Synthetic Studies of Antitumor Macrolide Rhizoxin: Stereoselective Syntheses of the C(1)−C(9) and C(12)−C(26) Subunits
- 5 September 1998
- journal article
- Published by American Chemical Society (ACS) in The Journal of Organic Chemistry
- Vol. 63 (20) , 6952-6967
- https://doi.org/10.1021/jo980754k
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.Keywords
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