An oxepinone route to carbohydrate based oxepines Steve Castro, Courtney S. Johnson, Bikash Surana, Mark W. Peczuh * Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U-3060, Storrs, CT 06269, USA article info Article history: Received 11 May 2009 Received in revised form 15 July 2009 Accepted 16 July 2009 Available online 23 July 2009 Keywords: Carbohydrate based oxepine Synthesis Septanose carbohydrate Cycloisomerization abstract Oxepines are ring expanded analogs of glycals that can be used to prepare septanose carbohydrates. A route to carbohydrate based oxepines that utilizes oxepinones as a key intermediate has been de- veloped. The oxepinone intermediates were prepared via an amine catalyzed cycloisomerization of fu- ranose hemi-ketals. 1,2-Reduction of the oxepinones followed by acetylation provided the novel ring expanded enol ether products. Moderate diastereoselectivity was observed for the reduction based on the starting oxepinone. 1,4-Addition onto the oxepinones was also demonstrated. Overall, the syntheses reported here will allow for ready access to novel ring expanded carbohydrate analogs. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction The development of synthetic routes for the preparation of septanose carbohydrates continues to be an active area of research. Interest in this novel class of compounds owes primarily to the potential biological activities that they possess. A growing body of results suggest that septanosides and other polyhydroxylated seven-membered ring structures may be bound by proteins in a pyranose-mimetic fashion. 1,2 As in the synthesis of natural car- bohydrates, attention has focused on the selective formation of glycosidic bonds involving the septanose residue. Glycosyl donor types include anomeric halides, 3 thioseptanosides, 4 and oxepi- nesdcyclic enol ethers. 5,6 Carbohydrate based oxepines have been key intermediates in our approach toward the synthesis of septanosides. Epoxidation of oxepines yields 1,2-anhydroseptanoses that are susceptible to nu- cleophilic attack. 5 Stereoselective epoxidation and inversion of the 1,2-anhydro species resulted in selective glycosidic bond forma- tion. 7 Alternatively, trapping of the 1,2-anhydroseptanose with thiol/thiolate nucleophiles gave S-septanosides, which are donors in glycosylation reactions. 4 It was the versatility of oxepines that made them attractive synthetic targets. Routes to carbohydrate based oxepines have employed ring closing metathesis (RCM), 8 cyclization–elimination, 9 and photo- cycloisomerization strategies. 6 For example, McDonald has utilized a photocycloisomerization reaction to convert diols such as 1 to oxepines 2 (Eq. 1). 6 We wanted to know whether molecules akin to 4 (Eq. 2) could arise from diol 3 via the same reaction. The acetonide protecting group motif that was essential for cyclization of 1 was included in 3. Reactant 3 differs, however, from 1 in two significant ways. First, the nucleo- phile in 1 is a primary alcohol whereas a secondary alcohol operates in 3. Second, the nature of the propargylic groups of 1 and 3 is different. The propargylic group in 3 is a free alcohol but in 1 it is part of an acetonide. Between these two differences, the prop- argylic alcohol was expected to be especially problematic. HO O O OH O HO O O W(CO) 6 , DABCO hv (350 nm) PhCH 3 , 70 °C > 60% 1 2 ð1Þ OH O O OH O O W(CO) 6 , DABCO hv (350 nm) PhCH 3 , 70 °C O OH O O O O 3 4 ð2Þ * Corresponding author. Tel.: þ1 8604861605; fax: þ1 8604862981. E-mail address: mark.peczuh@uconn.edu (M.W. Peczuh). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2009.07.041 Tetrahedron 65 (2009) 7921–7926 Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet