Synthesis and conformational studies of calixarene‐analogous trihydroxy[3.3.3]metacyclophanes and their <i>O</i>‐alkylated derivatives

<jats:title>Abstract</jats:title><jats:p>Tri‐<jats:italic>tert</jats:italic>‐butyltrihydroxy[3.3.3]metacyclophane <jats:bold>13</jats:bold> was prepared in 6 steps from <jats:italic>p‐tert</jats:italic>‐butylanisole in 25% overall yield by using the TosMIC method, followed by Wolff‐Kishner reduction and demethylation with boron tribromide. AlCl<jats:sub>3</jats:sub>/MeNO<jats:sub>2</jats:sub>‐catalyzed trans‐<jats:italic>tert</jats:italic>‐butylation of <jats:bold>13</jats:bold> in benzene gave the desired metacyclophane <jats:bold>14</jats:bold> in 85% yield, along with <jats:italic>tert</jats:italic>‐butylbenzene (<jats:bold>15</jats:bold>). Weak intramolecular hydrogen bonding was observed in the triols <jats:bold>13</jats:bold> and <jats:bold>14</jats:bold>.–6,15,24‐Tri‐<jats:italic>tert</jats:italic>‐butyl‐9,18,27‐trihydroxy[3.3.3]MCP <jats:bold>13</jats:bold> was tri‐<jats:italic>O</jats:italic>‐alkylated with alkyl halides (RX: R = Et, Pr, and Bu) in the presence of Cs<jats:sub>2</jats:sub>CO<jats:sub>3</jats:sub> to yield partial‐cone confomer <jats:bold>12b‐d</jats:bold> in quantitative yield. Ring inversion by oxygen‐through‐the‐annulus rotation is allowed for triethoxy derivative <jats:bold>12b</jats:bold> (coalescence temperature ca. 90°C) but inhibited for the tripropoxy‐<jats:bold>12c</jats:bold> and the tributoxy derivative <jats:bold>12d</jats:bold>. The reaction of the triol <jats:bold>13</jats:bold> with ethyl bromoacetate in the presence of Cs<jats:sub>2</jats:sub>CO<jats:sub>3</jats:sub> yielded cone and partial‐cone <jats:bold>12e</jats:bold>, respectively. In contrast, a significant amount of cone conformer <jats:bold>12f</jats:bold> resulted when NaH was used as base. Only when the template metal can hold the ester or amide group(s) and the oxide group(s) on the same side of the [3.3.3]MCP is the conformation immobilized to the cone.–Titration of cone amide <jats:italic>cone</jats:italic>‐<jats:bold>12f</jats:bold> with KSCN monitored by <jats:sup>1</jats:sup>H NMR clearly demonstrates that a 1:1 complex is formed which is stable on the NMR time scale, and the original C<jats:sub>3</jats:sub> symmetry is retained after the complete metal cation complexation.–The stability of multimembered carbon skeletons permits the interconversion of functional groups without special regard to ring‐opening side reactions as was observed for homotrioxacalix[3]arenes with ethereal linkages. For example, the introduction of nitro groups was accomplished on the upper rim by direct threefold <jats:italic>ipso</jats:italic>‐nitration of <jats:italic>tert</jats:italic>‐butyltrimethoxy derivative <jats:bold>12a</jats:bold>.</jats:p>