Halichondrin B: Synthesis of the C1-C22 subunit

Two efficient routes to the Cl-C22 subunit of halichondrin B are described. The cage ketal 7, which contains 11 asymmetric centers embedded within the ABCDEF-ring framework, was assembled from M-conduritol E (27) in 18 steps and 4% overall yield. In a separate route, 7 was also synthesized in 18 steps and 2% overall yield from a derivative Of alpha-D-glucoheptonic acid gamma-lactone (62). While the former route installs the fully elaborated C-ring endowed with the correct C12 stereochemistry early in the synthesis, the latter features a late-stage introduction of the C12 stereocenter during the ultimate one-pot Michael addition/ketalization cascade to form the CDE-ring system of the cage. The importance of the C12 stereocenter to the crucial ketalization event is discussed through comparison of these two strategies.