Synthetic Studies Towards the Total Synthesis of Myrtoidine Open Access

Liu, Junyi (2016)

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The Malagasy alkaloids extracted from Strychnos myrtoides have shown potential antimalarial activity. A total synthesis of the Malagasy alkaloid malagashinine has recently been completed in our lab, and we hypothesized that we would be able to potentially access the analogous alkaloid myrtoidine via a modified synthetic route. We envisioned that we could divergently synthesize myrtoidine from a common synthetic intermediate, which requires the development of a synthetic method that provides access to a crucial 2-(5H)-furanone moiety. Initially, we wished to explore a strategy involving vinylic C-H halogenation at the 6-position in a 3,4-dihydro-2H-pyran model. Using [RhCp*(MeCN)3](SbF6)2 as a catalyst, various iodination, bromination, and chlorination conditions were explored using carboxylic acids or carboxamides as directing groups; however, no desired products could be efficiently isolated due to undesired background addition reaction of the halogenation reagents with our substrate. We have also explored a 6-lithiation of our 3,4-dihydro-2H-pyran-5-carboxylic acid model as a possible method for functionalization at this position. We deprotonated the 6-proton with kOt-Bu and trapped it with stannane, but were unable to proceed to obtain stable compounds. Due to lack of success of the model studies, we are working to build the core structure that is common in both malagashinine and myrtoidine, which will enable the incorporation of the moiety via Stille coupling.

Table of Contents

1. Background 1

2. Model studies of the synthesis of the 2-(5H)-furanone moiety of myrtoidine 2

2.1 Rh(III)-catalyzed C-H halogenation strategies 3

i. Substrate synthesis 4

ii. Regioselective halogenation 5

2.2 Lithiation and stannylation-lithiation strategies 8

i. Lithiation 8

ii. Stannylation-lithiation 11

3. Synthesis of the core structure of myrtoidine in preparation for Stille coupling 12

i. Synthesis of carboxylic acid 813

ii. Synthesis of protected amine 715

4. Conclusion 17

5. Experimental methods 17

References 30


1. Structures of Malagasy alkaloids Malagashanine and myrtoidine 2

2. Synthesized carboxamide substrates 5

3. Structures of the addition products 22

4. Expected chlorination product 24


1. Retrosynthetic analysis for the 2-(5H)-furanone moiety 2

2. C-H halogenation completed by the Glorius group 3

3. Model system for C-H halogenation 4

4. Synthesis of substrate carboxylic acid 2 4

5. Attempts of iodination and bromination of 2 5

6. Addition reactions 6

7. Proposed mechanisms for the addition reaction 7

8. Proposed mechanisms for the elimination 8

9. Model system for lithiation 9

10. Attempts to deprotonate the -proton of 2 10

11. Stannylation-lithiation completed by the Johnston group 11

12. Model system for stannylation-lithiation 11

13. Stannylation-lithiation of 212

14. Stille coupling 12

15. Retrosynthetic analysis for myrtoidine 13

16. Synthesis of homopropargylic alcohol 10 14

17. Iodination of homopropargylic alcohol 10 14

18. Proposed synthesis of carboxylic acid 13 15

19. Proposed synthesis of carboxylic acid 8 15

20. Protection of tryptamine 16

21. Synthesis of protected amine 7 16

22. Coupling of carboxylic acid 8 and protected amine 7 17

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