Adjacently linked tetrahydrofuran units constitute the core motifs of widely encountered naturally occurring compounds, as the acetogenins of the Annonaceae1 and certain ionophore antibiotics. 2 The annonaceous acetogenins consist of polyoxygenated, long-chain fatty acids usually incorporating one or two tetrahydrofuran rings and are particularly attractive due to their extremely interesting pharmacological profiles and useful plant-protecting actions. 1 Most of the recently introduced strategies toward acetogenin compounds have been addressed to the linear synthesis of structurally defined targets, 3 while the development of parallel, unified methodologies aimed at preparation of collections of structurally and stereochemically diverse acetogenin analogues has yet to meet such success. 4 Since molecular diversity represents a pivotal concern to access potentially bioactive candidates, we became interested in developing a unified, modular strategy that could possibly secure the construction of a series of oligotetrahydrofurans, as well as related nonnatural sulfur and nitrogen, homogeneous and mixed variants, en route to ensembles of annonaceous acetogenins and their altered congeners. We opted to investigate this domain by using the “silyloxy diene methodology”, 5, 6 a well experienced protocol based on the exploitation of a triad of oxygen-, sulfur-, and nitrogen-based heterocyclic silyloxy dienes, namely, 2-[(tert-butyldimethylsilyl) oxy] furan, TBSOF; 2-[(tert-butyldimethylsilyl) oxy]-thiophene, TBSOT; and N-(tert-butoxycarbonyl)-2-[(tert-butyldimethylsilyl) oxy] pyrrole, TBSOP. As part of this program, we report here the viability of the above project in a chiral, nonracemic domain, en route to a series of bis-tetrahydrofuran, bis-thiolane, and bispyrrolidine precursors, as well as a number of related mixed dinuclear templates derived from the combination of the three heteroatoms of choice, oxygen, sulfur, and nitrogen. We first focused on the preparation of the key electrophilic modules 2a-c, which were readily obtained in 51%, 24%, and 26% yields by starting from the respective precursors TBSOF, TBSOT, and TBSOP and 2, 3-O-isopropylidene-D-glyceraldehyde (1) according to a previously reported, diastereoselective procedure (Scheme 1). 5c, 7 Having the proper building blocks at hand, namely, the three electrophiles 2a-c as well as the three silyloxy diene nucleophiles TBSOF, TBSOT, and TBSOP, we were ready to construct a collection of dinuclear core units systematically, by adopting a uniformed coupling protocol based on a Lewis acidmediated Mukaiyama aldolization. 8 As depicted in Chart 1, addition of TBSOF to activated lactol 2a in the presence of 0.6 equiv of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) in CH2Cl2 at-80 C afforded a separable 45: 55 mixture of two unsaturated lactone intermediates (not shown), which were individually hydrogenated to provide the corresponding saturated counterparts threo, trans-O, O and erythro, trans-O, O in 68% combined yield for the two steps. 9 By extending this chemistry, the entire collection of dinuclear scaffolds comprising all the possible heteroatom combinations (32) was easily assembled as indicated, consisting of 18 (16 shown) constitutionally and/or stereochemically diverse congeners. Inspection of the results in Chart 1 reveals that, under standard conditions, the nine processes behave similarly irrespective of the heteroatom composition, providing acceptable yields of the expected adducts. threo, trans-Configured compounds formed in all reactions, often accompanied by substantial quantities of the corresponding C-4 epimeric erythro, trans derivatives and/or threo, cis …