An improved synthesis of 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) and the fate of the precursor, 2,3'-anhydro-5'-O-(4,4'-dimethoxytrityl)-thymidine

Article abstract of DOI:10.1002/jlcr.519

The fate of the precursor, 2,3'-anhydro-5'-O-(4,4'-dimethoxytrityl)-thymidine was investigated during the synthesis of [18F]FLT with the aim of improving the radiochemical yield. This precursor was shown to undergo a rapid base catalysed elimination reaction and to be consumed within 5-10 min. The by-product was identified. Modification of the syntheis has produced between 1.85-3.70 GBq (50-199 mCi) of [18F]FLT in 60 min using an automated synthesis system.

Full text of DOI:10.1002/jlcr.519

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Labelled Cpd Radiopharm 2001; 44: 871–879.
DOI: 10.1002/jlcr.519
Research Article
Investigations into the regioselective
deuteriation of enolates derived from silyl
enol ethers and enolacetates
Gregory S. Coumbarides, Jason Eames* and Neluka Weerasooriya
Department of Chemistry, Queen Mary, University of London, Mile End Road,
London, E1 4NS, UK
Summary
Results are reported on the regioselective C-deuteriation of a series of enolates
derived from the addition of MeLi to the related enolacetate and silyl enol
ether and discussed in terms of the similarity between these methods;
comments are made on the possible role of the additive, lithium tert-
butoxide. Copyright # 2001 John Wiley & Sons, Ltd.
Key Words: deuterium; enols; isotopiclabelling; ketones
Introduction
Kinetic C-protonation of enolates is very well documented.1 By
comparison, efficient C-deuteriation has proved to be far more difficult
to achieve.2 This has been partially attributed to the method chosen
to generate the enolate.3 The presence of a residual amine4 (formed
by protonation of the initial amide base) is known to lower
*Correspondence to: J. Eames, Department of Chemistry, Queen Mary, University of London,
Mile End Road, London E1 4NS, UK.
Contract/grant sponsor: Queen Mary, University of London
Contract/grant sponsor: The London University Central Research Fund
Contract/grant sponsor: The Nuffield Foundation; contract/grant number: NUF-NAF 99
Contract/grant sponsor: GOSS Scientific Instruments Ltd
Contract/grant sponsor: The Royal Society
Copyright # 2001 John Wiley & Sons, Ltd.
Received 13 June 2001
Revised 9 August 2001
Accepted 13 August 2001

872
G. S. COUMBARIDES ET AL.
D-incorporation significantly. This amine is believed to act as a
competitive base, giving rise to internal proton return.5 The generation
of a less basicamine, suhc as hexamethyldisilylamine (HMDS) has
partially solved this problem.6 As an alternative, removal of this
offending amine proton by using a double-deprotonation strategy7 has
been shown to further increase D-incorporation. From these extensive
studies, it is evident that the presence of fully or partially deuteriated
amines and ammonium salts do have a detrimental effect on the
regioselectivity of C-deuteriation.4,5
We have recently shown8 that the deuteriation of ‘base-free’
enolatesy,9 like 3 (formed by the addition of MeLi to the silyl enol
ether 2) using Stork’s original protocol10,11 in the absence of an
additional competitive base gives the carbonyl derivative, 2-methylte-
tralone 1-d1 with near-perfect D-incorporation ([D]:[H]=95:5; 68%
yield) as shown in Scheme 1. We were interested in extending this
procedure towards other enol derivatives. The use of enolacetates as
related enolate precursors13 is well documented. Simple addition of two
equivalents of MeLi to the corresponding enolacetate 4 gives an
equimolar mixture of the required lithium enolate 3 and lithium tert-
butoxide 5 (Scheme 1). We had originally wondered whether the
additional lithium tert-butoxide would cause similar problems to that of
Scheme 1.
y They have also been termed as ‘ligand-free’ enolates. See Reference 9.
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INVESTIGATIONS INTO THE REGIOSELECTIVE DEUTERIATION
873
diisopropylamine in the regioselective deuteriation of enolates. How-
ever, there are a limited number of reports13 which suggest that this base
may not directly interfere in the regioselective C-deuteriation step.
However, the need to compare the deuteriation of enolates like 3 under
both reaction conditions is important to discover the involvement of
lithium tert-butoxide 5 in the reaction pathway.
Results and discussion
We now report on this comparison, between the deuteriation of enolates
derived from related silyl enol ethers and enolacetates. We discuss the
use of lithium tert-butoxide as an additive and the possible role it plays
in the deuteriation step. The required silyl enol ethers 2 and 13–19 and
enolacetates 4 and 20–26 for this study were synthesized from the
corresponding ketones 1 and 6–12 using well-documented procedures
(Scheme 1 and Table 1).14–16
We initially probed the deuteriation of a series of ‘base-free’ enolates
in the absence of an additive using a carbonyl directing deuterium
source, such as acetic acid-d4. The required ‘base-free’ enolates were
formed by addition of MeLi (1.6 M in ether, 1.1 equivalent) to the
corresponding neat silyl enol ethers 2 and 13–19 at room temperature.
After stirring for an initial period of 5 min, THF was added and the
solution was pre-cooled to À788C. Three equivalents of the deuterium
source, acetic acid-d4 was added to give the corresponding deuteriated
ketones 1 and 6–12-d1 in good yield with high levels of D-incorporation
(Table 2).
With this information in hand, we next probed the effect of a lithium
tert-butoxide additive 5 on this deuteriation step. Addition of two
equivalents of MeLi to the related enolacetate 4 and 20–26 – under near-
identical conditions to that of the silyl enol ether – followed by the
addition of acetic acid-d4 (3 equivalents) gave the same ketones 1-d1 and
6–12-d1 in a similar yield (Table 2). By comparison, the regioselective
C-deuteriation of these related enolates, with and without a lithium
tert-butoxide additive 5 was surprisingly similar and presumably the
additional lithium tert-butoxide appears to play a minor role. There
were a few exceptions, most notably for 6-methoxytetralone 7-d1
(Table 2: entry 3) and indanone 9-d1 (Table 2: entry 5). However, the
question still remained, whether acetic acid-d4 or tert-butanol-d1 26 was
the active deuteriation source in the enolacetate series (Scheme 2).
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G. S. COUMBARIDES ET AL.
Table 1. Reported yields for the synthesis of silyl enol ethers 2 and 13–19 and
enolacetates 4 and 20–26 together with NMR couplings and isotopic shifts
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875
Table 2. Reported yields and regioselectivity in the synthesis of the ketones 1-d1
and 6–12-d1
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G. S. COUMBARIDES ET AL.
Scheme 2.
In an attempt to investigate the nature of the deuterium source
present in the reaction mixture, we quenched our previous series of
‘base-free’ enolates (derived from the addition of MeLi to the silyl enol
ethers 2 and 13–19) with tert-butanol-d1 (3 equivalents). It is clear that
under these reaction conditions, selective deuteriation had not occurred,
and in many cases the presence of di-deuteriated ketone 6–d2, 11–d2 and
12–d2 was clearly evident by 1H NMR. This has presumably occurred as
a result of proton–deuterium exchange under basic conditions involving
the by-product lithium tert-butoxide 5, a ketone-d1 (e.g. 6-d1), an
enolate (e.g. 28-d1) and an excess of tert-butanol-d1 26 (Scheme 2). It is
therefore not surprising that for ketones which cannot undergo proton–
deuterium exchange, such as 2-methyl tetralone 1-d1 the D-incorpora-
tion was near perfect (Table 2: entry 1).
It is well documented that the analogous proton transfer between
highly electronegative atoms such as O-based acids and base is at least
1000-fold faster than that between an analogous C-based base.17 The
initial addition of acetic acid-d4 to the lithium tert-butoxide–enolate
complex (e.g. 3) must allow deuterium exchange to occur between the
lithium tert-butoxide 5 and acetic acid-d4 to form tert-butanol-d1 26 and
the non-basic counter-acetate counter-anion (Scheme 2). The remainder
of the acetic acid-d4 must be responsible for deuterium exchange to the
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INVESTIGATIONS INTO THE REGIOSELECTIVE DEUTERIATION
877
enolate. Othersz and we21,22 have previously postulated that such a
process occurs via a chelated complex 27.
During the course of this study, we noticed a number of characteristic
features due to the presence of the deuterium atom within ketones 1 and
6–12-d1: (a) the presence of an infrared C–D stretching frequency23 at
approximately 2100 cmÀ1, (b) the presence of a 1:1:1 C–D triplet (JC2D
19.5 Hz)24,25 and a negative isotope shift20 for the C–D bond (versus the
corresponding C–H bond) in the 13C NMR spectra between 23 and
75 Hz (Table 1).
Experimental
Typical experimental deuteriation procedure for an enolacetate
A solution of MeLi (0.66 ml, 1.6 M in ether, 1.06 mmol) was added
dropwise to the enolacetate 20 (0.1 g, 0.53 mmol) at room temperature.
This resulting solution was stirred for 1 h at room temperature and then
cooled at À788C. Acetic acid-d4 (0.12 g, 1.59 mmol) in THF (1 ml) was
added dropwise to this solution and the mixture stirred for a further
30 min. The reaction was quenched by the addition of water (10 ml). The
solution was extracted with ether (3 Â 20 ml), dried (MgSO4) and
evaporated under vacuum. The residue was purified by flash chromato-
graphy on silica gel eluting with light petroleum (40–608C):ether (9:1) to
give the tetralone-d1 6 (57 mg, 73%) as an oil; Rf [light petroleum
(40–608C):ether (9:1)] 0.3; vmax (film)/cmÀ1 2106 (C–D) and 1683 (CO);
dH(250 MHz, CDCl3) 8.00 (1 H, d, J=7.7 Hz, CH; Ar), 7.47 (1 H, dd,
J ¼ 7:7 and 7.6 Hz, CH; Ar), 7.30–7.20 (2 H, m, 2 Â CH; Ar), 2.95 (2 H,
t, J=6.1 Hz, CH2CH=C), 2.60 (1 H, m, CHD) and 2.20–2.10 (2 H, br
q, J=6.1 Hz, CH2CHD); dC(62.5 MHz, CDCl3) 199.4, 144.5, 133.4,
132.7, 128.8, 127.2, 38.9 (1 C, t, J=19.6 Hz, CHD), 29.7 and 23.6
(found MH+, 148.0873. C10H10DO requires MH, 148.0878); m=z 148.1
(100%, M+H). The isotopicshift was 34.9 Hz.
Typical experimental deuteriation procedure for a silyl enol ether
A solution of MeLi (0.31 ml, 1.6 M in ether, 0.50 mmol) was added
dropwise to the silyl enol ether 13 (0.1 g, 0.45 mmol) at room
z Others report on the use of carbonyl chelation proton donors; see References 18–20. For a recent
review, in this area see Reference 3.
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temperature. This resulting solution was stirred for 1 h at room
temperature and then cooled at À788C. Acetic acid-d4 (0.1 g, 1.35 mmol)
in THF (1 ml) was added dropwise to this solution and the mixture
stirred for a further 30 min. The reaction was quenched by the addition
of water (10 ml). The solution was extracted with ether (3 Â 20 ml), dried
(MgSO4) and evaporated under vacuum. The residue was purified
by flash chromatography on silica gel eluting with light petroleum
(40–608C):ether (9:1) to give the tetralone-d1 6 (57 mg, 87%) as an oil,
identical to that obtained previously.
Acknowledgements
We thank Queen Mary, University of London for a college studentship
(to N.W.), the London University Central Research Fund, The Nuffield
Foundation (NUF-NAF 99), GOSS Scientific Instruments Ltd and The
Royal Society for their generous financial assistance.
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