Design and synthesis of (S)- and (R)-α-(phenyl)ethylamine-derived NH-type ligands and their application for the chemical resolution of α-amino acids

Article abstract of DOI:10.1039/c4ob00669k

This work presents the first chemical approach for the resolution of α-amino acids offering the following advantages: (1) The specially designed resolving reagent is derived from α-(phenyl)ethylamine, the most inexpensive chiral auxiliary, which can be re

Full text of DOI:10.1039/c4ob00669k

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Biomolecular Chemistry
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PAPER
Design and synthesis of (S)- and (R)-α-(phenyl)-
ethylamine-derived NH-type ligands and their
application for the chemical resolution of
α-amino acids†
Cite this: Org. Biomol. Chem., 2014,
12, 6239
Ryosuke Takeda,a Akie Kawamura,a Aki Kawashima,a Hiroki Moriwaki,a
Tatsunori Sato,a José Luis Aceña*b and Vadim A. Soloshonok*b,c
This work presents the first chemical approach for the resolution of α-amino acids offering the following
advantages: (1) The specially designed resolving reagent is derived from α-(phenyl)ethylamine, the most
inexpensive chiral auxiliary, which can be recycled and reused, rendering the cost structure of the com-
plete process very attractive; (2) the time-efficient two-step process can be conducted under operation-
ally convenient conditions with virtually quantitative yields; and (3) the process can readily be adapted to
large-scale use.
Received 29th March 2014,
Accepted 19th June 2014
DOI: 10.1039/c4ob00669k
www.rsc.org/obc
methods. The advantage of enzymatic separation and fermen-
tation over chemical methods is that they can be conducted
Introduction
α-Amino acids (α-AAs) represent an exceptional class of com- under operationally convenient conditions, rendering
pounds critically involved in virtually all areas of life-related the resultant product much less expensive. For the chemical
research and the health-care industries. Many generations of methods the development of robust and uncomplicated
organic chemists have contributed to the development of syn- methods has remained a major challenge. A number of
thetic methodology for the preparation of α-AAs and their research groups are currently focused on the development of
derivatives, in particular peptides and peptidomimetics.1 The reaction methods that avoid air- or moisture-sensitive reagents,
wealth of methodology developed to date for the synthesis of specially purified solvents or extremely low temperatures.8
α-AAs displays a remarkable degree of creative ingenuity,
For quite some time we have been interested in the chemi-
allowing the preparation of tailor-made2 α-AAs of virtually any stry of Ni(II) complexes of glycine Schiff bases and their
structural or functional complexity.3,4 However, issues of prac- general application for the asymmetric synthesis of α-amino
ticality and cost of the target α-AAs have been largely ignored acids. Over the years this area has attracted the interest of a
in the academic research, rendering many of the chemical number of research groups9 and new generations of struc-
routes prohibitively expensive for large-scale preparation of turally varied Ni(II) complexes have been developed10 (Fig. 1).
α-AAs.5 As a result, less complicated and more cost-efficient
The major motivation for studying the chemistry of Ni(II)-
enzyme-based methodology forms the basis of the current complexes of glycine Schiff bases is that their transformation
α-AAs industry.6 Considering the growing importance of tailor- to higher amino acids can be conducted under operationally
made α-AAs in the de novo design of peptides, peptidomi- convenient conditions. For example, the (S)- or (R)-proline-
metics and pharmaceuticals,7 the issue of cost-efficiency has derived complex 111 can be converted to a variety of α-amino
become a key factor in the assessment of new synthetic acids via alkyl halide alkylation,12 aldol,13 Michael9c,14 or
Mannich15 reactions using commercial grade solvents and at
ambient temperatures. Achiral picolinic acid-derived complex
aHamari Chemicals Ltd, 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka,
216 can be used for the advanced synthesis of α,α-dialkyl-
Japan 533-0024
substituted quaternary AAs17 or for asymmetric transformations
bDepartment of Organic Chemistry I, Faculty of Chemistry, University of the Basque
under PTC conditions18 and Michael addition reactions.19
Country UPV/EHU, Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain.
E-mail: joseluis.acena@ehu.es, vadym.soloshonok@ehu.es
Since complex 2 has very limited solubility in common organic
cIKERBASQUE, Basque Foundation for Science, Alameda Urquijo 36-5, Plaza Bizkaia,
solvents, a new type of achiral Ni(II) complex 3 was develo-
48011 Bilbao, Spain
ped.20 The solubility of complex 3 derivatives in virtually any
†Electronic supplementary information (ESI) available: Crystallographic data of
solvent can be tailored simply by choice of the R′ groups on
14a, HPLC analyses and copies of NMR spectra. CCDC 993563. For ESI and crys-
the amino moiety. Complexes 3 have been successfully used
tallographic data in CIF or other electronic format see DOI: 10.1039/c4ob00669k
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Fig. 2 Three types of α-(phenyl)ethylamine-derived ligands 7–9.
target α-AAs on the gram scale. Another type of previously
reported α-(phenyl)ethylamine-derived ligands 8 are less steri-
cally bulky at the glycine moiety and possess a tertiary amine
moiety.29 It was found that the alkyl group R on the nitrogen
in 8 led to problems in the formation of complexes 4 (R = H;
R′ = Me, Et, n-Pr) and to the overall inefficiency of ligands 8. It
should also be noted that combination of the steric features of
7 with a tertiary amine moiety, as in ligands of type 8, failed
entirely to form the corresponding Ni(II) complexes with α-AAs.
Analysis of these and other24–26,29 data obtained for the syn-
thesis and reactivity of ligands 7 and 8 clearly suggested that
the steric bulk at the glycine moiety, as in 7, as well as on the
amino group, as in 8, were detrimental to the required reactiv-
ity of compounds 7 and 8. We therefore envisioned the design
of a simple NH-type version 9, possessing an unsubstituted
glycine moiety and a secondary amino group.
Synthesis of ligand (R)-9 was accomplished using the
sequence of reactions illustrated in Scheme 1. Focusing on our
work on the cost structure, we chose to use 2-amino-5-chloro-
benzophenone 10 as the starting compound, since it is about
one-fifth of the cost of the non-chlorinated analog. Reaction of
chloro-benzophenone 10 with bromoacetyl bromide gave
amide 11, which was further reacted with (R)-α-(phenyl)ethyl-
amine30 to give the target ligand (R)-9.
Optimization of the reaction conditions of ligand (R)-9 with
glycine and NiCl2 revealed that the corresponding diastereo-
meric Ni(II) complexes (RC,RN)-12 and (RC,SN)-13 could be
obtained in quantitative yield in less than an hour using just
10% excess of glycine and NiCl2. These results are in sharp
contrast to the reactivity of ligands 7 and 8, which required a
five-fold excess of the reagents and about 24 h reaction
time.24–26,29 The exceptional reactivity of ligand 9 is clearly the
result of its simple structure and the absence of any steric
obstruction in its complexation with Ni(II). On the other hand,
the lack of steric hindrance results in poor control of the nitro-
gen stereochemistry by the (R)-α-(phenyl)ethylamine residue,
giving rise to diastereomeric products (RC,RN)-12 and (RC,SN)-
13 in a 54 : 46 ratio, determined by HPLC analysis. Bearing in
mind that the goal of the present study was the chemical
resolution of α-AAs, the low diastereoselectivity observed was
quite acceptable. The nitrogen stereogenic center in com-
pounds (RC,RN)-12 and (RC,SN)-13 is configurationally stable,
Fig. 1 Structural variety of Ni(II) complexes of glycine Schiff bases.
for bis-alkylations21 as well as asymmetric Michael addition
reactions.22 Recently, using the modular design23 first develo-
ped for the preparation of complexes 3, a new family of chiral
derivatives, 4, has been introduced24 and successfully used for
deracemization25 and (S)-to-(R) interconversion26 of α-AAs. The
most recent development in this area has been the study of
diastereoselectivity in alkylation and Michael addition
reactions of NH-type complexes 5 and their N-adamantyl
analogs.27 Each type of the complexes 1–5 has both advan-
tageous features and limitations, leaving room for further
improvements in reactivity and the stereochemical outcome of
their synthetic application. In the present study, we explore
structurally new NH-type complexes 6 possessing a relatively
simple, non-rigid framework of three chelated rings and
demonstrate their application for resolution of α-AAs, includ-
ing the biologically highly valuable 2′,6′-dimethyltyrosine
(DMT).
Results and discussion
During our previous studies,24–26 we designed ligands 7
(Fig. 2), derived from one of the most inexpensive chiral auxili-
aries, α-(phenyl)ethylamine.28 While ligands 7 were quite suc-
cessful for the deracemization of α-AAs, they have two serious
shortcomings: their low-yield synthesis and slow rates of
formation of complexes 4 (R = Me; R′ = H). These problems
clearly rendered ligands 7 inefficient for the preparation of
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was determined by X-ray analysis (Fig. 3). Based on the simi-
larity of the chiroptical properties and spectral data, the
remainder of products 14b–g were assigned (RC,RN,RC) stereo-
chemistry. In particular, all the complexes 14a–g showed high
negative optical rotation (Table 1), indicating α-(R)-absolute
configuration of the corresponding amino acid residue. On the
other hand, the second major diastereomers (RC,SN,SC)-15a–g
showed similarly high positive optical rotation, confirming
the α-(S) absolute configuration of the corresponding amino
acids.24–26 Furthermore, one can also see a clear trend in the
chemical shifts of the Me group of the α-(phenyl)ethylamine
moiety in the diastereomers (RC,RN,RC)-14 and (RC,SN,SC)-15.
As can be seen from the crystallographic structure of 14a
(Fig. 3), the Me group of the α-(phenyl)ethylamine moiety is
located under and in close proximity to the Ni(II) atom, which
noticeably deshields it.31 Hence, in all cases studied the reso-
nance of the Me group in diastereomers (RC,RN,RC)-14a–g
appeared downfield in comparison to that of diastereomers
(RC,SN,SC)-15a–g.
The absolute configuration of the minor diastereomers
(RC,RN,SC)-16 and (RC,SN,RC)-17 can also be deduced from their
optical rotation (α-carbon stereogenic center) and the chemical
shift of the Me groups (N-stereogenic center). However, an
indisputable determination of their stereochemistry can be
achieved by synthesis of the minor diastereomers (RC,RN,SC)-16
and (RC,SN,RC)-17 from major products (RC,RN,RC)-14 and
(RC,SN,SC)-15, and by comparison of the properties of the com-
pounds obtained, (RC,RN,SC)-16 and (RC,SN,RC)-17, with those
prepared directly by the reaction of ligand (R)-9 with amino
acids. As discussed above, the stereogenic nitrogen in com-
plexes of this type is configurationally stable in the solid state
or in solutions of the complexes in nonpolar solvents (CHCl3,
CH2Cl2). However, in protic polar solvents NH complexes
undergo ready epimerization at the N-stereogenic center. For
example, one of the major diastereomers (RC,RN,RC)-14g was
heated at 50 °C in the mixture MeOH–CH2Cl2, and the reaction
was followed by HPLC at different reaction times. Thermodyn-
amic equilibrium, as a 92 : 8 mixture of epimers (RC,RN,RC)-14g
and (RC,SN,RC)-17g, was reached after 2 h (Scheme 2).
Considering the data presented in Table 1, one may con-
clude that in all the cases studied, regardless of the structure
of the amino acid side-chain, the two major diastereomers (RC,
RN,RC)-14 and (RC,SN,SC)-15 are formed in close to a 1/1 ratio.
Both diastereomers 14 and 15 have relative trans-disposition of
the amino acid side-chain and the N-α-(phenyl)ethyl group,
rendering them more thermodynamically stable than the
minor diastereomers (RC,RN,SC)-16 and (RC,SN,RC)-17, which
possess these groups in the sterically unfavorable cis-position.
Considering the stereochemistry of all four diastereomers, (RC,
RN,RC)-14, (RC,SN,SC)-15 (major), (RC,RN,SC)-16 and (RC,SN,RC)-
17 (minor), one can suggest that for the purpose of chemical
resolution diastereomers (RC,RN,RC)-14 and (RC,SN,RC)-17 can
be grouped together, as they contain the target amino acid of
the same α-(R) absolute configuration. Similarly, diastereomers
(RC,SN,SC)-15 and (RC,RN,SC)-16 also can be combined for iso-
lation of the corresponding α-(S)-AAs. From this standpoint, it
Scheme 1 Synthesis of ligand 9 and glycine Schiff base complexes
12 and 13.
allowing their isolation in diastereomerically pure form by
column chromatography.
Assignment of the absolute configuration of (RC,RN)-12 and
(RC,SN)-13 was based on their chiroptical properties. Thus, the
diastereomer 12 with (RC,RN) configuration had very high
optical rotation, [α]2D5 = −1685, whereas product 13, of (RC,SN)
stereochemistry, showed low rotation ([α]2D5 = +66.7). A similar
trend of optical rotation was previously observed for a series of
analogous complexes derived from ligands 8 (R = Me, Et, n-Pr),
the structures of which were determined by X-ray analysis.29
With these preliminary results obtained for glycine Schiff
base complexes 12 and 13, we next investigated the reactions
of ligand (R)-9 with a range of racemic α-AAs (Table 1). It was
expected that complexation of ligand (R)-9 with higher α-AAs
might result in the formation of up to four diastereomeric pro-
ducts, due to the presence of two epimerizable stereogenic
centers: the α-carbon of the amino acid residue and the nitro-
gen of the ligand. As can be seen from Table 1, in all the cases
studied two major diastereomers (RC,RN,RC)-14 and (RC,SN,SC)-
15 were obtained, along with two other minor complexes
(RC,RN,SC)-16 and (RC,SN,RC)-17. Absolute configuration of the
complex (RC,RN,RC)-14a, containing a phenylalanine residue,
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Table 1 Reactions of ligand (R)-9 with α-AAs
Entry
AA
R
Product
Ratio 14 : 15a
54 : 46
Yieldb (%)
[α]2D5
δMe (ppm)
1
2
3
4
5
6
7
Phe
Phg
Ala
Bn
(RC,RN,RC)-14a
(RC,SN,SC)-15a
(RC,RN,RC)-14b
(RC,SN,SC)-15b
(RC,RN,RC)-14c
(RC,SN,SC)-15c
(RC,RN,RC)-14d
(RC,SN,SC)-15d
(RC,RN,RC)-14e
(RC,SN,SC)-15e
(RC,RN,RC)-14f
(RC,SN,SC)-15f
(RC,RN,RC)-14g
(RC,SN,SC)-15g
97
93
95
94
94
97
99
−2239
+2750
−1969
+2494
−3075
+2669
−2638
+2900
−2126
+2893
−2841
+2539
−1291
+1853
1.91
1.73
2.05
1.95
2.04
1.95
1.98
1.86
1.99
1.90
1.85
1.62
2.01
1.80
Ph
56 : 44
Me
53 : 47
Val
i-Pr
55 : 45
Leu
Tyr
i-Bu
56 : 44
4-OH-C6H4CH2
4-OH-2,6-di-Me-C6H4CH2
52 : 48
DMT
51 : 49
a Measured by HPLC analysis of the crude reaction mixtures. Up to 15% of isomers 16 and 17 was also detected (see Experimental part for
details). b Overall isolated yield of pure products.
Scheme 2 Epimerization of the major product (RC,RN,RC)-14g to the
minor diastereomer (RC,SN,RC)-17g.
should be emphasized that in all the cases listed in Table 1
the diastereomeric complexes 14a–g–17a–g were obtained in
excellent yield, in every case well above 90%, using only a 10%
excess of the racemic amino acid and NiCl2. However, the
Fig. 3 Crystallographic structure of (RC,RN,RC)-14a.
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most important advantage of complexes 14a–g–17a–g is that starting ligand (R)-9, which could conveniently be recycled.
both the major and minor products have significantly different The same procedure was performed on the mixture of (RC,SN,
Rfs, simplifying their separation and isolation in diastereo- SC)-15 and (RC,RN,SC)-16, giving rise to the (S)-enantiomer 18
merically pure form. The minor diastereomers usually follow of DMT in addition to the ligand (R)-9. Starting from racemic
the corresponding major product, and could therefore be simi- DMT, the overall yield of the (R)- and (S)-enantiomers 18 was
larly grouped for separation of (S)- and (R)-α-AAs. Importantly, 48 and 36%, respectively.
the observed difference in the Rfs is not influenced by the AA
side-chain and is thus a broad-spectrum property, suggesting ration of diastereomerically pure complexes 14g or 15g without
some degree of generality in resolution. recourse to column chromatography, confirming the scalabil-
Finally, we felt it necessary to provide an example of prepa-
With these results in hand, we were in position to explore ity of this method for large-scale synthesis of the target amino
the final goal of this work, which was to demonstrate a practi- acids. The reaction of ligand 9 with racemic 2′,6′-dimethyl-
cal application of ligand (R)-9 for the resolution of α-AAs. As tyrosine (DMT) was conducted on the 97.5 g scale, resulting in
an example we selected 2′,6′-dimethyltyrosine (DMT), for the 147 g (93%) of diastereomers 14–17g. Without purification, the
following reasons: firstly, DMT is a very important tailor-made resultant mixture was dissolved in CHCl3 and treated with
amino acid critically involved in the de novo design of various Et2O to precipitate the major product (RC,RN,RC)-14g in
synthetic peptides, in particular opioid receptor agonists and diastereomerically pure form (45.9 g, 31%). After disassembly
antagonists,32 and secondly, while racemic DMT is relatively of product 14g under the usual hydrolytic conditions, the
inexpensive, the cost of pure (R)- and (S)-enantiomers of DMT target (R)-2′,6′-dimethyltyrosine (DMT) (R)-18 was obtained in
is high, partly because asymmetric synthesis of DMT requires enantiomerically pure form.
protection and deprotection of the phenolic group.33 With this
in mind, direct resolution of unprotected racemic DMT might
provide a competitive alternative approach for preparation of
enantiomerically pure DMT.
Conclusions
To this end, we carried out reaction of ligand (R)-9 with The chemistry described in this study represents the first
racemic DMT on the gram scale. Gratifyingly, on this scale we chemical approach to the resolution of α-AAs. We have demon-
observed virtually complete conversion of ligand (R)-9, and strated that the resolving reagent, the specially designed
reaction products 14g–17g were obtained in quantitative yield. ligand (R)-9, reacts with racemic α-AAs in virtually quantitative
Diastereomers 14, 17 and 15, 16 were readily separated by yield, giving rise to two major and two minor diastereomeric
column chromatography and disassembled under standard products. Complexes (RC,RN,RC)-14 and (RC,SN,RC)-17 contain-
conditions (MeOH–HCl).29 Starting from the mixture of ing α-(R) amino acids, and (RC,SN,SC)-15 and (RC,RN,SC)-16
(RC,RN,RC)-14 and (RC,SN,RC)-17, free amino acid (R)-18 having amino acids of α-(S) configuration, can be dis-
(Scheme 3) was isolated in quantitative yield, along with the assembled to furnish the target free amino acids, together
with the recovery and recycling of the resolving reagent (R)-9.
The approach presented offers the advantages that it is
based on an inexpensive source of chirality, α-(phenyl)ethyl-
amine, and that all the reactions are operationally convenient
and give virtually quantitative yield. Whereas asymmetric syn-
thesis and enzymatic resolution require certain technical
expertise and are procedurally intricate, the chemical resolu-
tion described is convenient, reliable and reproducible,
particularly when both enantiomers of the target α-AA are
required.
Experimental
General methods
All reagents and solvents were used as received. The reactions
were monitored with the aid of thin-layer chromatography
(TLC) on precoated silica gel plates, and visualization was
carried out using UV light. Flash column chromatography was
performed with the solvents indicated on silica gel (particle
1
size 0.040–0.063 mm). H and 13C spectra were recorded on a
300 MHz Brüker instrument. Chemical shifts are given in ppm
(δ), referenced to the residual proton resonances of the sol-
vents. Coupling constants (J) are given in hertz (Hz). The
Scheme 3 Disassembly of complexes 14 and 17 and isolation of free
(R)-DMT.
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letters m, s, d, t, q and br stand for multiplet, singlet, doublet,
Data for 13. Rf: 0.16 (CH2Cl2–acetone, 2 : 1). [α]2D5 = +66.7 (c =
triplet, quartet and broad, respectively. High-resolution mass 0.048, CHCl3).
spectra (HRMS) were recorded using an UPLC/Q-TOF MS
system in the ESI mode.
1H NMR (300 MHz, CDCl3) δ 8.25 (d, J = 9.2 Hz, 1H),
7.67–7.37 (m, 5H), 7.32–7.07 (m, 5H), 6.95–6.82 (m, 1H), 6.73
Synthesis of (R)-N-(2-benzoyl-4-chlorophenyl)-2-((1-phenyl- (d, J = 2.5 Hz, 1H), 4.05 (qd, J = 6.9, 5.7 Hz, 1H), 3.88–3.76
ethyl)amino)acetamide (9). To a mixture of 1134 (1 equiv.), (m, 1H), 3.67 (s, 2H), 3.52 (dd, J = 17.3, 7.9 Hz, 1H), 3.09 (d,
K2CO3 (4 equiv.) and MeCN (12 mL/1 g of 11) was added J = 18.5 Hz, 1H), 2.03 (d, J = 7.0 Hz, 3H).
(R)-α-(phenyl)ethylamine (1.1 equiv.). The reaction mixture
13C NMR (75 MHz, CDCl3) δ 178.9, 177.9, 170.9, 141.4,
was stirred 6 h at room temperature and monitored by TLC. 137.8, 133.9, 132.2, 132.0, 130.1, 130.0, 129.7, 128.9, 128.8,
The insoluble salts were filtered off and washed with EtOAc, 128.3, 126.7, 126.1, 125.7, 125.6, 60.9, 59.8, 51.0, 18.0.
and the filtrate was concentrated under reduced pressure.
Hexane was added to the residue to form a precipitate, which 506.0771.
HRMS: calc. for C25H23ClN3NiO3 [M + H]+ 506.0781, found
was filtered and dried at 60 °C to give the title compound.
Ni(II) complexes of the Schiff’s base of 9 and DL-phenyl-
alanine (14a) and (15a). From 500 mg (1.27 mmol) of 9,
Yield: 88.8%. [α]D25 = –33.8 (c = 1.604, CHCl3).
1H NMR (300 MHz, CDCl3) δ 11.56 (s, 1H), 8.65 (d, J = 736 mg of a 47 : 41 : 12 mixture of three diastereomers was
9.3 Hz, 1H), 7.86–7.81 (m, 2H), 7.68 (tt, J = 7.4, 1.3 Hz, 1H), obtained (yield: 96.9%). A part of the mixture was subjected
7.62–7.48 (m, 4H), 7.40–7.35 (m, 2H), 7.32–7.21 (m, 3H), 3.83 to column chromatography to isolate diastereomerically pure
(q, J = 6.5 Hz, 1H), 3.37 (d, J = 17.5 Hz, 1H), 3.29 (d, J = products 14a (121 mg) and 15a (131 mg) for full analytical
17.5 Hz, 1H), 2.00 (br, 1H), 1.49 (d, J = 6.5 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 196.8, 171.6, 144.2, 137.7,
137.6, 133.1, 133.0, 131.7, 130.1, 128.5, 127.3, 127.3, 126.7,
126.3, 123.0, 58.5, 51.2, 23.7.
characterization.
Data for 14a. Rf: 0.41 (CH2Cl2–acetone, 2 : 1). [α]2D5 = −2239
(c = 0.050, CHCl3).
1H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 9.1 Hz, 1H),
7.58–7.38 (m, 6H), 7.35–7.11 (m, 9H), 7.02 (d, J = 6.9 Hz, 1H),
6.67 (d, J = 2.4 Hz, 1H), 4.30–4.22 (m, 1H), 3.64–3.46 (m, 1H),
3.08 (dd, J = 16.3, 6.4 Hz, 1H), 3.01 (dd, J = 13.6, 2.6 Hz, 1H),
2.63 (d, J = 16.3 Hz, 1H), 2.60–2.53 (m, 1H), 2.06–1.97 (m, 1H),
1.91 (d, J = 6.9 Hz, 3H).
HRMS: calc. for C23H22ClN2O2 [M + H]+ 393.1370, found
393.1373.
General procedure for preparation of Ni(II) complexes by
reaction of ligand 9 with amino acids
13C NMR (75 MHz, CDCl3) δ 178.6, 175.8, 169.5, 141.4,
138.2, 135.7, 133.0, 132.3, 132.2, 131.0, 130.3, 129.4, 129.2,
129.0, 128.6, 128.2, 127.6, 127.1, 125.5, 124.9, 71.0, 61.1, 52.0,
39.0, 22.2.
To a mixture of 9 (1 equiv.), NiCl2 (1.1 equiv.), the corres-
ponding amino acid (1.1 equiv.) and MeOH (30 mL/1 g of 9)
K2CO3 (4 equiv.) were added and the reaction mixture was
stirred under reflux. The progress of the reaction was moni-
tored by TLC and, upon completion (consumption of 9), the
reaction mixture was poured into cooled water. The target
product was filtered off and washed with H2O. The filtered pre-
cipitate was dried at 60 °C to give the corresponding Ni(II)
complex.
HRMS: calc. for C32H29ClN3NiO3 [M + H]+ 596.1251, found
596.1255.
Data for 15a. Rf: 0.25 (CH2Cl2–acetone, 2 : 1). [α]2D5 = +2750
(c = 0.047, CHCl3).
1H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 9.0 Hz, 1H),
7.58–7.41 (m, 7H), 7.35 (d, J = 6.5 Hz, 2H), 7.28–7.15 (m, 5H),
7.10 (dd, J = 9.2, 2.5 Hz, 1H), 7.01 (d, J = 6.9 Hz, 1H), 6.64 (s,
1H), 4.24 (s, 1H), 3.66 (q, J = 6.9 Hz, 1H), 3.10–2.88 (m, 2H),
2.78 (d, J = 17.2 Hz, 1H), 2.60 (dd, J = 13.6, 5.5 Hz, 1H), 2.05
(br, 1H), 1.73 (d, J = 6.6 Hz, 3H).
Ni(II) complexes of the Schiff’s base of 9 and glycine, (12)
and (13). From 1 g (2.55 mmol) of 9, 1.29 g of a 54 : 46 mixture
of 12 and 13 was obtained (yield: quantitative). Part of the
mixture was subjected to column chromatography to isolate
diastereomerically pure products 12 (45 mg) and 13 (46 mg)
for full analytical characterization.
13C NMR (75 MHz, CDCl3) δ 178.4, 177.0, 169.3, 141.4,
137.7, 136.1, 133.0, 132.3, 132.1, 131.5, 130.5, 129.5, 129.3,
128.9, 128.9, 128.6, 128.1, 127.7, 127.6, 127.3, 125.5, 125.0,
71.7, 60.2, 51.6, 39.4, 18.1.
Data for 12. Rf: 0.29 (CH2Cl2–acetone, 2 : 1). [α]2D5 = −1685
(c = 0.048, CHCl3).
HRMS: calc. for C32H29ClN3NiO3 [M + H]+ 596.1251, found
596.1256.
1H NMR (300 MHz, CDCl3) δ 8.31 (d, J = 9.2 Hz, 1H),
7.57–7.43 (m, 3H), 7.40–7.10 (m, 7H), 6.93–6.80 (m, 1H), 6.75
(d, J = 2.5 Hz, 1H), 4.02–3.89 (m, 1H), 3.83 (dd, J = 16.8, 6.7 Hz,
1H), 3.72 (d, J = 20.6 Hz, 1H), 3.65 (d, J = 20.6 Hz, 1H), 3.44
(dd, J = 8.6, 7.3 Hz, 1H), 2.99 (d, J = 16.8 Hz, 1H), 2.09 (d, J =
6.1 Hz, 3H).
Ni(II) complexes of the Schiff’s base of 9 and L-phenylglycine
(14b) and (15b). From 500 mg (1.27 mmol) of 9, 691 mg of a
48 : 38 : 8 : 6 mixture of four diastereomers was obtained
(yield: 93.1%). A part of the mixture was subjected to column
chromatography to isolate diastereomerically pure products
14b (106 mg) and 15b (93 mg) for full analytical
characterization.
13C NMR (75 MHz, CDCl3) δ 177.8, 177.4, 171.0, 141.3,
138.6, 133.9, 132.2, 132.1, 130.1, 129.6, 129.1, 128.8, 128.2,
127.4, 127.0, 126.1, 125.9, 125.8, 125.6, 61.8, 60.9, 52.3, 22.5.
HRMS: calc. for C25H23ClN3NiO3 [M + H]+ 506.0781, found
506.0778.
Data for 14b. Rf: 0.52 (CH2Cl2–acetone, 2 : 1). [α]2D5 = −1969
(c = 0.056, CHCl3).
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1H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 9.2 Hz, 1H), 128.2, 128.0, 127.7, 127.0, 125.4, 125.0, 60.0, 51.5, 29.2, 21.3,
7.57–7.40 (m, 5H), 7.36–7.22 (m, 5H), 7.20–7.11 (m, 4H), 6.95 18.3.
(t, J = 7.5 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 5.94 (d, J = 7.8 Hz,
1H), 4.78 (s, 1H), 3.99–3.84 (m, 2H), 3.43 (dd, J = 8.0, 7.3 Hz, 520.0947.
HRMS: calc. for C26H25ClN3NiO3 [M + H]+ 520.0938, found
1H), 3.02 (d, J = 16.8 Hz, 1H), 2.05 (d, J = 6.9 Hz, 3H).
Ni(II) complexes of the Schiff’s base of 9 and DL-valine (14d)
13C NMR (75 MHz, CDCl3) δ 178.7, 177.6, 171.6, 141.5, and (15d). From 500 mg (1.27 mmol) of 9, 654 mg of a
138.5, 137.8, 133.5, 132.3, 132.1, 129.7, 129.0, 128.7, 128.6, 50 : 41 : 7 : 2 mixture of four diastereomers was obtained (yield:
128.6, 128.1, 128.0, 127.9, 127.6, 127.4, 126.9, 126.0, 125.6, 93.7%). A part of the mixture was subjected to column chromato-
125.1, 74.0, 61.2, 51.9, 21.8.
graphy to isolate diastereomerically pure products 14d (97 mg)
HRMS: calc. for C31H27ClN3NiO3 [M + H]+ 582.1094, found and 15d (74 mg) for full analytical characterization.
Data for 14d. Rf: 0.45 (CH2Cl2–acetone, 2 : 1). [α]2D5 = −2638
582.1097.
Data for 15b. Rf: 0.34 (CH2Cl2–acetone, 2 : 1). [α]2D5 = +2494 (c = 0.048, CHCl3).
(c = 0.031, CHCl3).
1H NMR (300 MHz, CDCl3) δ 8.24 (d, J = 9.2 Hz, 1H),
1H NMR (300 MHz, CDCl3) δ 8.11 (d, J = 9.2 Hz, 1H), 7.66 7.52–7.38 (m, 5H), 7.32–7.18 (m, 4H), 7.14 (dd, J = 9.2, 2.5 Hz,
(d, J = 7.0 Hz, 2H), 7.60 (dd, J = 6.3, 3.1 Hz, 2H), 7.46 (t, J = 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 3.98 (dd,
7.4 Hz, 1H), 7.36–7.17 (m, 8H), 7.10 (dd, J = 9.2, 2.6 Hz, 1H), J = 16.8, 6.5 Hz, 1H), 3.91–3.74 (m, 2H), 3.63 (dd, J = 8.2,
6.94 (t, J = 7.4 Hz, 1H), 6.59 (d, J = 2.6 Hz, 1H), 5.95 (d, J = 6.9 Hz, 1H), 3.01 (d, J = 16.8 Hz, 1H), 2.00 (d, J = 6.2 Hz, 3H),
7.8 Hz, 1H), 4.74 (s, 1H), 3.95 (qd, J = 7.0, 2.5 Hz, 1H), 3.64 1.97 (d, J = 6.3 Hz, 3H), 1.79–1.61 (m, 1H), 0.76 (d, J = 6.9 Hz,
(dd, J = 7.7, 2.1 Hz, 1H), 3.54 (dd, J = 17.0, 7.9 Hz, 1H), 3.03 3H).
(d, J = 16.9 Hz, 1H), 1.95 (d, J = 7.0 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 177.9, 176.7, 169.6, 141.4,
13C NMR (75 MHz, CDCl3) δ 178.7, 178.5, 171.5, 141.5, 138.5, 133.1, 132.3, 132.2, 130.1, 129.2, 129.1, 128.7, 128.5,
138.1, 138.0, 133.5, 132.2, 132.0, 129.7, 128.8, 128.6, 128.6, 128.0, 127.5, 127.1, 125.5, 124.8, 74.8, 61.2, 52.3, 34.2, 22.0,
128.3, 127.7, 127.3, 126.8, 126.0, 125.4, 125.2, 74.1, 61.1, 52.4, 19.7, 18.2.
18.8.
HRMS: calc. for C28H29ClN3NiO3 [M + H]+ 548.1251, found
HRMS: calc. for C31H27ClN3NiO3 [M + H]+ 582.1094, found 548.1253.
Data for 15d. Rf: 0.30 (CH2Cl2–acetone, 2 : 1). [α]2D5 = +2900
(c = 0.021, CHCl3).
582.1097.
Ni(II) complexes of the Schiff’s base of 9 and DL-alanine (14c)
and (15c). From 500 mg (1.27 mmol) of 9, 629 mg of a
48 : 42 : 7 : 3 mixture of four diastereomers was obtained (yield:
94.9%), Part of the mixture was subjected to column chromato-
graphy to isolate diastereomerically pure products 14c (43 mg)
and 15c (22 mg) for full analytical characterization.
1H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 9.2 Hz, 1H), 7.72
(d, J = 7.0 Hz, 2H), 7.51–7.38 (m, 3H), 7.28–7.14 (m, 4H), 7.07
(dd, J = 9.2, 2.6 Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H), 6.60 (d, J =
2.5 Hz, 1H), 3.94–3.69 (m, 4H), 3.12 (d, J = 16.5 Hz, 1H), 1.98
(d, J = 6.8 Hz, 3H), 1.86 (d, J = 7.0 Hz, 3H), 1.77–1.65 (m, 1H),
Data for 14c. Rf: 0.42 (CH2Cl2–acetone, 1 : 1). [α]2D5 = −3075 0.75 (d, J = 6.9 Hz, 3H).
(c = 0.050, CHCl3).
13C NMR (75 MHz, CDCl3) δ 178.1, 177.6, 169.5, 141.3,
1H NMR (300 MHz, CDCl3) δ 8.29 (d, J = 9.2 Hz, 1H), 138.0, 133.1, 132.2, 132.1, 130.1, 129.2, 129.1, 128.8, 128.5,
7.53–7.40 (m, 3H), 7.39–7.21 (m, 6H), 7.16 (dd, J = 9.2, 2.6 Hz, 128.3, 128.0, 127.1, 125.4, 124.8, 75.0, 61.3, 52.8, 34.2, 19.8,
1H), 6.89 (d, J = 7.1 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 4.08–3.74 18.7, 18.3.
(m, 3H), 3.25 (dd, J = 8.9, 6.8 Hz, 1H), 3.01 (d, J = 16.7 Hz, 1H),
2.04 (d, J = 6.9 Hz, 3H), 1.45 (d, J = 7.1 Hz, 3H).
HRMS: calc. for C28H29ClN3NiO3 [M + H]+ 548.1251, found
548.1255.
Ni(II) complexes of the Schiff’s base of 9 and DL-leucine (14e)
13C NMR (75 MHz, CDCl3) δ 181.1, 177.2, 169.8, 141.2,
138.7, 132.9, 132.2, 130.2, 129.3, 129.1, 128.8, 128.7, 128.1, and (15e). From 500 mg (1.27 mmol) of 9, 670 mg of a
127.9, 127.7, 127.4, 126.9, 125.6, 125.1, 65.9, 61.3, 52.2, 22.2, 51 : 40 : 7 : 2 mixture of four diastereomers was obtained (yield:
21.2.
93.6%). A part of the mixture was subjected to column chromato-
HRMS: calc. for C26H25ClN3NiO3 [M + H]+ 520.0938, found graphy to isolate diastereomerically pure products 14e (91 mg)
520.0949.
and 15e (77 mg) for full analytical characterization.
Data for 14e. Rf: 0.57 (CH2Cl2–acetone, 2 : 1). [α]2D5 = −2126
(c = 0.049, CHCl3).
Data for 15c. Rf: 0.24 (CH2Cl2–acetone, 1 : 1). [α]2D5 = +2669
(c = 0.050, CHCl3).
1H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 9.2 Hz, 1H), 7.58
1H NMR (300 MHz, CDCl3) δ 8.22 (d, J = 9.2 Hz, 1H),
(d, J = 7.0 Hz, 2H), 7.54–7.36 (m, 3H), 7.34–7.20 (m, 4H), 7.11 7.54–7.33 (m, 5H), 7.33–7.17 (m, 4H), 7.13 (dd, J = 9.2, 2.5 Hz,
(dd, J = 9.2, 2.6 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 6.59 (d, J = 1H), 6.86 (d, J = 6.9 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 3.95 (dd,
2.5 Hz, 1H), 4.03 (qd, J = 6.9, 2.6 Hz, 1H), 3.90 (q, J = 7.1 Hz, J = 16.7, 6.6 Hz, 1H), 3.90–3.80 (m, 2H), 3.42 (t, J = 7.6 Hz, 1H),
1H), 3.72 (dd, J = 17.2, 8.0 Hz, 1H), 3.32 (d, J = 6.9 Hz, 1H), 3.01 (d, J = 16.8 Hz, 1H), 2.28 (ddd, J = 12.1, 10.3, 3.4 Hz, 1H),
3.12 (d, J = 17.5 Hz, 1H), 1.95 (d, J = 7.1 Hz, 3H), 1.44 (d, J = 1.99 (d, J = 6.9 Hz, 3H), 1.85 (br, 1H), 1.31–1.18 (m, 1H), 0.82
7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 181.3, 178.5, 169.8, 141.3,
(d, J = 6.7 Hz, 3H), 0.38 (d, J = 6.4 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 179.7, 176.7, 169.2, 141.2,
137.9, 133.0, 132.2, 132.1, 130.2, 129.3, 129.1, 128.8, 128.7, 138.6, 133.0, 132.3, 130.3, 129.2, 129.0, 128.8, 128.5, 128.3,
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127.9, 127.3, 125.7, 125.0, 68.4, 61.6, 52.4, 45.2, 24.3, 23.7, column chromatography to isolate diastereomerically pure
22.4, 20.6.
products 14g (1.11 g) and 15g (887 mg) for full analytical
HRMS: calc. for C29H31ClN3NiO3 [M + H]+ 562.1407, found characterization.
Data for 14g. Rf: 0.40 (CH2Cl2–acetone, 4 : 1). [α]2D5 = −1290.8
562.1414.
Data for 15e. Rf: 0.39 (CH2Cl2–acetone, 2 : 1). [α]2D5 = +2893 (c = 0.026, CHCl3).
(c = 0.051, CHCl3).
1H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 9.2 Hz, 1H),
1H NMR (300 MHz, CDCl3) δ 8.06 (d, J = 9.2 Hz, 1H), 7.67 7.45–7.33 (m, 4H), 7.30–7.17 (m, 5H), 7.14 (dd, J = 9.2, 2.5 Hz,
(d, J = 7.0 Hz, 2H), 7.54–7.35 (m, 3H), 7.31–7.13 (m, 4H), 7.07 1H), 6.54 (s, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.22 (s, 2H), 6.10 (d,
(dd, J = 9.2, 2.6 Hz, 1H), 6.86 (d, J = 6.8 Hz, 1H), 6.59 (d, J = J = 7.0 Hz, 1H), 4.21 (dd, J = 8.7, 5.8 Hz, 1H), 3.97 (dd, J = 16.6,
2.5 Hz, 1H), 3.95–3.65 (m, 4H), 3.08 (d, J = 17.1 Hz, 1H), 2.32 6.4 Hz, 1H), 3.85–3.70 (m, 1H), 3.67–3.53 (m, 1H), 3.34 (dd, J =
(ddd, J = 12.1, 10.9, 3.4 Hz, 1H), 1.90 (d, J = 6.9 Hz, 3H), 1.78 14.5, 5.8 Hz, 1H), 3.04–3.00 (m, 1H), 3.03 (d, J = 16.7 Hz, 1H),
(br, 1H), 1.28–1.11 (m, 1H), 0.82 (d, J = 6.7 Hz, 3H), 0.34 (t, J = 2.01 (d, J = 6.9 Hz, 3H), 1.93 (s, 6H).
13.7 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 179.6, 176.7, 170.0, 155.2,
13C NMR (75 MHz, CDCl3) δ 179.9, 178.0, 169.0, 141.2, 141.0, 139.2, 138.4, 132.8, 132.4, 129.9, 129.2, 129.1, 128.7,
137.9, 133.0, 132.1, 130.2, 129.2, 129.2, 128.9, 128.8, 128.4, 128.7, 128.5, 128.2, 127.4, 127.3, 125.8, 124.9, 123.2, 115.4,
128.1, 127.9, 127.3, 125.4, 124.9, 68.7, 60.8, 52.1, 45.3, 24.4, 69.9, 61.2, 52.3, 36.2, 21.9, 19.9.
23.8, 20.6, 18.4.
HRMS: calc. for C29H31ClN3NiO3 [M + H]+ 562.1407, found 640.1511.
562.1415.
HRMS: calc. for C34H33ClN3NiO4 [M + H]+ 640.1513, found
Data for 15g. Rf: 0.20 (CH2Cl2–acetone, 4 : 1). [α]2D5 = +1852.5
(c = 0.052, CHCl3).
Ni(II) complexes of the Schiff’s base of 9 and DL-tyrosine
(14f) and (15f). From 500 mg (1.27 mmol) of 9, 759 mg of a
49 : 46 : 5 mixture of three diastereomers was obtained (yield:
97.3%). A part of the mixture was subjected to column chromato-
graphy to isolate diastereomerically pure products 14f
(110 mg) and 15f (100 mg) for full analytical characterization.
1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 9.2 Hz, 1H), 7.66
(d, J = 7.2 Hz, 2H), 7.43–7.33 (m, 2H), 7.27–7.08 (m, 6H), 7.02
(dd, J = 9.2, 2.4 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 6.24 (s, 2H),
6.10 (br, 1H), 4.18 (t, J = 7.0 Hz, 1H), 3.86–3.50 (m, 4H), 3.31
(dd, J = 14.3, 5.6 Hz, 1H), 3.07 (d, J = 17.0 Hz, 1H), 1.93 (s, 6H),
Data for 14f. Rf: 0.44 (CH2Cl2–acetone, 1 : 1). [α]2D5 = −2841 1.80 (d, J = 6.9 Hz, 3H).
(c = 0.027, CHCl3).
13C NMR (75 MHz, CDCl3) δ 179.8, 177.8, 169.8, 155.3,
1H NMR (300 MHz, CDCl3) δ 8.37 (br, 1H), 8.11 (d, J = 140.9, 139.5, 138.0, 132.5, 132.5, 132.2, 129.9, 129.2, 128.8,
9.1 Hz, 1H), 7.58–7.42 (m, 3H), 7.31–7.08 (m, 9H), 7.02 (d, J = 128.7, 128.4, 128.1, 127.4, 125.7, 124.8, 123.4, 115.4, 70.1, 61.2,
6.9 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 2.5 Hz, 1H), 53.0, 35.9, 20.0, 18.7.
4.27–4.11 (m, 1H), 3.70–3.51 (m, 1H), 3.27 (dd, J = 16.7, 6.4 Hz,
1H), 2.90 (dd, J = 13.7, 2.3 Hz, 1H), 2.70 (d, J = 16.7 Hz, 1H), 640.1512.
HRMS: calc. for C34H33ClN3NiO4 [M + H]+ 640.1513, found
2.58–2.46 (m, 2H), 1.85 (d, J = 6.9 Hz, 3H).
Synthesis of 2′,6′-dimethyltyrosine (DMT) (18). A mixture of
13C NMR (75 MHz, CDCl3) δ 178.9, 176.5, 169.7, 156.6, 14g and 17g (0.5 g, 0.780 mmol) was suspended in MeOH
141.0, 138.1, 133.1, 132.5, 132.4, 132.3, 130.6, 129.6, 129.4, (15 mL). 1N HCl (6 equiv.) was added and the reaction was
129.2, 128.9, 128.5, 127.7, 127.3, 127.2, 126.8, 126.2, 125.1, stirred at 50 °C for 4 h. The reaction mixture was cooled to
115.8, 71.4, 61.3, 51.9, 38.4, 22.1.
ambient temperature and then concentrated in vacuo. To the
HRMS: calc. for C32H29ClN3NiO4 [M + H]+ 612.1200, found residue, CH2Cl2 (3 mL) and 28% NH4OH (4 mL) were added,
612.1194.
and the mixture evaporated again. To the residue CH2Cl2
(30 mL) and water (30 mL) were added. The aqueous layer was
extracted twice with dichloromethane (15 mL). The organic
layer was washed with a small amount of water, and then
brine, and dried over Na2SO4; it was then evaporated to give
compound 9 (>99% yield, 99.0% purity by HPLC). The com-
bined water layers were concentrated to give a pale blue
material (380 mg). The residue was dissolved in EtOH–H2O
Data for 15f. Rf: 0.24 (CH2Cl2–acetone, 1 : 1). [α]2D5 = +2539
(c = 0.028, CHCl3).
1H NMR (300 MHz, CDCl3) δ 8.46 (br, 1H), 7.80–7.58 (m,
3H), 7.58–7.37 (m, 3H), 7.29–6.89 (m, 10H), 6.59 (d, J = 2.4 Hz,
1H), 4.25–4.09 (m, 1H), 3.47–3.16 (m, 2H), 2.94 (d, J = 11.8 Hz,
1H), 2.82 (d, J = 17.1 Hz, 1H), 2.71 (d, J = 6.5 Hz, 1H), 2.50 (dd,
J = 13.6, 5.7 Hz, 1H), 1.62 (d, J = 6.9 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 178.8, 177.5, 169.3, 156.6,
140.9, 137.7, 132.9, 132.6, 132.2, 132.1, 130.6, 129.5, 129.4,
129.0, 128.9, 128.4, 128.3, 127.6, 127.3, 127.1, 125.9, 125.1,
115.6, 71.8, 60.8, 52.2, 38.5, 18.5.
and applied to
a SK-1B (cation-exchange resin) column
(30 mL). The column was washed with water until the eluent
gave a neutral pH. The column was then washed with 8%
NH4OH and 28% NH4OH–H2O–MeOH as a 1 : 2 : 1 solution.
The eluted fractions were collected and concentrated in vacuo
HRMS: calc. for C32H29ClN3NiO4 [M + H]+ 612.1200, found
612.1204.
Ni(II) complexes of the Schiff’s base of 9 and DL-2′,6′-
dimethyltyrosine (14g) and (15g). From 2 g (4.33 mmol) of 9,
to give (−)-18 as a white solid. Yield: 95.3%. >98% ee. [α]D25
−75.8 (c = 0.4, AcOH).
=
Data for 18. 1H NMR (D2O) δ 2.30 (s, 6H), 3.04 (dd, 1H, J =
2.74 g of a 48 : 45 : 4 : 3 mixture of four diastereomers was 14.5, 8.0 Hz), 3.27 (dd, 1H, J = 14.5, 8.0 Hz), 3.82 (t, 1H, J =
obtained (yield: 98.9%). A part of the mixture was subjected to 8.0 Hz), 6.66 (s, 2H).
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A similar procedure was adopted for the synthesis of (+)-18,
starting from a mixture of 15g and 16g. Yield: 75.1%. >98% ee.
[α]2D5 = +76.9 (c = 0.4, AcOH).
and V. A. Soloshonok, J. Fluorine Chem., 2010, 131, 127–
139; (h) V. A. Soloshonok and A. E. Sorochinsky, Synthesis,
2010, 2319–2344; (i) J. L. Aceña, A. E. Sorochinsky and
V. A. Soloshonok, Synthesis, 2012, 44, 1591–1602.
Large-scale synthesis of (R)-2′,6′-dimethyltyrosine (DMT)
(R)-18. To a mixture of 9 (97.5 g, 0.25 mol), NiCl2 (35.4 g,
0.27 mol) and racemic 2′,6′-dimethyltyrosine (DMT) (57.1 g,
0.27 mol) in MeOH (1 L) was added K2CO3 (137 g, 0.99 mol),
and the reaction mixture was stirred under reflux for 2 h. The
reaction mixture was then poured into cooled water (1 L), and
the target product was filtered off and washed with water. The
filtered precipitate was dried at 60 °C to give 147 g (93%) of a
mixture of Ni-complexes 14g–17g. The resultant mixture was
dissolved in CHCl3 and diethyl ether was slowly added under
stirring until the solution became cloudy due to a precipitate
forming. Stirring was continued at ambient temperature (5 h)
and then at −5 °C (24 h). The precipitate was filtered and
washed three times with CHCl3–Et2O (1/1 by volume) to obtain
45.9 (31%) of diastereomerically pure (RC,RN,RC)-14g. The
product was disassembled as described above, giving (R)-2′,6′-
dimethyltyrosine (DMT) (R)-18.
4 For recent publications on synthesis of α-AAs, see:
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Acknowledgements and funding
We wish to thank IKERBASQUE, the Basque Foundation for
Science; the Basque Government (SAIOTEK S-PE13UN098), the
Spanish Ministry of Science and Innovation (CTQ2010-19974)
and Hamari Chemicals (Osaka, Japan) for their generous
financial support.
We are also grateful to Servicios Generales de Investigación
(SGIker, UPV/EHU) for X-ray diffraction measurements and
HRMS analyses.
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