The Chemistry of Kratom [<i>Mitragyna speciosa</i>]: Updated Characterization Data and Methods to Elucidate Indole and Oxindole Alkaloids

Abstract

Two separate commercial products of kratom [<i>Mitragyna speciosa</i> (Korth.) Havil. Rubiaceae] were used to generate reference standards of its indole and oxindole alkaloids. While kratom has been studied for over a century, the characterization data in the literature for many of the alkaloids are either incomplete or inconsistent with modern standards. As such, full ¹H and ¹³C NMR spectra, along with HRESIMS and ECD data, are reported for alkaloids <b>1</b>-<b>19</b>. Of these, four new alkaloids (<b>7</b>, <b>11</b>, <b>17</b>, and <b>18</b>) were characterized using 2D NMR data, and the absolute configurations of <b>7</b>, <b>17</b>, and <b>18</b> were established by comparison of experimental and calculated ECD spectra. The absolute configuration for the <i>N</i>(4)-oxide (<b>11</b>) was established by comparison of NMR and ECD spectra of its reduced product with those for compound <b>7</b>. In total, 19 alkaloids were characterized, including the indole alkaloid mitragynine (<b>1</b>) and its diastereoisomers speciociliatine (<b>2</b>), speciogynine (<b>3</b>), and mitraciliatine (<b>4</b>); the indole alkaloid paynantheine (<b>5</b>) and its diastereoisomers isopaynantheine (<b>6</b>) and epiallo-isopaynantheine (<b>7</b>); the <i>N</i>(4)-oxides mitragynine-<i>N</i>(4)-oxide (<b>8</b>), speciociliatine-<i>N</i>(4)-oxide (<b>9</b>), isopaynantheine-<i>N</i>(4)-oxide (<b>10</b>), and epiallo-isopaynantheine-<i>N</i>(4)-oxide (<b>11</b>); the 9-hydroxylated oxindole alkaloids speciofoline (<b>12</b>), isorotundifoleine (<b>13</b>), and isospeciofoleine (<b>14</b>); and the 9-unsubstituted oxindoles corynoxine A (<b>15</b>), corynoxine B (<b>16</b>), 3-epirhynchophylline (<b>17</b>), 3-epicorynoxine B (<b>18</b>), and corynoxeine (<b>19</b>). With the ability to analyze the spectroscopic data of all of these compounds concomitantly, a decision tree was developed to differentiate these kratom alkaloids based on a few key chemical shifts in the ¹H and/or ¹³C NMR spectra.