A Bioinspired Approach toward the Complex Cyclotaxane Taxpropellane

Taxpropellane is a structurally unique and complex member of the taxane family. Taxpropellane features two additional transannular C-C bonds and a hemiketal C-O bond embedded in the classical 6-8-6 taxane skeleton. Consequently, its sterically highly compact and caged hexacyclic scaffold with 11 contiguous stereocenters, including five all-carbon quaternary centers, renders it one of the most complex taxane diterpenes. Here we report a bioinspired approach for the efficient semisynthesis of a C1,C7-oxygenated taxpropellane analogue 18 in 15 steps from 10-deacetylbaccatin III. Key transformations included: (1) a bioinspired singlet oxygen ene reaction to prepare the 2+2 cycloaddition precursor 17 with a sterically hindered C3-C4 tetrasubstituted double bond; (2) a 2+2 cycloaddition/hemiketalization cascade reaction to efficiently assemble the desired two transannular C-C bonds and a hemiketal C-O bond, allowing conversion of the classical 6-8-6 core to the highly intricate 6-4-5-5-6-5 taxpropellane core in a single step. This work offered broader insight into the biosynthetic relationships between classical and nonclassical taxanes. Several synthetic taxpropellane analogues (e.g., 41 and 42) displayed potent cytotoxicity against different cancer cell lines.