Total Synthesis of Monensinby the Kishi group in 1979

Zibin Tan

02/25/17

Schmid, G.; Fukuyama, T.; Akasaka, K.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 259.

Fukuyama, T.; Wang, C.-L. J.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 260.

Karanewsky, D. S.; Wang, C.-L. J.; Schmid, G.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 262.

Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis 2003, chapter 12.1

Introduction

• A member of polyether antibiotics, an ionophore.

• Produced by Streptomyces cinnamonensis.

• Isolated and characterized in 1967 by Agtarp et al.

• Commercialized in 1971.

• First total synthesis: Kishi et al. in 1979.

Agtarp, A.; Chamberlin, J. W.; Pinkerton, M.; Steinrauf, L. J. Am. Chem. Soc. 1967, 89, 5737Schmid, G.; Fukuyama, T.; Akasaka, K.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 259.Fukuyama, T.; Wang, C.-L. J.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 260.Karanewsky, D. S.; Wang, C.-L. J.; Schmid, G.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 262.

2

Structure and Biological Utilities of Monensin

• A cyclic structure maintained by H-bonding.

• Exterior is almost non polar hydrocarbon like, while

• Interior is lined with numerous Lewis-basic Oxygen atoms

• Can form complex with metal cations and transport them across lipid membranes, thus destroying the normal ion and charge distribution across the membranes.

X-ray crystal structure of monensin A sodium salt acetonitrile clathrateHuczynski, A.; Ratajczak-Sitarz, M.; Katrusiak, A.; Brzezinski, B. J. Mol. Struct. 2007, 832, 84.Picture of ouroboros: https://commons.wikimedia.org/w/index.php?curid=1533358

3

Challenges in Total Synthesis

• Of 25 carbon atoms constructing the backbone, 17 are chiral.

• 6 chiral carbon atoms are contiguous.

• A spiro bicyclic ketal, 2 substituted tetrahydrofuran ring and a substituted tetrahydropyran ring.

4

Retrosynthetic Analysis and Strategy

Red bonds: bonds to be retrosynthetically cleavedBlue groups: Carbons need to be introduced

5

Thermodynamics Drove the Stereo Selectivity Here

6

Retrosynthetic Analysis of the Left Arm

7

Retrosynthetic Analysis of the Right Arm

8

9

10

11

Summary of Retrosynthetic Analysis

12

Total Synthesis

13

14

15

16

17

18

19

20

21

22

23

24

Conclusion

• First total synthesis of Monensin

• Longest linear route: 37 steps

• Total steps: 73

• Overall yield: 0.12%

• The combination of

a. Wittig reaction/similar chemistry with

b. 1,3-allylic strain controlled stereospecific hydroboration/epoxidation

provided very powerful strategy for introduction of vicinal stereo centers.

• Recruiting of stereochemical induction/communication provided good control of relative stereochemistry.

25

Thank You!

26