The asymmetric, stereocontrolled total syntheses of (+) and (-)-spirotryprostatin B (2) are described. Formation of the core pyrrolidine ring was accomplished via a diastereoselective asymmetric [1,3]-dipolar cycloaddition reaction. Addition of 3-methoxy-3-methylbutanal to (5R,6S)-2,3,5,6-tetrahydro-5,6-diphenyl-1,4-oxazin-2-one generated an azomethine ylide that reacted with ethyl oxindolylidene acetate to furnish the desired cycloadduct (11) that possessed the correct relative and absolute stereochemistry of natural spirotryprostatin B. The key dipolar cycloaddition reaction sets four contiguous stereogenic centers. Reductive cleavage of the oxazinone generated the spiro-oxindole pyrrolidine (19) that was coupled to d-proline benzyl ester and cyclized to the pentacyclic diketopiperazine 22. A Barton-modified Hunsdiecker protocol effected oxidative decarboxylation to yield 12-epi-spirotryprostatin B (30). Thermodynamic epimerization of the d-proline stereogenic center with sodium methoxide yielded spirotryprostatin B as the major product. The antipode of the natural product, ent-spirotryprostatin B, was prepared from (5S,6R)-2,3,5,6-tetrahydro-5,6-diphenyl-1,4-oxazin-2-one. Several synthetic intermediates and spirotryprostatin analogs were tested for their activity as G2/M phase cell cycle inhibitors and microtuble assembly against 3Y1 and tsFT210 mammalian cells.
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