Stereoselective Assembly of a 1,3-Diene
via Coupling between an Allenic Acetate
and a (B)-Alkylborane: Synthetic
Studies on Amphidinolide B1
Amit K. Mandal,† John S. Schneekloth, Jr.,‡ and Craig M. Crews*,†,‡,§
Departments of Chemistry, Molecular, Cellular, and DeVelopmental Biology, and
Pharmacology, Yale UniVersity, New HaVen, Connecticut 06520-8103
craig.crews@yale.edu
Received May 18, 2005
ABSTRACT
The preparation of three fragments for the total synthesis of amphidinolide B1 has been described. The C16 stereochemistry was set by
asymmetric allylic alkylation. C21 and C25 stereogenic centers were set by an enantioselective/diastereoselective double allylation reaction.
The C9 configuration was set by an asymmetric heteroene reaction. A differentially substituted stereodefined 1,3-diene iodide was synthesized
by iodide-mediated SN2′ reaction. A novel stereoselective method to assemble a 1,3-diene by coupling an allenic acetate and (B)-alkylborane
is also reported.
Amphidinolide B1 1, a polyketide-based 26-membered
macrolide, was isolated from a culture of the symbiotic
marine dinoflagellate Amphidinium sp. (strain Y-5) in 1987
by Kobayashi et al.1 Compound 1 exhibits potent and
selective cytotoxicity against L1210 murine leukemia and
KB human epidermoid carcinoma cell lines in vitro (IC50
0.00014 and 0.0042 µg/mL, respectively).1,2 The relative
stereochemistry of the nine stereogenic centers in amphi-
dinolide B1 was determined by X-ray crystallographic
analysis,3 and the absolute stereochemistry was assigned on
the basis of the chemical synthesis of the C22-C26
segment.4 Due to its potent cytotoxic activity and topological
complexities, amphidinolide B1 1 has attracted the attention
of synthetic chemists for over 15 years.5 There have been
several efforts toward the total synthesis of this natural
product; however, no completed total synthesis has yet been
reported. Both Pattenden et al. and Kobayashi et al. reported
elegant approaches toward 1.5d,6 Nishiyama, Chakraborty,
Myles, Lee, and Carter have also rep