Stereoselective synthesis of the C 9 –C 19 lactone-dipropionate fragment of calyculin C Kaisa Karisalmi and Ari M. P. Koskinen * Laboratory of Organic Chemistry, Helsinki University of Technology, PO Box 6100, FIN-02015 HUT, Finland Received 23 June 2004; revised 24 August 2004; accepted 2 September 2004 Abstract—A highly diastereoselective synthesis of the title fragment of calyculin C has been developed based on an internal asym- metric induction between a chiral aldehyde and Z-crotyl trifluorosilane. Ó 2004 Elsevier Ltd. All rights reserved. Calyculins form a class of highly cytotoxic metabolites from the marine sponge Discodermia calyx originally isolated by Fusetani and co-workers. 1 They have proven to be strong serine/threonine protein phosphatase inhibi- tors 2 and based on this property, calyculins might be potential anti-cancer agents. 3 The C 9 –C 19 lactone-dipropionate fragment 5 of calycu- lin C (boxed in Fig. 1) contains 8 out of the total of 16 stereocenters and is thereby a key substructure of this sponge metabolite. Several different syntheses of this fragment have been published with varying strategies. 4 The most challenging part in the synthesis of this C 9 –C 20 fragment is the anti, anti,anti-stereotetrad, which can be reached either by linear 4e,d or by convergent 4a–c approaches. However, the syntheses published so far have many weaknesses (too many steps, poor diastereoselectivity, or need for inversion of stereocenters). Therefore, improved routes to this fragment are still needed. We have recently published a convergent approach toward the C 9 –C 19 fragment 5 of calyculin C, which unfortunately led to a wrong diastereomer. In this com- munication we would like to present a short, highly dia- stereo-, and enantioselective linear synthesis of the lactone-dipropionate fragment 5 of calyculin C. Our synthesis of C 9 –C 19 fragment of calyculin C is based on a short and highly enantioselective synthesis of the key intermediate 1 5 followed by two asymmetric crotyl- ation reactions (Scheme 1). Armstrong and co-workers have used a similar strategy in their synthesis of the C 9 –C 25 fragment of calyculin 6 but in the last crotylation step they obtained only a disappointing 1:1.3 diastereo- selection. We wished to improve this selectivity by using Z-crotyl trifluorosilane as the crotylation reagent in the second crotylation step. 7 The synthesis of the key intermediate 1 is shown in Scheme 2. 5 The first crotylation reaction was realized with the crotyl borane derived from E-butene and (+)- MeOB(Ipc) 2 (Scheme 3). 8 The reaction yielded a 6:1 mixture of two diastereomeric anti-homoallylic alcohols, the major product 8 being isolated from the mixture by 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.09.012 Keywords: Aldol reactions; Crotylation; Diastereoselectivity; Natural products; Stereoselective synthesis. * Corresponding author. Tel.: +358 9451 2526; fax: +358 9451 2538; e-mail: ari.koskinen@hut.fi MeO N H OH OH Me 2 N O N O O O OMe OH OH CN OH (HO) 2 PO 2 Calyculin C Figure 1. Tetrahedron Letters 45 (2004) xxx–xxx Tetrahedron Letters ARTICLE IN PRESS © 2004 Elsevier Science