SmI₂‑Mediated Intermolecular Coupling of γ‑Lactam <i>N</i>‑α-Radicals with Activated Alkenes: Asymmetric Synthesis of 11-Hydroxylated Analogues of the Lead Compounds CP-734432 and PF-04475270

We report, for the first time, the synthesis of 8-aza-analogues of PGE₂. The SmI₂-mediated cross coupling reactions of γ-lactam-hemiaminal <b>9</b>, lactam 2-pyridyl sulfide <b>17</b>, and lactam 2-pyridyl sulfone <b>18</b> with activated alkenes/alkyne were first developed, giving the corresponding γ-lactams in 49–78%, 45–75%, and 75–90%, respectively. The reactions of lactam 2-pyridyl sulfide and 2-pyridyl sulfone proceeded with ≥12:1 <i>trans</i>-diastereoselectivities. This represents the first intermolecular coupling reaction of the γ-lactam <i>N</i>-α-alkyl radicals of types <b>B</b>, <b>B1</b>, and <b>B2</b> with activated alkenes. Two radical-based mechanisms were suggested. The asymmetric synthesis of the 11-hydroxylated analogue of the highly selective EP₄ receptor agonist PF-04475270 (<b>30</b>), the 11-hydroxylated analogue of ocular hypotensive CP-734432 (<b>31</b>), compounds <b>35</b> and <b>36</b> have been achieved on the basis of this method

SmI₂‑Mediated Intermolecular Coupling of γ‑Lactam <i>N</i>‑α-Radicals with Activated Alkenes: Asymmetric Synthesis of 11-Hydroxylated Analogues of the Lead Compounds CP-734432 and PF-04475270

We report, for the first time, the synthesis of 8-aza-analogues of PGE₂. The SmI₂-mediated cross coupling reactions of γ-lactam-hemiaminal <b>9</b>, lactam 2-pyridyl sulfide <b>17</b>, and lactam 2-pyridyl sulfone <b>18</b> with activated alkenes/alkyne were first developed, giving the corresponding γ-lactams in 49–78%, 45–75%, and 75–90%, respectively. The reactions of lactam 2-pyridyl sulfide and 2-pyridyl sulfone proceeded with ≥12:1 <i>trans</i>-diastereoselectivities. This represents the first intermolecular coupling reaction of the γ-lactam <i>N</i>-α-alkyl radicals of types <b>B</b>, <b>B1</b>, and <b>B2</b> with activated alkenes. Two radical-based mechanisms were suggested. The asymmetric synthesis of the 11-hydroxylated analogue of the highly selective EP₄ receptor agonist PF-04475270 (<b>30</b>), the 11-hydroxylated analogue of ocular hypotensive CP-734432 (<b>31</b>), compounds <b>35</b> and <b>36</b> have been achieved on the basis of this method