1148
E. Machuca, E. Juaristi / Tetrahedron Letters 56 (2015) 1144–1148
concentrated and extracted with EtOAc. The organic phase was washed with
downfield from tetramethylsilane as an internal reference. Coupling constants
J are given in Hertz (Hz). Molecular weights were determined by means of
high-resolution mass spectrometry on an Agilent LC/MSD-TOF model 1069A.
Infrared spectra (IR) are reported in reciprocal centimeters and were recorded
satd 1 N HCl, satd NaHCO3 and brine, dried over anhydrous Na2SO4, and
concentrated. The residue was purified by silica gel column chromatography
using CH2Cl2/MeOH (95:5 v/v) as eluent to afford the corresponding N(Cbz)-
(S)-Pro-(S)-2-Nal-CO2Me dipeptide. The dipeptide was then N-deprotected by
hydrogenolysis with hydrogen over 10% Pd/C (50 mg). The reaction mixture
was filtered and washed with methanol, and the filtrate was concentrated. The
crude product was purified by column chromatography using CH2Cl2/MeOH
(95:5 v/v) as eluent to afford the desired dipeptide, (S,S)-proline-2-
naphthylalanine ester 1d.
on
a
spectrophotometer Varian 640-IR FT-IR. Enantiomeric ratios were
Waters 600
measured by chiral HPLC at room temperature using
a
E
equipment fitted with a UV–Vis Waters 2487 detector at 210 or 254 nm,
with Chiralpak AD-H and Chiralcel OD-H columns. Reactions carried out under
ball-milling conditions were performed in a MM200 RETSCH mill, using 5-mL
grinding jars and 2 grinding balls of 7 mm of diameter, both of agate.
Rf = 0.34 [silica gel, DCM/MeOH 95:5], [
a
]
D
ꢀ14.98 (c 1.0, CH3Cl), (FT-IR/ATR,
11. General procedure for the intermolecular aldol reaction catalyzed by dipeptide 1d
cmꢀ1 3316, 2951, 1740, 1666. 1H NMR (500 MHz, CDCl3) d 8.43 (1H, br d,
)
m
under ball milling activation. A mixture of cyclohexanone 2 (0.5 mmol),
J = 7.3 Hz), 7.76 (3H, m), 7.65 (1H, br s), 7.42 (2H, m), 7.27 (2H, m), 4.82 (1H, dd,
J = 7.5, 13.7 Hz), 4.26 (1H, m), 3.65 (3H, s), 3.33–3.25 (2H, m), 3.14–3.09 (1H,
m), 3.03–2.98 (1H, m), 2.27–2.20 (1H, m), 1.90 (1H, m), 1.79–1.60 (2H, m) ppm.
13C NMR (125 MHz, CDCl3) d 171.7, 171.1, 133.7, 133.3, 132.3, 129.2, 128.5,
128.1, 127.6, 127.2, 126.1, 125.7, 59.8, 53.8, 52.3, 46.8, 37.5, 30.5, 24.8 ppm.
HR-ESI-TOF: calculated for C19H23N2O3 [M+H]+: 327.1703 found: 327.1711
(2.3 ppm error).
substituted benzaldehyde 3a–n (0.25 mmol) and catalyst 1d (10 mol %), was
milled for 0.5 h at 15 Hz at room temperature in a MM200 RETSCH mill, in a 5-
mL grinding jar and 2 grinding balls of 7 mm of diameter, both of agate.
Following reaction, the resulting mixture was extracted with EtOAc. The
organic phase was dried over an hour. MgSO4 and concentrated to give the
crude product, which was purified by flash chromatography (silica gel, hexane/
EtOAc, 10:1 to 3:1) to afford the aldol product as an anti/syn diastereomeric
mixture. Enantiomeric ratios in the major diastereomeric product were
determined by HPLC on a chiral column.
10. General information. 1H and 13C NMR spectra were recorded on a Jeol ECA-500
(500 MHz) spectrometer. Chemical shifts (d) are given in parts per million