o-Boronato- and o-Trifluoroborato - Phosphonium Salts Supported by L-α-Amino Acid Side Chain

Article abstract of DOI:10.1021/acs.joc.5b00246

(Figure Presented) The synthesis of o-boronato- and o-trifluoroborato-phosphonium salts supported by the l-amino acid side chain is described. The synthesis of these new class of amino acid derivatives was achieved by stereoselective quaternization of o-(

Full text of DOI:10.1021/acs.joc.5b00246

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Article
o-Boronato- and o-Trifluoroborato-Phosphonium
Salts Supported by L-alpha-Amino Acid Side Chain
Julie Bernard, Raluca Malacea-Kabbara, Gonçalo Clemente, Benjamin P
Burke, Marie-Joëlle Eymin, Stephen James Archibald, and Sylvain Jugé
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00246 • Publication Date (Web): 06 Apr 2015
Downloaded from http://pubs.acs.org on April 8, 2015
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The Journal of Organic Chemistry
oꢀBoronatoꢀ and oꢀTrifluoroboratoꢀPhosphonium Salts
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Supported by LꢀαꢀAmino Acid Side Chain
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†
†* ‡
‡
Julie Bernard, Raluca MalaceaꢀKabbara, Goncalo Clemente, Benjamin P. Burke,
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MarieꢀJoëlle Eymin, Stephen J. Archibald and Sylvain Jugé
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Institut de Chimie Moléculaire de l’Université de Bourgogne (ICMUB) StéréochIM
UMR CNRS 6302, 9 avenue A. Savary BP47870, 21078 Dijon Cedex, France
‡
Department of Chemistry and Positron Emission Tomography Research Centre, University of Hull,
Cottingham Road, Hull, East Yorkshire, HU6 7RX, UK
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
CORRESPONDING AUTHOR FOOTNOTE
[*] To whom correspondence should be addressed. Eꢀmail: raluca.malacea@uꢀbourgogne.fr
Tel: +33 (0)3 80 39 90 38. Eꢀmail: sylvain.juge@uꢀbourgogne.fr, Tel: +33 (0)3 80 39 61 13.
TABLE OF CONTENTS/ABSTRACT GRAPHIC
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ABSTRACT
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The synthesis of oꢀboronatoꢀ and oꢀtrifluoroboratoꢀphosphonium salts supported by the Lꢀ
amino acid side chain is described. The synthesis of these new class of amino acid derivatives was
achieved by stereoselective quaternization of oꢀ(pinacolato)boronatophenylphosphine with βꢀ or γꢀiodo
amino acid derivatives which are prepared from Lꢀserine or Lꢀaspartic acid, respectively. The
quaternization of the phosphine was performed using either iodo amino ester or carboxylic acid
derivatives. In addition, free carboxylic acid and amine derivatives were obtained by saponification or
HCl acidolysis of oꢀboronatoꢀphosphonium amino esters, respectively. The usefulness of these
compounds in peptide coupling was demonstrated by coupling an oꢀboronatoꢀphosphonium amino
ester with an aspartic acid moiety. When the oꢀboronatoꢀphosphonium amino acid or dipeptide
derivatives were mixed with fluoride, the corresponding oꢀtrifluoroborated products were cleanly and
rapidly obtained in high isolated yields. The hydrolysis of these compounds at room temperature using
a phosphate buffer pH 7/CD3CN mixture has showed only traces of free fluoride Fꢀ after several days.
Finally, a preliminary radiolabelling essay has proved the facile [18F]ꢀfluoride incorporation and high
stability of the radiolabelled product in aqueous conditions. Indeed, this new class of boronꢀ
phosphonium amino acid derivatives shows promising properties for their applications in synthesis and
labelling of peptides.
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KEYWORDS
Phosphonium salts / amino acid derivatives / boronates / trifluoroborates / [18F]ꢀlabelling.
INTRODUCTION
The development of new technologies to improve the diagnosis of certain diseases, to follow
their progression or to validate new drugs is a constant challenge. In this context, the use of modified
αꢀamino acids to mark all kinds of peptides and proteins while preserving their recognition properties,
is of considerable interest.1,2 Among the many classes of unnatural αꢀamino acids, the boron
derivatives are increasingly attractive as they can be used as enzyme inhibitors,3 pharmaceutical
agents,4 in boron neutron capture therapy (BNCT) for cancer treatment,5 in synthesis of modified
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peptides or natural products,6 or in medical imaging.5,7 For the latter application, radiolabelled amino
acids are currently used to explore metabolic pathways, monitoring the tumor response after treatment
or for planning surgery, using positron emission tomography (PET) or single photon emission
computed tomography (SPECT) technologies, because these compounds have small sizes and
hydrophilicꢀlipophilic balance which modestly alters the peptides and proteins.8,9 During the last
decade, straightforward boronꢀbased methods for incorporation of shortꢀlived isotopes in biomolecules
or by the means of prosthetic groups with Bꢀ[18F] bond forming, have also been intensively
developed.10,11 However, their applications for the direct skeleton labelling of amino acid is still rarely
described.10b,12
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Following up from with their pioneering work on anion capture using cationic borane
derivatives,13 Gabbaï and collaborators have recently reported the [18F]ꢀlabelling of oꢀtrifluoro
boratophenylphosphonium salts 1 (Figure 1) by isotopic exchange reaction.14 Interestingly, compounds
1aꢀc are effectively stabilized in vivo against fluoride ion dissociation. Moreover, derivative 1c can
potentially be used for the [18F]ꢀlabelling of biomolecules through bioconjugation by the carboxylic
acid group.14
Figure 1. Selection of phosphonium and boronated amino acid derivatives
In connection with our ongoing investigations into organophosphorus and amino acid
chemistry,15 we recently reported the phosphonium salt 2 as new amino acid Wittig reagent.16 Thus, an
efficient synthesis of boronatoꢀarylꢀLꢀamino acid derivatives such as 3, potentially useful for further
synthesis or labelling reactions, was achieved using Wittig and catalyzed borylation reactions as key
steps.12 As a part of our program on the chemistry of phosphonium salts supported by amino acid
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chain, we now report the stereoselective synthesis of oꢀboronatoꢀ and oꢀtrifluoroborato
phenylphosphonium amino acid derivatives 4, 5 starting from Lꢀserine 6 or Lꢀaspartic acid 7 (Scheme
1). In addition, the deprotection of the functional groups, the stability in aqueous media of the
boronatoꢀ and trifluoroboratoꢀamino acid derivatives 4 and 5, as well as a preliminary [18F]ꢀ
radiolabelling essay are reported.
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Scheme 1. Synthesis of the boronatoꢀphosphonium amino acid derivatives 4
RESULTS AND DISCUSSION
The oꢀ(pinacolato)boronatophenylphosphonium salts 4aꢀd were stereoselectively obtained by
quaternization of phosphine 10, which was previously prepared from 1,2ꢀdibromobenzene,18 with the
corresponding iodo Lꢀαꢀamino acid derivatives 9 (Scheme 1, Table 1). The βꢀiodoꢀαꢀamino acid
derivatives 9a and 9b were easily prepared from Lꢀserine 6 by ringꢀopening of the corresponding
oxazoline derivatives 8a (or 8b) with trimethylsilyl iodide.15b Alternatively, the synthesis of the allyl
and benzyl γꢀiodoꢀαꢀamino esters 9c,d was achieved by starting from the Lꢀaspartic acid 7 via the
formation of the N,NꢀdiBocꢀhomoserine intermediates 11c,d (Scheme 1).15e,16,17 Each step has a 75ꢀ
98% chemical yield.
Thus, the phosphonium salt allyl ester 4a was obtained in 55% isolated yield by heating the oꢀ
(pinacolato)boronatophenyl phosphine 10 with the βꢀiodoꢀαꢀamino ester 9a in toluene at 60°C
overnight (Scheme 1a; Table 1, entry 1). The oꢀboronatophenylphosphine 10 also reacts with the βꢀ
iodoꢀαꢀamino acid 9b by heating in acetonitrile to directly afford the corresponding phosphonium salt
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4b bearing a free carboxylic acid function in 70% yield (entry 2). Under alternate conditions, when
heated in toluene at 76°C for 6 hours, the γꢀiodoꢀαꢀamino esters 9c and 9d react with 10 to afford the
phosphonium amino esters 4c and 4d in 88 and 80% chemical yields, respectively (Scheme 1b; Table
1, entries 3 and 4).
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Table 1. oꢀBoronatoꢀ and trifluoroboratophenyl phosphonium Lꢀamino acid derivatives 4
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oꢀboronato phosphonium salts 4a
oꢀBF3 derivative 5 c
% yieldb
entry
conditions
% yieldb
10 + 9a, Toluene
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ꢀe
60°C, overnight
10 + 9b, ACN
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10 + 9c, Toluene
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76°C, 6 h
10 + 9d, Toluene
76°C, 6 h
4d (or 4c), dioxane/
88d
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NaOH 1M, overnight
4d, acetone/
6
HCl 6M, 2 h
a
The enantiomeric excesses (e.e.) of the boronates 4 were checked using either BINPHAT or Nꢀ
b
c
methyl ephedrine (except 4f). Isolated yield. The (pinacolato)boronato 4 reacts with KHF2 (4
equiv.) in a methanol/water (5:4) mixture for 1 hour at room temperature for 4b,4e or 50°C for 4a,4cꢀ
d,4f. d Mixture of boronate and boronic acid derivatives. e Mixture with byꢀproducts.
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All attempts to deprotect the ester moiety in the boronatoꢀphosphonium salts 4a,cꢀd from
palladium catalyzed deallylation or debenzylation via hydrogenolysis, were unsuccessful.19 In
contrast, the deallylation or the debenzylation of compound 4c and 4d was achieved by saponification
with NaOH 1M at room temperature overnight to afford the phosphonium salts 4e as a mixture with
its boronic acid derivative and an isolated yield up to 88% (Scheme 2a; Table 1, entry 5). The
formation of the boronic acid derivative has been confirmed by LCꢀMS and is explained by the partial
hydrolysis of the pinacolatoboronato moiety under the aqueous basic conditions. On the other hand,
acidolysis with HCl of the pinacolatoboronatophosphonium iodide 4d led to the corresponding
ammonium chloride salt 4f in 78% chemical yield, which proceeds by the deprotection of the Boc
group (Scheme 2c; Table 1, entry 6). Alternatively, the formation of trifluoroborate derivatives 5aꢀf
was performed by reaction of boronates 4aꢀf with 4 equivalents KHF2 in methanol/water (5:4)
mixture according to a literature procedure (Scheme 2, Table 1).20 The presence of the trifluoroborato
moiety was characterized by 19F and 11B NMR showing signals in the ꢀ133 and +2.5 ppm region,
respectively. The boronatoꢀphosphonium amino acid 4b gave the corresponding trifluoroborato
derivative 5b in one hour at room temperature in 71% isolated yield (Scheme 2b; Table 1, entry 2).
Under the same conditions, the boronate and boronic acid mixture 4e lead to the trifluoroborato
compound 5e in 50% yield (Scheme 2a; entry 5).
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Scheme 2. Deprotection and fluorination of the boronatoꢀphosphonium amino acid derivatives 4
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In the case of the boronatoꢀphosphonium amino ester derivatives 5c, 5d or 5f, the formation of
the trifluoroborato derivatives as colorless solids was achieved in one hour by heating at 50°C, in
isolated yields up to 90% (Scheme 2b,c; entries 3,4,6). However under these conditions, the boronatoꢀ
phosphonium amino ester 4a led to a mixture of phosphonium salt 5a along with byꢀproducts (entry
1). Their presence is explained by undesired side reactions affording free BF4, which is characterized
by a signal at ꢀ152 ppm in the 19F NMR spectra. Noteworthy, the presence of the amino acid on the
salts 4aꢀf (whether the functional groups is an ester, an acid, a Boc group, an amine or its
hydrochloride salt) does not disrupt the recognition of the fluoride ions by the boronatoꢀphosphonium
moiety.
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Scheme 3. Synthesis of boronatoꢀ and trifluoroboratoꢀphosphonium dipeptides 13, 14
The feasibility and the effectiveness of the boronatoꢀphosphonium derivatives 4 in peptide
coupling was investigated by reaction of the amino derivative 4g, previously obtained by treatment of
4f with DABCO, with the benzylꢀβꢀpentafluorophenate L aspartate 1221 (Scheme 3). After 6 hours in
acetonitrile at 50°C, the corresponding dipeptide 13 was obtained in 61% yield. The fluorination
reaction of the compound 13 was then achieved in 30 minutes by reaction KHF2 to afford the
trifluoroboratoꢀphosphonium dipeptide 14 in 78% yield (Scheme 3).
With the short lifetime of the [18Fꢀ] radioisotope (halfꢀlife = 110 min),22 the kinetics of the
fluorination and the stability of the products under physiological conditions, are crucial for
appropriate design of radiolabelled agents useful for PET medical imaging.23 Thus, we investigated
the hydrolysis rate of the trifluoroboratoꢀphosphonium aminoacid derivatives prepared with those of
the known compounds 1a and 15 used as reference (Figure 2).
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Figure 2. Comparative hydrolysis of trifluoroboratoꢀphosphonium derivatives
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1a
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Time (min)
Firstly, the hydrolysis of the trifluoroboratoꢀphosphonium amino acid derivatives 5b,d,e was
investigated in a phosphate buffer (pH 7)/acetonitrileꢀD3 (8:2) mixture at room temperature and the
monitoring was performed using 19FꢀNMR analysis of their BꢀF signals by comparison to the
trifluoroborates 1a and 15 as reference compounds (Figure 2).24 Under these aqueous conditions,
compounds 5b,d,e exhibit only traces of the free fluoride Fꢀ ion after 72 hours (SI).
The kinetic curves of the trifluoroborate hydrolysis into boronic acid derivatives result from
nonlinear regression analyses of the cumulative plot (Figure 2). These results are consistent with a
kinetic model where the total hydrolysis of the trifluoroborato group is governed by the dissociation
of the first fluoride which is the limiting step, thus resulting in a pseudo first order rate (Figure 2).24a
Treatment of the kinetic data indicates that kobs= 1.28 x 10ꢀ5 minꢀ1 for 5b, 2.22 x 10ꢀ5 minꢀ1 for 5e and
4.93 x 10ꢀ5 minꢀ1 for 5d (Figure 2). The comparison of these rate constants with those obtained for 1a
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(0.97 x 10ꢀ5 minꢀ1) and 15 (5.7 x 10ꢀ2 minꢀ1) under the same conditions as previously described by
Perrin24a and Gabbaï,24c reinforce the significant advantage of having a phosphonium group at the
ortho position stabilizing the trifluoroborate moiety against hydrolysis and the fluoride loss. The
stability of the trifluoroboratoꢀphosphonium derivatives varies as 5b > 5e > 5d and appear somewhat
less stable that the reference compound 1a. This observation may be explained by the hydrophilic
character of the amino acid moiety which appears to facilitate a slow hydrolysis (Figure 2). On the
other hand, the hydrolysis of the trifluoroboratoꢀphosphonium dipeptide 14 in these conditions shows
a similar behavior in regard to the compounds 5, because only small traces of free fluoride are
observed after 48 h (kobs= 2.55 x 10ꢀ5 minꢀ1) (Figure 2).
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The formation of [18F]ꢀcontaining radiotracers from boron compounds is based either on the [18F]ꢀ
fluorination of boronates in presence of KHF2,11b,e,i or on the isotopic exchange of
trifluoroborates.11d,f,h,14 Since some studies showed that the first method can give from satisfactory to
high specific activity in the range 7.7 to 70.3 GBq ꢁmolꢀ1,11j we first applied it to estimate the
potential of the boronatoꢀphosphonium amino acid derivatives such as 4e in radiolabelling. The
labelling was demonstrated in the case of trifluoroborate [18F]ꢀ5e, which was obtained by reaction of
the mixture 4e at room temperature with an aqueous solution of KHF2 0.02M mixed to [18F]ꢀfluoride
(Figure 3).
Figure 3. Radiochromatogram of [18F]ꢀ5e after HPLC purification (radiochemical purity
>97%)
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Under these conditions, the radiolabeled trifluoroborato derivative [18F]ꢀ5e was obtained in ~50 min
with 97% radiochemical purity (including azeotropic drying of [18Fꢀ], synthesis and purification),
10% radiochemical yield (EOS, decay corrected) and a specific activity of 130 MBq ꢁmolꢀ1 (Figure
3). Interestingly, the labeled compound [18F]ꢀ5e did not show significant degradation after 4 hours in
aqueous solution, confirming the high stability of this class of compounds.
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CONCLUSION
The synthesis of the first examples of boronatoꢀphosphonium salts 4aꢀg supported by an amino acid
side chain is described. The syntheses proceed by stereoselective quaternization of oꢀ(pinacolato)
boronatophenylphosphine 10 with βꢀ or γꢀiodo amino acid derivatives 9 prepared from Lꢀserine or Lꢀ
aspartic acid, respectively, in isolated yields up to 88%. The saponification of the boronatoꢀ
phosphonium amino esters 4c or 4d leads to the compound 4e with a free carboxylic acid in 88%
yield, while HCl acidolysis then treatment with DABCO affords the amino derivative 4g in 69%
overall yield. Both reactions take place stereoselectively without significant decomposition of the
boronatoꢀphosphonium moiety. The effectiveness of the boronatoꢀphosphonium derivatives 4 in
peptide coupling was demonstrated by reaction of the amino derivative 4g with the benzylꢀβꢀ
pentafluorophenate Lꢀaspartate 12, leading to the corresponding dipeptide 13 in 61% yield. In
addition, the reaction of the boronatoꢀphosphonium amino acid and peptide derivatives 4aꢀf and 13
with fluoride cleanly affords the corresponding trifluoroborates 5aꢀf and 14 in approximatively one
hour in isolated yields up to 90%, without significant degradation by hydrolysis in a phosphate buffer
pH 7. Preliminary radiolabelling essay with the boronatoꢀphosphonium amino acid derivative 4e
demonstrates its labelling into [18F]ꢀ5e in 10% radiochemical yield and with a specific activity of 130
Mbq.ꢁmolꢀ1. Indeed, this new class of oꢀboronatoꢀ and trifluoroboratoꢀphenylphosphonium amino
acid derivatives 4, 5 shows promising properties for their applications in synthesis and labelling of
peptides.
EXPERIMENTAL SECTION
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General Information. The reactions were carried out under argon and solvents were dried and
purified by conventional methods prior to use. All commercial reagents, 1ꢀbenzyl Nꢀ(tꢀ
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butoxycarbonyl)ꢀLꢀaspartate and (Λ,R)ꢀBINPHATꢀtetrabutyl ammonium salt were purchased from
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commercial sources and used without purification. The flash chromatography was performed with the
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indicated solvents using silica gel 60 (60AAC, 35ꢀ70 µm). The H, 13C, 19F and 11B NMR spectra
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were recorded on 600, 500 or 300 MHz spectrometers at ambient temperature using TMS as internal
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reference for H, 13C NMR, phosphoric acid (85%), CFCl3 and BF3.Et2O as external references for
31Pꢀ, 19Fꢀ and 11BꢀNMR, respectively. Data are reported as s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br.s = broad signal, coupling constant(s) in Hertz, integration. HPLC analyses
were performed on a chromatograph equipped with a UV detector at λ = 210 nm and λ = 254 nm. The
infraꢀred spectra were recorded on a FTꢀIR instrument. Melting points were measured on a Kofler
melting point apparatus and are uncorrected. Optical rotation values were determined at 20°C on
polarimeter at 589 nm (sodium lamp). High Resolution Mass Spectra (HRMS) were performed under
ESI conditions with a micro QꢀTOF detector. Elemental analyses were measured with a precision
superior to 0.3% on a CHNSꢀO instrument apparatus. The allyl (R)ꢀβꢀiodoꢀαꢀbenzamidopropanoate
9a,15b allyl and benzyl (S)ꢀ2ꢀ(tertꢀbutyloxycarbonyl)aminoꢀ4ꢀiodobutanoates 9c16 and 9d17 were
synthesized as described from Lꢀserine 6 or Lꢀaspartic acid 7, respectively. The oꢀ
(pinacolato)boronatophenylꢀdiphenylphosphine 1018 and trifluoroborato compounds 1a24c or 15,25
were prepared according to the published procedure. The (ꢀ)ꢀNꢀmethyl ephedrine (mp= 88°C), was
prepared by heating (ꢀ)ꢀephedrine with a mixture of formic acid and formaldehyde according to a
similar described procedure.26
For radiolabelling, fluorineꢀ18 (18F) was produced by the 18O(p,n)18F nuclear reaction using a 7.5
MeV cyclotron and 300 µL of [18O]ꢀH2O ≥ 98%. HPLC was performed through an Agilent 1200
series with a 254 nm UV detector and radioactivity was detected by a NaI crystal coupled to a
photomultiplier tube. An analytical 5 µ C18 150x4.60 mm reverse phase column, was used with a
solvent system of CH3CN + 0.1% TFA (A) and H2O + 0.1% TFA (B) (0ꢀ2 min 40% A; 2ꢀ10 min 40
to 70% A; 10ꢀ20 min 70% A; 20ꢀ25 min 70 to 40% A; flow rate: 1 mL/min). The purification was
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realised on a semiꢀpreparative HPLC column (C18 10ꢁm 125A, 7.8 x 300mm) with a solvent system
of CH3CN + 0.1% TFA (A) and H2O + 0.1% TFA (B) (0ꢀ2 min 40% A; 2ꢀ10 min 40 to 70% A; 10ꢀ20
min 70% A; 20ꢀ25 min 70 to 40% A; flow rate: 3 mL/min).
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19F NMR spectroscopic kinetic analyses: A small quantity of the trifluoroborate salt (5 mg) was
added to the NMR tube. At the start of the solvolysis reaction (t= 0 min), the trifluoroborate salt was
dissolved in 0.5 mL of a buffer solution pH 7/ acetonitrile D3 (8:2), and the decomposition was
monitored by 19F NMR spectroscopy. The buffer solution pH 7 with 200 mM strength was prepared
by mixing in 100 mL H2O, Na2HPO4.7H2O (5.3 g) and NaH2PO4.H2O (40 mg). 19F NMR spectra
were acquired at different times, and the integration was calculated on the spectra. Integrals
corresponding to the trifluoroborate peak were divided by the sum of the trifluoroborate and the free
fluoride integrations, to calculate the fraction of 19F existing as trifluoroborato moiety. The ratio of
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19Fꢀsignal existing as the trifluorborate to the total F signal was plotted against time to determinate
the kinetic of the hydrolysis. The kinetic curves reported in the Figure 2 are the result of nonlinear
regression analyses of the cumulative plot of all data sets for identical experiments, using
excel®14.1.3 version.
(R)ꢀαꢀBenzamidoꢀβꢀiodoꢀpropanoic acid 9b. This compound has been synthesised from Lꢀ
serine according a modified procedure.15b Under Ar atmosphere, oxazoline 8b as sodium salt (0.5 g,
2.35 mmol), iodotrimethylsilane (1.34 mL, 9.39 mmol) and 85 µL of water were dissolved in 10 mL
of chloroform stabilized by amylene. After 48h of stirring at room temperature, the solvent was
evaporated. The residue was dissolved in acetone and the NaI was removed by filtration. The filtrate
was hydrolyzed by a KHCO3 solution (1M), and the aqueous phase was washed with AcOEt (2 x 30
mL) and acidified with NaHSO4 solution (1M) until pH 3. The aqueous layer was extracted by AcOEt
(2 x 30 mL). The organic layer was dried over MgSO4 and the solvent evaporated to give 0.37g of a
1
yellow solid (yield= 50%). mp= 98 °C; [α]D= ꢀ7.8 (c 0.4, acetone). H NMR (300 MHz, acetone D6):
δ 3.73 (dd, J= 6.9, J= 10.5 Hz, 1H), 3.86 (dd, J= 4.5, J= 10.5 Hz, 1H), 4.86ꢀ 4.92 (m, 1H), 7.48ꢀ7.61
(m, 3H), 7.85ꢀ7.86 (m, 1H, NH), 7.93ꢀ7.96 (m, 2H). 13C NMR (75 MHz, Acetone D6): δ 5.2, 53.9,
127.3, 128.5, 131.7, 135.1, 166.5, 169.8. HRMS (ESIꢀQꢀTOF) calcd for C10H10INO3 [M+Na]+:
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The Journal of Organic Chemistry
341.95976 found 341.95858. FTꢀIR (neat) cmꢀ1: 3282, 3032, 2973, 2925, 2598, 1965, 1903, 1707,
1643, 1603, 1578, 1520, 1487, 1446, 1419, 1331, 1295, 1244, 1192, 1169, 1096, 1026, 999, 929, 852,
818, 798, 754, 719, 691 Analysis calcd. for C10H10INO3 (318.97): C 37.64, H 3.16, N 4.39; found C
37.54, H 3.31, N 4.66.
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(R)ꢀ2ꢀ(benzamido)ꢀ3ꢀ[2ꢀ(pinacolatoboronatophenyl)diphenyl phosphoniumꢀiodide]
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propanoate 4a. To a solution of boronatoꢀphosphine 10 (0.28 g, 0.72 mmol) in 1 mL of toluene
under argon, was added 0.28 g (0.6 mmol) of allyl (R)ꢀαꢀbenzamidoꢀβꢀiodoꢀpropanoate 9a. After
stirring 1 night at 60°C, the solvent was evaporated and the residue was purified by chromatography
on silica gel using a mixture dichloromethane /acetone (2:1) as eluent, to afford 0.23 g of the product
4a (yield= 55%). White solid. Rf: 0.43 (dichloromethane/acetone 2:1); mp= 132 °C; [α]D= ꢀ11.7 (c
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0.3, CHCl3). H NMR (300 MHz, CDCl3): δ 0.96 (s, 6H), 0.99 (s, 6H), 4.56ꢀ4.74 (m, 4H), 5.09ꢀ5.19
(m, 2H), 5.23ꢀ5.25 (m, 1H), 5.77ꢀ5.81 (m, 1H), 7.37ꢀ8.02 (m, 18H), 8.23ꢀ8.25 (m, 1H), 9.01ꢀ9.03 (m,
1H). 13C NMR (75 MHz, CDCl3): δ 24.2, 24.5, 26.9 (d, J= 52.2 Hz), 48.2 (d, J= 2.3 Hz), 66.9, 85.4,
118.5, 120.9 (d, J= 86.0 Hz), 121.7 (d, J= 87.5 Hz), 122.5 (d, J= 83.8 Hz), 128.1, 128.3, 129.9 (d, J=
10.6 Hz), 130.0 (d, J= 10.6 Hz), 131.3, 131.8, 132.1 (d, J= 16.6 Hz), 132.2, 133.5 (d, J= 9.3 Hz),
133.7 (d, J= 3.0 Hz), 133.9ꢀ134.0 (m), 136.8 (d, J= 12.8 Hz), 139.2 (d, J= 13.6 Hz), 167.4, 170.1 (d,
J= 12.8 Hz), 1 Cq not observed. 31P NMR (121 MHz, CDCl3):
δ +26.2. HRMS (ESIꢀQꢀTOF) calcd.
for C37H40BNO5P [MꢀI]+: 620.27381, found 620.27255. FTꢀIR (neat) cmꢀ1: 3229, 2981, 1981, 1733,
1658, 1582, 1520, 1483, 1436, 1375, 1340, 1272, 1219, 1169, 1140, 1108, 1052, 1028, 995, 962, 852,
826, 749, 713, 689. The enantiomeric excess of the phosphonium salt 4a (> 98% e.e.) was checked by
31P NMR analysis in the presence of BINPHAT by comparison of a racemic sample.15c
(R
)ꢀ2ꢀ(benzamido)ꢀ3ꢀ[2ꢀ(pinacolatoboronatophenyl)diphenyl
phosphoniumꢀiodide]
propanoic acid 4b. To a solution of boronatoꢀphosphine 10 (0.22 g, 0.55 mmol) in 2 mL of
acetonitrile under argon, was added 0.13 g (0.4 mmol) of (R)ꢀαꢀbenzamidoꢀβꢀiodoꢀpropanoïc acid 9b.
After stirring 1 night at 60°C, the solvent was evaporated. The residue was concentrated in
dichloromethane and then, precipitated with ether to afford 0.19 g of product 4b as colorless solid
1
(yield= 70%); mp: 152°C; [α]D= ꢀ8.3 (c 0.3, acetone). H NMR (500 MHz, CDCl3): δ 0.94ꢀ0.98 (2s,
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12H), 4.66ꢀ4.70 (m, 1H), 4.75ꢀ4.88 (m, 1H), 5.24ꢀ5.27 (m, 1H), 7.37ꢀ7.91 (m, 16H), 8.01ꢀ8.03 (m,
2H), 8.21ꢀ8.23 (m, 1H), 8.97 (d, J= 10.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 24.3, 24.4, 26.4 (d,
J= 55.1 Hz), 49.4, 85.6, 120.6 (d, J= 88.5 Hz), 121.8 (d, J= 83.1 Hz), 122.1 (d, J= 88.5 Hz), 128.3,
128.4, 130.0 (d, J= 12.7 Hz), 130.2 (d, J= 12.7 Hz), 131.4, 132.3 (d, J= 13.0 Hz), 132.4, 133.2 (d, J=
9.3 Hz), 133.9 (d, J= 3.0 Hz), 134.0 (d, J= 10.0 Hz), 134.1 (d, J= 2.7 Hz), 134.2 (d, J= 2.7 Hz),
137.1 (d, J= 12.5 Hz), 139.2 (d, J= 14.0 Hz), 168.7, 170.8 (d, J= 10.7 Hz), 1 Cq not observed. 31P
NMR (202 MHz, CDCl3): δ +25.4. HRMS (ESIꢀQꢀTOF) calcd for C34H36BNO5P [MꢀI]+: 580.24246
found 580.24158. FTIR (neat) cmꢀ1: 3054, 2979, 2931, 1981, 1906, 1731, 1657, 1580, 1524, 1484,
1437, 1375, 1340, 1271, 1212, 1167, 1140, 1108, 1052, 997, 961, 852, 824, 746, 714, 690. The
enantiomeric excess of the phosphonium salt 4b (> 90%) was checked by 31P NMR analysis in the
presence of (ꢀ)ꢀNꢀmethyl ephedrine by comparison with a racemic sample.
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Allyl
(S)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀ[2(pinacolatoboronatophenyl)
diphenyl
phosphoniumꢀiodide]butanoate 4c. To a solution of boronatoꢀphosphine 10 (0.28 g, 0.72 mmol) in
5 mL of dry toluene was added 0.16 g (0.42 mmol) of allyl γꢀiodo amino ester 9c. After stirring 6
hours at 76°C, the solvent was evaporated and the residue was purified by chromatography on silica
gel using a mixture dichloromethane/acetone (3:1) as eluent. After evaporation of the solvent, 0.28 g
of phosphonium salt 4c was obtained as a colorless solid (yield= 88%); Rf: 0.53
(dichloromethane/acetone 3:1); mp= 90 °C; [α]D= ꢀ16.7 (c 0.4, CHCl3). 1H NMR (500 MHz, CDCl3):
δ 0.99 (s, 6H), 1.02 (s, 6H), 1.41 (s, 9H), 2.15ꢀ2.19 (m, 1H), 2.34ꢀ2.38 (m, 1H), 3.78ꢀ3.81 (m, 1H),
4.04ꢀ4.08 (m, 1H), 4.55ꢀ4.62 (m, 3H), 5.17ꢀ5.30 (m, 2H), 5.80ꢀ5.94 (m, 1H), 6.42 (d, J= 5.0 Hz, 1H),
7.30ꢀ7.35 (m, 1H), 7.63ꢀ7.79 (m, 12H), 8.22ꢀ8.24 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 21.8 (d, J=
53.1 Hz), 24.3, 24.5, 25.7, 28.3, 53.6 (d, J= 17.7 Hz), 66.2, 79.9, 85.5, 118.5, 121.2 (d, J= 85.4 Hz),
121.5 (d, J= 88.5 Hz), 122.2 (d, J= 82.3 Hz), 130.3 (d, J= 3.6 Hz), 130.4 (d, J= 3.4 Hz), 131.8, 132.3
(d, J= 13.0 Hz), 133.0 (d, J= 6.2 Hz), 133.2 (d, J= 6.5 Hz), 134.0 (d, J= 2.6 Hz), 134.4 (d, J= 3.0 Hz),
134.4 (d, J= 2.9 Hz), 136.7 (d, J= 11.9 Hz), 139.2 (d, J= 13.6 Hz), 155.9, 170.7 (d, J= 1.4 Hz), 1 Cq
not observed. 31P NMR (121 MHz, CDCl3): δ +28.0. HRMS (ESIꢀQꢀTOF) calcd for C36H46BNO6P
[MꢀI]+: 630.31566, found 630.31494. FTIR (neat) cmꢀ1: 2980, 2461, 2192, 1704, 1506, 1485, 1439,
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1265, 1211, 1161, 1111, 1052, 993, 962, 911, 853, 786, 726, 690. Analysis calcd. for C36H46BNO6PI
(757.44): C 57.08, H 6.12, N 1.85; found C 56.79, H 6.42, N 1.94. The enantiomeric excess of the
phosphonium salt 4c (> 98% e.e.) was checked by 31P NMR analysis in the presence of BINPHAT by
comparison of a racemic sample.15c
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Benzyl
(S)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀ[2ꢀ(pinacolatoboronato
phenyl)diphenyl
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phosphoniumꢀiodide]butanoate 4d. To a solution of boronatoꢀphosphine 10 (0.315 g, 0.81 mmol) in
5 mL of dry toluene was added 0.21 g (0.50 mmol) of benzyl γꢀiodo amino ester 9d. After stirring 6
hours at 76°C, the solvent was evaporated, and the residue was purified by chromatography on silica
gel using a mixture dichloromethane/acetone (3:1) as eluent. After evaporation of the solvent, 0.32 g
of phosphonium salt 4d was obtained as a colorless solid (yield= 80%); Rf: 0.54
(dichloromethane/acetone 3:1); mp= 97 °C; [α]D= ꢀ10.0 (c 0.1, CHCl3). 1H NMR (600 MHz, CDCl3):
δ 0.99 (s, 6H), 1.04 (s, 6H), 1.36 (s, 9H), 2.17ꢀ2.27 (m, 1H), 2.40ꢀ2.50 (m, 1H), 3.75ꢀ3.86 (m, 1H),
4.08ꢀ4.19 (m, 1H), 4.56ꢀ4.63 (m, 1H), 5.15ꢀ5.18 (m, 2H), 6.52ꢀ6.54 (m, 1H), 7.29ꢀ7.37 (m, 5H), 7.63ꢀ
7.81 (m, 13H), 8.23ꢀ8.25 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 21.8 (d, J= 53.6 Hz), 24.3, 24.6,
25.8 (d, J= 1.8 Hz), 28.3, 53.7 (d, J= 18.7 Hz), 67.9, 79.9, 85.5, 121.1 (d, J= 87.7 Hz), 121.4 (d, J=
86.5 Hz), 122.2 (d, J= 82.9 Hz), 128.2, 128.3, 128.4, 130.3 (d, J= 3.7 Hz), 130.4 (d, J= 3.6 Hz), 132.3
(d, J= 13.1 Hz), 133.1 (d, J= 10.6 Hz), 133.2 (d, J= 10.6 Hz), 134.0 (d, J= 3.2 Hz), 134.4 (d, J= 2.7
Hz), 134.5 (d, J= 3.1 Hz), 135.5, 136.7 (d, J= 12.4 Hz), 139.3 (d, J= 13.5 Hz), 155.8, 170.9, 1 Cq not
observed. 31P NMR (121 MHz, CDCl3): δ +28.1. HRMS (ESIꢀQꢀTOF) calcd for C40H48BNO6P [Mꢀ
I]+: 680.33039, found 680.33137; FTIR (neat) cmꢀ1: 2977, 1702, 1605, 1500, 1348, 1340, 1254, 1212,
1161, 1110, 1052, 997, 962, 850, 732, 692. The enantiomeric excess of the phosphonium salt 4d (>
98% e.e.) was checked by 31P NMR analysis in the presence of BINPHAT by comparison with a
racemic sample.15c
(S)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀ[2ꢀ(pinacolatoboronatophenyl) diphenylphosphoniumꢀ
iodide]butanoic acid 4e. 0.4 mL of NaOH 1M was added to a solution of boronatoꢀphosphonium
amino ester 4d (200 mg, 0.25 mmol) (or 4c) in 4 mL of a mixture dioxane/water (8:2). After stirring
overnight at room temperature, the aqueous layer was extracted with ether and acidified with acetic
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acid until pH= 3 and then extracted using dichloromethane. The organic layer was dried with MgSO4
and the solvent was evaporated to afford a mixture of 4e with the boronic acid derivative (120 mg,
88% yield) in ratio close to 1:1. 31P NMR (121 MHz, CDCl3): δ +29.6 (4e), +27.8 (boronic acid
derivative). The LCꢀMS of the crude mixture 4e was performed using C18 column and methanol as
eluent. The chromatogram has showed two peaks at 7.3ꢀ7.8 min and 8.6ꢀ8.7 min which were
characterized by ESIꢀOrbitrap (positive ion) as compounds 4e which corresponds to the boronate
C33H42BNO6P [MꢀI]+: 590.39 and boronic acid derivative C27H30BNO5P [MꢀIꢀH2O]+: 490.34,
respectively. The crude mixture of boronate 4e with the boronic acid derivative was used without
further purification in the following fluorination reaction.
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Benzyl (S)ꢀ2ꢀ(ammoniumꢀchloride)ꢀ4ꢀ[2ꢀ(pinacolatoboronatophenyl) diphenylphosphonium
ꢀiodide]butanoate 4f. To a solution of boronatoꢀphosphonium amino ester 4d (0.33 g, 0.4 mmol) in
2.5 mL of acetone was added 2 mL of HCl 6M. After stirring 2 hours at room temperature, the
mixture was extracted with 2 x 10 mL of dichloromethane. The organic phase was dried with MgSO4,
and evaporated. The compound was obtained as a colorless solid (0.24 g, 78% yield); mp= 129 °C;
[α]D= +2.3 (c 0.4, CHCl3). 1H NMR (500 MHz, CD3CN): δ 0.92 (d, J= 18.5 Hz, 12H), 2.29ꢀ2.32 (m,
1H), 2.45ꢀ2.50 (m, 1H), 3.96ꢀ4.03 (m, 2H), 4.36ꢀ4.39 (m, 1H), 5.11ꢀ5.21 (m, 2H), 7.28ꢀ7.91 (m,
18H), 8.18ꢀ8.20 (m, 1H). 13C NMR (125 MHz, CD3CN): δ 22.3 (d, J= 53.2 Hz), 24.3, 24.4, 25.0, 53.9
(d, J= 19.2 Hz), 68.6, 86.0, 121.0 (d, J= 86.3 Hz), 121.7 (d, J= 89.2 Hz), 121.8 (d, J= 87.1 Hz), 128.9,
129.13, 129.14, 129.20, 129.21, 130.1 (d, J= 11.4 Hz), 133.1 (d, J= 13.0 Hz), 133.7 (d, J= 9.8 Hz),
134.1 (d, J= 9.8 Hz), 134.9 (d, J= 4.9 Hz), 135.1 (d, J= 2.7 Hz), 135.2 (d, J= 2.8 Hz), 135.5, 137.7 (d,
J= 12.4 Hz), 139.3 (d, J= 14.5 Hz), 168.6, 1 Cq not observed. 31P NMR (202 MHz, CD3CN): δ +26.6.
11B NMR (160 MHz, CD3CN): δ +30.1. HRMS (ESIꢀQꢀTOF) calcd for C35H40BNO4P [MꢀClꢀHꢀI]+:
580.27756; found 580.27887. FTIR (neat) cmꢀ1: 2974, 2869, 2817, 2608, 1984, 1746, 1705, 1584,
1482, 1437, 1340, 1259, 1195, 1139, 1109, 1051, 995, 961, 852, 824, 731, 691.
Benzyl
(S)ꢀ2ꢀaminoꢀ4ꢀ[2ꢀ(pinacolatoboronatophenyl)diphenylphosphoniumꢀiodide]
butanoate 4g. To a solution of boronatoꢀphosphonium 4f (0.39 g, 0.52 mmol) in 1.5 mL of
dichloromethane were added 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO, 60 mg, 0.53 mmol). After
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stirring 1 hour at room temperature and precipitate removing, the solvent was evaporated to afford the
amino compound 4g as a colorless oil (0.32 g, yield 88%); [α]D= +2.8 (c 0.5, CHCl3); 1H NMR (300
MHz, CDCl3): δ 0.92 (s, 6H), 0.94 (s, 6H), 1.77ꢀ1.93 (m, 1H), 2.23ꢀ2.51 (m, 1H), 3.33ꢀ4.01 (m, 2H),
5.02ꢀ5.14 (m, 2H), 5.26 (br s, 2H), 7.21ꢀ7.31 (m, 5H), 7.31ꢀ7.40 (m, 1H), 7.61ꢀ7.74 (m, 12H), 8.17ꢀ
8.21 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 21.4 (d, J= 51.5 Hz), 24.3, 24.4, 29.0 (d, J= 2.7 Hz),
53.8 (d, J= 16.7 Hz), 67.0, 85.4, 121.1 (d, J= 85.7 Hz), 121.2 (d, J= 87.1 Hz), 122.2 (d, J= 82.7 Hz),
128.3, 128.4, 128.6, 130.4 (d, J= 12.1 Hz), 132.4 (d, J= 12.5 Hz), 133.1 (d, J= 10.5 Hz), 134.0, 134.4,
135.4, 135.4, 136.7 (d, J= 12.2 Hz), 139.2 (d, J= 13.5 Hz), 173.5; 31P NMR (121 MHz, CDCl3): δ
+27.8; HRMS (ESIꢀQꢀTOF) calcd for C35H40BNO4P [MꢀI]+: 580.27825, found 580.27683.
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Allyl
(R
)ꢀ2ꢀ(benzamido)ꢀ3ꢀ[2ꢀ(trifluoroboratophenyl)diphenyl
phosphoniumꢀiodide]
propanoate 5a. To a solution boronatoꢀphosphonium 4a (0.06 g, 0.08 mmol) in methanol (0.3 mL)
was added a solution of KHF2 (0.025 g, 0.32 mmol) in water (0.23 mL). After 1 hour stirring at 50°C,
a precipitate was formed and analyzed by 31P and 19F NMR (CD3CN), showing a complex mixture
with two (δ +25.9 and +25.8) and four signals (δ ꢀ121.7, ꢀ137.0, ꢀ139.0 and ꢀ152.6), respectively.
(R)ꢀ2ꢀ(benzamido)ꢀ3ꢀ[2ꢀ(trifluoroboratophenyl)diphenylphosphoniumꢀiodide]propanoic
acid 5b. To a solution boronatoꢀphosphonium 4b (0.10 g, 0.10 mmol) in methanol (0.5 mL) was
added a solution of KHF2 (0.05 g, 0.64 mmol) in water (0.4 mL). After 1 hour stirring at rt, the
mixture was extracted with dichloromethane (2 x 5 mL), then the organic phase was dried with
MgSO4 and the solvent evaporated. The residue was dissolved in dichloromethane and then
precipitated with ether. The trifluoroborate 5b was obtained as a yellow solid with 71% yield (0.05 g).
1
mp= 160°C. H NMR (500 MHz, CD3CN): δ 3.57ꢀ3.67 (m, 1H), 4.34ꢀ4.42 (m, 1H), 4.77ꢀ4.83 (m,
1H), 7.17ꢀ7.25 (m, 5H), 7.35 ꢀ7.42 (m, 3H), 7.49ꢀ7.56 (m, 7H), 7.66ꢀ7.82 (m, 3H), 7.94ꢀ7.97 (m, 1H).
13C NMR (125 MHz, CD3CN): δ 25.9 (dq, J= 5.7, 58.6 Hz), 48.3 (d, J= 5.2 Hz), 119.9 (d, J= 83.5
Hz), 120.7 (d, J= 84.8 Hz), 122.1 (d, J= 88.7 Hz), 127.4, 127.9 (d, J= 13.8 Hz), 128.9, 130.0 (d, J=
12.8 Hz), 130.3 (d, J= 12.8 Hz), 132.5, 133.2, 133.5 (d, J= 9.5 Hz), 133.7 (d, J= 3.3 Hz), 134.5 (d,
J= 3.3 Hz), 134.7 (d, J= 9.5 Hz), 134.8 (d, J= 2.9 Hz), 135.9 (d, J= 14.7 Hz), 136.1 (dq, J= 3.4, 16.8
Hz), 167.9, 170.9 (d, J= 17.4 Hz), 1 Cq not observed. 31P NMR (202 MHz, CD3CN): δ +25.8. 11B
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NMR (160 MHz, CD3CN): δ +2.7. 19F NMR (470 MHz, CD3CN): δ ꢀ132.0. HRMS (ESIꢀQꢀTOF)
calcd C28H23BF2NO3PNa [MꢀHꢀF+Na]+: 524.13738 found 524.13638. FTIR (neat) cmꢀ1: 3371, 3059,
3001, 2931, 1721, 1661, 1642, 1580, 1529, 1484, 1437, 1408, 1332, 1271, 1236, 1182, 1106, 1073,
1052, 1020, 980, 934, 825, 797, 744, 710, 688. The enantiomeric excess of the trifluoroborate 5b (>
90%) was checked by 31P NMR analysis in the presence of (ꢀ)ꢀNꢀmethyl ephedrine by comparison
with a racemic sample.
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Allyl (S)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀ[2ꢀ(trifluoroboratophenyl) diphenylphosphoniumꢀ
iodide]butanoate 5c. To a solution of boronatoꢀphosphonium 4c (0.35 g, 0.46 mmol) in methanol
(1.4 mL) was added a solution of KHF2 (0.14 g, 1.84 mmol) in water (1.1 mL). After stirring 1 hour
at 50°C, 5 mL of dichloromethane was added, and the mixture was washed with H2O. The organic
phase was dried with MgSO4 and the solvent was evaporated. The trifluoroboratoꢀphosphonium 5c
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(0.22 g) was obtained as a colorless solid (84% yield); mp= 75 °C; [α]D= +14.4 (c 0.1, CHCl3). H
NMR (500 MHz, DMSO D6): δ 1.39 (s, 9H), 1.92ꢀ1.96 (m, 2H), 3.48ꢀ3.55 (m, 2H), 4.12ꢀ4.16 (m,
1H), 4.49ꢀ4.52 (m, 2H), 5.14ꢀ5.21 (m, 2H), 5.81ꢀ5.88 (m, 1H), 7.05ꢀ7.10 (m, 1H), 7.35ꢀ7.38 (m, 2H),
7.60ꢀ7.70 (m, 9H), 7.80ꢀ7.81 (m, 2H), 7.85ꢀ7.88 (m, 1H). 13C NMR (75 MHz, DMSO D6): δ 20.31 (d,
J= 48.1 Hz), 25.0, 28.1, 53.9 (d, J= 17.7 Hz), 64.8, 78.7, 117.4, 118.9 (d, J= 83.6 Hz), 121.7 (d, J=
85.5 Hz), 121.8 (d, J= 85.9 Hz), 126.9 (d, J= 13.5 Hz), 129.4 (d, J= 9.3 Hz), 129.6 (d, J= 9.3 Hz),
132.2, 132.8 (d, J= 3.3 Hz), 133.1 (d, J= 9.8 Hz), 133.3 (d, J= 9.7 Hz), 133.6 (d, J= 2.3 Hz), 133.7 (d,
J= 2.8 Hz), 134.3 (d, J= 14.4 Hz), 135.0 (d, J= 14.9 Hz), 155.5, 171.1, 1 Cq not observed. 31P NMR
(202 MHz, DMSO D6): δ +29.3. 11B NMR (160 MHz, DMSO D6): δ +2.5; 19F NMR (470 MHz,
DMSO D6): δ ꢀ132.0. HRMS (ESIꢀQꢀTOF) calcd for C30H34BClF3NO4P [M+Cl]ꢀ: 606.19590; found
606.19684. FTIR (neat) cmꢀ1: 3376, 2976, 1707, 1511, 1439, 1366, 1251, 1161, 1109, 1049, 1017,
991, 940, 858, 740, 690.
Benzyl
(S)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀ[2ꢀ(trifluoroboratophenyl)
diphenyl
phosphoniumꢀiodide]butanoate 5d. To a solution of boronatoꢀphosphonium 4d (0.26 g, 0.32 mmol)
in methanol (1 mL) was added a solution of KHF2 (0.1 g, 1.3 mmol) in water (0.8 mL). After stirring
1 hour at 50°C, 5 mL of dichloromethane was added and the mixture was washed with H2O. The
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organic phase was dried with MgSO4 and the solvent evaporated. The trifluoroboratoꢀphosphonium
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5d (0.18 g) was obtained as a colorless solid (yield 90%); mp= 80°C; [α]D: ꢀ20.2 (c 0.3, CHCl3). H
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NMR (500 MHz, DMSO D6): δ 1.38 (s, 9H), 1.94ꢀ1.96 (m, 2H), 3.46ꢀ3.55 (m, 2H), 4.16ꢀ4.17 (m,
1H), 5.03ꢀ5.19 (m, 2H), 7.06ꢀ7.10 (m, 1H), 7.26ꢀ7.67 (m, 16H), 7.78ꢀ7.80 (m, 2H), 7.81ꢀ7.82 (m,
1H). 13C NMR (75 MHz, DMSO D6): δ 19.3 (d, J= 48.0 Hz), 23.9, 27.0, 52.9 (d, J= 17.9 Hz), 64.9,
77.5, 117.8 (d, J= 84.8 Hz), 120.6 (d, J= 85.7 Hz), 121.7 (d, J= 84.8 Hz), 125.8 (d, J= 13.2 Hz),
126.5, 126.8, 127.2, 128.3 (d, J= 11.7 Hz), 128.4 (d, J= 11.7 Hz), 131.6 (d, J= 2.1 Hz), 130.0 (d, J=
8.5 Hz), 132.2 (d, J= 8.5 Hz), 132.5 (d, J= 2.3 Hz), 132.6 (d, J= 2.3 Hz), 133.2 (d, J= 14.5 Hz), 134.0
(d, J= 16.5 Hz), 134.6, 154.4, 170.2, 1 Cq not observed. 31P NMR (202 MHz, DMSO D6): δ +29.3.
11B NMR (160 MHz, DMSO D6): δ +2.7. 19F NMR (470 MHz, DMSO D6): δ ꢀ131.9. HRMS (ESIꢀQꢀ
TOF) calcd for C34H36BF3NNaO4P [M+Na]+: 644.23253; found 644.23150. FTIR (neat) cmꢀ1: 3361,
2976, 1707, 1512, 1439, 1366, 1249, 1161, 1109, 1049, 1019, 942, 740, 693.
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(S)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀ[2ꢀ(trifluoroboratophenyl)diphenyl
phosphoniumꢀ
iodide]butanoic acid 5e. The mixture of boronate (and boronic acid) phosphonium 4e prepared as
above, was dissolved in MeOH (0.5 mL) and treated with a solution of KHF2 (4 eq., 0.5 mmol) in
water (0.4 mL). The resulting solution was stirred for 1 hour at room temperature. The mixture was
extracted with dichloromethane (3 x 5 mL) and the organic layer was dried with MgSO4. After
evaporation, the compound 5e is obtained as a colorless solid (50% overall yield from 4c; 40%
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overall yield from 4d); mp= 150 °C; [α]D= +27.9 (c 0.3, CHCl3). H NMR (500 MHz, CD3CN): δ
1.44 (s, 9H), 1.99ꢀ2.01 (m, 1H), 2.14ꢀ2.16 (m, 1H), 3.40ꢀ3.51 (m, 2H), 4.17 (br.s, 1H), 5.82 (br.s,
1H), 7.18 (dd, J= 8.0, 14.5 Hz, 1H), 7.36 (tdd, J= 1.5, 4.5, 7.5 Hz, 1H), 7.55ꢀ7.79 (m, 12H), 7.97ꢀ8.00
(m, 1H). 13C NMR (125 MHz, CD3CN): δ 21.3 (d, J= 45.8 Hz), 26.2, 28.2, 54.4 (d, J= 15.8 Hz), 79.8,
118.9 (d, J= 85.0 Hz), 123.2 (d, J= 85.0 Hz), 123.2 (d, J= 86.3 Hz,), 127.6 (d, J= 13.5 Hz), 130.1 (d,
J= 12.0 Hz), 133.5 (d, J= 3.8 Hz), 133.6 (d, J= 11.3 Hz), 133.8 (d, J= 12.0 Hz), 134.1 (d, J= 1.5 Hz),
134.1 (d, J= 1.5 Hz), 135.5 (d, J= 15.0 Hz), 135.8 (dq, J= 2.3, 16.5 Hz), 156.4, 173.3, 1 Cq not
observed. 31P NMR (202 MHz, CD3CN): δ +28.7. 11B NMR (160 MHz, CD3CN): δ +2.5. 19F NMR
(470 MHz, CD3CN): δ ꢀ134.1. HRMS (ESIꢀQꢀTOF) calcd for C27H29BF3NO4P [MꢀH]ꢀ: 530.18787
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found 530.19022. FTIR (neat) cmꢀ1: 2976, 2930, 1706, 1509, 1438, 1367, 1162, 1109, 1050, 1019,
943, 741, 691, 608, 531, 515. The enantiomeric excess of the trifluoroboratoꢀphosphonium salt 5e (>
98% e.e.) was checked by 31P NMR analysis in presence of (ꢀ)ꢀNꢀmethyl ephedrine, by comparison
with a racemic sample.
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(S)ꢀ2ꢀ(ammoniumꢀchloride)ꢀ4ꢀ[2ꢀ(trifluoroborato)phenylꢀdiphenylphosphoniumꢀ
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iodide]butanoate 5f. To a solution of boronatoꢀphosphonium 4f (0.18 g, 0.24 mmol) in methanol (1
mL) was added a solution of KHF2 (0.08 g, 1 mmol) in water (0.8 mL). After stirring 1 hour at 50°C,
the mixture was extracted with dichloromethane (2 x 5 mL), then the organic phase was dried with
MgSO4, and the solvent evaporated. The residue was dissolved in dichloromethane and then
precipitated with ether. The compound 5f was obtained as a colorless solid (0.09 g, yield 67%); mp=
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123°C. H NMR (500 MHz, CD3CN): δ 2.22ꢀ2.30 (m, 2H), 3.49ꢀ3.64 (m, 2H), 4.13 (brs, 1H), 5.09ꢀ
5.21 (m, 2H), 7.15ꢀ7.18 (m, 1H), 7.20ꢀ7.37 (m, 6H), 7.51ꢀ7.70 (m, 11H), 7.96ꢀ7.98 (m, 1H). 13C
NMR (125 MHz, CD3CN): δ 20.90 (d, J= 55.9 Hz), 25.7, 54.0 (d, J= 19.6 Hz), 68.3, 122.32 (d, J=
87.5 Hz), 122.8 (d, J= 87.5 Hz), 127.8 (d, J= 13.6 Hz), 128.9, 129.0, 129.1, 130.1 (d, J= 10.6 Hz),
130.2 (d, J= 10.6 Hz), 133.7ꢀ134.0 (m), 134.36 (d, J= 11.7 Hz), 135.7, 136.0 (d, J= 14.8 Hz), 170.1, 1
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Cq not observed. 31P NMR (121 MHz, CD3CN): δ +28.4. B NMR (160 MHz, CD3CN): δ +2.6. 19F
NMR (470 MHz, CD3CN): δ ꢀ133.7. HRMS (ESIꢀQꢀTOF) calcd for C29H28BNO2PClF3 [MꢀClꢀHꢀF]+:
502.19075; found 502.19184. FTIR (neat) cmꢀ1: 3055, 2929, 2890, 1982, 1952, 1743, 1587, 1523,
1498, 1486, 1438, 1184, 1109, 1071, 1049, 1017, 995, 940, 738, 691.
1ꢀBenzylꢀβ
ꢀpentafluorophenyl Lꢀaspartate 12.21 To an iceꢀcooled solution of 1ꢀbenzyl Nꢀ(tꢀ
butoxycarbonyl)ꢀLꢀaspartate (646 mg, 2 mmol) and pentafluorophenol (366 mg, 2 mmol) in a
mixture of ethyl acetate/DMF (5 mL, 0.16mL) was added N,N’ꢀdicyclohexylcarbodiimide (412 mg, 2
mmol). The mixture was stirred at 0°C for 1h and then warmed at room temperature. After 1 hour, the
formed dicyclohexylurea was filtered off and the solvent was removed in vacuo to give the compound
12 as a white solid (940 mg, yield 96%); mp= 81°C; [α]D= +18.6 (c 0.5, CHCl3); [α]D= ꢀ9.1 (c 1,
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AcOEt)21a; H NMR (300 MHz, CDCl3): δ 1.43 (s, 9H), 3.30 (ABX, J= 4.8 Hz, J= 5.0 Hz, J= 17.2
Hz, 2H), 4.66ꢀ4.78 (m, 1H), 5.19 (s, 2H), 5.46 (d, J= 8.8, 1H), 7.30ꢀ7.39 (m, 5H). 13C NMR (125
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MHz, CDCl3): δ 28.2, 36.2, 50.1, 67.9, 80.6, 128.4, 128.6, 128.6, 134.9, 136.8, 138.8, 139.9, 140.7,
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142.0, 155.2, 166.9, 170.0. F NMR (286 MHz, CDCl3): δ ꢀ152.2 (d, J= 17.5 Hz, 2F), ꢀ157.38 (t, J=
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21.3 Hz, 1F), ꢀ162.0 (m, 2F).
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Boronatoꢀphosphonium dipeptide 13. To a solution of boronatoꢀphosphonium amine 4g (71
mg, 0.1 mmol) in 1.5 mL of dry acetonitrile were added the aspartate derivative 12 (49 mg, 0.1
mmol). After 6 hours at 50°C the acetonitrile was evaporated and the product was dissolved in
dichloromethane and filtrated through celite. After solvent removing, the residue was purified by
column chromatography on silica gel using a mixture acetone/dichloromethane (1:9) as eluent to
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afford the dipeptide 13 as a viscous oil (62 mg, yield 61%); [α]D= +10.5 (c 0.4, CHCl3); H NMR
(300 MHz, CD3CN): δ 0.91 (s, 6H), 0.93 (s, 6H), 1.32 (s, 9H), 2.03ꢀ2.10 (m, 2H), 2.71ꢀ2.97 (m, 2H),
3.43ꢀ3.59 (m, 2H), 4.47ꢀ4.65 (m, 2H), 5.01ꢀ5.17 (m, 4H), 5.95 (bd, J= 8.3 Hz, 1H), 7.18ꢀ7.48 (m,
10H), 7.55ꢀ7.94 (m, 13H), 8.22ꢀ8.25 (m, 1H); 13C NMR (75 MHz, CD3CN): δ 21.7 (d, J= 53.1 Hz),
24.2, 24.3, 26.2, 28.1, 37.5, 51.2, 53.0 (d, J= 17.9 Hz), 67.1, 67.5, 79.8, 85.9, 121.2 (d, J= 85.9 Hz),
121.7 (d, J= 87.9 Hz), 122.1 (d, J= 83.9 Hz), 128.3, 128.5, 128.6, 128.8, 129.0, 129.1, 130.8 (d, J=
11.9 Hz), 132.9 (d, J= 13.9 Hz), 133.5 (d, J= 9.5 Hz), 133.8 (d, J= 10.4 Hz), 134.8, 135.1, 136.4 (d,
J= 19.5 Hz), 137.5 (d, J= 13.5 Hz), 139.3 (d, J= 13.5 Hz), 156.1, 170.6, 171.1, 172.2; 31P NMR (121
MHz, CD3CN): δ +27.0; HRMS (ESIꢀQꢀTOF) calcd for C51H59BN2O9P [MꢀI]+: 885.40457, found
885.40308.
Trifluoroboratoꢀphosphonium dipeptide 14. To a solution of boronatoꢀphosphonium peptide
13 (50 mg, 0.05 mmol) in methanol (0.8 mL) was added a solution of KHF2 (15 mg, 0.2 mmol) in
water (0.5 mL). After 1 hour stirring at 50°C, the mixture was extracted with dichloromethane (2 x 5
mL), then the organic phase was dried with MgSO4 and the solvent evaporated. The trifluoroborato
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dipeptide 14 was obtained as colorless oil (31 mg, yield 78%); [α]D= +26 (c 0.5, CHCl3); H NMR
(300 MHz, CD3CN): δ 1.35 (s, 9H), 2.15ꢀ2.23 (brs, 2H), 2.64ꢀ2.89 (m, 2H), 3.29ꢀ3.45 (m, 2H), 4.45ꢀ
4.51 (m, 2H), 5.04ꢀ5.15 (m, 4H), 5.87 (bd, J = 8.1 Hz, 1H), 7.12ꢀ7.21 (m, 1H), 7.25ꢀ7.34 (m, 10H),
7.42ꢀ7.66 (m, 12H), 7.92ꢀ8.00 (m, 1H); 13C NMR (75 MHz, CD3CN): δ 21.1 (d, J= 52.3 Hz), 25.7,
28.1, 37.4, 51.1, 53.1 (d, J= 19.5 Hz), 67.1, 67.4, 79.8, 119.0, 122.8 (d, J= 86.4 Hz), 122.8 (d, J= 87.6
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Hz), 127.7 (d, J= 14.2 Hz), 128.4, 128.6, 128.8, 129.0, 129.1, 130.0 (d, J= 4.2 Hz, 130.2 (d, J= 3.6
Hz, 133.7 (d, J= 4.9 Hz), 133.9 (d, J= 4.9 Hz), 134.4, 135.8 (d, J= 14.3 Hz), 136.1, 136.53 (d, J= 14.8
Hz), 156.0, 171.0, 172.1; 31P NMR (121 MHz, CD3CN): δ +28.7; 19F NMR (282 MHz, CD3CN): δ ꢀ
133.7; HRMS (ESIꢀQꢀTOF) calcd for C45H47BF3N2O7P [M+Na]+: 849.30582, found 849.30704.
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Radiofluorination of 4e into [18F]ꢀ5e. 18Fꢀ aqueous solution (~180 MBq) prepared with an ABT
biomarker generator cyclotron, was dried at 100ºC for 5 minutes under compressed air flow and then
briefly stirred (15 s) with 10 µL of 0.2 M KHF2 in deionized water. Boronato phosphoniumꢀamino
acid 4e (0.2 mg) diluted in deionized water (100 µL) was added to the [18/19F]ꢀKHF2 solution and then
allowed to react for 20 min at room temperature under constant stirring. The radiochemical purity of
the resulting [18F]ꢀ5e was assessed by analytical radioꢀHPLC using nonꢀradiolabelled reference
sample 5e for comparison. The purification step was carried out via semiꢀpreparative HPLC to give
final [18F]ꢀ5e in > 97% radiochemical purity, 10% radiochemical overall yield (decay corrected) and a
specific activity of 130 MBq ꢁmolꢀ1 (Figure 3).
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The specific activity of the radiolabelled product [18F]ꢀ5e at the time of analysis was determined in
MBq ꢁmolꢀ1, according to the following calculation: firstly, the UVꢀHPLC calibration of the nonꢀ
radioactive (cold) analogous precursor 5e was made in order to determine the concentration of the
product using the resulting UV peak area; secondly, the total amount of radioactivity at the end of the
reaction and purification was measured in MBq using a dose calibrator. The specific activity of the
product was calculated by dividing the total activity of the radiotracer recovered from the semiꢀprep
by the amount of product in ꢁmol, based on the integration of the UVꢀHPLC.
ACKNOWLEDGMENTS
The authors are grateful for the J.B. fellowship and the financial support provided by the “Ministère
de l’Education Nationale et de la Recherche”, the CNRS (Centre National de la Recherche
Scientifique), the "Conseil Regional de Bourgogne" (grant 3MIM) and the Daisy Appeal Charity
(grant: DAhul0211). The authors would like also thank M. J. Penouilh, M. and F. Picquet at the
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Welience/Pôle Chimie Moléculaire for the NMR and mass spectrometry analyses, J. Bayardon, B.
Rugeri (ICMUBꢀStéréochIM) and P. D. Harvey (Sherbrooke) for their help to the preparation of this
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Supporting Information
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1H, 13C, 31P, 19F NMR spectra, LCꢀMS of compound 4e, kinetic hydrolysis data and radiolabelling
HPLC of [18F]ꢀ5e. This material is available free of charge via the internet at http://pubs.acs.org.
REFERENCES
(1) (a) Zaccaro, L.; del Gatto, A.; Pedone, C.; Saviano, M. Curr. Med. Chem. 2009, 16, 780ꢀ795.
(b) Lee, S.; Xie, J.; Chen, X. Chem. Rev. 2010, 110, 3087ꢀ3111.
(2) Synthesis and Chemistry of Modified Amino Acids in Amino Acids, peptides and Proteins in
Organic Chemistry; Hughes, A. B. (Ed.); WileyꢀVCH, Weinheim, 2009, Vol. 2, pp 1ꢀ280.
(3) (a) Collet, S.; Carreaux, F.; Boucher, J.ꢀL.; Pethe, S.; Lepoivre, M.; DanionꢀBougot, R.;
Danion, D. J. Chem. Soc., Perkin Trans. 1, 2000, 177ꢀ182. (b) Kim, N. N.; Cox, J. D.; Biaggio, R. F.;
Emig, F. A.; Mistry, S. K.; Harper, S. L.; Speicher, D. W.; Morris Jr., S. M.; Ash, D. E.; Traish, A.;
Christianson, D. W. Biochem. 2001, 40, 2678ꢀ2688. (c) Touchet, S. ; Carreaux, F. ; Carboni, B.;
Bouillon, A.; Boucher, J.ꢀL. Chem. Soc. Rev. 2011, 40, 3895ꢀ3914. d) Baker, S. J.; Tomsho, J. W.;
Benkovic, S. J. Chem. Soc. Rev. 2011, 40, 4279ꢀ4285. e) Smoum, R.; Rubinstein, A.; Dembitsky, V.
M.; Srebnik, M. Chem. Rev. 2012, 112, 4156ꢀ4220.
(4) (a) Yang, W.; Gao, X.; Wang, B. Med. Res. Rev. 2003, 23, 346ꢀ368. (b) Baker, S. J.; Ding, C.
Z.; Akama, T.; Zhang, Y.ꢀK.; Hernandez, V.; Xia, Y. Future Med. Chem. 2009, 1, 1275ꢀ1288.
(5) (a) Soloway, A. H.; Tjarks, W.; Barnum, B. A.; Rong, F.ꢀG.; Barth, R. F.; Codogni, I. M.;
Wilson, J. G. Chem. Rev. 1998, 98, 1515ꢀ1562. (b) Studenov, A.; Ding, Y.ꢀS.; Ferrieri, R.; Miura, M.;
Coderre, J.; Fowler, J. S. J. Labelled Compd. Radiopharm. 2001, 44 (suppl. 1), S345ꢀS347. (c)
Eskola, O.; Vähätalo, J.; Lehikoinen, P.; Bergman, J.; Forsback, S.; Solin, O. J. Labelled Compd.
Radiopharm. 2001, 44 (suppl. 1), S849ꢀS851. (d) Vähätalo, J. K.; Eskola, O.; Bergman, J.; Forsback,
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 27
S.; Lehikoinen, P.; Jääskeläinen, J.; Solin, O. J. Labelled Compd. Radiopharm. 2002, 45, 697ꢀ704. (e)
Kabalka, G. W.; Wu, Z. Z.; Yao, M.ꢀL.; Natarajan, N. Appl. Radiat. Isot. 2004, 61, 1111ꢀ1115. (f)
Kabalka, G. W.; Wu, Z.; Yao, M.ꢀL. Appl. Organometal. Chem. 2008, 22, 516ꢀ522. (g) Kabalka, G.
W.; Shaikh, A. L.; Barth, R. F.; Huo, T.; Yang, W.; Gordnier, P. M.; Chandra, S. Appl. Radiat. Isot.
2011, 69, 1778ꢀ1781.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) (a) Lin, S.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40, 1967ꢀ1970. (b) Morin, C.;
Thimon, C. Eur. J. Org. Chem. 2004, 3828ꢀ3832. (c) Krebs, A.; Ludwig, V.; Pfizer, J.; Dürner, G.;
Göbel, M. W. Chem. Eur. J. 2004, 10, 544ꢀ553. (d) Barfoot, C. W.; Harvey, J. E.; Kenworthy, M. N.;
Kilburn, J. P.; Ahmed, M.; Taylor, R. J. K. Tetrahedron 2005, 61, 3403ꢀ3417. (e) Skaff, O.; Jolliffe,
K. A.; Hutton, C. A. J. Org. Chem. 2005, 70, 7353ꢀ7363. (f) Cerezo, V.; Amblard, M.; Martinez, J.;
Verdié, P.; Planas, M.; Fediu, L. Tetrahedron 2008, 64, 10538ꢀ10545. (g) Devasagayaraj, A.; Jin, H.;
Shi, Z.ꢀC.; Tunoori, A.; Wang, Y.; Zhang, C. US Patent 7.553.840 B2, June, 30, 2009. (h) Meyer, F.
M.; Liras, S.; GuzmanꢀPerez, A.; Perreault, C.; Bian, J.; James, K. Org. Lett. 2010, 12, 3870ꢀ3873.
(7) Hattori, Y.; Yamamoto, H.; Ando, H.; Kondoh, H.; Asano, T.; Khirihata, M.; Yamaguchi, Y.;
Wakamiya, T. Bioorg. Med. Chem. 2007, 15, 2198ꢀ2205.
(8) (a) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Chem. Rev. 2008, 108, 1501ꢀ1516. (b) Li,
Z.; Conti, P. S. Adv. Drug Deliv. Rev. 2010, 62, 1031ꢀ1051. (c) Galldiks, N., Rapp, M.; Stoffels, G.;
Fink, G. R.; Shah, N. J.; Coenen, H. H.; Sabel, M.; Langen, K.ꢀJ. Eur. J. Nucl. Med. Mol. Imaging
2013, 40, 22ꢀ33.
(9) (a) Laverman, P.; Boerman, O. C.; Corstens, F. H. M.; Oyen, W. J. G. Eur. J. Nucl. Med.
2002, 29, 681ꢀ690. (b) Couturier, O.; Luxen, A.; Chatal, J. F.; Vuillez, J. P.; Rigo, P.; Hustinx, R.
Eur. J. Nucl. Med. Mol. Imaging 2004, 31, 1182ꢀ1206. (c) Pöpperl, G.; Goldbrunner, R.; Gildehaus,
F. J.; Kreth, F. W.; Tanner, P.; Holtmannspötter, M.; Tonn, J. C.; Tatsch, K. Eur. J. Nucl. Med. Mol.
Imaging 2005, 32, 1018ꢀ1025. (d) Pauleit, D.; Floeth, F.; Hamacher, K.; Riemenschneider, M. J.;
Reifenberger, G.; Müller, H.ꢀW.; Zilles, K.; Coenen, H. H.; Langen, K. J. Brain, 2005, 128, 678ꢀ687.
(e) Oka, S.; Hattori, R.; Kurosaki, F.; Toyama, M.; Williams, L. A.; Yu, W.; Votaw, J. R.; Yoshida,
Y.; Goodman, M. M.; Ito, O. J. Nucl. Med. 2007, 48, 46ꢀ55. (f) Schuster, D. M.; Votaw, J. R.; Nieh,
24
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Page 25 of 27
The Journal of Organic Chemistry
P. T.; Yu, W.; Nye, J. A.; Master, V.; Dubois Bowman, F.; Issa, M.M.; Goodman, M. M. J. Nucl.
Med. 2007, 48, 56ꢀ63. (g) McConathy, J.; Goodman, M. M. Cancer Met. Res. 2008, 27, 555ꢀ573. (h)
van Waarde, A.; Elsinga, P. H. Curr. Pharm. Des. 2008, 14, 3326ꢀ3339. (i) Plotkin, M.;
Blechschmidt, C.; Auf, G.; Nyuyki, F.; Geworski, L.; Denecke, T.; Brenner, W.; Stockhammer, F.
Eur. Radiol. 2010, 20, 2496ꢀ2502. (j) Ikotun, O. F.; Marquez, B.V.; Huang, C.; Masuko, K.; Daiji,
M.; Masuko, T.; McConathy, J.; Lapi, S. E. Plos one 2013, 8(10), e77476. (k) Ermert, J.; Coenen, H.
H. J. Label. Compd. Radiopharm. 2013, 56, 225ꢀ236.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10) (a) Kabalka, G. W. J. Label. Compd. Radiopharm. 2007, 50, 888ꢀ894. (b) Tredwell, M.;
Preshlock, S. M.; Taylor, N. J.; Gruber, S.; Huiban, M.; Passchier, J.; Mercier, J.; Génicot, C.;
Gouverneur, V. Angew. Chem. Int. Ed. 2014, 53, 7751ꢀ7755.
(11) (a) Ting, R.; Adam, M. J.; Ruth, T. J.; Perrin, D. M. J. Am. Chem. Soc. 2005, 127, 13094ꢀ
13095. (b) Ting, R.; Harwig, C.; auf dem Keller, U.; McCormick, S.; Austin, P.; Overall, C. M.;
Adam, M. J.; Ruth, T. J.; Perrin, D. M. J. Am. Chem. Soc. 2008, 130, 12045ꢀ12055. (c) Smith, G. E.;
Sladen, H. L.; Biagini, S. C. G.; Blower, P. J. Dalton Trans. 2011, 40, 6196ꢀ6205. (d) Liu, Z.; Li, Y.;
Lozada, J.; Pan, J.; Lin,K. S.; Schaffer, P.; Perrin, D. M. J. Label. Compd. Radiopharm. 2012, 55,
491ꢀ496. (e) Li, Y.; Guo, J.; Tang, S.; Lang, L.; Chen, X.; Perrin, D. M. Am. J. Nucl. Med. Mol.
Imaging 2013, 3, 44ꢀ56. (f) Liu, Z.; Li, Y.; Lozada, J.; Wong, M. Q.; Greene, J.; Lin, K.ꢀS.; Yapp, D.;
Perrin, D. M. Nucl. Med. Biol. 2013, 40, 841ꢀ849. (g) Li, Y.; Liu, Z.; Lozada, J.; Wong, M. Q.; Lin,
K.ꢀS.; Yapp, D.; Perrin, D. M. Nucl. Med. Biol. 2013, 40, 959ꢀ966. (h) Liu, Z.; Li, Y.; Lozada, J.;
Schaffer, P.; Adam, M. J.; Ruth, T. J.; Perrin, D. M. Angew. Chem. Int. Ed. 2013, 52, 2303ꢀ2307. (i)
Liu, Z.; HundalꢀJabal, N.; Wong, M.; Yapp, D.; Lin, K.ꢀS.; Benard, F.; Perrin, D. M. Med. Chem.
Commun. 2014, 5, 171ꢀ179. (j) Burke, B. P.; Clement, G. S.; Archibald, S. J. Contrast Media Mol.
Imaging 2014, doi: 10.1002/cmmi.1615.
(12) Audi, H.; Rémond, E.; Eymin, M. J.; Tessier, A.; MalaceaꢀKabbara, R.; Jugé, S. Eur. J. Org.
Chem. 2013, 7960ꢀ7972.
(13) For pertinent articles on fluorine complexation using organoboron compounds, see: (a)
Hudnall, T. W.; Kim, Y. M.; Bebbington, M.W.P.; Bourissou, D.; Gabbaï, F. P. J. Am. Chem. Soc.
25
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Page 26 of 27
2008, 130, 10890ꢀ10891. (b) Hudnall, T. W.; Chiu, C.ꢀW.; Gabbaï, F. P. Acc. Chem. Res. 2009, 42,
388ꢀ397. (c) Wade, C. R.; Broomsgrove, A. E. J.; Aldridge, S.; Gabbaï, F. P. Chem. Rev. 2010, 110,
3958ꢀ3984. (d) Zhao, H.; Leamer, L. A.; Gabbaï, F. P. Dalton Trans. 2013, 42, 8164ꢀ8178.
(14) Li, Z.; Chansaenpak, K.; Liu, S.; Wade, C. R.; Conti, P. S.; Gabbaï, F. P. Med. Chem.
Commun. 2012, 3, 1305ꢀ1308.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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29
30
31
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) (a) Meyer, F.; Uziel, J.; Papini, A. M.; Jugé, S. Tetrahedron Lett. 2001, 42, 3981ꢀ3984. (b)
Meyer, F.; Laaziri, A.; Papini, A. M.; Uziel, J.; Jugé, S. Tetrahedron: Asymmetry 2003, 14, 2229ꢀ
2238. (c) Hebbe, V.; Londez, A.; GoujonꢀGinglinger, C.; Meyer, F.; Uziel, J.; Jugé, S.; Lacour, J.
Tetrahedron Lett. 2003, 44, 2467ꢀ2471. (d) Meyer, F.; Laaziri, A.; Papini, A. M.; Uziel, J.; Jugé, S.
Tetrahedron 2004, 60, 3593ꢀ3597. (e) RealꢀFernandez, F.; Colson, A.; Bayardon, J.; Nuti, F.; Peroni,
E.; MeunierꢀPrest, R.; Lolli, F.; Chelli, M.; Darcel, C.; Jugé, S.; Papini, A. M. PeptideScience 2008,
90(4), 488ꢀ495.
(16) Rémond, E.; Bayardon, J.; OndelꢀEymin, M.ꢀJ.; Jugé, S. J. Org. Chem. 2012, 77, 7579ꢀ7587.
(17) (a) Colson, A. PhD thesis, Université de Bourgogne 2007; (b) Rémond, E. PhD thesis,
Université de Bourgogne, 2010; (c) Koseki, Y.; Yamada, H.; Usuki, T. Tetrahedron: Asymmetry
2011, 22, 580ꢀ586.
(18) Porcel, S.; Bouhadir, G.; Saffon, N.; Maron, L.; Bourissou, D. Angew. Chem. Int. Ed. 2010,
49, 6186ꢀ6189.
(19) The palladium catalyzed deallylation of the compound 4b was not a clean reaction in this
case. The debenzylation of phosphonium iodide by hydrogenolysis in presence of palladium catalyst
do not work (see references 15a, 16, 17a,b).
(20) (a) Molander, G. A.; Yun, C.ꢀS.; Ribagorba, M.; Biolatto, B. J. Org. Chem. 2003, 68, 5534ꢀ
5539. (b) Darses, S.; Genêt, J. P.; Chem. Rev. 2008, 108, 288ꢀ325.
(21) (a) Kisfaludy, L.; Low, M.; Nyeki, O.; Szirtes, T.; Schön, I. Liebigs Ann. Chem., 1973, 1421ꢀ
1429. (b) Schön, I.; Colombo, R.; Csehi, A. J. Chem. Soc., Chem. Commun. 1983, 505ꢀ507.
(22) Mu, L.; Schubiger, A.; Ametamey, S. M. Curr. Radiopharm. 2010, 3, 224ꢀ242.
26
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The Journal of Organic Chemistry
(23) Schirrmacher, R.; Wängler, C.; Schirrmacher, E. in Fluorineꢀ18 Radiochemistry: Theory and
Practice in Pharmaceutical Radiochemistry (I), Wester, H. J. (Ed.), Vol.1. Munich Molecular
Handbook series, Scintomics Print Media and Publishing, 2010, pp 5ꢀ73.
1
2
3
4
5
6
7
8
9
(24) For representative works on trifluoroborates hydrolysis, see: (a) Ting, R.; Harwig, C. W.; Lo,
J.; Li, Y.; Adam, M. J.; Ruth, T. J.; Perrin, D. M. J. Org. Chem. 2008, 73, 4662ꢀ4670. (b) Molander,
G. A.; Cavalcanti, L. N.; Canturk, B.; Pan, P.ꢀS.; Kennedy, L. E.. J. Org. Chem. 2009, 74, 7364ꢀ7369.
(c) Wade, C. R.; Zhao, H.; Gabbaï, F. P. Chem. Commun. 2010, 46, 6380ꢀ6381.
(25) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schimpf, M. R. J. Org. Chem. 1995, 60,
3020ꢀ3027.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(26) (a) Icke, R. N.; Wisegarver,B. B.; Alles, G. A. Org. Synth., Coll. Vol. III, pp 723ꢀ725. (b)
Vegh, D.; Boireau, G.; HenryꢀBasch, E. J. Organomet. Chem. 1984, 267, 127ꢀ131.
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