FULL PAPER DOI: 10.1002/ejoc.201403590 Lewis-Acid-Catalysed Tandem Meinwald Rearrangement/Intermolecular [3+2]- Cycloaddition of Epoxides with Donor–Acceptor Cyclopropanes: Synthesis of Functionalized Tetrahydrofurans Ashok Kumar Pandey, [a] Asit Ghosh, [a] and Prabal Banerjee* [a] Dedicated to Professor Ganesh Pandey on the occasion of his 60th birthday Keywords: Asymmetric synthesis / Cyclization / Oxygen heterocycles / Small ring systems / Epoxides A Lewis-acid-catalysed tandem Meinwald rearrangement/ [3+2]-cycloaddition of epoxides with donor–acceptor cyclo- propanes to synthesize varieties of cis-2,5-aryl-benzyl-substi- Introduction The tetrahydrofuran ring system is an important hetero- cyclic constituent of many biologically active natural prod- ucts. [1] In particular, cis-2,5-disubstituted tetrahydrofurans are found in lignans, [2] polyether antibiotics, [3a] fragrances (1), [3b] antibacterial terpenes (2), [3c] and Sclerophytin A (3) [3d] with potency against mouse leukemia cells (cytotoxic at 1 ng/mL vs. L1210 cell line) [3e] (Figure 1). A number of methods for the preparation of polysubstituted tetra- hydrofurans (THFs) have been explored. [4] In particular, methods for the synthesis of cis-2,5-disubstituted THF de- rivatives have attracted considerable attention, and a variety of these methods have been developed. [5] Donor–acceptor cyclopropanes (DACs) are among the most important three-carbon synthetic equivalents for the construction of natural products. [6] They act as 1,3-dipoles, and undergo [3+n]-annulation reactions with various re- acting partners. [7] In a series of reports, the Johnson group have demonstrated stereoselective [3+2]-annulations of DACs with diverse aldehydes for the synthesis of cis-2,5- diaryl, 2,5-aryl-alkyl, or 2,5-alkyl-alkyl tetrahydrofurans (Scheme 1, approach a). [8] Other groups have also reported the [3+2]-cycloaddition of DACs with carbonyl compounds such as ketones and aldehydes for the synthesis of THFs. [9,10] Epoxides have unique reactivities in the presence of Lewis acid catalysts. They mainly undergo strain-induced C–O bond cleavage and rearrangements, such as Meinwald [a] Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road, Rupnagar, Punjab 140001, India E-mail: prabal@iitrpr.ac.in http://www.iitrpr.ac.in/chemistry/praba Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201403590. Eur. J. Org. Chem. 2015, 2517–2523 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2517 tuted tetrahydrofurans is described. An enantioselective ver- sion of the same transformation was achieved using an InCl 3 – PyBOX catalyst system. Figure 1. Selected natural products containing a cis-2,5-disubsti- tuted THF ring. rearrangements involving proton shifts to produce alde- hydes. [11] Recently, the Zhang group reported a Lewis-acid- catalysed Meinwald rearrangement/cycloaddition reaction between two differently functionalized oxirane derivatives to produce substituted 1,3-dioxolane derivatives (Scheme 1, approach b). [12] Wang et al. reported an intramolecular [3+2] cross-cycloaddition between an epoxide and a DAC incorporating a Meinwald rearrangement to synthesize a bridged oxa-[3.2.1] skeleton (Scheme 1, approach c). [13] Re- cently, Shi, Cao, and coworker described a tandem intra- molecular reaction between a DAC and an epoxide incor- porating a rearrangement between the epoxide and a carb- onyl moiety (Scheme 1, approach d). [14] To the best of our knowledge, intermolecular cycloaddition reactions of DACs with epoxides are not known. In this report, we disclose the stereocontrolled synthesis of highly functionalized cis-2,5- disubstituted tetrahydrofuran derivatives through a tandem Meinwald rearrangement/cycloaddition between epoxides