Organic Process Research & Development
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complex (S)-2, the major byproduct detected in this reaction is
the corresponding bis-alkylation compound (S)-6, observed,
however, in amounts not exceeding 3%. The reported protocol
does not require purification of the intermediate alkylation
product, which can be disassembled to release the target amino
acid along with recovery and reuse of chiral ligand (S)-8. Using
this procedure, the N-Fmoc derivative of amino acid (S)-9, of
97.8% ee, was prepared on >10 g scale.
12.8 Hz, 1H), 4.20 (dd, J = 6.8, 2.8 Hz, 1H), 3.58 (dd, J =
10.0, 6.8 Hz, 1H), 3.51−3.39 (m, 1H), 3.35 (dd, J = 10.8, 6.4
Hz, 1H) 3.23 (d, J = 12.8 Hz, 1H), 2.78−2.74 (m, 1H), 2.65−
2.51 (m, 2H), 2.19−2.03 (m, 3H). 13C NMR (100 MHz,
CDCl3): δ = 22.7, 30.9, 35.7 (J = 29.0 Hz, q), 58.5, 63.3, 64.5,
71.6, 77.2, 124.1, 125.6 (J = 277.0 Hz, q), 125.7, 126.6, 127.0,
127.4, 129.6, 129.7, 129.8, 130.7, 131.0, 132.2, 132.9, 133.0,
133.3, 133.5, 133.7, 134.9, 141.3, 172.3, 177.2, 180.0. 19F NMR
(376 MHz, CDCl3): δ = −60.7 (CF3). IR (NaCl): ν = 3019,
1215, 908, 774, 745, 669 cm−1. MS (ESI): m/z = 682.1 [M +
H]+.
The additional minor products were isolated by preparative
thin layer chromatography on Merck silica gel 60-F254 coated 1
mm plates. The (S)-6 was eluted at a retention time (tR) of
19.4 min, and the (S)-7, at 20.1 min under the conditions
described in the general methods.
EXPERIMENTAL SECTION
■
General Methods. All reagents and solvents were used as
received. Reactions were magnetically stirred and monitored
by thin layer chromatography on Merck silica gel 60-F254
coated 0.25 mm plates, detected by UV. Flash chromatography
was performed with the indicated solvents on silica gel
(particle size 0.064−0.210 mm). Yields reported are for
isolated, spectroscopically pure compounds. HPLC was
performed on a SHIMADZU LC-2010CHT chromatograph
with a CLASS-VP analysis data system using the Inertsil ODS-
3 column (particle size 3 μm, 150 mm × 4.6 mm i.d.) operated
at 1.0 mL/min, 30 °C and monitored at a wavelength of 254
nm with a linear gradient of 10 mM aqueous ammonium
formate containing 0.1% formic acid (eluent A) and
acetonitrile (eluent B) from A/B = 95:5 to 20:80 (0 to 15
(S)-6 (a red solid): [α]25D = +2306.4 (c = 0.05, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 8.46 (dd, J = 8.4, 2.4 Hz, 1H),
8.30 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.63−7.60
(m, 2H), 7.53−7.49 (m, 3H), 7.13 (dd, J = 9.2, 2.4 Hz, 1H),
7.08 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 4.37 (d, J =
12.4 Hz, 1H), 4.35−4.39 (m, 2H), 3.72−3.75 (m, 1H), 3.34−
3.35 (m, 1H), 3.25 (d, J = 12.4 Hz, 1H), 2.76−2.46 (m, 5H),
2.23−2.00 (m, 3H). 13C NMR (100 MHz, CDCl3): δ = 22.7,
30.8, 40.4 (J = 28.0 Hz), 43.3(J = 28.0 Hz), 59.2, 63.9, 70.3,
71.2, 125.2, 125.9, 128.3, 128.4, 128.7, 129.0, 129.7, 130.9,
131.0, 131.2, 131.9, 132.4, 132.7, 133.5, 133.7, 135.0, 135.1,
140.4, 175.6, 177.8, 180.4. 19F NMR (376 MHz, CDCl3): δ =
−59.9, −60.1 (CF3). IR (NaCl): ν = 3019, 1215, 764, 751, 669
1
min) and 20:80 (15 to 25 min), unless otherwise stated. H,
19F, and 13C NMR spectra were recorded on a Bru
̈
ker
AVANCE III-400 spectrometer. Chemical shifts are given in
1
ppm (d), referenced to tetramethylsilane (TMS) for H NMR
and the 13C-resonances of CDCl3 (d = 77.0 ppm) for 13C
NMR as internal standards. The letters s, d, t, q, m, and br
stand for singlet, doublet, triplet, quartet, multiplet, and broad,
respectively. Optical rotations were recorded on a DIP-370
polarimeter (Jasco, Inc.). Melting points were recorded on a
Mettler Toledo MP70 Melting Point System and are not
corrected. IR spectra were recorded on a JASCO FT/IR-4100
spectrometer. All physicochemical data reported for the Ni(II)
complexes are due to the single diastereomers after purification
by chromatography or crystallization.
cm−1. MS (ESI): m/z = 764.1 [M + H]+.
1
(S)-7 (a yellow oil): [α]25 = −13.4 (c = 0.06, CHCl3). H
D
NMR (400 MHz, CDCl3): δ = 8.04 (dd, J = 8.8, 0.4 Hz, 1H),
8.03 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.8, 2.4 Hz, 1H), 7.75−
7.23 (m, 2H), 7.61−7.58 (m, 3H), 7.36 (d, J = 2.0 Hz, 1H),
7.16 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 8.4, 2.0 Hz, 1H), 3.95
(dd, J = 8.0, 8.0 Hz, 1H), 3.82 (d, J = 13.2 Hz, 1H), 3.58 (d, J
= 13.2 Hz, 1H), 3.30 (dd, J = 7.6, 7.6 Hz, 1H), 2.50 (dd, J =
17.2, 8.8 Hz, 1H), 2.47−2.36 (m, 1H), 2.32−2.22 (m, 1H),
2.17−2.06 (m, 1H), 1.97−1.87 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ = 22.9, 32.3, 54.7, 58.2, 71.2, 122.2, 125.7, 128.6,
128.8, 129.7, 130.2, 130.5, 131.1, 131.8, 132.9, 134.5, 136.8,
149.9, 167.8. IR (NaCl): ν = 3649, 3019, 1215, 775, 746, 668
cm−1.
Alkylation of Glycine Complex (S)-3 with ICH2CF3. To
a solution of the Ni-Glycine complex (S)-3 (30.0 g, 49.9 mmol,
1.0 equiv) and 1,1,1-trifluoro-2-iodoethane (5.2 mL, 52.4
mmol, 1.05 equiv) in deoxygenated N,N-dimethyl-formamide
(DMF) (300 mL, 10 v/w) was added 10% KOH methanol
solution (29.4 mL, 52.4 mmol, 1.05 equiv) at room
temperature under an argon atmosphere. The mixture was
stirred at the same temperature for 2 h and then was poured
into water (110 mL, 3.6 v/w) at same temperature to give a
precipitate. After 0.5 h, the mixture was added to water (40
mL, 1.3 v/w) and was stirred for 4 h. Afterward, the precipitate
was filtered, washed with DMF−H2O (60 mL, 2 v/w, 2:1), and
dried in vacuo at 50 °C overnight to afford a crude Ni complex
(29.6 g, 87%, a red solid) as a mixture of (S,2S)-4 and (S,2R)-
5, the diastereomeric ratio of which was determined to be
97.3:0.01 (99.9%de) by HPLC analysis, in which the major
(S,2S)-4 was eluted at a retention time (tR) of 19.4 min, and
the minor (S,2R)-5, at 20.1 min under the conditions
described in the general methods.
Preparation of Fmoc-(S)-2-amino-4,4,4-trifluorobuta-
noic Acid (S)-9. To a solution of Ni complex (S,2S)-4 (27.9 g,
40.8 mmol, 1.0 equiv) in dimethoxyethane (DME) (140 mL, 5
v/w) and water (34.0 mL, 1.2 v/w) was added HCl (6N, 34.0
mL, 204.1 mmol, 5.0 equiv), and the resulting mixture was
heated at 60 °C for 3 h. Afterward, the solution was changed to
a suspension due to a white precipitate (HCl salt of (S)-8)
appearing. The precipitate was filtered and washed with DME
(70.0 mL, 2.5 v/w), and the filtrate was concentrated to 2.0 v/
w. The resulting solution was filtered and washed with water
(30 mL, 1.0 v/w), and the filtrate was concentrated to 40 mL
(1.4 v/w) to give a solution of (S)-1.
To a solution of (S)-1 in aqueous solution were added
ethylenediaminetetraacetic acid disodium salt hydrate (15.2 g,
40.8 mmol, 1.0 equiv) and acetonitrile (40 mL, 1.4 v/w), and
the mixture was stirred for 1 h at room temperature. Sodium
carbonate (17.0 g, 160.0 mmol, 4.0 equiv) and Fmoc-OSu
(13.8 g, 40.8 mmol, 1.0 equiv) were added to the resulting
mixture at 0 °C. The mixture was stirred for 4 h at room
temperature and then was concentrated. To the residue were
(S,2S)-4: Mp 264−266 °C. [α]25 = +2982.6 (c = 0.05,
D
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.95 (d, J = 2.0 Hz,
1H), 8.17 (dd, J = 9.0, 1.6 Hz, 1H), 7.72 (dd, J = 8.0, 2.0 Hz,
1H), 7.60−7.52 (m, 3H), 7.37 (dd, J = 8.0, 1.6 Hz, 1H), 7.31−
7.29 (m, 1H), 7.14 (ddd, J = 9.2, 4.0, 1.6 Hz, 1H), 6.91 (d, J =
7.6 Hz, 1H), 6.57 (ddd, J = 2.4, 1.2, 1.2 Hz, 1H), 4.28 (d, J =
C
Org. Process Res. Dev. XXXX, XXX, XXX−XXX