Extending the scope of the Ferrier reaction: fragmentation-rearrangement reactions of selectively substituted 1,2-cyclopropanated glucose derivatives Muganza Munyololo, David W. Gammon ⇑ , Ilka Mohrholz Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa article info Article history: Received 12 December 2011 Received in revised form 10 January 2012 Accepted 11 January 2012 Available online 21 January 2012 Keywords: Ferrier reaction Cyclopropanated sugars Glycals abstract Two further variations of the Ferrier-type allylic rearrangements of 1,2-cyclopropanated glucose derivatives bearing an acetoxylated carbon at the 1 0 -position are described. In the first, treatment of the cyclopropanated sugar with a nucleophile (ROH, PhSH, azide) and Lewis acid (BF 3 Et 2 O or Al(OTf) 3 ), gives 2-C-vinyl glucosides in good yields and a-selectivities. Alternatively, treatment with a combination of Lewis acid and acetic acid leads to a novel fragmentation-rearrangement to form a 2,3-dehydro-2-for- myl-C-glycoside. NuH, BF 3 . Et 2 O or Al(OTf) 3 , O OBn BnO BnO Nu R O OBn BnO BnO H H R OAc R = H, Bu O OBn BnO BnO H H O OEt Al(OTf) 3, AcOH, H 2 O (R = H) O BnO BnO O Me H H CH 2 Cl 2 CH 2 Cl 2 or CH 3 CN Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Since first reported in 1980s the Ferrier rearrangement of gly- cals 1 has continued to attract interest, as a basis for modification of the sugar skeleton to provide key intermediates for the synthesis of important natural products or templates for diversity-oriented synthesis. The key features required for this reaction are an exo- or endo- double bond at C-1, and a leaving group at the allylic position. Explorations of the scope and range of the rearrangement have focused on two broad aspects: the extensive array of catalysts which promote the reaction together with the associated subtle differences in reactivity and selectivity, and the synthetic scope of the reaction inherent in the endo or exo orientation of the olefin, or the replacement of the olefin by a cyclopropyl group. 2,3 These possibilities, and the outcomes of the Ferrier rearrangement, are summarized in a generalized way in Scheme 1. Option A (Scheme 1) represents the classical and by far most widely investigated Ferrier rearrangement involving an endo olefin, and resulting mainly in 2,3-anhydroglycosides, with rare instances of insertion of the incoming nucleophile at the site of the leaving group. 4 Option B also incorporates an endocyclic olefin, but has the allylic leaving group external to the ring, resulting in the formation of a 2-C-methylene glycoside. 5 Option C could be classed as an ‘exo-Ferrier’ rearrangement, and gives rise to branched 1-C- vinyl-glycosides. 6 These options are then supplemented by a series of Ferrier-type fragmentations of 1,2-cyclopropanated sugars, most of which are described in reviews of cyclopropanated sugars. 2,3 In option D the application of standard Ferrier conditions to the otherwise-unsubstituted cyclopropanes results in ring-expansion to form oxepines, 7 while in option E an acetonide-bearing cyclopropanated sugar could be fragmented under Lewis acid catal- ysis to yield 2-C-acetonyl glycosides. 8 Option F illustrates the en- hanced reactivity of lactonized cyclopropanes, which are easily activated by Lewis acids in contrast to their ester counterparts. 3 Finally, there is a single example in the literature, shown in option G, where a 1,2-cyclopropanated sugar bearing an ‘allylic’ hydroxyl 0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2012.01.006 ⇑ Corresponding author. E-mail address: david.gammon@uct.ac.za (D.W. Gammon). Carbohydrate Research 351 (2012) 49–55 Contents lists available at SciVerse ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres