Effect of ether versus ester tethering on Heck cyclizations Steven R. Woodcock and Bruce P. Branchaud * Department of Chemistry, University of Oregon, Eugene, OR 97403, USA Received 8 July 2005; accepted 16 August 2005 Available online 6 September 2005 Abstract—Ether tethers allow Heck cyclizations to proceed in high yields. Ester tethers lead to low yields. Styrene trapping experi- ments indicate that ester reactions form viable organopalladium intermediates that cannot cyclize efficiently. Ó 2005 Elsevier Ltd. All rights reserved. Heck cyclizations 1 to form a six-membered ring were investigated for the synthesis of the phenanthri- done alkaloid (+)-pancratistatin and analogs. 2 Model ether-tethered and ester-tethered cyclizations were studied (Scheme 1). Allyl 2-iodobenzyl ether (1), 3 allyl 2-iodobenzoate (3), 4 cyclohexenyl 2-iodobenzyl ether (5), 5 and cyclohexenyl 2-iodobenzoate (7) 6 were sub- jected to previously-studied Heck conditions [Pd(OAc) 2 (10mol%), PPh 3 (20mol%), Et 3 N (2 equiv), AgNO 3 (1equiv),MeCN,80 °C], 2 andtheproductswereisolated byflashchromatography.Forether-tetheredaryliodides 1 and 5,cyclizationgavehighyieldsofproducts 2a+2b 7 and 6a+6b 8 (Table1).Ester-tetheredaryliodides 3 and 7 gave only unreacted starting material and deiodinated, uncyclized products 9 and 10. Ester-tethered cyclization products 4 9 and 8a+8b 8 wereproducedintraceamounts. Oxidation 10 of cyclic ethers 6a+6b with PCC provided cyclic esters 8a+8b in good yield (59%). 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.08.072 Keywords: Heck cyclization; Tethered cyclization; Ester rotation barrier. * Corresponding author. Tel.: +1 541 346 4627; fax: +1 541 346 0487; e-mail: bbranch@uoregon.edu Scheme 1. Reagents and conditions: (a) Pd(OAc) 2 (10mol%), PPh 3 (20mol%), Et 3 N (2 equiv), AgNO 3 (1 equiv), MeCN, 80 °C. (b) Pd(OAc) 2 (10mol%),KOAc(2equiv),Bu 4 NBr(1equiv),4A ˚ MS,DMF,80 °C.(c)PCC,Celite,CH 2 Cl 2 ,rt.(d)Styrene(3equiv),Pd(OAc) 2 (10mol%),PPh 3 (20mol%),Et 3 N(2equiv),AgNO 3 (1equiv), MeCN, 80 °C. Tetrahedron Letters 46 (2005) 7213–7215 Tetrahedron Letters