A convenient method for the asymmetric synthesis of fluorinated α-amino acids from alcohols

Article abstract of DOI:10.1002/ejoc.201301718

Due to their numerous applications, fluorinated amino acids have recently attracted significant attention. The preparation of fluorine-containing phenylalanines, heteroaryl alanines and aliphatic fluorinated amino acids using Mitsunobu-Tsunoda alkylation of a chiral nucleophilic glycine equivalent with readily available alcohol substrates is described. The reaction proceeds in high yields and with excellent diastereoselectivity. This method provides an efficient synthetic route to fluorinated amino acids for which asymmetric approaches are scarce. The asymmetric synthesis of fluorinated amino acids using readily available fluoro alcohols was accomplished by Mitsunobu-type alkylation of a chiral glycine template. This approach accesses fluorinated and trifluoromethylated (hetero)aryl alanines and provides a general method for preparation of amino acids bearing linear fluorinated or trifluoromethylated side-chains. Copyright

Full text of DOI:10.1002/ejoc.201301718

FULL PAPER
DOI: 10.1002/ejoc.201301718
A Convenient Method for the Asymmetric Synthesis of Fluorinated α-Amino
Acids from Alcohols
Fleur Drouet,[a] Anaïs F. M. Noisier,[a] Craig S. Harris,[b] Daniel P. Furkert,[a] and
Margaret A. Brimble*[a]
Keywords: Asymmetric synthesis / Fluorine / Alcohols / Amino acids
Due to their numerous applications, fluorinated amino acids
have recently attracted significant attention. The preparation
of fluorine-containing phenylalanines, heteroaryl alanines
and aliphatic fluorinated amino acids using Mitsunobu–
lent with readily available alcohol substrates is described.
The reaction proceeds in high yields and with excellent dia-
stereoselectivity. This method provides an efficient synthetic
route to fluorinated amino acids for which asymmetric ap-
Tsunoda alkylation of a chiral nucleophilic glycine equiva- proaches are scarce.
cursors, they often have limited shelf-lives and are best used
Introduction
immediately after their preparation, thus restricting their
application in high throughput synthesis. Owing to the lim-
ited range of commercially available alkyl halides, studies
into the scope of the reaction are often limited to only a
few examples. A general method allowing access to a wide
range of side-chain fluorinated enantiopure α-amino acids
is therefore of great interest.
We recently reported an efficient preparation of chiral
amino acids by Mitsunobu–Tsunoda alkylation of a nickel-
(II) complex of the glycine Schiff base (1) with various
Fluorine-containing compounds have emerged as a
major target for new synthetic methods. Indeed, due to the
interesting physical, chemical and biological properties con-
ferred by the presence of fluorine, introduction of this atom
is becoming a key strategy in agrochemical and pharmaceu-
tical discovery as well as in materials science.[1] In particu-
lar, fluorinated amino acids are remarkable building blocks
for peptide and protein design as they demonstrate en-
hanced chemical and thermal stability compared to their
non-fluorinated counterparts resulting in novel chemical
and biological properties.[2] Interesting effects have also
been observed on the structure and overall assemblies of
protein materials containing fluorinated amino acids.[2a,3]
Consequently, synthetic studies focusing on fluorinated
amino acids have attracted much attention.[4]
The high demand for fluorinated amino acids, has
prompted several research groups to focus their effort on
the development of asymmetric syntheses for the prepara-
tion of side-chain fluorinated α-amino acids.[4a,4e] A com-
mon approach for construction of compounds relies on the
stereoselective alkylation of an enantiopure auxiliary.[5] Pre-
vious work by Soloshonok describing the use of the NiII
chiral complex developed by Belokon,[6] is of particular
interest.[5a,5b] However such methods suffer from drawbacks
associated with the use of expensive alkyl halides. Although
organohalides can be readily synthesized from alcohol pre-
alcohols
using
(cyanomethylene)tributylphosphorane
(CMBP) 2.[7] This new route to non-proteinogenic α-amino
acids by C–C bond formation offers many advantages over
currently used approaches. Firstly, it is well-suited for the
synthesis of libraries of compounds since a vast pool of
structurally diverse commercially available alcohols can be
used as pro-electrophiles. Secondly, it consistently proceeds
with high stereoselectivity and does not require harsh reac-
tion conditions. Finally, chiral auxiliary 1 is easily prepared
in excellent yields from inexpensive starting materials in
only three steps.[8] To the best of our knowledge, alkylation
of the Belokon complex by fluorinated alcohols has not
been studied. Herein, we report the synthesis of aromatic
and aliphatic fluorinated amino acids by Mitsunobu–
Tsunoda alkylation chemistry.
Results and Discussion
[a] School of Chemical Sciences and the Maurice Wilkins Centre
for Molecular Biodiscovery, The University of Auckland,
23 Symonds St, Auckland Central 1042, New Zealand
E-mail: m.brimble@auckland.ac.nz
We initially studied alkylation of the nickel complex 1
with 4,4,4-trifluorobutanol 3l in the presence of CMBP (2)
(Table 1). According to Tsunoda, better results can be ob-
tained when the Mistunobu-type reaction is performed at
high temperature.[9] In addition, the high diastereoselectivi-
ties observed in our previous report,[7] despite the elevated
http://brimble.chem.auckland.ac.nz
[b] Galderma R&D, Les templiers - 2400,
Route des Colles Sophia-Antipolis, 06410 Biot, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301718.
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M. A. Brimble et al.
FULL PAPER
temperature employed, suggest that alkylation of the Belo- commercial CMPB (Table 1, Entries 10, 11). Notably, 4l
kon complex under Mitsunobu–Tsunoda conditions takes was generated in both cases with yields and stereoselectivi-
place under thermodynamic control. Consequently, it was ties that were comparable regardless of CMBP purity levels;
envisaged that carrying out the reaction in high boiling the use of distilled 2 afforded only very slightly improved
point solvents might lead to substantially higher yields and yields and stereoselectivity relative to crude 2. The concen-
diastereoselectivities. When the reaction was performed at tration of the reaction was also investigated (Table 1, En-
120 °C in toluene, expected product 4l was obtained in 71% tries 12, 13). Although no difference in stereochemical out-
yield with a diastereoisomeric ratio of 84:16 in favour of comes was observed, an improved yield of 90% (versus
the (S,S)-diastereoisomer (Table 1, Entry 1).
79%) was achieved using a concentration of 0.5 versus
1.0 m.
Table 1. Optimization of reaction conditions.[a]
With optimized reaction conditions in hand, we pro-
ceeded to investigate the scope of the reaction using various
commercially available fluorinated alcohols (Table 2). The
1H NMR spectra of crude reaction mixtures were used to
determine the diastereoisomeric ratios of (S,S)- and (S,R)-
NiII complexes 4.
Initially, fluorinated benzyl alcohols were studied. Such
fluorinated phenylalanine derivatives are of particular inter-
est for structure and interaction studies of proteins and
peptides.[2a,11] The reaction proceeded smoothly in high
yields and with good selectivities when the aromatic ring
was mono-, di- or tri-fluorinated (Table 2, Entries 1–4).
Pure (S,S)-NiII complexes 4a–d were isolated in yields rang-
ing from 90–94%. However, the use of pentafluorobenzyl
alcohol (Table 2, Entry 5) failed to afford desired alkylated
product 4e. Moreover, Mitsunobu–Tsunoda reaction of 3e
resulted only in full consumption of the CMBP and alcohol
whereas NiII complex 1 was completely recovered.
We next investigated the use of trifluoromethyl-substi-
tuted aromatic and heteroaromatic derivatives in this reac-
tion to generate mono or bis(trifluoromethyl)benzyl-substi-
tuted glycine derivatives 4f and 4g (Table 2, Entries 6, 7)
as well as (trifluoromethyl)pyridinyl derivative 4h (Table 2,
Entry 8) in high diastereoisomeric purity. Interestingly, the
reaction was found to also proceed well when using various
aliphatic linear fluorinated alcohols. Although lower yields
and selectivities were observed relative to trials employing
benzylic alcohols, the production of different linear fluorin-
ated amino acids with this method represents a significant
Entry
Solvent
T [°C] Conc. [m]
Yield[d] [%]
dr[e]
1
2
3
4
5
6
7
8
toluene
120
90
1
1
71
0
84:16
–
dichloroethane
tert-butyl acetate
di-n-butyl ether
butyronitrile
DMF
105
120
120
120
105
120
105
105
105
105
105
1
1
1
1
1
1
1
1
25
79
76
83
71
84
84
84
82
90
79
88:12
89:11
85:15
86:14
85:15
88:12
91:9
92:8
91:9
91:9
91:9
dioxane
xylene
9
trifluorotoluene
trifluorotoluene
trifluorotoluene
trifluorotoluene
trifluorotoluene
10[b]
11[c]
12
13
1
0.5
0.3
[a] Reaction conditions: a mixture of 1/crude 2/3l (1:2:2) dissolved
in solvent was heated in a sealed tube for 20 h. [b] Using distilled
CMBP 2. [c] Using commercial CMBP 2. [d] Yields refer to chro-
matographically pure mixture of diastereoisomers 4. [e] dr (S,S)/
(S,R) determined by 1H NMR analysis of the isolated isomeric
mixture.
Although no reaction was found to occur when using advance in this field. Indeed, with the exception of So-
dichloroethane as the reaction solvent (Table 1, Entry 2), loshonok’s report on the synthesis of linear trifluoromethyl-
most solvents examined enabled formation of alkylated NiII ated amino acids,[5a] to the best of our knowledge, no gene-
complex 4l with good diastereoselectivity. Use of tert-butyl ral synthetic method for generating α-amino acids bearing
acetate as solvent led to the desired compound in only 25% a fluorinated linear chain has been described to date. Use
yield (Table 1, Entry 3). However, it was interesting to ob- of this Mitsunobu–Tsunoda glycine alkylation reaction re-
serve that yields up to 70% were attainable when the reac- sulted in isolation of major (S,S)-NiII complexes 4i (Table 2,
tion was performed in di-n-butyl ether, butyronitrile, DMF, Entry 9) and 4l–n (Table 2, Entries 12–14) in 50–80% yield.
dioxane or xylene (Table 1, Entries 4–8). Finally, we pos-
Interestingly, attempts to carry out Mitsunobu–Tsunoda
tulated that use of a fluorinated solvent might improve both alkylation using 2,2,2-trifluoroethanol 3j (Table 2, Entry 10)
the yield and stereoselectivity of the reaction. The reaction did not result in the formation of anticipated 4j. In this
was thus performed in trifluorotoluene (Table 1, Entry 9), case the cyanomethyl-substituted nickel(II) complex 5j was
resulting in an improved diastereoisomeric ratio of 91:9 and isolated as a single diastereoisomer in i) 25% yield after
an 84% yield.
The quality of cyanophosphorane reagent 2 was also ex- yield using 4 equiv. of trifluoroethanol (Scheme 1).
amined. Tsunoda previously reported that higher yields The structure of this adduct was confirmed by both
heating with 2 equiv. of trifluoroethanol for 64 h, or ii) 65%
were obtained using freshly distilled CMBP 2 for the Mitsu- NMR and MS analyses. The MS data revealed an excess
nobu reaction on p-toluenesulfonamide.[10] In the present mass of 39 g/mol relative to that anticipated for expected
work the reaction was performed using both distilled and product 4j consistent with the presence of a cyanomethyl
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Asymmetric Synthesis of Fluorinated α-Amino Acids from Alcohols
Table 2. Synthesis of fluorinated amino acid derivatives by Mitsu- 2-enenitrile to nickel(II) complex 1. Indeed, a similar ad-
nobu–Tsunoda alkylation of the Belokon complex.[a]
dition has been reported by Soloshonok et al. who reported
that Michael reaction between (E)-ethyl trifluorobut-2-eno-
ate and NiII complex 1 resulted in stereoselective formation
of (S,S,S)-diastereoisomer 6 (Scheme 2).[12]
Scheme 2. Previously reported Michael reaction between 1 and (E)-
ethyl trifluorobut-2-enoate.[12]
In the present work, trifluorobut-2-enenitrile could po-
tentially be formed by formation of phosphonium salt 8
(Scheme 3).
Scheme 3. Postulated mechanism for formation of trifluorobut-2-
enenitrile (9).
In the expected reaction mechanism, stabilized methylene
phosphoranes 2 are in equilibrium with their ylide forms.
The ylide first deprotonates the alcohol, the resulting alk-
oxide then attacks the phosphonium part of ylide 2 to form
oxyphosphonium ion 7 and acetonitrile anion. The latter
deprotonates the pronucleophile, thus liberating acetonitrile
and forming a nucleophilic species (A–), which in turn
[a] Reaction conditions: A mixture of 1/crude 2/3 (1:2:2) dissolved
in trifluorotoluene was heated at 105 °C in a sealed tube until com-
forms desired alkylated product together with phosphine
pletion (15 to 20 h). [b] Yields were determined after isolation of
oxide by SN2 reaction with oxyphosphonium intermediate
the major (S,S)-4 isomer by flash chromatography. [c] dr were de-
7. However, instead of reacting with deprotonated NiII
1
termined by H NMR analysis of the crude isomeric mixture 4.
complex (A–), oxyphosphonium salt 7 is attacked by a sec-
ond equivalent of the ylide form of CMPB, forming phos-
phonium salt 8. The deprotonated NiII complex then facili-
tates elimination of n-tributylphosphine to afford trifluoro-
but-2-enenitrile (9).
Finally, when 3,3,3-trifluoropropan-1-ol 3k was em-
ployed as the pro-electrophile, no formation of desired
product 4k was observed. Again, the NiII complex 1 was
recovered whereas CMBP 2 and alcohol 3k were both con-
Scheme 1. Formation of cyanomethylated adduct 5j.
sumed. It appears that when the strongly electron-with-
drawing fluorinated group is too close to the alcohol func-
group. The presence of this extra appendage was confirmed tionality the reaction cannot proceed. Interestingly, in this
by analysis of the C–F coupling constant in the 13C NMR case, the formation of the cyanomethyl-substituted product,
of 5j (see Supporting Information). One possible explana- which was previously isolated using trifluoroethanol, was
tion for formation of 5j entails the addition of trifluorobut- not observed.
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M. A. Brimble et al.
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400 MHz, carbon NMR (13C) spectra were recorded at 100 MHz
and phosphorus NMR (31P) spectra were recorded at 202 MHz.
NMR experiments were carried out in CDCl3 or D2O. Chemical
shifts (δ) are reported in parts per million (ppm) relative to residual
solvent as an internal reference (1H: 7.26, 13C: 77.0 ppm for CHCl3
The chiral auxiliary can ultimately be cleaved in mildly
acidic conditions according to our previously established
protocol,[7] affording the amino acids in good yields and
with little to no racemization. For instance, after heating
compound 4d at reflux for 1 h with 2 m aqueous HCl in
methanol, the reaction was concentrated and filtered to
render the precipitated BPB ligand. Reverse-phase column
chromatography then afforded the pure HCl salt of fluor-
inated amino acid 10d in 86% yield and with 95% ee, as
determined by chiral HPLC (Scheme 4).
1
and H: 4.79 for DMSO). Data are reported as follows: chemical
shift, multiplicity (s singlet, d doublet, t triplet, q quartet, m mul-
tiplet), coupling constants (Hz) and integration. Infrared spectra
were recorded using neat samples, with a 100 FT-IR spectrometer
and the characteristic IR absorption frequencies are reported in
cm–1. Optical rotations were performed with
a polarimeter
(589 nm) using a 700-μL cell with a path length of 1 dm. Enantio-
meric excesses were determined using chiral HPLC with a Dionex
Ultimate 3000 system using a Chirobiotic T 250ϫ4.6 mm 5 μm
column. The samples were injected at a volume of 5 μL and a con-
centration of 1 mg/mL. Mass spectra were obtained from with an
AEI MS-9 using electron spray ionization (ESI). The HRMS spec-
tra were measured using a MALDI-TOF instrument.
General Procedure for the Synthesis of (S,S)-4: NiII complex of glyc-
ine 1 (125 mg, 0.25 mmol), (cyanomethylene)tributylphosphorane
2 (130 μL, 0.50 mmol), and fluorinated alcohol 3 (0.50 mmol) were
combined in trifluorotoluene (0.5 mL). The red mixture was heated
in a sealed tube at 105 °C for 15 to 20 h. The red solution was
cooled to room temperature and then purified by flash chromatog-
raphy on silica gel using CH2Cl2/acetone (8:2) or EtOAc/toluene
(8:2) as eluent.
Scheme 4. Cleavage of Ni complex 4d under mild conditions.
Conclusions
General Procedure for the Synthesis of (S)-10: Substituted nickel
complex (S,S)-4 was dissolved in MeOH and 2 m HCl (2:1) to gen-
erate a solution of 4 (0.016 m). The bright red solution was heated
at reflux (80 °C) for 30 min, until the red colour of the solution
disappeared. The resulting yellow to green solution was cooled to
room temperature and the solvents evaporated to dryness. Water
was added to the residue which was then separated by column
chromatography on C18 reverse phase silica gel. Pure water was
employed as an eluent to remove the green NiCl2 and excess HCl.
In summary, we have developed an efficient and rapid
synthesis of enantiopure α-amino acids bearing fluorinated
side-chains. Using the readily synthesized chiral NiII Belo-
kon complex of glycine, the Mitsunobu–Tsunoda reaction
has been demonstrated to proceed with high diastereoselec-
tivity thus providing an efficient method for the asymmetric
synthesis of a variety of aliphatic, benzylic or pyridinyl-sub-
stituted fluorinated α-amino acids. The commercial avail- A water/MeOH gradient elution was then used to obtain optically
pure product 10 which was lyophilized. Released BPB ligand was
recovered by elution with MeOH.
ability of both a wide range of fluorinated alcohols as well
as the CMBP Tsunoda reagent make this synthetic process
highly convenient for the preparation of α-amino acids con-
taining fluorinated side-chains to enable systematic study of
their biological and materials science applications.
NiII-(S)-BPB/(S)-2-Amino-3-(4-fluorophenyl)propanoic Acid Schiff
Base Complex (4a): Yield 95%, red crystal (m.p. 246–248 °C).
[α]2D5 = +2052 (c = 0.1, CHCl ). IR (neat): ν = 3025, 2964, 2932,
˜
3
2860, 1737, 1639, 1679, 1585, 1540, 1508, 1439, 1365, 1338, 1259,
1
1224, 1165, 751, 709, 624 cm–1. H NMR (400 MHz, CDCl3): δ =
8.23 (d, J = 8.7 Hz, 1 H), 8.05–7.95 (m, 2 H), 7.59–7.48 (m, 2 H),
7.47–7.41 (m, 1 H), 7.33–7.27 (m, 3 H), 7.19–7.04 (m, 6 H), 6.91–
6.83 (m, 1 H), 6.70–6.62 (m, 2 H), 4.29 (d, J = 12.7 Hz, 1 H), 4.24
(dd, J1 = 5.8, J2 = 4.4 Hz, 1 H), 3.46 (d, J = 12.7 Hz, 1 H), 3.32
(dd, J1 = 8.9, J2 = 7.8 Hz, 1 H), 3.17–3.08 (m, 1 H), 3.04 (dd, J1
= 13.8, J2 = 4.4 Hz, 1 H), 2.83 (dd, J1 = 13.8, J2 = 5.8 Hz, 1 H),
2.51–2.30 (m, 3 H), 2.03–1.91 (m, 1 H), 1.82–1.70 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 180.2, 178.2, 171.1, 162.3 (d, J
= 246 Hz), 142.7, 134.0, 133.3, 133.1, 132.3, 131.8 (d, J = 8 Hz, 2
C), 131.4 (d, J = 3 Hz), 131.3 (2 C), 129.7, 129.0, 128.8, 128.7,
128.6 (2 C), 127.6, 127.0, 125.9, 123.2, 120.5, 115.5 (d, J = 21 Hz,
2 C), 71.2, 70.2, 63.2, 57.1, 38.8, 30.6, 23.0 ppm. HRMS (ESI) m/z
calculated for C34H30FN3NaNiO3 [M + Na]+ 628.1517, found
628.1522.
Experimental Section
General: All reactions were carried out under an argon atmosphere
in dried glassware with magnetic stirring. Solvents were dried with
activated molecular sieves (4 Å). Reagents were purchased from
commercial suppliers and used without further purification unless
otherwise noted.
Analytical thin layer chromatography (TLC) was performed on
0.2 mm aluminium plates of silica gel 60 F254 (Merck) and com-
pounds were visualized by ultraviolet fluorescence or by staining
with a ninhydrin solution. Flash chromatography was carried out
using Kieselgel S 63–100 μm (Riedel-de Haën) silica gel. Reversed-
phase chromatography was performed using Davisil® chromato-
graphic C18 bonded silica (633NC18E 60 Å 35–70 micron) (Grace
GmbH & Co. KG) with indicated solvents. Infrared spectra were
obtained with a Perkin–Elmer Spectrum One Fourier Transform
infrared spectrometer with a universal ATR sampling accessory
using neat samples and absorption maxima are expressed in wave-
NiII-(S)-BPB/(S)-2-Amino-3-(2,4-difluorophenyl)propanoic
Acid
Schiff Base Complex (4b): Yield 90%, red crystal (m.p. 119–
121 °C). [α]2D1 = +2060 (c = 0.1, CHCl ). IR (neat): ν = 3025, 2969,
˜
3
2945, 1742, 1676, 1644, 1439, 1370, 1219, 1232 cm–1. 1H NMR
numbers (cm–1). Proton NMR (1H) spectra were recorded at (400 MHz, CDCl3): δ = 8.30–8.24 (m, 1 H), 8.02–7.96 (m, 2 H),
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Asymmetric Synthesis of Fluorinated α-Amino Acids from Alcohols
7.57–7.49 (m, 2 H), 7.48–7.42 (m, 1 H), 7.35–7.27 (m, 3 H), 7.22–
7.10 (m, 3 H), 7.02–6.97 (m, 1 H), 6.95–6.86 (m, 2 H), 6.69–6.62
(m, 2 H), 4.30 (d, J = 12.7 Hz, 1 H), 4.24 (dd, J1 = 6.0, J2 = 4.5 Hz,
1 H), 3.51 (d, J = 12.7 Hz, 1 H), 3.34 (dd, J1 = 8.9, J2 = 8.3 Hz, 1
H), 3.20–3.10 (m, 2 H), 2.90 (dd, J1 = 14.0, 4.5 Hz, 1 H), 2.57–2.45
(m, 1 H), 2.43–2.34 (m, 2 H), 2.02–1.93 (m, 1 H), 1.85–1.74 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 180.2, 178.2, 172.0,
162.6 (dd, J1 = 249, J2 = 12 Hz), 161.8 (dd, J1 = 249, J2 = 12 Hz),
142.8, 134.0, 133.5, 133.3 (dd, J1 = 10, J2 = 6 Hz), 133.1, 132.4,
131.5 (2 C), 129.7, 129.0, 128.9, 128.8, 128.7 (2 C), 128.0 (d, J =
3 Hz), 127.1, 126.1, 123.3, 120.5, 118.9 (dd, J1 = 16, J2 = 4 Hz),
111.8 (dd, J1 = 21, J2 = 3 Hz), 103.9 (dd, J1 = J2 = 26 Hz), 70.6,
70.3, 63.3, 57.0, 32.8, 30.8, 23.1 ppm. HRMS (ESI) m/z calculated
for C34H29F2N3NaNiO3 [M + Na]+ 646.1423, found 646.1424.
12.8 Hz, 1 H), 3.29 (dd, J1 = 10, J2 = 6.5 Hz, 1 H), 3.13–3.01 (m,
2 H), 2.87 (dd, J1 = 13.8, J2 = 5.7 Hz, 1 H), 2.38–2.15 (m, 3 H),
1.96–1.83 (m, 1 H), 1.75–1.60 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 180.3, 178.0, 171.5, 142.8, 139.9, 134.0, 133.5, 133.2,
132.5, 131.3 (2 C), 130.8 (2 C), 129.9, 129.7 (q, J = 32 Hz), 129.2,
128.9, 128.7 (2 C), 127.6, 127.0, 125.9, 125.6 (q, J = 2 Hz, 2 C),
124.1 (q, J = 271 Hz, 2 C), 123.3, 120.6, 70.8, 70.2, 63.3, 57.0, 39.2,
3 0 . 6 , 2 2 . 9 p p m . H R M S ( E S I ) m / z c a l c u l a t e d f o r
C35H30F3N3NaNiO3 [M + Na]+ 678.1485, found 678.1475.
NiII-(S)-BPB/(S)-2-Amino-3-[3,5-bis(trifluoromethyl)phenyl]prop-
anoic Acid Schiff Base Complex (4g): Yield 90%, red crystal (m.p.
129–131 °C). [α]2D2 = +2024 (c = 0.1, CHCl ). IR (neat): ν = 3028,
˜
3
2972, 2927, 2873, 1739, 1676, 1644, 1437, 1375, 1370, 1277, 1229,
1219, 1168, 1137, 900, 754, 703 cm–1. 1H NMR (400 MHz, CDCl3):
NiII-(S)-BPB/(S)-2-Amino-3-(3,5-difluorophenyl)propanoic
Acid δ = 8.24 (d, J = 8.8 Hz, 1 H), 8.07–8.00 (m, 2 H), 7.78 (s, 1 H),
Schiff Base Complex (4c): Yield 90%, red crystal (m.p. 114–116 °C).
7.63–7.56 (m, 2 H), 7.55–7.48 (m, 1 H), 7.38–7.30 (m, 3 H), 7.25–
7.21 (m, 2 H), 7.21–7.13 (m, 2 H), 6.99–6.93 (m, 1 H), 6.73–6.65
(m, 2 H), 4.36 (d, J = 12.6 Hz, 1 H), 4.16 (dd, J1 = 8.2, J2 = 3.7 Hz,
[α]2D4 = +2063 (c = 0.1, CHCl ). IR (neat): ν = 2960, 2926, 2864,
˜
3
1727, 1677, 1636, 1593, 1540, 1462, 1437, 1338, 1167, 1120, 1079,
1
1033, 809, 753 cm–1. H NMR (400 MHz, CDCl3): δ = 8.28–8.17 1 H), 3.53 (d, J = 12.6 Hz, 1 H), 3.41 (dd, J1 = 10.5, J2 = 6.2 Hz,
(m, 1 H), 8.08–7.93 (m, 2 H), 7.62–7.50 (m, 2 H), 7.50–7.42 (m, 1
H), 7.36–7.26 (m, 3 H), 7.19–7.08 (m, 2 H), 6.97–6.86 (m, 1 H),
6.77 (tt, J1 = 8.8, J2 = 2.4 Hz, 1 H), 6.70–6.62 (m, 2 H), 6.62–6.54
(m, 2 H), 4.30 (d, J = 12.6 Hz, 1 H), 4.21 (dd, J1 = 6.3, J2 = 4.3 Hz,
1 H), 3.49 (d, J = 12.6 Hz, 1 H), 3.34 (dd, J1 = 10.2, J2 = 7.0 Hz,
1 H), 3.28–3.18 (m, 1 H), 2.98 (dd, J1 = 13.8, J2 = 4.3 Hz, 1 H),
2.89 (dd, J1 = 13.8, 6.3 Hz, 1 H), 2.78–2.62 (m, 1 H), 2.53–2.33
(m, 2 H), 2.04–1.94 (m, 1 H), 1.93–1.81 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 180.2, 177.8, 171.3, 162.9 (dd, J1 = 249, J2
= 13 Hz, 2 C), 142.8, 139.5 (dd, J1 = J2 = 9 Hz), 133.8, 133.3,
133.1, 132.5, 131.4 (2 C), 129.9, 129.2, 128.9, 128.7, 128.6 (2 C),
127.5, 127.0, 125.8, 123.4, 120.5, 113.0 (dd, J1 = 18, J2 = 7 Hz, 2
C), 102.7 (dd, J1 = J2 = 25 Hz), 70.6, 70.2, 63.2, 57.1, 39.7, 30.6,
23.2 ppm. HRMS (ESI) m/z calculated for C34H29F2N3NaNiO3 [M
+ Na]+ 646.1423, found 646.1446.
1 H), 3.39–3.32 (m, 1 H), 3.28 (dd, J1 = 13.7, J2 = 8.3 Hz, 1 H),
3.10 (dd, J1 = 13.7, J2 = 3.7 Hz, 1 H), 3.06–2.92 (m, 1 H), 2.54–2.36
(m, 2 H), 2.07–1.96 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 180.4, 177.5, 171.5, 142.8, 138.4, 133.7, 133.3, 133.2, 132.7, 131.6
(q, J = 33 Hz, 2 C), 131.4 (2 C), 130.2, 129.8 (q, J = 3 Hz, 2 C),
129.4, 129.1, 128.9, 128.8 (2 C), 127.4, 127.3, 125.8, 123.7, 123.0
(q, J = 271 Hz, 2 C), 121.2 (qq, J1 = J2 = 3 Hz), 120.7, 70.5, 70.1,
63.2, 57.3, 40.8, 30.5, 23.7 ppm. HRMS (ESI) m/z calculated for
C36H29F6N3NaNiO3 [M + Na]+ 746.1359, found 746.1350.
NiII-(S)-BPB/(S)-2-Amino-3-[6-(trifluoromethyl)pyridin-3-yl]prop-
anoic Acid Schiff Base Complex (4h): Yield 90%, red crystal (m.p.
201–203 °C). [α]2D1 = +2403 (c = 0.1, CHCl ). IR (neat): ν = 3022,
˜
3
2972, 2951, 1739, 1676, 1644, 1442, 1365, 1341, 1230, 1219, 1134,
1
1089, 754, 706 cm–1. H NMR (400 MHz, CDCl3): δ = 8.42 (d, J
= 1.8 Hz, 1 H), 8.26 (d, J = 8.6 Hz, 1 H), 8.03–7.95 (m, 2 H), 7.88
NiII-(S)-BPB/(S)-2-Amino-3-(3,4,5-trifluorophenyl)propanoic Acid (d, J = 8.0 Hz, 1 H), 7.62–7.55 (m, 3 H), 7.52–7.46 (m, 1 H), 7.35–
Schiff Base Complex (4d): Yield 92%, red crystal (m.p. 115–
7.29 (m, 3 H), 7.21–7.14 (m, 2 H), 6.98–6.93 (m, 1 H), 6.72–6.66
(m, 2 H), 4.31 (d, J = 12.7 Hz, 1 H), 4.28 (dd, J1 = 6.6, J2 = 4.2 Hz,
1 H), 3.51 (d, J = 12.7 Hz, 1 H), 3.33 (dd, J1 = 9.2, J2 = 7.5 Hz, 1
H), 3.19–3.12 (m, 1 H), 3.07 (dd, J1 = 13.8, J2 = 4.2 Hz, 1 H), 3.00
(dd, J1 = 13.8, J2 = 6.6 Hz, 1 H), 2.50–2.34 (m, 3 H), 1.98–1.89
(m, 1 H), 1.89–1.79 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 180.3, 177.5, 171.9, 151.0, 147.4 (q, J = 35 Hz), 143.0, 138.9,
134.9, 133.9, 133.5, 133.1, 132.8, 131.4 (2 C), 130.1, 129.4, 129.1,
128.9, 128.8 (2 C), 127.5, 127.1, 125.8, 123.5, 121.6 (q, J = 275 Hz),
120.7, 120.3, 70.3, 70.2, 63.3, 57.0, 37.0, 30.6, 23.2 ppm. HRMS
117 °C). [α]2D4 = +2012 (c = 0.1, CHCl ). IR (neat): ν = 2958, 2927,
˜
3
2855, 1726, 1676, 1639, 1586, 1530, 1469, 1441, 1357, 1335, 1258,
1165, 1075, 1047, 1016, 799, 752, 705 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.21 (d, J = 8.7 Hz, 1 H), 8.07–7.97 (m, 2 H), 7.61–
7.53 (m, 2 H), 7.53–7.45 (m, 1 H), 7.36–7.27 (m, 3 H), 7.20–7.11
(m, 2 H), 6.97–6.91 (m, 1 H), 6.71–6.64 (m, 2 H), 6.64–6.56 (m, 2
H), 4.32 (d, J = 12.7 Hz, 1 H), 4.17 (t, J = 5.5 Hz, 1 H), 3.50 (d, J
= 12.7 Hz, 1 H), 3.58 (d, J1 = 10.1, J2 = 6.8 Hz, 1 H), 3.33–3.23
(m, 1 H), 2.99–2.89 (m, 2 H), 2.89–2.75 (m, 1 H), 2.54–2.39 (m, 2
H), 2.08–1.92 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = (ESI) m/z calculated for C34H29F3N4NaNiO3 [M + Na]+ 679.1437,
180.3, 171.4, 152.3, 151.0 (ddd, J1 = 251, J2 = 9, J3 = 4 Hz, 2 C),
142.8, 139.2 (ddd, J1 = 251, J2 = J3 = 15 Hz), 133.8, 133.4, 133.1,
132.6, 132.0 (ddd, J1 = J2 = 8, J3 = 5 Hz), 131.4 (2 C), 130.0, 129.3,
129.0, 128.8, 128.7 (2 C), 127.5, 127.1, 125.9, 123.6, 120.7, 114.0
(dd, J1 = 15, J2 = 6 Hz, 2 C), 70.6, 70.2, 63.3, 57.2, 39.7, 30.6,
23.3 ppm. HRMS (ESI) m/z calculated for C34H28F3N3NaNiO3 [M
+ Na]+ 664.1328, found 664.1323.
found 679.1452.
NiII-(S)-BPB/(S)-2-Amino-5-fluoropentanoic Acid Schiff Base Com-
plex (4i): Yield 76%; red crystal (m.p. 201–203 °C). [α]2D1 = +3020
(c = 0.1, CHCl ). IR (neat): ν = 2970, 2929, 2880, 1675, 1639,
˜
3
1589, 1544, 1441, 1335, 1259, 1166, 1062, 754, 706 cm–1. H NMR
1
(400 MHz, CDCl3): δ = 8.17–8.10 (m, 1 H), 8.08–8.02 (m, 2 H),
7.54–7.43 (m, 3 H), 7.37–7.31 (m, 2 H), 7.26–7.22 (m, 1 H), 7.19
(tt, J1 = 7.5, J2 = 1.3 Hz, 1 H), 7.13 (ddd, J1 = 8.7, J2 = 6.2, J3 =
2.5 Hz, 1 H), 6.98–6.89 (m, 1 H), 6.69–6.60 (m, 2 H), 4.42 (d, J =
12.7 Hz, 1 H), 4.40–4.10 (m, 2 H), 3.86 (dd, J1 = 9.1, J2 = 3.4 Hz,
1 H), 3.66–3.50 (m, 2 H), 3.57 (d, J = 12.7 Hz, 1 H), 3.47 (dd, J1
NiII-(S)-BPB/(S)-2-Amino-3-[4-(trifluoromethyl)phenyl]propanoic
Acid Schiff Base Complex (4f): Yield 93%, red crystal (m.p. 130–
132 °C). [α]2D5 = +2020 (c = 0.1, CHCl ). IR (neat): ν = 3027, 2959,
˜
3
2927, 2871, 1736, 1675, 1641, 1585, 1546, 1442, 1368, 1325, 1259,
1165, 1126, 1067, 754, 706 cm–1. 1H NMR (400 MHz, CDCl3): δ = = 10.9, J2 = 5.7 Hz, 1 H), 2.79–2.69 (m, 1 H), 2.59–2.45 (m, 1 H),
8.25 (d, J = 8.5 Hz, 1 H), 7.99 (d, J = 7.5 Hz, 2 H), 7.67 (d, J = 2.40–2.14 (m, 3 H), 2.11–2.02 (m, 1 H), 1.92–1.68 (m, 2 H) ppm.
8.0 Hz, 2 H), 7.61–7.51 (m, 2 H), 7.50–7.42 (m, 1 H), 7.34–7.26 (m, 13C NMR (100 MHz, CDCl3): δ = 180.4, 179.1, 170.7, 142.3, 133.6,
5 H), 7.20–7.11 (m, 2 H), 6.92 (d, J = 7.5 Hz, 1 H), 6.73–6.61 (m, 133.3, 133.2, 132.3, 131.6 (2 C), 129.8, 129.1, 129.0 (2 C), 128.9 (2
2 H), 4.35–4.30 (m, 1 H), 4.28 (d, J = 12.8 Hz, 1 H), 3.46 (d, J = C), 127.5, 127.1, 126.3, 123.8, 120.8, 82.9 (d, J = 166 Hz), 70.3,
Eur. J. Org. Chem. 2014, 1195–1201
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1199

M. A. Brimble et al.
FULL PAPER
69.6, 63.1, 57.1, 31.6 (d, J = 5 Hz), 30.8, 26.4 (d, J = 20 Hz),
23.8 ppm. HRMS (ESI) m/z calculated for C30H30FN3NaNiO3 [M
+ Na]+ 580.1517, found 580.1528.
(153 μL, 0.58 mmol), and fluorinated alcohol 3 (85 μL, 1.16 mmol)
were combined in toluene (0.3 mL). The red mixture was heated in
a sealed tube at 120 °C for 64 h. The red solution was cooled to
room temperature and purified by flash chromatography on silica
gel using a CH2Cl2/acetone gradient (50:1 to 50:3) as eluent to af-
ford a red crystals of 5j (m.p. 289–291 °C). [α]2D5 = +3340 (c = 0.1,
NiII-(S)-BPB/(S)- 2-Amino-6,6,6-trifluorohexanoic Acid Schiff Base
Complex (4l): Yield 80%, red crystal (m.p. 201–203 °C). [α]2D1
=
+2440 (c = 0.1, CHCl ). IR (neat): ν = 2962, 2930, 2874, 1674,
˜
3
CHCl ). IR (neat): ν = 3063, 2979, 2942, 2253, 1675, 1636, 1584,
˜
3
1636, 1588, 1544, 1440, 1334, 1257, 1165, 1132, 1060, 1025, 801,
1542, 1469, 1439, 1368, 1335, 1255, 1163, 1120, 752, 703 cm–1. H
1
1
753, 703 cm–1. H NMR (400 MHz, CDCl3): δ = 8.19–8.11 (m, 1
NMR (400 MHz, CDCl3): δ = 8.23 (dd, J1 = 8.6, J2 = 0.8 Hz, 1
H), 8.10–8.01 (m, 2 H), 7.64 (td, J1 = 7.3, J2 = 1.5 Hz, 1 H), 7.59
(tt, J1 = 7.5, J2 = 1.3 Hz, 1 H), 7.53 (td, J1 = 7.3, J2 = 1.5 Hz, 1
H), 7.38–7.29 (m, 3 H), 7.21–7.10 (m, 2 H), 6.96–6.86 (m, 1 H),
6.68–6.56 (m, 2 H), 4.34 (d, J = 12.8 Hz, 1 H), 4.30 (d, J = 4.3 Hz,
1 H), 3.55 (d, J = 12.8 Hz, 1 H), 3.51–3.44 (m, 1 H), 3.41 (dd, J1
= 10.4, J2 = 6.7 Hz, 1 H), 3.38–3.24 (m, 1 H), 3.11 (dd, J1 = 16.8,
J2 = 10.3 Hz, 1 H), 2.85–2.72 (m, 1 H), 2.61–2.48 (m, 2 H), 2.44
(dd, J1 = 16.8, J2 = 4.7 Hz, 1 H), 2.11–1.98 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 180.2, 174.7, 173.1, 143.2, 133.5,
133.3, 133.2, 133.0, 131.4 (2 C), 130.6, 130.2, 129.4, 128.8 (2 C),
128.7, 127.1, 126.9, 125.8, 125.5 (q, J = 283 Hz), 123.5, 120.6,
115.3, 70.6, 65.5, 63.5, 57.1, 43.2 (q, J = 27 Hz), 30.4, 22.4, 14.8
H), 8.09–8.00 (m, 2 H), 7.56–7.49 (m, 2 H), 7.49–7.42 (m, 1 H),
7.39–7.31 (m, 2 H), 7.29–7.23 (m, 1 H), 7.22–7.17 (m, 1 H), 7.17–
7.11 (m, 1 H), 6.95–6.88 (m, 1 H), 6.71–6.59 (m, 2 H), 4.43 (d, J
= 12.7 Hz, 1 H), 3.89 (dd, J1 = 8.4, J2 = 3.5 Hz, 1 H), 3.58 (d, J =
12.7 Hz, 1 H), 3.55–3.49 (m, 2 H), 3.46 (dd, J1 = 11.1, J2 = 5.9 Hz,
1 H), 2.82–2.67 (m, 1 H), 2.59–2.46 (m, 1 H), 2.40–2.28 (m, 1 H),
2.22–2.12 (m, 1 H), 2.12–1.94 (m, 3 H), 1.90–1.76 (m, 2 H), 1.70–
1.60 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 180.4, 178.8,
170.8, 142.4, 133.7, 133.2, 133.1, 132.3, 131.5 (2 C), 129.8, 129.0,
129.0, 128.9, 128.8 (2 C), 127.3, 127.1, 126.8 (q, J = 276 Hz), 126.3,
123.7, 120.8, 70.2, 69.5, 63.1, 57.0, 34.2, 33.1 (q, J = 29 Hz), 30.7,
23.6, 18.1 (q, J = 3 Hz) ppm. HRMS (ESI) m/z calculated for
C31H30F3N3NaNiO3 [M + Na]+ 630.1485, found 630.1508.
(q,
J
=
3 Hz) ppm. HRMS (ESI) m/z calculated for
NiII-(S)-BPB/(S)-2-Amino-6,6,7,7,7-pentafluoroheptanoic Acid
Schiff Base Complex (4m): Yield 50 %, red crystal (m.p. 101–
C31H27F3N4NaNiO3 [M + Na]+ 641.1281, found 641.1291.
(S)-2-Amino-3-(3,4,5-trifluorophenyl)propanoic Acid Hydrochloride
(10d): Yield 86%; white solid (m.p. 225–227 °C). [α]2D5 = +5 (c =
103 °C). [α]2D4 = +2160 (c = 0.1, CHCl ). IR (neat): ν = 3067, 2963,
˜
3
2926, 2867, 1723, 1670, 1636, 1588, 1544, 1440, 1334, 1258, 1194,
0.25, 2 m aq. HCl). IR (neat): ν = 3371, 3017, 3968, 2916, 1673,
˜
1
1166, 752, 704 cm–1. H NMR (400 MHz, CDCl3): δ = 8.20–8.11
1620, 1583, 1526, 1509, 1446, 1411, 1347, 1237, 1056, 1035, 864,
(m, 1 H), 8.08–8.02 (m, 2 H), 7.58–7.43 (m, 3 H), 7.39–7.31 (m, 2
H), 7.31–7.26 (m, 1 H), 7.23–7.17 (m, 1 H), 7.15 (ddd, J1 = 8.7, J2
= 6.5, J3 = 2.2 Hz, 1 H), 6.96–6.88 (m, 1 H), 6.70–6.60 (m, 2 H),
4.43 (d, J = 12.7 Hz, 1 H), 3.90 (dd, J1 = 8.2, J2 = 3.3 Hz, 1 H),
3.58 (d, J = 12.7 Hz, 1 H), 3.56–3.48 (m, 2 H), 3.47 (dd, J1 = 11.0,
J2 = 5.7 Hz, 1 H), 2.81–2.70 (m, 1 H), 2.60–2.48 (m, 1 H), 2.42–
2.30 (m, 1 H), 2.22–2.12 (m, 1 H), 2.12–2.00 (m, 2 H), 1.96–1.80
(m, 2 H), 1.80–1.60 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 180.4, 178.9, 170.9, 142.4, 133.7, 133.3, 133.2, 132.4, 131.6 (2
C), 129.9, 129.1, 129.0, 129.0, 128.9 (2 C), 127.4, 127.2, 126.3,
123.8, 120.8, 119.0 (qt, J1 = 285, J2 = 35 Hz), 115.5 (tq, J1 = 252,
J2 = 37 Hz), 70.3, 69.4, 63.2, 57.1, 34.6, 30.8, 29.9 (t, J = 22 Hz),
2 3 . 6 , 1 6 . 5 p p m . H R M S ( E S I ) m / z c a l c u l a t e d f o r
C32H30F5N3NaNiO3 [M + Na]+ 680.1458, found 680.1505.
779, 650 cm–1. 1H NMR (400 MHz, D2O): δ = 7.15–7.00 (m, 2 H),
4.00 (dd, J1 = 7.6, J2 = 5.6 Hz, 1 H), 3.26 (dd, J1 = 14.7, J2
5.6 Hz, 1 H), 3.14 (dd, J1 = 14.7, J2 = 7.6 Hz, 1 H) ppm. 13C NMR
(100 MHz, D2O): δ = 173.2, 150.9 (ddd, J1 = 248, J2 = 10, J3
=
=
4 Hz, 2 C), 138.9 (ddd, J1 = 248, J2 = J3 = 15 Hz), 131.7 (ddd, J1
= J2 = 8, J3 = 5 Hz), 113.6 (dd, J1 = 16, J2 = 6 Hz, 2 C), 55.5,
35.7 ppm. HRMS (ESI) m/z calculated for C9H9F3NO2 [M + H]+
220.0580, found 220.0581; Chiral HPLC: 95% ee, (Chirobiotic T,
water/CH3CN = 15:85, flow rate = 1.0 mL/min, 210 nm): major
isomer (S): tR = 11.6 min, minor isomer (R): tR = 13.4 min.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR for all final compounds and chiral HPLC
traces of compound 10d.
NiII-(S)-BPB/(S)-2-amino-6,6,7,7,8,8,8-heptafluorooctanoic Acid
Schiff Base Complex (4n): Yield 63 %, red crystal (m.p. 101–
Acknowledgments
103 °C). [α]2D5 = +2296 (c = 0.1, CHCl ). IR (neat): ν = 3063, 2979,
˜
3
2874, 1671, 1636, 1589, 1544, 1441, 1353, 1335, 1257, 1224, 1167,
The authors thank the Maurice Wilkins Centre for Molecular Bio-
discovery for financial support.
1
1062, 752, 704 cm–1. H NMR (400 MHz, CDCl3): δ = 8.20–8.10
(m, 1 H), 8.08–8.01 (m, 2 H), 7.57–7.48 (m, 2 H), 7.48–7.43 (m, 1
H), 7.38–7.31 (m, 2 H), 7.29–7.26 (m, 1 H), 7.22–7.17 (m, 1 H),
7.17–7.11 (m, 1 H), 6.95–6.87 (m, 1 H), 6.70–6.60 (m, 2 H), 4.43
(d, J = 12.7 Hz, 1 H), 3.91 (dd, J1 = 8.4, J2 = 3.6 Hz, 1 H), 3.58
(d, J = 12.7 Hz, 1 H), 3.55–3.49 (m, 2 H), 3.46 (dd, J1 = 10.9, J2
= 5.8 Hz, 1 H), 2.80–2.70 (m, 1 H), 2.59–2.46 (m, 1 H), 2.42–2.29
(m, 1 H), 2.20–2.02 (m, 3 H), 1.98–1.84 (m, 2 H), 1.80–1.60 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 180.4, 178.8, 170.9,
142.3, 133.6, 133.2, 133.1, 132.3, 131.5 (2 C), 129.8, 129.0, 129.0,
128.9, 128.8 (2 C), 127.3, 127.1, 126.3, 123.7, 120.8, 117.7 (qt, J1 =
287, J2 = 34 Hz), 117.4 (tt, J1 = 253, J2 = 31 Hz), 108.7 (ttq, J1 =
263, J2 = 36, J3 = 35 Hz), 70.3, 69.4, 63.1, 57.0, 34.5, 30.7, 29.8
(t, J = 22 Hz), 23.6, 16.3 ppm. HRMS (ESI) m/z calculated for
C33H30F7N3NaNiO3 [M + Na]+ 730.1421, found 730.1411.
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Published Online: January 14, 2014
Eur. J. Org. Chem. 2014, 1195–1201
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