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      General approach to the total synthesis of 9-methoxy-substituted indole alkaloids: synthesis of mitragynine, as well as 9-methoxygeissoschizol and 9-methoxy-N(b)-methylgeissoschizol.

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          Abstract

          Herein, the full details of the synthesis of the 9-methoxy-substituted Corynanthe indole alkaloids mitragynine (1), 9-methoxygeissoschizol (3), and 9-methoxy-N(b)-methylgeissoschizol (4) are described. Initially, an efficient synthetic route to the optically active 4-methoxytryptophan ethyl ester 20 on a multigram scale was developed via a Mori-Ban-Hegedus indole synthesis. The ethyl ester of D-4-methoxytryptophan 20 was obtained with a radical-mediated regioselective bromination of indoline 12 serving as a key step. Alternatively, the key 4-methoxytryptophan intermediate 22 could be synthesized by the Larock heteroannulation of aryl iodide 10b with the internal alkyne 21a. The use of the Boc-protected aniline 10b was crucial to the success of this heteroannulation. The alpha,beta-unsaturated ester 6 was synthesized via the Pictet-Spengler reaction as the pivotal step. This was followed by a Ni(COD)(2)-mediated cyclization to set up the stereocenter at C-15. The benzyloxy group in 31 was removed to provide the intermediate ester 5. This chiral tetracyclic ester 5 was employed to accomplish the first total synthesis of 9-methoxygeissoschizol (3) and 9-methoxy-N(b)-methylgeissoschizol (4) as well as the opioid agonistic indole alkaloid mitragynine (1).

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          Author and article information

          Journal
          J. Org. Chem.
          The Journal of organic chemistry
          American Chemical Society (ACS)
          1520-6904
          0022-3263
          Jan 02 2009
          : 74
          : 1
          Affiliations
          [1 ] Department of Chemistry and Biochemistry, University of WisconsinMilwaukee, 3210 North Cramer, Milwaukee, Wisconsin 53211, USA.
          Article
          10.1021/jo801839t NIHMS91993
          10.1021/jo801839t
          2654583
          19046119
          1d90b50f-a8fd-4c0b-b0d9-6bfe4bcbd563
          History

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