Halichondrin B: synthesis of the C1-C22 subunit.
[Reaction: see text]. Two efficient routes to the C1-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 (+)-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.
Lambert
William T
WT
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706-1396, USA.
Hanson
Gregory H
GH
Benayoud
Farid
F
Burke
Steven D
SD
D004988:Ethers, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry*; D018942:Macrolides; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry; D000095662:Polyether Polyketides
D004988:Ethers, Cyclic; D007783:Lactones; D018942:Macrolides; D050257:Tubulin Modulators; C475532:conduritol E; C070519:halichondrin B; D000095662:Polyether Polyketides