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Coupling of Boc-phenylalanine with phenylalanine ethyl ester hydrochloride; Ethyl (2S)‐2‐[(2S)‐2‐{[(tert‐butoxy)carbonyl]amino}‐3‐phenylpropanamido]‐3‐phenylpropanoate

SyntheticPage 921
Submitted Apr 27, 2020, published Apr 29, 2020
Bart Dietrich (bart.dietrich@glasgow.ac.uk)
A contribution from Dave Adams Group, Glasgow
Reaction Scheme: Coupling of Boc-phenylalanine with phenylalanine ethyl ester hydrochloride

Chemicals Used

Boc-L-phenylalanine (Fluorochem)
L-Phenylalanine ethyl ester hydrochloride (Fluorochem)
Isobutyl chloroformate (Fluorochem)
N-Methylmorpholine (TCI)
Chloroform (HPLC grade)

Procedure

To a solution of Boc-L-phenylalanine (5.28 g, 19.9 mmol) in chloroform (50 mL) were added iso-butyl chloroformate (1 eq, 2.58 mL) and N-methylmorpholine (1 eq, 2.19 mL) and the mixture was stirred for one hour. L-Phenylalanine ethyl ester hydrochloride (1 eq, 4.57 g) and N-methylmorpholine (1 eq, 2.19 mL) were then added and the mixture was stirred overnight. The now clear solution was diluted with chloroform and washed in turn with 1M hydrochloric acid, water, and brine, dried (MgSO4), and evaporated under reduced pressure. The crude title compound was obtained as an off-white solid (8.49 g, 97 %) and used in the next step without further purification. A small amount was purified via column chromatography (eluting with 1:99 ethyl acetate/dichloromethane) to yield an analytical sample. Pronounced effects of restricted rotation are observed in the NMR data of the product, with the signals for several protons and carbons being split approximately 1:4 into two rotational isomers. These are denoted Rot-1 and Rot-2 in the NMR data below. When the NMR experiment is carried out at higher temperature, the split signals coalesce, as expected for rotamers.

Author's Comments

  • No special precautions with regards to anhydrous conditions or inert atmosphere are required on this scale.
  • Carrying out the reaction at ice/water temperature reduces the formation of a pink-coloured impurity somewhat although the gains are minimal.
  • The crude compound may be used in the next step without purification as impurities tend to wash out in the workup of the next step.

Data

dH (500 MHz, DMSO-d6, 25 °C) 8.38 (0.2H, d, J 6.75, Rot-1 NHCH*CO2Et), 8.32 (0.8H, d, J 7.50, Rot-2 NHCH*CO2Et), 7.30-7.16 (10H, m, HAr), 6.85 (0.8H, d, J 8.80, Rot-2 NHBoc), 6.41 (0.2H, d, J 8.50, Rot-1 NHBoc), 4.47 (1H, dd, J 14.33, 7.73, CH*NHBoc), 4.18 (0.8H, td, J 9.65, 4.00, Rot-2 CH*CO2Et), approx. 4.08-4.02 (0.2H, Rot-1 CH*CO2Et), 4.03 (2H, q, J 7.10, CH2CH3), 3.05-2.95 (2H, m, PhCaH2), 2.89 (1H, dd, J 13.80, 3.95, PhCbHaHb), 2.67 (1H, dd, J 13.73, 10.68, PhCbHaHb), 1.28 (7.2H, s, Rot-2 C(CH3)3), 1.14 (1.8H, s, Rot-1 C(CH3)3), 1.09 (3H, t, J 7.10, CH2CH3).
dH (500 MHz, DMSO-d6, 80 °C) 7.95 (1H, d, J 7.30, NHCH*CO2Et), 7.29-7.16 (10H, m, HAr), 6.39 (1H, br s, NHBoc), 4.55 (1H, td, J 7.82, 6.33, CH*NHBoc), 4.22 (1H, td, J 9.08, 4.70, CH*CO2Et), 4.07 (2H, q, J 7.09, CH2CH3), 3.09-2.93 (3H, m, PhCH2), 2.74 (1H, dd, J 13.95, 9.55, PhCH2), 1.30 (9H, s, C(CH3)3), 1.14 (3H, t, J 7.10, CH2CH3).
dC (100 MHz, DMSO-d6, 25 °C) 171.79, 171.25, and 155.07 (C=O), 138.03, 136.96, 129.12 (broad, likely two overlapping peaks), 128.20, 127.93, 126.52, and 126.12 (CAr), 77.96 (C(CH3)3), 60.47 (CH2CH3), 55.44 (CH*CO2Et), 53.54 (CH*NHBoc), 37.41 (PhCbH2), 36.75 (PhCaH2), 28.08 (Rot-2 C(CH3)3), 27.73 (Rot-1 C(CH3)3), 13.88 (CH2CH3).
dC (125 MHz, DMSO-d6, 80 °C) 170.97, 170.57, and 154.40 (C=O), 137.47, 136.59, 128.64, 128.60, 127.69, 127.46, 126.00, 125.64 (CAr), 77.82 (C(CH3)3), 60.03 (CH2CH3), 55.29 (CH*CO2Et), 53.04 (CH*NHBoc), 37.30 (PhCbH2), 36.68 (PhCaH2), 27.66 (C(CH3)3), 13.36 (CH2CH3).
HRMS (ESI) m/z: [M+Na]+ calcd for C25H32N2NaO5 463.2203; found 463.2190.

Supplementary Information

Proton NMR, DMSO-d6, 25 deg C (dh-002 1h 25deg C.png)
Proton NMR, DMSO-d6, 80 deg C (dh-002 1h 80deg C.png)
Carbon NMR, DMSO-d6, 25 deg C (dh-002 13c 25deg C.png)
Carbon NMR, DMSO-d6, 80 deg C (dh-002 13c 80deg C.png)

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Keywords: amide coupling, amides, amino acids, peptides