Studies on selective metalation and cross coupling reactions of oxazoles for complex natural product synthesis Raphael Wagner, Philipp Wollnitzke, Dirk Menche University of Bonn, Germany As exemplified by the ajudazols, 1,2 complex natural products of myxobacterial origin, oxazoles present key structural features in a broad range of bioactive natural products as well as potent pharmaceutical agents. Usually, these central heterocycles are prepared by condensation of an α-hydroxy amine with a carboxylate followed by oxidation of the resulting oxazoline. This biomimetic approach, as largely developed by the Wipf group. 3 guarantees mild reaction conditions and has been successfully applied in a wide variety of complex natural product total syntheses, including ajudazol B. 4 However, the required linear sequence considerably increases the overall steps and complicates direct adaptability for useful analog synthesis. In contrast, a direct oxazole functionalization enables a much more convergent and modular approach and directly allows for application to analogue synthesis. 5 Our recent progress in the design, evaluation and applicability on specific functionalization of unsubstituted oxazole will be shown. Selective halogenation at C2 and C5 is enabled by a sequential deprotonation strategy that is based on the different pKa values of these positions, while a halide at C4 may be introduced by an optimized halogen dance reaction. Efficient approaches for subsequent cross coupling reactions involving sp 2 -sp 2 and sp 2 -sp 3 couplings will be given and the applicability of these approaches for complex target syntheses will be discussed. Along these lines, a highly potent but dramatically simplified ajudazol derivative has been found that demonstrates extremely potent apoptotic activity in neuroblastoma cells in low nanomolar concentrations. This compound was obtained in only nine steps from commercial material, which compares favorably to conventional condensation approaches 4 and demonstrates the high potential and true applicability of direct oxazole derivatization in complex functional compound synthesis. It is expected that these procedures will find further applications in complex target synthesis.
References 1. R. Jansen, B. Kunze, H. Reichenbach, G. Höfle, Eur. J. Org. Chem. 2002 , 917-921. 2. B. Kunze, R. Jansen, G. Höfle, H. Reichenbach, J. Antibiot. 2004 , 57 , 151-155. 3. P. Wipf, C. P. Miller, J. Org. Chem. 1993 , 58 , 3604. 4. S. Essig, S. Bretzke, R. Müller, D. Menche, J. Am. Chem. Soc. 2012 , 134 , 19362-19365. 5. P. Wollnitzke, S. Essig, J. P. Gölz, K. von Schwarzenberg, D. Menche, Org. Lett. 2020 , 22 , 6344.
P78
© The Author(s), 2023
Made with FlippingBook Learn more on our blog