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

Andrew Horti, D. E. Redmond, R. Soufer

Research output: Contribution to journalArticle

Abstract

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]Fluoro-L-DOPA. Direct condensation of 3,4-dimethoxy-2-[18H]fluorobenzaldehyde (1a) or 6-[18F]fluoropiperonal (1b) in the presence of NaH with 2 gave the corresponding [18F]-3-[(2-fluorophenyl)methylenel-3,5,6,7,8a-hexahydro-7,7,8a-trimethyl-[6S -(3Z,3α,6α,8α,8αβ)]1-6,8-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%).

Original languageEnglish (US)
Pages (from-to)409-423
Number of pages15
JournalJournal of Labelled Compounds and Radiopharmaceuticals
Volume36
Issue number5
StatePublished - 1995
Externally publishedYes

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Derivatives
Stereoisomerism
Hydrogenation
Condensation
Alcohols
fluorodopa F 18
selectride

Keywords

  • 6-[F]fluoro-L-DOPA
  • Dopamine
  • Enantioselective synthesis
  • Positron emission
  • Radio tracer
  • Tomography

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Molecular Medicine
  • Analytical Chemistry
  • Organic Chemistry
  • Drug Discovery
  • Pharmacology

Cite this

@article{6f00719d3b8e4311bf61e6363327ec99,
title = "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",
abstract = "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]Fluoro-L-DOPA. Direct condensation of 3,4-dimethoxy-2-[18H]fluorobenzaldehyde (1a) or 6-[18F]fluoropiperonal (1b) in the presence of NaH with 2 gave the corresponding [18F]-3-[(2-fluorophenyl)methylenel-3,5,6,7,8a-hexahydro-7,7,8a-trimethyl-[6S -(3Z,3α,6α,8α,8αβ)]1-6,8-methano-2H-1,4-benzoxazin-2-one derivative 3a or 3b as' a single stereoisomer. L-Selectride{\circledR} 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{\%}).",
keywords = "6-[F]fluoro-L-DOPA, Dopamine, Enantioselective synthesis, Positron emission, Radio tracer, Tomography",
author = "Andrew Horti and Redmond, {D. E.} and R. Soufer",
year = "1995",
language = "English (US)",
volume = "36",
pages = "409--423",
journal = "Journal of Labelled Compounds and Radiopharmaceuticals",
issn = "0362-4803",
publisher = "John Wiley and Sons Ltd",
number = "5",

}

TY - JOUR

T1 - 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

AU - Horti, Andrew

AU - Redmond, D. E.

AU - Soufer, R.

PY - 1995

Y1 - 1995

N2 - 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]Fluoro-L-DOPA. Direct condensation of 3,4-dimethoxy-2-[18H]fluorobenzaldehyde (1a) or 6-[18F]fluoropiperonal (1b) in the presence of NaH with 2 gave the corresponding [18F]-3-[(2-fluorophenyl)methylenel-3,5,6,7,8a-hexahydro-7,7,8a-trimethyl-[6S -(3Z,3α,6α,8α,8αβ)]1-6,8-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%).

AB - 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]Fluoro-L-DOPA. Direct condensation of 3,4-dimethoxy-2-[18H]fluorobenzaldehyde (1a) or 6-[18F]fluoropiperonal (1b) in the presence of NaH with 2 gave the corresponding [18F]-3-[(2-fluorophenyl)methylenel-3,5,6,7,8a-hexahydro-7,7,8a-trimethyl-[6S -(3Z,3α,6α,8α,8αβ)]1-6,8-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%).

KW - 6-[F]fluoro-L-DOPA

KW - Dopamine

KW - Enantioselective synthesis

KW - Positron emission

KW - Radio tracer

KW - Tomography

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M3 - Article

AN - SCOPUS:0028958193

VL - 36

SP - 409

EP - 423

JO - Journal of Labelled Compounds and Radiopharmaceuticals

JF - Journal of Labelled Compounds and Radiopharmaceuticals

SN - 0362-4803

IS - 5

ER -