Pergamon Tetrahedron 55 (1999) 9089-9100 TETRAHEDRON Synthesis and Biological Evaluation of C-l and Ring Modified A-norpaclitaxels Haiqing Yuan ‘and David G. 1. Kingston* Department of Chemistry, Virginia Polytechnic Institute and State University. Blacksburg, Virginia 24061-0212 Byron H. Long, Craig A. Fairchild, and Kathy A. Johnston Bristol-Myers Squihh Phannaceutical Research Institute, P.O. Box 4OOO. Princeton, New Jersey 05843 Received 18 Febtuaty 1999; accepted 4 June 1999 Abstract. I-deisopropenyl- I-acetoxy-A-norpaclitaxel, I-deisopropenyl-A-norpaclitaxel, l-deiso- pmpenyl-1-acetyl-8,9-oxido_A-norpaclitaxel. and A-nor-C-norpaclitaxel were synthesized. The biological activities of these analogs were determined, and structure-activity relationships for the C-l Position am suggested. Q 1999 Ehevier Science Ltd. All rights reserved. KeywordF: taxoids; Baeyer-Villiger reactions; ozonolysis; rearrangements The novel diterpenoid paclitaxel (1) has become one of the most important anticancer agents for the clinical treatment of ovarian and breast cancer? and extensive Chemical and SAR studies have been carried out.’ Among many studies of structural modifications of this complex tetracyclic molecule, analogs prepared by A-ring, B-ring, and C-ring contractions and by oxetane ring manipulations have all appeared in the literatme. We4 and other? have reported that paclitaxel undergoes rearrangement under a number of acidic conditions to give the A-ring contracted analog A-norpaclitaxel (2). Biological studies indicated that A-norpaclitaxel was about one third as active as paclitaxel in a tubulin assembly assay but was much less cytotoxic than paclitaxel against Burkitt Ac H H 1 7 ‘3% 3 ljH +XL / 1 A 7 C6H5 $? ,..' : 4 d YH - - 2 C6H5 z ,,O $g C6H5 OH OCOc5H5 6H % ',? 1 : 0“ 16 15; Ac6 6~0~~~5 1 2 lymphoma CA 46 cells.4 In Order to extend our knowledge of the SAR of this region, and to explore the differente between the tubulin assembly activity and the cytotoxicity of A-norpaclitaxel, we prepared A- norpaclitaxel derivatives modified on the C-2 benzoyl group and on the double bond of the C-l isopropenyl moiety.6 Interestingly, unlike paclitaxel, whete certain modifications of the C-2 benzoyl group usually increase tubulin assembly activity: the same modifications on A-norpaclitaxel uniformly decreased tubulin assembly activity slightly. On the other hand, certain modifications at the C-l isopropenyl moiety enhanced tubulin assembly activity, in some cases to the Same level as that of paclitaxel.6 Geomett-y and conformation optimized molecular modeling studies using MacSpartan indicated that A-norpaclitaxel has an “inverted cup- shape” which is Email: dkineston8vt.edu FAX: (54O)231-7702 OO4O-4O2O/W/$ - sec front matter 8 1999 Elsevier Science Ltd. All rights reserved. PU: soo4o4020(99)00500-1