Cephalotaxines

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]. 

The assembly of the benzazepane framework 2-338 (e. g., found in cephalotaxine [187]) starting from 2-336 has been achieved by the group of Schinzer [188] utilizing a combination of a Beckmann rearrangement to give the iminiumion 2-337 and an allylsilane cydization (Scheme 2.79). 

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>. 

A tandem Beckmann rearrangement/allylsilane was used to produce the optically active cephalotaxine framework 482 (equation 208). Asymmetry could be induced as a result of stereochemical effects. 

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. 

Narasaka efal. have extended these crochet-mode cascade cyclizations to di- and trienyl-substituted o-pentafluoro-benzoyloximes 136 and 140, to furnish spirofused cyclic imines 139 and 141, respectively (Scheme 36)/" The latter structure has been found in some bioactive natural products such as cephalotaxine. 

Cephalotaxus fortunei Hook. C. oliveri Mast. C. qinensis (Rehd. et Wils.) Li San Jian Shan (Plum yew) (branch) Cephalotaxine, harringtonine, epicephalotaxine, epiwilsonine, demethylcephalotaxine, wilsonine, cephalotaxinone.33 This herb is toxic. Treat malignant tumors. 

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... 

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