Total Synthesis of — -Cephalotaxine

Abstracted with permission from J. Org. Chem.. 1995, 60. 115 1995 American Chemical Society 

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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... 

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. 

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 first total synthesis of cephalotaxine was reported by Auerbach and Weinreb (22,23) in 1972, as illustrated in Scheme 1. Condensation of prolinol... 

Danishefsky et al. (33) reported a method of one-carbon chain incorporation necessary for the elaboration to the five-membered D-ring of cephalo-taxine (Scheme 39). (See also Scheme 9, Section III, for the formal total synthesis of cephalotaxine by this method.) Reaction of dihydroisoquinoline 219 with acid chlorides 220 or 221 followed by the addition of aqueous sodium bicarbonate gave carbinolamides 222 or 223, respectively, which, on treatment with 1,3-propanedithiol and boron trifluoride etherate, yielded the ring-opened dithiane 224 or 225. These dithianes were converted by treatment with sodium hydride or potassium rert-butoxide to 226 or 227, respectively. Removal of the dithiane moiety in 226 or 227 by iV-bromosuc-cinimide gave the a-keto esters 228 or 229, which on treatment with Lawes-... 

An example of the construction of a 1,2-diketone from a 1,2-diol comes from the total synthesis of ( )-cephalotaxine (54) where the Corey-Kim conditions were used to convert diol 52 to diketone 53 in 89% yield while other oxidation methods were reported to have failed to affect this conversion.15 The more accessible ketone was then converted to the enol ether and LAH reduction afforded the racemic natural product 54. 

Worden, S.M., Mapitse, R. and Hayes, C.J. (2002) Towards a total synthesis of (—)-cephalotaxine constraction of the BCDE-tetracycUc core. Tetrahedron Lett., 43, 6011. ... 

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]. 

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). 

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... 

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. 

Even though synthetic activity has waned somewhat since the 1980s, this chapter still covers the earlier syntheses of the parent alkaloid, its esters, and the model studies directed toward total synthesis. The readership will be better served by having all published activity in this area placed in context with new developments therefore, the syntheses already discussed in the 1987 review are included in this chapter as well, along with the appropriate updates in the three major areas synthesis of the title alkaloid, preparation of its esters, and new approaches to the skeleton and unnatural derivatives of cephalotaxine that may have been designed from the point of view of medicinal chemists. 

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