Efficient and ScalableDiastereoselective Synthesisof ((2<i>R</i>,7a<i>S</i>)‑2-fluorotetrahydro‑1<i>H</i>‑pyrrolizin-7a(5<i>H</i>)‑yl)methanolHydrochloride

An efficient large-scale synthesis of <b>2a</b>·HCl, a key fragment to several KRAS inhibitors, is described. Optimization to a previously reported racemic route by Merck includes the development of a catalytic exocyclic olefin oxidation using RuCl₃/NaIO₄, followed by a highly diastereoselective reduction of the resulting ketone. A second-generation approach was then developed. The highlight of this synthesis includes a one-step intramolecular nucleophilic ring cyclization of <b>35a</b> or <b>35b</b> via a stable chelate with lithium cation <b>38</b> to give a stereoselective product, bicyclic scaffold <b>36a,</b> with excellent diastereoselectivity and good yields. Consecutive deoxyfluorination followed by the reduction of benzyl ester <b>37a</b> afforded <b>2a</b>·HCl without the need for chiral separation utilized in the first-generation approach.