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No‐carrier‐added (NCA) synthesis of 6‐[ 18 F]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
Author(s) -
Horti Andrew,
Redmond D. Eugene,
Soufer Robert
Publication year - 1995
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.2580360503
Subject(s) - chemistry , yield (engineering) , enantiomer , nucleophile , enantioselective synthesis , alcohol , chemical synthesis , methylene , stereochemistry , double bond , nucleophilic addition , medicinal chemistry , organic chemistry , catalysis , in vitro , biochemistry , materials science , metallurgy
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‐[ 18 F]Fluoro‐L‐DOPA. Direct condensation of 3,4‐dimethoxy‐2‐[ 18 F]fluorobenzaldehyde ( 1a ) or 6‐[ 18 F]fluoropiperonal ( 1b ) in the presence of NaH with 2 gave the corresponding [ 18 F]‐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 [ 18 F]‐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‐[ 18 F]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‐[ 18 F]fluoro‐D,L‐DOPA (10–12% radiochemical yield) and, after chiral separation, 6‐[ 18 F]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%).