Tylophorine-related alkaloids

ANTITUMOR AGENTS 248. CHEMISTRY AND ANTITUMOR ACTIVITY OF TYLOPHORINE-RELATED ALKALOIDS... 

The objective of this review article is to provide comprehensive information about isolation, total synthesis, antitumor activity, and structure-activity relationship (SAR) correlations of tylophorine-related alkaloids in order to facilitate the anticipated drug discovery and development of the tylophora class. 

Wei, L. Brossi, A. Morris-Natschke, S. L. Bastow, K. F. Lee, K.-H. Antitumor Agents 248. Chemistry and Antitumor Activity of Tylophorine-Related Alkaloids. In Studies in Natural Products Chemistry, Vol. 34, Atta-ur-Rahman, Ed. Elsevier B.V. Amsterdam, 2008 pp 3—34. 

While sluggish under thermal conditions,274-275 the asymmetric conjugate addition of amines to alkyl crotonates is achieved at room temperature under high pressure (15 kbar).276 Thus, benzylamine can be added to the crotonate derived from 8-p-naphthyl menthol, with virtually complete diastereoselectivity. A related intramolecular 1,4-addition of an amine to a chiral enoate was used in a total synthesis of the alkaloid (-)-tylophorine.277 Additions of amines to chiral iron complexes of type (116) proceed with excellent selectivity and allow the preparation of homochiral p-lactams.l27128,l3() l32 In contrast, the addition of amine nucleophiles to chiral vinylic sulfoxides278-2811 and to chiral vinylsulfoximines281 proceeds with comparably low selectivities. 

Systematic fractionation of an extract of Tylophora crebriflora has furnished six new alkaloids related to tylophorine (Ilia) which possess antitumour activity [37]. These alkaloids and several known phenanthroindolizidines have been tested against a number of experimental neoplasms [38]. Tylo-crebrine (Illb) is active against Ca 755, Murphy Sturm Lymphosarcoma, P-388 lymphocytic leukaemia and L 1210 tylophorine (Ilia) against... 

Grieco s synthesis of cryptopleurine 70 and julandine 68 (see end of section 2.3.1), via an intramolecular imino Diels-Alder reaction for construction of the quinolizidine nucleus, failed in the case of the related indolizidine alkaloid, tylophorine [38]. Submitting phenanthryl amine 113 to the identical aza Diels-Alder conditions used for cryptopleurine only yields by-products (114), as a result of a Clarke-Eschweiler type of cyclization. No tylophorine is detected under these conditions ... 

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