Halichondrin B: synthesis of the C(37)–C(54) subunit

A synthesis of the C(37)–C(54) segment of the antimitotic polyether macrolide halichondrin B is described. β-Ketophosphonate , comprising rings L, M, and N of the natural product, contains the C(44) spiroketal, about which local C2 symmetry plays a key strategic role. Based upon recognition of this local C2 symmetry, a Claisen self-condensation of led to the dienone . Asymmetric bis(dihydroxylation) set the C(40), C(41), C(47), and C(48) stereocenters, and the resulting bicyclic spiroketal was oxidized to tetracyclic bis(lactone) . Alcohol was isolated from the mono-functionalization of bis(lactone) via a carbonyl methylenation/hydroboration protocol. Chelation-controlled allylation of the derived aldehyde, followed by diastereoselective iodocarbonate formation and hydrolysis established the C(51)–C(54) sidechain in . Protection of the side-chain hydroxyl groups, and conversion of the remaining lactone to the corresponding β-ketophosphonate provided , a suitable coupling subunit (with a total of 10 asymmetric centers) for the total synthesis of halichondrin B. Overall, a 22 step synthetic route from known epoxide produced (4% overall yield), in its natural configuration.