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Xiao-hua Cai 1 and Bing Xie 1 and Hui Guo 2
Recommended by T. J. Brocksom and A. Iuliano and N. Nishiwaki
1, College of Chemistry and Environmental Science, Guizhou University for Nationalites, Guiyang 550025, China
2, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China
Received 22 January 2011; Accepted 13 February 2011
1. Introduction
During the past few years, indigenous to southeast Asia, the plant genus Aglia includes several species that produce a range of cyclopenta[b]tetrahydrobenzofuran containing metabolites [1-3], including rocaglamide (1) , isolated from the roots and stems of Aglia elliptifolia by King et al. [4]. King's initial report indicated that rocaglamide showed significant in vivo activity in P388 lymphocytic leukemia-infected mice [4]. Since then, rocaglamide and related compounds have shown cytostatic, and cytotoxic activity against a variety of human cancer cell lines, with IC 50 values in the range 1.0-6.0 ng/mL [5-9], has attracted more attention in recent years because of its insecticidal and growth inhibitory activity [10-15]. In order to be useful as drugs, a constant supply of such compounds in a large quantity is required. However, their natural abundance in the plant is quite low, and large-scale isolation from natural sources may not be feasible. Chemical synthesis, either total- or semisynthesis, is an option to produce this type of compounds. Both the structural complexity of rocaglamide and its significant activity make it an attractive synthetic target. Stereoselective synthesis of the dense substitution pattern of these targets is a formidable synthetic challenge: the molecules bear five contiguous stereocenters and cis aryl groups on adjacent carbons. In past years of effort, only a handful of completed total syntheses have been reported, evidence of the difficulties associated with the synthesis of rocaglate natural products. In the present work, several total synthetic approaches of rocaglamide will be reviewed (Scheme 1).
Scheme 1: [figure omitted; refer to PDF]
2. Intramolecular Cyclization Approaches
2.1. Synthesis of Di-Epi-Rocaglamide
An earlier attempt to synthesize rocaglamide (1) by Kraus and Sy in 1989 resulted in the synthesis of the di-epi analog of rocaglamide (6) , as shown in Scheme 2 [16]. Michael addition of benzofuranone 2 to cinnamonitrile 3 gave keto-nitrile 4 in a 5 : 1 diastereomeric ratio. The major isomer was used to prepare