Efficient and Scalable Diastereoselective Synthesis of ((2R,7as)-2-fluorotetrahydro-1h-pyrrolizin-7a(5h)-yl)methanol Hydrochloride

An efficient large-scale synthesis of 2aHCl, 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 35a or 35b via a stable chelate with lithium cation 38 to give a stereoselective product, bicyclic scaffold 36a, with excellent diastereoselectivity and good yields. Consecutive deoxyfluorination followed by the reduction of benzyl ester 37a afforded 2aHCl without the need for chiral separation utilized in the first-generation approach.