Synthesis, Equilibration, and Coupling of 4-Lithio-1,3-dioxanes:  Synthons for syn- and anti-1,3-Diols

Abstract

Configurationally defined alpha-alkoxylithium reagents were prepared by reductive lithiation of 4-(phenylthio)-1,3-dioxanes. A new and more general synthesis of 4-(phenylthio)-1,3-dioxanes has been developed on the basis of the reduction and in situ acetylation of 1,3-dioxan-4-ones. For each of the substitution patterns examined (23a-d), reductive lithiation gave the axial alkyllithium (24a-d) with 99:1 stereoselectivity. Equilibrations of these alkyllithium reagents were possible with unhindered substrates to give the equatorial alkyllithiums 26a and 26b with excellent stereoselectivities. The more hindered axial alkyllithium reagents (24c, 24d) did not equilibrate efficiently. The equilibrium between alkyllithium reagents 24c and 26c strongly favors the equatorial isomer 26c. The inefficient equilibration with this hindered substrate is attributed to a slow rate of equilibration rather than insufficient driving force. These alkyllithium reagents could be coupled with a variety of electrophiles with retention of configuration by direct addition, copper-mediated coupling, or transmetalation to the corresponding alkylzinc reagent followed by copper-mediated coupling.

Utilization of α‐Oxygenated Radicals in Synthesis

“…Both alkyl substituents on the tetrahydropyran ring function to effectively lock the ring into a defined conformation. Reductive lithiations of 4-phenylthio-l,3-dioxanes provide efficient entries into 4-lithio-l,3-dioxanes, which are useful synthons for syn-or anti-l,3-diols [22]. An application of reductive lithiation in the partial synthesis of the polyene macrolide antibiotic lienomycin is shown in Scheme 14 [9].…”

Umpolung Reactivity in the Stereoselective Synthesis of S‐Linked 2‐Deoxyglycosides

“…[21,22] The 2-deoxyglycosyl lithium species 5 may then react with a sugar-derived asymmetric disulfide (e.g. 6) to afford the desired S-linked 2-deoxy-a-oligosaccharide (in this case 7).…”

“…[30] With 2-deoxyglycosyl phenylsulfides 4 a-f and sugarderived disulfides 6 a-d in hand, we carried out the key Sglycosylation reactions based on umpolung reactivity. Reductive lithiation [21,22] of a mixture of 2-deoxy a-and b-glycosyl donors 4 a (1.2 equiv) at À78 8C with lithium 4,4'-di-tertbutylbiphenyl (LiDBB) [34] …”

“…In all these experiments, the yield of product 24 as calculated on the basis of recovered disulfide acceptor 6 a was nearly quantitative. Therefore, competitive deprotonation of THF [22] by the glycosyl lithium species during epimerization was believed to be the major side reaction. In the hope that the use of less acidic solvents would suppress competitive deprotonation, [22] the epimerization was attempted at À20 8C in hexane/THF Table 1, entry 4).…”

“…Therefore, competitive deprotonation of THF [22] by the glycosyl lithium species during epimerization was believed to be the major side reaction. In the hope that the use of less acidic solvents would suppress competitive deprotonation, [22] the epimerization was attempted at À20 8C in hexane/THF Table 1, entry 4). When the amount of the glycosyl phenylsulfide donor 4 d used was increased to 1.5 equivalents, the yield of product 24 improved to 71 % (Table 1, entry 5), and it was finally discovered that the use of 2.0 equivalents of 4 d was sufficient to afford the desired 2-deoxy-b-disaccharide 24 in 93 % yield with excellent b/a selectivity (entry 6).…”