Enantioselective Total Synthesis of (+)-EBC-23, a Potent Anticancer Agent from the Australian Rainforest

Abstract

We describe here an enantioselective synthesis of (+)-EBC-23, a potent anticancer agent from the Australian rainforest. Our convergent synthesis features a [3+2] dipolar cycloaddition of an olefin-bearing 1,3-syn diol unit and an oxime segment containing 1,2-syn diol functionality as the key step. The segments were synthesized in a highly enantioselective manner using Noyori asymmetric hydrogenation of a β-keto ester and Sharpless asymmetric dihydroxylation of an α,β-unsaturated ester. Cycloaddition provided isoxazoline derivative which upon hydrogenolysis furnished the β-hydroxy ketone expediently. A one-pot, acid-catalyzed reaction removed the isopropylidene group, promoted spirocyclization, constructed the complex spiroketal lactone core, and furnished EBC-23 and its C11 epimer. The C11 epimer was also converted to EBC-23 by chemoselective oxidation and reduction sequence. The present synthesis provides convenient access to this family of natural products in an efficient manner.

Figure 1.

Structures of EBC-23 (1a) and related family of natural products.

Scheme 1.

Retrosynthesis of EBC-23 (1a)

Scheme 2.

Synthesis of Functionalized Alkene 13

Scheme 3.

Synthesis of Functionalized Aldoxime 18

Scheme 4.

Convergent Synthesis of EBC-23 (1a)

Scheme 5.

Synthesis of EBC-23 Epimer (22) and Epimerization of C11 Stereochemistry