SmI<sub>2</sub>‑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
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Abstract
We report, for the first time, the synthesis of 8-aza-analogues
of PGE<sub>2</sub>. The SmI<sub>2</sub>-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 EP<sub>4</sub> 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