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... 

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. 

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). 

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 (-)-... 

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). 

Cyclization with polyphosphoric acid of 98, obtained from proline, to give the dioxo derivative 99 is part of a stereoselective synthesis of ( + )-cephalotaxine and its analogue (86TL2023). 

Cepahalotaxine alkaloids are based on cephalotaxine which has a pentacyclic system including a seven-membered ring and a five-membered ring sharing an N atom (MD-Phe C6N C4 N G5 ). Cephalotaxine alkaloids include the cytotoxic, anticancer protein synthesis inhibitors cephalotaxine, harringtonine and homoharringtonine. 

---