Synthesis of picropodophyllin homolactone Emmanuel Roulland, a Emmanuel Bertounesque, a, * Christiane Huel b and Claude Monneret a, * a UMR 176 CNRS-Institut Curie, Section de Recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France b U 350 INSERM-Institut Curie, Ba Ãtiment 110, Universite  Paris XI, F-91405 Orsay Cedex, France Received 24 May 2000; accepted 5 July 2000 Abstract Based on a Wittig ole®nation strategy, the ®rst synthesis of picropodophyllin homolactone 2 is described in nine steps and 30% overall yield from podophyllotoxine 1. The relative con®guration of 2 was unambiguously determined using 2D NOESY NMR and a Monte Carlo search protocol. This work corrects the literature on the synthesis of 2. # 2000 Elsevier Science Ltd. All rights reserved. We have been engaged in activities 1 in the area of podophyllotoxin 1, 2 a natural product endowed with potent antimitotic activity. The trans-fused lactone moiety is being considered as an important factor for displaying signi®cant cytotoxic activity, 3 the cis analogues being less potent. Less is known concerning six-membered ring lactone analogues. In 1985, Anjanamurthy and Lokanatha Rai 4 reported the synthesis of picropodophyllin homolactone 2. However, it appeared to us that the IR absorption at 1760 cm ^1 was not consistent with a d-lactone functionality. In this communication, we describe the ®rst synthesis of picropodophyllin homolactone 2 via a route which would accomodate a good degree of ¯exibility with respect to the size and nature of the D-ring. The synthesis of picropodophyllin homolactone 2 began with podophyllotoxin 1, which was transformed into 3 5 (97%) through silylation (TBSOTf, 2,6-lutidine, CH 2 Cl 2 ,0  C) of the benzylic 0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(00)01136-9 Tetrahedron Letters 41 (2000) 6769±6773 * Corresponding authors. Tel: +33-(0)1-42-34-66-55; fax: +33-(0)1-42-34-66-31; e-mail: claude.monneret@curie.fr