Convergent Assembly of Highly Oxygenated Natural Products Enabled by Intermolecular Radical Reactions

ConspectusNatural products with a high ratio of sp3-hybridized atoms and oxygen-substituted stereogenic centers represent privileged structures for the development of pharmaceuticals and chemical probes. The multiple oxygen functionalities of these natural products endow their potent and selective biological activities, although they significantly heighten the challenge of their chemical assemblies. We focused on developing efficient strategies for the total syntheses of this biologically and chemically important class of molecules. A convergent strategy is more advantageous than a linear strategy for designing a shorter synthetic route because a convergent strategy enables direct coupling of functionalized fragments whereas a linear strategy involves stepwise construction of a molecule from its terminus. Radical reactions are preferred over polar reactions for the coupling of heavily functionalized and sp3-rich fragments, as they allow for C(sp3)-C(sp3) coupling without damaging diverse polar functional groups. With these considerations in mind, we designed radical-based convergent strategies for assembling highly oxygenated natural products. Here we summarize the concise total syntheses of asimicin (1, antibiotic activity), 1-hydroxytaxinine (2, cytotoxicity), polyoxins (3, antifungal activity), and hikizimycin (4, anthelmintic activity) as representative examples. Retrosynthetic disconnection at the central part of these molecules produces highly substituted α-alkoxy radicals as synthons. In the synthetic direction, the α-alkoxy radicals were generated from the corresponding α-alkoxyacyl tellurides in a unified fashion, and then utilized for four distinct coupling reactions. Formation of the Et radical from Et3B and O2 homolytically cleaves the C-Te bond of α-alkoxyacyl telluride, and the facile expulsion of carbon monoxide from the acyl radical leads to the α-alkoxy radical. Dimerization of the stabilized α-alkoxy radical resulted in the core structure of 1 with 10 contiguous stereocenters. The coupling adduct was derivatized to 1 through the attachment of two different carbon chains (17 steps as the longest linear sequence). Alternatively, intermolecular addition reactions of the α-alkoxy radicals to electron-deficient C═C, C═N, and C═O bonds, followed by Et3B-mediated radical termination, led to the core structures of 2, 3, and 4, respectively. Intermolecular coupling between the α-alkoxy radical and the cyclohexenone derivative and intramolecular pinacol coupling gave rise to the 6/8/6-fused ring system of 2, which was transformed to 2 (26 steps). The two amino acid moieties of 3 were prepared by combining the α-alkoxy radical and the oxime and were then condensed to complete the synthesis of 3 (11 steps). Furthermore, a combination of α-alkoxyacyl telluride and Et3B/O2 realized a novel addition reaction of α-alkoxy radicals to aldehydes. This method was incorporated in the construction of the core 4-amino-5-deoxyundecose with 10 contiguous stereocenters, which was fabricated with two appendage structures to deliver 4. The four total syntheses described here demonstrate the versatility and robustness of intermolecular radical reactions. These syntheses will also provide new insights for retrosynthetic analyses in the field of organic chemistry and streamline synthetic routes to various bioactive natural products with multiple oxygen functionalities.