Halichondrin B: Synthesis of the C(1)-C(15) subunit

A short and efficient synthesis of the C(1)-C(15) subunit of halichondrin B in its natural configuration is described. The polycyclic caged ketal 3, c ontaining nine asymmetric centers, is prepared in 14 steps from alpha-D-glu coheptonic acid gamma-lactone (7). Key steps in the two similar routes desc ribed include EtMgBr-promoted pinacol ring expansions of hydroxy mesylates 23 and 34, intramolecular Michael additions of 29 and 37, and a one-pot, HF -induced conversion of 4 to 3 involving in situ silyl ether cleavage, aceta l hydrolysis,Michael addition, and caged ketal formation. Alternative proto cols for carbinol inversion at C(11), one early and one late in the synthet ic sequence, are also described.