Asymmetric Total Synthesis of (+)-Milbemycin D

The enantioselective total synthesis of the potent
antiparasitic agent milbemycin D (1) has been
achieved.
The spiroketal fragment is prepared through a novel
spiroketalization of a hydroxy pyrone to set the anomeric
stereocenter and establish functionality for the stereocontrolled
attachment and subsequent extension of the connecting
chain between the spiroketal and the hexahydrobenzofuran fragment.
The hexahydrobenzofuran fragment is constructed
through the exploitation of a sequential electrophilic
cyclization−[2,3]-sigmatropic rearrangement to close the
oxygen-containing ring and incorporate the C5 hydroxyl. A lithium bromide
accelerated Wittig olefination joins the spiroketal-containing subunit and the hexahydrobenzofuran subunit at the
C10,11 double bond in high yield. Subsequent
oxidation
of the C1 hydroxyl provides access to the seco acid, which smoothly
undergoes macrolactonization. The sensitive
C2 stereochemistry and the C3,4 double bond are incorporated without
epimerization at C2 or migration of the C3,4
double bond.