Deoxyharringtonine

Esters of cephalotaxine (85) that are found in Cephalotaxus species are exemplified by deoxyharringtonine (89), isoharringtonine (90), and harring-tonine (91). The acyl portion (92) of deoxyharringtonine (89) derives from the amino-acid leucine. The results published previously in preliminary form (cf. Vol. 8, p. 13) are now available in full.25 Additional information is that (92) serves as a specific precursor for the acyl portions of (91) and (90) and that (93) is not involved in the biosynthesis of the latter. Results of an examination of (89) as a possibly intact precursor for (91) were inconclusive.25... 

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). 

The biosynthesis of the acyl side chain of deoxyharringtonine (110) has been found (124) to involve L-leucine (Scheme 37). 

However, deoxyharringtonine (110) has been synthesized (166-168) by the method summarized in Scheme 57. The lithium salt (274) of 3-methyl-l-butyne was condensed with ethyl tert-butyloxalate to give 275 which, after... 

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 (-)-... 

The Reformatsky reaction of methyl bromoacetate with the 2-oxohexanoylcephalotaxine (26) in the presence of freshly prepared active zinc afforded a mixture of deoxyharringtonine (27) and its C-2 epimer, which were separated by fractional crystallization of their picrates.19 Partial syntheses of homoharringtonine from cephalotaxine have also been reported.20,21... 

Gin utilised the reduction of an alkyl phenyl sulfone in a synthesis of the anti-leukaemia natural product (-)-deoxyharringtonine 61 Treatment of complex sulfone 61 with SmI2-HMPA gave 62 in 74% yield (Scheme 4.51). 

Interest has been expressed by the People s Republic of China in the preparation of cephalotaxine ester alkaloids and analogues, no doubt for the purpose of evaluation of antitumour activity. Thus a number of esters, e.g. (34), (R = Me2CHCH2CH2COCO or PhCOCO), were subjected to Reformatsky reaction with methyl bromoacetate to give, e.g., [34 R = Me2CHCH2CH2C(OH)-(CH2C02Me)C0] (deoxyharringtonine) and [34 R = PhC(0H)(CH2C02Me)C0]. 

Most recently, Japanese researchers have isolated and characterized a number of new compounds from C. harringtonia var. drupacea these are listed in Table II along with their activities against P-388 leukemia cells. For comparison, the activities of the established active compounds harringtonine (2), homoharringtonine (3), deoxyharringtonine (4), and isoharringtonine (7) are also shown. 

Mikolajczak et al (55) reported the first synthesis of deoxyharringtonine (4) in 1974, as shown in Scheme 25. Lithium 3-methylbutyne acetylide (169)... 

Huang (56) and Li (57) also reported the synthesis of deoxyharringtonine (4) starting from saturated keto acid 172. The only difference in their procedure was the use of the Reformatsky reaction, rather than the lithio acetate, to introduce the acetate portion of the final product (Scheme 25). 

Auerbach et al. (58) described the synthesis of the acid side chain of deoxyharringtonine as shown in Scheme 26, in their attempt to prepare deoxyharringtonine. The unsaturated diester 174 was treated with trifluo-... 

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