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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Synthetic Studies of Antitumor Macrolide Rhizoxin: Stereoselective Syntheses of the C(1)-C(9) and C(12)-C(26)
Steven D. Burke1, Jian Hong, Joseph R. Lennox
1Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, and Department of Chemical Sciences, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
Abstract:
A triply convergent synthetic approach which culminates in the enantioselective syntheses of the C(1)-C(9) and C(12)-C(26) subunits of the macrolide antitumor agent rhizoxin is described. The central C(12)-C(20) subunit 4 has been prepared efficiently via diastereoselective enzymatic acetate hydrolysis of 15 with porcine pancreatic lipase, a chelation-controlled Ireland-Claisen rearrangement (10 --> 12) combined with kinetic bromolactonization (12 --> 14), and Mitsunobu inversion (23 --> 26) to introduce the three contiguous C(15)-C(17) stereocenters. Formation of the C(18)-C(19) trisubstituted (E)-olefin was achieved by a stereoselective Horner-Wadsworth-Emmons reaction. The central segment 4 and the oxazole chromophore side chain 3 were coupled using another highly stereoselective Horner-Wadsworth-Emmons reaction. Two different lactone subunits [C(1)-C(9) segment 5 and C(3)-C(10) segment 47] were also prepared, employing a thermodynamically controlled diastereotopic group differentiation tactic for establishing the C(5) stereochemistry.
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