The Total Synthesis of Daphniphyllum Alkaloids

Daphniphyllum alkaloids have a rich history dating back to the isolation of Daphniphyllum macropodum Miquel in 1909 by Yagi.¹ Pioneering work in the 1960s by Hirata and colleagues resulted in the isolation of daphniphylline and yuzurimine alkaloids, and subsequently, a total of over 330 Daphniphyllum alkaloids have been reported from the Daphniphyllum genus.^2-5 In view of their intriguing biological activities including anti-cancer and  anti-HIV activity, coupled with their complex azapolycyclic structures, various synthetic groups have been engaged in the syntheses of Daphniphyllum alkaloids culminating in over  30 impressive total syntheses.^4-5 This seminar will present a historical perspective on the synthesis of Daphniphyllum alkaloids, beginning with the pioneering studies performed by Heathcock^6-8 utilizing biomimetic tactics.  A series of recent total syntheses of Daphniphyllum alkaloids spanning the period from 2019-2021 reported by the Sarpong⁹, Xu¹⁰, Li¹¹, and Qiu¹² groups will then be presented which feature state-of-the-art synthetic methods towards these complex azapolycyclic natural products.

References:

1) Yagi, S. Daphniphyllum Alkaloid. Kyoto Igaku Zasshi 1909, 6, 208-222.

2) Irikawa, H.; Sakurai, H.; Sakabe, N.; Hirata, Y. Isolation of Two New Alkaloids from Daphniphyllum macropodum Miguel. Tetrahedron Lett. 1966, 7, 5363-5368.

3) Sakabe, N.; Irikawa, H.; Sakurai, H.; Hirata, Y. Isolation of Three New Alakloids from Daphniphyllum macropodum Miguel. Tetrahedron Lett. 1966, 7, 963-964.

4) Chattopadhyaya, A. K.; Henessian, S. Recent Progress in the Chemistry of Daphniphyllum Alakloids. Chem. Rev. 2017, 117, 4104-4146.

5) Guo, L.-D.; Chen, Y.; Xu, J. Total Synthesis of Daphniphyllum Alkaloids: From Bicycles to Diversified Caged Structures. Acc. Chem. Res. 2020, 53, 2726-2737.

6) Heathcock, C. H.; Davidsen, S. K.; Mills, S.; Sanner, M. A. Total Synthesis of (+)-methyl homodaphniphyllate. J. Am. Chem. Soc. 1986, 108, 5650-5651.

7) Ruggeri, R.; Hansen, M. M.; Heathcock, C. H. Total Synthesis of (±)-methyl homosecodaphniphyllate. A Remarkable New Tetracyclization Reaction. J. Am. Chem. Soc. 1988, 110¸8734-8736.

8) Piettre, S.; Heathcock, C. H. Biomimetic Total Synthesis of proto-daphniphylline. Science 1990, 248, 1532-1534.

9) Hugelshofer, C. L.; Palani, V.; Sarpong, R. Calyciphylline B-Type Alkaloids: Total Synthesis of (-)-Daphlongamine H and (-)-Isodaphlongamine H. J. Am. Chem. Soc. 2019, 141, 8431-8435.

10) Guo, L.-D.; Hu, J.; Zhang, Y.; Tu, W.; Zhang, Y.; Pu, F.; Xu, J. Enantioselective Total Synthesis of (-)-Caldaphnidine O via a Radical Cyclization Cascade. J. Am. Chem. Soc. 2019, 141, 13043-13048.

11) Xu, G.; Wu, J.; Li, L.; Lu, Y.; Li, C. Total Synthesis of (-)-Daphnezomines A and B. J. Am. Chem. Soc. 2020, 142, 15240-15245.

12) Wang, B.; Xu, B.; Xun, W.; Guo, Y.; Zhang, J.; Qiu, F. G. A General Strategy for the Construction of Calyciphylline A-Type Alkaloids: Divergent Total Syntheses of (-)-Daphenylline and (-)-Himalensine A. Angew. Chem. Int. Ed. 2021 DOI: 10.1002/anie.202016212.