Practical synthesis of a potent indolocarbazole-based, DNA topoisomerase inhibitor Atsushi Akao, a,p Shouichi Hiraga, a Takehiko Iida, a Asayuki Kamatani, a Masashi Kawasaki, a ToshiakiMase, a TakayukiNemoto, a NobuyaSatake, a StevenA.Weissman, b,p DavidM.Tschaen, b Kai Rossen, b Daniel Petrillo, b Robert A. Reamer b and R. P. Volante b a Process R & D, Banyu Pharmaceutical Co. Ltd, Okazaki, Aichi 444-0858, Japan b Process Research, Merck and Co. Inc., Rahway, NJ 07065, USA Received 8 August 2001; accepted 6 September 2001 Abstract ÐDNA topoisomerase I inhibitors are currently under investigation as cancer chemotherapy agents of which indolocarbazole glycoside 1) has been identi®ed as a promising candidate. A practical, scalable synthesis of 1 that limits the isolation of cytotoxic compounds to only that of the ®nal product is described. The convergent process features a novel phase transfer-promoted glycosylation ofaglyconecore4);subsequenthydrolysisprovidesanhydride8).Thehydrazinefragment3),whichiscoupledwith 8,issynthesizedviaa modi®cation of existing procedures. The coupled product 2) is subsequently hydrogenated to provide 1 in excellent purity via direct crystallization .99.3 A%). q 2001 Elsevier Science Ltd. All rights reserved. 1. Introduction The development of DNA topoisomerase I topo I) inhibi- tors as cancer chemotherapy agents is currently an active area of research. 1 Speci®cally, the indolocarbazole glyco- side class of compounds, such as the rebeccamycin analogs, 2 have been identi®ed as attractive clinical targets. 3 Among them, 1 has emerged based on its potent cytotoxic activity against human cancer cells 4 and its wide safety margin and is currently in clinical trials. We required a practical route to 1 in support of developmental studies as the existing route 5 was not amenable to larger scale syn- thesis. The overriding strategy in this second-generation synthesis was to minimize the handling of topoisomerase- active intermediates. As the chemistry in the early steps dictated using fully protected compounds, coupled with the knowledge that the perbenzylated analog of 1 was not topoIactive, 6 wesoughttoremovetheprotectinggroupsas thelaststepofthesynthesis.Thus,theperbenzylatedanalog 2) became our penultimate target. Tetrahedron 57 2001) 8917±8923 Pergamon TETRAHEDRON 0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII:S0040-402001)00895-X Keywords: indolocarbazole; topoisomerase; glycosylation. p Corresponding authors. Tel.: 11-732-594-3589; fax: 11-732-594-1499; e-mail: steven_weissman@merck.com Scheme 1.