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.
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).
Ma
Jun
J
Department of Chemistry and Biochemistry, University of WisconsinMilwaukee, 3210 North Cramer, Milwaukee, Wisconsin 53211, USA.
Yin
Wenyuan
W
Zhou
Hao
H
Liao
Xuebin
X
Cook
James M
JM
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000077743:Diterpene Alkaloids; D026121:Indole Alkaloids; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D046948:Secologanin Tryptamine Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
C412061:9-methoxy-Nb-methylgeissoschizol; C524008:9-methoxygeissoschizol; D000470:Alkaloids; D000077743:Diterpene Alkaloids; D026121:Indole Alkaloids; D007211:Indoles; D046948:Secologanin Tryptamine Alkaloids; C001801:mitragynine