No‐carrier‐added (NCA) synthesis of 6‐[¹⁸F]fluoro‐L‐DOPA using 3,5,6,7,8,8a‐hexahydro‐7,7,8a‐trimethyl‐[6s‐(6α,8α,8αβ)]‐6,8‐methano‐2H‐1,4‐benzoxazin‐2‐one

3,5,6,7,8,8a‐Hexahydro‐7,7,8a‐trimethyl‐[6S‐(6α,8α,8αβ)]‐6,8‐methano‐2H‐1,4‐benzoxazino‐2‐one (2) was investigated as chiral auxiliary for asymmetric NCA nucleophilic synthesis of 6‐[¹⁸F]Fluoro‐L‐DOPA. Direct condensation of 3,4‐dimethoxy‐2‐[¹⁸F]fluorobenzaldehyde (1a) or 6‐[¹⁸F]fluoropiperonal (1b) in the presence of NaH with 2 gave the corresponding [¹⁸F]‐3‐[(2‐fluorophenyl)methylene]‐3,5,6,7,8,8a‐hexahydro‐7,7,8a‐trimethyl‐[6S‐(3Z,3α,6α,8α,8αβ)]‐6,8‐methano‐2H‐1,4‐benzoxazin‐2‐one derivative 3a or 3b as a single stereoisomer. L‐Selectride® promoted hydrogenation of the olefinic double bond of these derivatives, in presence of tertbutyl alcohol, afforded the corresponding [¹⁸F]‐3‐[(2‐fluorophenyl)methyl]‐3,5,6,7,8,8a‐hexahydro‐7,7,8a‐trimethyl‐[3S‐(3α,6α,8α,8αβ)]‐6,8‐methano‐2H‐ 1,4‐benzoxazin‐2‐one derivatives (4a, b) without affecting the orientation of diastereofacial discrimination. Deprotection of the derivatives 4a,b yielded 6‐[¹⁸F]fluoro‐L‐DOPA (e.e. > 90%, 3% radiochemical yield (EOB), total synthesis time 125 min, specific activity > 2000 mCi/μmol). Direct deprotection/reduction of the compounds 3a,b provides the enantiomeric mixture of 6‐[¹⁸F]fluoro‐D,L‐DOPA (10–12% radiochemical yield) and, after chiral separation, 6‐[¹⁸F]fluoro‐L‐DOPA (e.e. 98%, 4–5% radiochemical yield). A “cold” enantioselective synthesis of 6‐fluoro‐L‐DOPA has been effected with total chemical yield 15% (e.e. 93.4%).