| A novel approach to the synthesis of 1,7-dioxaspiro[5.5]undecanes is described. The utilization of an intermolecular dehydrative ketalization followed by ring-closing metathesis resulted in the formation of a 6,8-dioxabicyclo[3.2.1]octane. This served as a conformationally biased template for the introduction of functionalization. Acid-catalyzed bicyclic acetal-tospiroketal rearrangement provided spiroketals in high yields and excellent diastereoselectivity.; Efforts towards the synthesis of the C22--C36 segment of halichondrin B are also described. Two-directional elaboration of a meso-symmetric substrate resulted in the formation of all stereocenters needed for the G- and H-rings. A formal desymmetrization was accomplished with Sharpless asymmetric epoxidation to introduce oxygen functionalities at C24 and C32. Pd(0)-mediated double cycloetherification to form the G, H-ring system was accomplished with Trost's (R,R)-DPPBA chiral ligand to set the C23 and C33 stereocenters. Functionality on the two rings was differentiated by selective protection of the equatorial H-ring C32 alcohol followed by Sharpless asymmetric dihydroxylation of the equatorial G-ring vinyl group. Finally, radical induced deoxygenation of the C24 xanthate removed the extraneous hydroxyl group to give the elaborated G, H-ring system in 21 steps and an overall yield of 1.7% from cis-4-cyclopentene-1,3-diol. |
