Mitragynine, a corynanthe-type indole alkaloid, constitutes the major constituent of the plant Kratom which has a long history of use in many regions of South East Asia for treatment of various ailments including pain and opioid dependence. The use of kratom in the U.S. has been on the rise and numerous anecdotal reports suggest efficacy in self-medication for treatment-resistant pain syndromes, depression, anxiety, and substance use disorders. Mitragynine is a partial mu-opioid receptor (MOR) agonist with a G protein-biased signaling profile. Mitragynine analogs thus provide the opportunity for gaining new insights into the chemical biology of opioid receptors and access to new chemical modulators of these receptors<br/>Mitragynine(MG) is readily available from kratom by extraction, providing a strong incentive to develop “late-stage C-H functionalization”, to allow for rapid SAR exploration and lead compound optimization. The SAR of the indole ring of MG has not been systematically examined and the C11 position (C6 position in indole numbering) in particular has remained unexplored mainly due to inability of chemical methods to target C11 position overriding the intrinsic propensity of indoles to direct functionalization at the C12 position. In our work we show that iridium-catalyzed borylation is compatible with the complexity of mitragynine’s structure, affording exclusively the C12 boronate ester. Re-routing the positional selectivity from C12 to C11 by temporarily converting mitragynine to the mitragynine-ethylene glycol adduct (MG-EG) gave high C11 selectivity (&gt;16:1). Thus, we were able to synthesize various analogs of MG-EG. The ethylene glycol moiety can be readily removed under mild reductive condition in one step to yield C11-substituted MG analogs. MG analogs can be converted to the corresponding 7OH series (more potent than mitragynine). <i>Our strategy enables, for the first time, CH functionalization of the C11 position with a wide range of substituents starting directly from the mitragynine natural product, thus permitting systematic exploration of SAR at this position</i>

Ir-catalyzed C-H functionalization of the alkaloid mitragynine – late stage selective functionalization at indole via complex core restructuring

ACS Fall 2020 Virtual Meeting

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