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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5624_Библиотеки_им_академика_М_И_Перельмана.pdf
Reaction of the free thiol with [11C]CH3I occurs in the presence of base through the highly
(a)
O
O
nucleophilic thiolate anion (Figure7.34a) in RCYs of 38%[38, 130]. A challenge in labelling free thiols is their propensity to oxidize to the disulde, which is no longer easily
11
C-methylated. Alternatively, l-homoserine thiolactone or other masked thiols[296] have
been used as precursors to [methylmethods[297] have been reported. Other
including the amyloid plaque agent [
11
[
C]CH3I, a masked thiol precursor, and a phosphazine base (Figure7.34b)[298]. As part of
cysteine residues in peptides and proteins, thiols can be radiolabelled with [
provide access to e.g. [
11
C]methylalbumin in a single step[299].
11
C]-l-methionine. Both loop[130] and solid-supported
11
C-methyl thioether-based PET radiotracers,
11
C]MeS-IMPY, have been radiolabelled using
11
C]CH3OTf to
Radiolabelled sulfoxides and sulfones have been explored as motifs for introducing
carbon-11 into biomolecules.
11
C-Methyl sulfones are usually accessed from reaction of
(b)
11
[
HO
NH
2
HS
O
S
N
O
N
C]CH3I
NaOH
EtOH/H
2
1 min, RT
N
N
11
[
11
H
3
[
N
PN
N
C]CH3I
C
11
O
MeCN
O
HO
NH
S
C]methionine
11
H
3
2
S
C
N
N
N
11
[
C]MeS-IMPY
5 min, 80 °C
(c)
(d)
®
Oxone
MeOH/H2O
11
H
C
SH
11
[
C]CH3I
O
N
N
NaOH, DMF
5 min, 80 °C
O
N
N
O
3
S
O
3 min, 50 °C
Oxone ®
MeOH/H
5 min, 80 °C
O
2
1. MeLi, THF
SH
2.
PhO
2
3.
EtOAc/H
O
N
Ph
S
O
2
O
Li
S
O
11
[
C]CH3I
THF/H
O
2
8 min, 150 °C
O
11
CH
3
S
O
11
H
C
3
S
R
O
11
H
C
3
S
O
R
Figure 7.34 SC]CH3I is used for the synthesis of [C]Methyl sulfones
and [
C]methyl sulfoxides can also be produced by
185
a thiol with [11C]CH3I or [11C]CH3OTf, followed by complete oxidation to the 11C-methyl
sulfone[300]. With careful control of the conditions (lower temperature and shorter
time), the
11
C-methyl sulfoxide can be accessed, though 11C-methyl sulfone is often also
produced as a by-product (Figure7.34c)[301]. Lasne etal. have described an alternative
approach via selective oxidation of a lithium thiolate by N -sulfonyloxaziridine to give
a lithium sulnate that can react with [
11
C]CH3I (Figure7.34d) to give a 11C-methyl sulfone[302]. The advantage of this approach is that it introduces carbon-11 at the last
synthetic step. Mesylating agent [
prepared by
11
C-methylation of NaSH with [11C]CH3I, followed by oxidation and chlorina-
tion[303], and was shown to rapidly
11
C]methanesulfonyl chloride ([11C]MsCl) has also been
11
C-mesylate alcohols and amines.
C
The development of 11C-alkylation reactions at carbon centres has largely been driven
by transition metal-mediated
11
C-methylation reactions. Additionally, the synthesis of
(chiral) amino acids by alkylation at the alpha-carbon of glycine derivative is also a commonly used strategy for the formation of C─
11
C bonds.
7.4.3.5.1 Transition Metal–Mediated 11C-Methylation
Metal-mediated couplings between [11C]CH3I and appropriate organometallic reagents
have been used extensively for
Suzuki couplings have been applied for the synthesis of PET radiotracers, including
11
(-)-o -[
C]methylvesamicol (Figure7.35a) and [11C]cetrozole (Figure7.35b). Other crosscouplings, including the Negishi coupling, have also been reported but are used less
frequently. The general mechanism for these cross-couplings (Figure7.35c) occurs
as follows: the Pd(0) (usually in the presence of triarylphosphine ligands) undergoes
oxidative addition into a C─X bond to generate Pd(II) species; then transmetallates with
an appropriate coupling partner e.g. an organostannane or organoboron; and nally,
reductive elimination regenerates the Pd(0), which is free to enter into another catalytic
cycle. In the case of radiochemical cross-coupling, the alkyl halide ([
is the limiting reagent, and the Pd-reagent is used stoichiometrically; the catalytic cycle
does not begin again, as all the [
The combination of trace amounts of [
coupling partners increases the rate of individual steps in the reaction cycle so that the
reactions are complete in minutes rather than hours. The rate of the oxidative addition
of Pd(0) into [
11
C]CH3I is the rate-determining step in the Suzuki reaction. Due to the
large excess of Pd(0), the rate of this step is increased, providing the
I intermediate rapidly. Maximum conversions are achieved when the
intermediate is prepared before the addition of the organometallic coupling partner. In
contrast, the transmetallation step is rate-determining for the Stille coupling. Here, the
rate-determining step is accelerated by the large excess of the organostannane reagent.
The reductive elimination step in Pd-mediated couplings is usually rapid.
11
C─C bond formation[304, 305]. Specically, Stille and
11
C]CH3I in most cases)
11
C]CH3I is consumed in a single cycle.
11
C]CH3I and stoichiometric Pd-reagents and
11
C-CH3-Pd(II)-
11
C-CH3-Pd(II)-I
186 Handbook of Radiopharmaceuticals
3
(a) Stille Coupling
Sn
HO
N
(b) Suzuki Coupling
NN
N
N
NC
(c) General Mechanism
11
[
C]CH3I
Pd
(dba)3, P(o-tol)
2
K
CuCl,
DMF, 80 °C, 3 min
11
[
Pd
(dba)3, P(o-tol)
O
B
O
2
K
DMF, 65 °C, 2 min
CO
2
3
C]CH3I
CO
2
3
11
CH
HO
3
N
11
C]methylvesamicol
o
-[
(–)-
3
3
NN
11
N
N
Figure 7.35 Suzuki
and Stille coupling
reactions with
[
C]CH3
proposed mecha
ated couplings
with [
CH
C]CH3I.
NC
11
[
C]cetrozole
11
H
C
3
R
L
reductive
elimination
0
Pd
L L
11
[
C]CH3I
L
II
11
H
C
Pd
3
R
oxidative
isomerisation
11
H
C
3
L
Pd
L
II
R
addition
11
H
3
L
II
I
Pd
C
L
transmetallation
[M]-I
[M] = SnR
[M]
, BR2, ZnX etc.
3
R
7.4.3.5.2 Stille Coupling Reactions
The rst application of the Stille coupling with [11C]CH3I was reported by the Långström
group in 1995[306]. Coupling of aryl- and vinyl-trialkylstannanes in polar aprotic solvents
187
at 90 °C over four minutes gave the corresponding methyl-11C-toluenes and 11C-methyl
C]thiamine
μ
μ
towa
O
alkenes, respectively, in 30–54% RCY. Extensive optimization of the Stille reaction toward
use for PET radiochemistry with [
using substoichiometric amounts of [
11
C]CH3I was reported by Suzuki, Noyori, and Långström
12/13
C]CH3I[307]. Aryltrimethylstannanes were found
to be more reactive than their tributyl congeners; however, they promote the formation
11
of [
C]ethane and can also transfer a 12C-methyl group and thus reduce the molar activity
of the nal product. Trimethylstannanes are also more toxic, requiring rigorous quality
control, especially in the case of clinical/Good Manufacturing Practice (GMP) productions. The use of the sterically demanding P(o-tolyl)
ligand facilitates the transmetal-
3
lation and reductive elimination steps. The addition of CuCl is thought to generate an
aryl-Cu intermediate that transfers the aryl group more rapidly than the aryl-Sn species,
further accelerating the rate-limiting step. The optimized reaction therefore involved
methylation of aryltributylstannanes using Pd
at 60 °C for ve minutes, providing
optimized method was used with [
12/13
C-methylated products in excellent yields. This
11
C]CH3I to synthesise the methyl ester of (15R)-[11C]TIC
(dba)3, P(o-tolyl)3, CuCl, and K2CO3 in DMF
2
(Figure7.36a), the prodrug form of a prostaglandin receptor ligand, in 85% RCY and with
a molar activity of 100 GBq· μmol
−1
; it was used for imaging prostaglandin receptors in the
human brain[308].
(a) (b)
O
11
CH
3
OH
OH
(15R)-[11C]TIC methyl ester
R-Sn(n-Bu)
, Pd2(dba)3, P(o-tol)3,
3
CuCl, DMF, 65 °C, 5 min
upto 85% RCY (decay corrected)
11
O
O
CH
3
O
N
CF
H
3
toward 6-[11C]methyldopamine
R-Sn(CH
CuBr, CsF, DMF, 60 °C, 5 min
, Pd2(dba)3, P(o-tol)3,
3)3
89% crude RCY (decay corrected)
(c)
fragment toward [11C]thiamine
R-Sn(n-Bu)
CuBr, CsF, NMP, 100 °C, 3 min
86% crude RCY (decay corrected)
49–54 GBq.μmol
(d) (e) (f)
11
CH
N
O
2
3
11
CH
HO
3
H
N
N
N
NBoc
rd 5-[11C]methyl-6-nitroquipazine
R-Sn(n-Bu)
60–80% crude RCY (decay corrected)
, Pd2(dba)3, P(o-tol)3,
3
DMF, 130 °C, 4 min
15–22 GBq.μmol
−1
o-
[11C]methyl-trans-decalinvesamicol
R-Sn(n-Me)
CuCl, CsF, NMP, 130 °C, 5 min
, Pd2(dba)3, P(o-tol)3,
3
60–75% isolated RCY
(decay corrected from [
5–10 GBq.
mol
H
11
C]CH3I)
−1
R-Sn(n-Bu)
CuCl, K
(decay corrected from [
Figure 7.36
N
11
CH
S
, Pd2(dba)3, P(o-tol)3,
3
−1
for [
11
H
C
3
O
HO
N
3
[11C]Zidovudine
, Pd2(dba)3, P(o-tol)3,
3
, DMF, 130 °C, 4 min
2CO3
58% isolated RCY
74–128 GBq.
3
OH
O
N
mol
11
NH
O
11
C]CO2)
−1
188 Handbook of Radiopharmaceuticals
The Stille coupling of electron-rich arenes and heteroarenes such as a protected
dopamine analogue[309] (Figure7.36b) and the fragment toward [
11
C]thiamine[310]
(Figure7.36c) was achieved using a CuBr/CsF system[311, 312]. Electron-poor arenes such
as the protected precursor to 5-[
11
C]methyl-6-methylquinazepine[313] (Figure7.36d)
have also been successfully synthesised using the Stille coupling. Vinyltrialkylstannanes[311] and alkynyltrialkylstannanes[308, 314] have also been shown to be active
in the Stille coupling, giving
11
C-methylated products in RCY >85% or 75%, respectively.
Despite concerns over the toxicity of organostannanes, the wide functional group tolerance of the reaction, illustrated by successful synthesis of the unprotected
vesamicol derivative[315] (Figure7.36e) and [
11
C]zidovudine[316] (Figure7.36f), has
11
C-labelled
contributed to the application of the Stille coupling to the synthesis of a wide range of
11
C-labelled bioactive molecules.
The preparation of stannylated precursors for the Stille reaction remains a challenge.
To address this,
11
C-methylstannanes, which are able to react with more readily available
aryl or vinyl halides, were developed. Långström and colleagues reported the synthesis
11
of 5-[
C]methyl-1-aza-5-stanna-bicyclo[3.3.3]undecane in 20–90% RCY by reaction of
the chlorostannane with [
11
C]CH3Li (Figure7.37a)[317]. 5-[11C]Methyl-1-aza-5-stannabicyclo[3.3.3]undecane was shown to undergo ecient Stille coupling with a range
of aryl halides, providing
11
C-methylstannate derived from Lappert’s stannane and more readily available [11C]CH3I
(Figure7.37b). TBAF-activated
11
C-methylated products in 9–90% RCY. Huiban etal. used a
11
C-methylstannate underwent an ecient Stille coupling
with a series of bromoquinolines and halonaphthalenes at 120 °C in 63–78% RCY using
Pd
(dba)3 in the absence of any ligand[312]. The tin by-product is less toxic than the
2
organotin by-products of the conventional Stille coupling. In a follow-up investigation,
the authors compared the conventional Stille coupling with [
Stille coupling with the [
11
C]methylstannate toward the 11C-methylation of bioactive
11
C]CH3I with the modied
quinolines and quinolinamides. Radiochemical yields were found to be higher when
using the
11
C-methylstannate in the case of [11C]SB222200, a NK-3 receptor antagonist.
(Figure7.37b)[318]. Automation of the process resulted in even higher radiochemical
purity (>99% vs. >95%) of the
11
C-methylated product.
7.4.3.5.3 Suzuki Coupling Reactions
The same report by Andersson etal. that described the rst Stille cross-coupling with
11
[
C]CH3I also described the rst Suzuki cross-coupling with [11C]CH3I[306]. [1-11C]Heptane was prepared from 9-hexyl-9-borabicyclo[3.3.1]nonane (9-hexyl-9-BBN) with
Pd(PPh
etal. reported the synthesis of ω arenes via microwave-mediated Suzuki coupling was achieved by the same group using
aryl boronic acids or esters to give methylwith either Pd(PPh
precipitate. During their optimization of the Suzuki cross-coupling, they showed that it
was necessary to form the reactive [
boronic acid or ester to achieve consistently high RCYs. The authors demonstrated the
in the presence of NaOH or K3PO4 at 90 °C for 4 minutes. Similarly, Hostetler
3)4
or Pd(dppf)2Cl2 in DMF; the former, however, gave an insoluble Pd(0)
3)4
11
C-palmitic acid derivatives[319]. 11C-Methylation of
11
C-toluenes[320]. Similar RCY was observed
11
C]CH3-Pd(II)-I complex prior to the addition of the
189
[
11
(a)
C]CH3I
n-BuLi
X
R
Sn
Cl
11
[
N
C]CH3Li
N
Sn
11
CH
3
(allyl-PdCl)
2
DMF, 100 °C, 2–10 min
R
11
CH
3
9–90 % RCY
(b)
Sn[N(TMS)
2]2
1.
11
[
THF,
TBAF
2.
C]CH3I
r.t.
20–90% RCY
based on
11
C]CH3I
[
11
H
C
3
F
Sn
F
N(TMS)
N(TMS)
I
2
Pd2(dba)3, dioxane
2
O
150 °C, 5 min
based on
11
C-CH3-stannane
Ph
NH
Ph
N
11
H
C
3
based on [
Ph
O
11
C]SB222200
[
59 % RCY
NH
N
11
C]CH3I
Ph
Figure 7.37 Synthesis and utilization of
aryl halides.
synthesis of a range of substituted 11C-toluenes, highlighting the reaction’s tolerance to
both ortho-substituted and protic functional groups. Doi etal. performed a systematic
study of the Pd-mediated reaction between sub-stoichiometric quantities of [
and excess of a boronic acid/ester as a proxy for the development of the reaction with
11
[
C]CH3I[321]. The highest RCYs (87–94%) were achieved with Pd2(dba)3 and P(o-tolyl)3 at
60 °C in ve minutes. Using these conditions, p-[
from the BPin precursor; and [
lated in 63% RCY with a molar activity of 83 GBq· μmol
tion of aniline-bearing boronic acids and esters was accomplished in 49–82% crude RCY
using the Pd
(dba)3/P(o-tolyl)3/K2CO3 system, as illustrated for the synthesis of [11C]CIMBI-
2
712 (Figure7.38b)[322]. Electron-decient arenes have also been shown to undergo
ecient Suzuki coupling with [
Pd
(dppf)2Cl2 as catalyst, under microwave heating, and has been used for the synthesis
2
11
of [
C]MTEB, an mGluR5 antagonist (Figure7.38c)[323].
Vinyl boronic esters have also been shown to be competent coupling partners in the
Suzuki reaction with [
11
C]CH3I and have been used to prepare all-trans-[11C]retinoic acid
190 Handbook of Radiopharmaceuticals
12/13
C]CH3I
11
C]xylene was radiolabelled in 96% RCY
11
C]celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, was iso-
−1
(Figure7.38a)[321]. 11C-Methyla-
11
C]CH3I, using the corresponding boronic acid precursor,
ed,
566 GBq.μmol
after deprotection)
CF
3
(a) (b) (c)
μ
N
N
11
H
C
3
O
S
N
H
2
O
[11C]celecoxib
R-BPin, Pd
K
2CO3
63% isolated RCY (decay corrected
(dba)3, P(o-tol)3,
2
, DMF, 65 °C, 4 min
11
from[
C]CH3I)
84 GBq.μmol
−1
11
H
C
3
N
N
O
[11C]CIMBI-712
R-BPin, Pd
K
2CO3
30% isolated RCY (decay corrected
(dba)3, P(o-tol)3,
2
, DMF: H2O, 60 °C, 5 min
11
from[
C]CH3I)
120 GBq.μmol
−1
S
NC
N
H
K
29% isolated RCY (non decay correct
11
CH
3
11
[
C]MTEB
R-B(OH)
3PO4
, Pd2(dppf)2Cl2,
2
, DMF, 100 °C, mW, 90 sec
from[11C]CH3I)
70 GBq.μmol
N
−1
(d) (e) (f)
11
CH
3
O
OEt
H
N
O
toward all-trans-[11C]retinoic acid
N-(4-[11C]Ethylphenyl)propionamide
R-BPin, Pd(P(t-Bu)
sodium ascorbate, K2CO3, DMF-H2O, 65 °C, 4 min
R-BPin, Pd
14% isolated RCY (decay corrected,
(dba)3, P(o-tol)3,
2
CsF, DMF, 90 °C, 5 min
49% isolated RCY (decay corrected
from[11C]CH3I)
84 GBq.
Figure 7.38
in good RCY (Figure7.38d)[324]. Benzyl and cinnamyl boronic acids and esters have also
been employed for the sp
3
-sp3 Suzuki coupling reaction with [11C]CH3I[325]. Optimized
reaction conditions employed the electron-rich and bulky P(t-Bu)
with CsF as base. N-(4-[
11
C]Ethylphenyl)propionamide was synthesized in 90% crude
and 49% isolated RCY at 90 °C for 5 minutes (Figure7.38e). Aryl-triuoroborates as the
radiolabelling precursors have been used in the synthesis of [
for imaging of the synaptic vesicle protein SV2A (Figure7.38f)[326]. The boronic acid
precursor can also be used; however, it results in the production of protodeborylated
by-products. Protodeborylation is a common side reaction in Suzuki couplings, giving rise
to analogues that are dicult to separate and can compete for the same binding site as
the desired PET ligand. Using the triuoroborate precursor was found to signicantly
reduce the amount of by-product formed. There is some debate as to whether the triuoroborate truly undergoes the cross-coupling, or whether trace amounts of boronic acid
are the reactive cross-coupling partner[327].
11
CH
3
),
3
−1
mol
ligand in combination
3
11
C]UCB-J, a PET radiotracer
/R-B(OH)2, Pd2(dba)3, P(o-tol)3,
R-BF
3
K
2CO3
11% isolated RCY (decay corrected
F
F
F
O
N
11
H
3
N
C
[11C]UCB-J
, DMF-H2O, 100 °C, 5 min
from [11C]CH3I)
−1
191
7.4.3.5.4 Negishi Coupling Reactions
Kealey etal. described the rapid, microwave-assisted synthesis of organozinc reagents
for use in Negishi-type Pd-mediated
Rieke zinc at 180 °C[328]. The organozinc reagent in THF was then cannulated into a
second vial containing Pd(PPh
the solution at room temperature. After ve minutes
were obtained. Electron-poor substrates were slowest to react, requiring additional
heating to 100–120 °C. The process was successfully automated, and an mGluR
11
[
C]MPEP was prepared in 26% RCY and with a molar activity of 46 GBq· μmol−1, as shown
in Figure7.39a. In contrast to Stille and Suzuki cross-couplings, [
to a solution that already contained the organometallic reagent, simplifying further
automation. The application of the traditional Negishi coupling is restricted by the harsh
conditions needed (180 °C and a strong reductant) to prepare the reactive organozinc precursor of a complex radiopharmaceutical.
As stated by Kealey etal.[328], preparation of [
the Negishi coupling toward a wider range of radiopharmaceuticals. Recently, Llop etal.
have reported the synthesis of [
containing iodine-activated zinc, Pd(PPh
heating of the cartridge at 65 °C for ve minutes and elution of the reaction mixture,
methyl-
11
C-toluenes were obtained in good RCY for electron-poor arenes and moderateto-low RCY for electron-rich arenes. Automated radiosynthesis of [
achieved in 53% crude and 6.1% isolated RCY and with a molar activity of >50 GBq· μmol
11
using [
C]CH3ZnI (Figure7.39b).
11
C-methlyations by reaction of aryl halides with
in DMA and [11C]CH3I, which had been trapped in
3)2Cl2
11
C]CH3ZnI by the trapping of [11C]CH3I gas on a cartridge
, and the aryl halide in anhydrous DMF. After
3)4
11
C-labeled toluene derivatives
agonist
5
11
C]CH3I could be added
11
C]CH3ZnI would facilitate the use of
11
C]thymidine was
−1
7.4.3.5.5 Miscellaneous Mediated Coupling Reactions
Wüst etal. reported a Sonogashira-like coupling reaction for the synthesis of substi-
11
tuted
as a ligand and TBAF as a non-nucleophilic base in THF at 60 °C for threeminutes. A steroid derivative, 17α-(3′-[
27–47% isolated RCY, as shown in Figure7.40a.
and alkenyl-zirconocene derivatives, which are accessed through regioselective intermolecular insertion of alkynes into the Zr─H bond of the Schwartz reagent (Cp
Addition of Pd(PPh
solution yield
containing substrates were not compatible with the Schwartz reagent.
phonium ylide generated from [
Pd-mediated Heck reactions with a series of substituted aryl iodides (Figure7.40c)[331].
A one-pot procedure, using Pd
bene products in 43–55% crude and 34–40% isolated RCY.
192 Handbook of Radiopharmaceuticals
C-methylpropynes[329] in 49–64% crude RCY using [11C]CH3I, Pd2(dba)3, or AsPh3
11
11
C-Methylalkenes have been prepared via a Pd-mediated cross-coupling of [11C]CH3I
to the alkenyl-zirconocene and distillation of [11C]CH3I into the
3)4
11
C-methylalkenes in 62–75% crude RCY (Figure7.40b). Ester- or nitro-
Alkenes prepared by a Wittig reaction between benz- or butyraldehydes and the phos-
C]prop-1-yn-1-yl)-3-methox y-3-17β-estradiol, was prepared in
ZrHCl)[330].
2
11
C]CH3I and P(o-tolyl)3 were shown to undergo ecient
(dba)3/P(o-tolyl)3, aorded 11C-labelled alkene and stil-
2
Y
(a)
>50 GBq.μmol
11
[
C]CH3I
Br
Rieke Zinc
N
THF, 100 °C (μW)
10 min
N
ZnBr
Pd(PPh
3)2Cl2
DMA, 110 °C, 10 min
62% isolated decay corrected RC
(from [11C]CH3I)
(b)
HO
11
[
O
I
NH
11
[
Pd(PPh3)
N
O
O
DMA, 65 °C, 5 min
C]CH
3
Zn/I
C]CH3ZnI
I
2
H
4
HO
O
11
C
3
NH
N
O
O
HO
53 GBq.μmol
HO
[11C]Thymidine
6.1% isolated RCY
−1
Figure 7.39 C]CH3I and [C]CH3
The synthesis of aryl [11C]methyl ketones (Figure7.40d) by the coupling of aryl chlorides with [
reported by Dahl etal.[332]. [
MeCN, transferred to a vial containing Co
11
C]CH3I in the presence of Co2(CO)8 as a CO source and mediator was recently
11
C]CH3I was trapped in a solution of the aryl chloride in
(CO)8, and then heated in a microwave. Radio-
2
chemical yields of 22–63% were observed, and electron-poor arenes gave higher RCYs.
[methylmolar activity of 230 GBq·μmol
11
C]Acetophenone was synthesized in 43% RCY on a preparative scale with a
−1
.
7.4.3.5.6 Metal-Free Coupling Reactions
Wittig reactions using 11C-methyltriphenylphosphonium ylides and aldehydes aord
11
C-alkenes labelled in the terminal-alkene position[333, 334]. The Horner-WadsworthEmmons reaction between an αfurnish disubstituted
11
C-methylalkenes in 60–89% crude RCY[335, 336]. Carbanions generated by lithium-halogen exchange of bromoarenes have also successfully been alkylated with [
11
C]CH3I[337].
Enolates have proved useful substrates for
phile, and this strategy has been extensively applied toward the synthesis of
amino acid derivatives[14, 338]. Welch etal.[339] reported the
enolate derived from a glycinate Schi base derivative with various electrophiles. Using
this approach,
11
dl-[
C]phenylalanine (Figure7.41a) was prepared in 23–31% RCY after
11
C-methyl phosphonate and aldehydes was shown to
11
C-alkylation with a 11C-labelled electro-
11
C-labelled
11
C-alkylation of the
11
CH
[
N
3
11
C]MPEP
−1
193
(a)
(b)
(c)
Y
(d)
Figure 7.40 Mis
mediated
coupling reactions.
MeO
R
H
H
H
H
THF, r.t., 10 min
Zr
OH
[11C]CH3I
Pd
(dba)
AsPh
.
2
3
TBAF
THF, 60 °C, 3 min
3
H
MeO
OH
11
CH
3
H
H
27–47% isolated decay corrected RCY
3)4
11
C]CH3I)
11
CH
R
3
(based on [
11
[
C]CH3I
Cl
Zr
R
Cl
Pd(PPh
THF, 60 °C, 6 min
62–75% crude RCY
11
(from [
C]CH3I)
11
[
O
H
C]CH3I
P(o-tol)
3
*
epichlorohydrin
I
Pd2(dba)3, P(o-tol)
DMF, 150 °C, 5 min
3
*
o-dichlorobenzene,
R
150 °C, 5 min
43–55% crude RC
(from [11C]CH3I)
11
[
C]CH3I
Co
R
Cl
X
MeCN, 130 °C (μw), 1 min
(CO)
2
8
R
O
*
X
22–63% crude RCY
deprotection, by alkylation of the glycinate Schi base with [α -11C]BnCl. Enolates derived
from N-(diphenylmethylene)imines have been extensively used to access racemic and
enantiomerically enriched amino acids, including aminolevulinic acid analogues[340] and
α-aminoisobutyric acid[341].
Chiral aldehydes and chiral alcohols have been used as chiral auxiliaries to access enantiomerically enriched amino acids from the respective chiral imine and ester derivatives
of glycine[342]. Enantioenriched
CH
I using this approach, but larger electrophiles like [α -11C]BnI showed lower yields[67,
3
11
l-[3-
C]alanine (>90% ee) has been prepared from [11C]
343–345]. Chiral imidazolidinones have also been used as chiral auxiliaries and have been
stereoselectively
lysine, all in >90% enantiomeric excess (ee) (Figure7.41b)[346]. Alternatively,
tion of
l-proline-based chiral nickel complexes of a glycine equivalent (Figure7.41c) gave
11
l-[3-
C]alanine, l-[3-11C]phenylalanine, and l-[3-11C]-tyrosine in 80–90% ee and 12–60%
RCY[347].
11
C-alkylated, yielding l-[3-11C]alanine, l-[3 -11C]phenylalanine, and l-[3-11C]
11
C-alkyla-
11
C-Methylation of chiral nickel complexes derived from aromatic amino acid
derivatives showed poor RCYs[348].
R
194 Handbook of Radiopharmaceuticals