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, containing nine asymmetric centers, is prepared in 14 steps from alpha-D-glucoheptonic acid gamma-lactone (7). Key steps in the two similar routes described 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 3involving in situ silyl ether cleavage, acetal hydrolysis, Michael addition, and caged ketal formation. Alternative protocols for carbinol inversion at C(11), one early and one late in the synthetic sequence, are also described.
Burke
S D
SD
Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706-1396, USA. burke@chem.wisc.edu
Jung
K W
KW
Lambert
W T
WT
Phillips
J R
JR
Klovning
J J
JJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D004988:Ethers, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D007202:Indicators and Reagents; D018942:Macrolides; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D000095662:Polyether Polyketides
D000970:Antineoplastic Agents; D004988:Ethers, Cyclic; D007202:Indicators and Reagents; D018942:Macrolides; C070519:halichondrin B; D000095662:Polyether Polyketides