Synthesis of Novel Retinoid X Receptor-Selective Retinoids

Retinoids <b>1</b>−<b>5</b> have been identified as potent RXR agonists for evaluation in the treatment of non-insulin-dependent (type II) diabetes mellitus (NIDDM). Highly convergent syntheses of <b>1</b>−<b>5</b> have been developed. The core tetrahydronaphthalene <b>7</b>, employed in the synthesis of <b>1</b> and <b>2</b>, was prepared in 98% yield using an AlCl<sub>3</sub>-catalyzed (0.03 equiv) Friedel−Crafts alkylation of toluene with 2,5-dichloro-2,5-dimethylhexane <b>6</b>. A nitromethane-mediated Fridel−Crafts acylation of <b>7</b> with chloromethylnicotinate <b>9</b> was developed to prepare ketone <b>10</b> in 68% yield. Chelate-controlled addition of MeMgCl to <b>10</b> followed by dehydration afforded olefin <b>11</b> in 65% yield. Cyclopropanation of <b>11</b> with trimethylsulfoxonium ylide, followed by saponification, completed a five-step synthesis of <b>1</b> in 33% yield. FeCl<sub>3</sub>-catalyzed (0.05 equiv) Friedel−Crafts acylation of <b>7</b> with chloromethylterephthalate <b>14</b> afforded ketone <b>15</b> in 81% yield. Saponification of <b>15</b> and reaction with 50% aqueous NH<sub>2</sub>OH in AcOH afforded a 9:1 mixture of <i>cis</i> and <i>trans</i> oximes, from which the desired <i>cis</i>-oxime <b>2</b> was isolated in 43% yield. The core bromo-dihydronaphthalene <b>29</b> required for the synthesis of <b>3</b>−<b>5</b> was prepared by a Shapiro reaction. Transmetalation of <b>29</b> and reaction with Weinreb amides <b>30b</b> or <b>36</b> afforded ketones <b>32</b> and <b>37</b>, which were converted into <b>3</b>−<b>5</b> using chemistry comparable to the tetrahydronaphthylene series. Suzuki coupling of boronic acids <b>41</b> and <b>42</b> with vinyl triflate <b>43</b> provided an alternative approach to the synthesis of this class of compounds.