Arkivoc 2020, iii, 0-0
Nair, S. et al.
MHz, CDCl3) 16.1, 28.7, 29.0, 35.7, 45.0, 50.9, 76.4, 126.1, 128.6, 128.6, 128.8, 129.1, 129.5, 135.0, 141.7,
159.4, 177.1; HRMS (ES): Found 356.1801; calc. for C21H26NO4 356.1792 (M+H)+.
(R)-2-(tert-Butoxycarbonylamino)-3,3-dimethylbutanoic acid.18 Di-tert-butyl dicarbonate (1.82 g, 8.38 mmol)
and KOH (1.16 g, 8.38 mmol) were added to a solution of L-tert-leucine (1.00 g, 7.62 mmol) in H2O:THF (4:1, 30
mL) and stirred at room temperature for 12 hr. THF was removed in vacuo and the resulting solution washed
once with EtOAc. The aqueous layer was then acidified to pH 2 with 1M HCl and re-extracted with EtOAc (3 x
30 mL). The combined organic layers were filtered over MgSO4 and reduced to produce (R)-2-(tert-
butoxycarbonylamino)-3,3-dimethylbutanoic acid (1.53 g, 87%) a white solid. Mp 119 – 121 °C (Lit. Mp 118 –
121 °C);18 [훼]퐷20 = + 5.2°, (EtOAc, c = 1) (Lit [훼]퐷24 = + 5.8°, (EtOAc, c = 0.6);18 IR vmax (KBr) /cm-1 1673, 1720 (2 x
C=O), 2970 (OH), 3345 (NH); δH (400 MHz, CDCl3) 1.01 (s, 9H), 1.44 (s, 9H), 4.12 (d, J 8.1 Hz, 1H), 5.11 (d, J 8.1
Hz, 1H), 9.82 (br s, 1H); δC (101 MHz, CDCl3) 26.7, 28.4, 34.6, 61.8, 80.2, 155.8, 176.7.
(R)-tert-Butyl 3,3-dimethyl-1-(methylamino)-1-oxobutan-2-ylcarbamate.18 To a solution of (R)-2-(tert-
butoxycarbonylamino)-3,3-dimethylbutanoic acid (2.00 g, 8.64 mmol) and HOBt (1.52 g, 11.2 mmol) in DCM
(24 mL) at 0 °C was added EDC.HCl (2.15 g, 11.2 mmol), methylamine.HCl (0.70 g, 10.4 mmol) and Et3N (3 mL,
21.6 mmol). The reaction mixture was stirred at 0 °C for 30 minutes, then warmed to room temperature and
stirred overnight. The reaction was quenched with sat. NH4Cl, extracted with DCM (3 x 50 mL) and the organic
extracts washed with sat. NaCl, filtered over MgSO4 and purified by flash chromatography to afford (R)-tert-
butyl 3,3-dimethyl-1-(methylamino)-1-oxobutan-2-ylcarbamate (1.90 g, 90%) as a white solid Mp 127 – 129 °C
(Lit. Mp 129 °C);18 [훼]퐷20 = + 16.0°, (EtOAc, c = 1) (Lit. [훼]2퐷4 = + 13.4°, (EtOAc, c = 1);18 IR vmax (KBr) /cm-1 1679,
1709 (2 x C=O), 3099, 3322 (2 x NH); δH (400 MHz, CDCl3) 0.98 (s, 9H) 1.42 (s, 9H), 2.78 (d, J 4.8 Hz, 3H), 3.85 (d,
J 9.4 Hz, 1H), 5.31 (br s, 1H), 6.21 (s, 1H); δC (101 MHz, CDCl3) 26.0, 26.7, 28.5, 34.6, 62.4, 79.7, 156.1, 171.7.
(S)-2-Amino-N,3,3-trimethylbutanamide (10).18 Trifluoroacetic acid (1.40 mL, 18.3 mmol) was added to a
solution of (R)-tert-butyl 3,3-dimethyl-1-(methylamino)-1-oxobutan-2-ylcarbamate (0.20 g, 0.82 mmol) in DCM
(7 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 3 hr; cold 1M NaOH (8
mL) was added and the pH was adjusted to pH10 and the organic material extracted into DCM (3 x 30 mL). The
combined organic layers were filtered over MgSO4 and reduced to produce 10 (0.101 g, 86%) as a yellow solid
(recrystallised from DCM and hexane). Mp 121 – 123 °C (Lit. Mp 123 °C);18 [훼]퐷20 = 52.1°, (H2O, c = 0.5) (Lit.
[훼]2퐷0 = 52.0°, (H2O, c = 0.5)18; IR vmax (KBr) /cm-1 1677 (C=O); δH (400 MHz, CDCl3) 0.97 (s, 9H), 1.73 (br s, 2H),
2.77 (d, J 4.9 Hz, 3H), 3.04 (s, 1H), 6.77 (br s, 1H); δC (101 MHz, CDCl3) 25.8, 26.8, 34.2, 64.5, 174.3.
(R)-2-((R)-1-(N-(Benzyloxy)formamido)ethyl)-N-((R)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-
phenylpentanamide (11). To a solution of 9 (180 mg, 0.51 mmol) in DCM (0.3 M) at 0 °C was added HOBt (90.0
mg, 0.66 mmol), DCC (140 mg, 0.66 mmol), 10 (110 mg, 0.77 mmol) and DMAP (30.0 mg, 0.26 mmol). The
reaction was allowed to warm to room temperature and stirred for a further 12 hr, filtered through Celite and
the solvent evaporated in vacuo, and subjected directly to column chromatography to afford 11 (160 mg, 65%)
as a colourless solid (recrystallised from methanol and water). Mp 177 – 179 oC; Rf (DCM/MeOH 9.8:0.2) 0.64;
[훼]2퐷0 = - 1.3°, (CH3OH, c = 0.2); IR vmax (ATR) /cm-1 1674, 1685, 1697 (3 x C=O); δH (300 MHz, CD3OD) 0.92 (s,
9H), 1.36 (d, J 6.8 Hz, 3H), 1.48 – 1.64 (m, 4H), 2.48 – 2.65 (m, 5H), 2.73 – 2.85 (m, 1H), 3.90 – 4.03 (m, 1H),
4.17 (s, 1H), 4.88 (d, J 9.2 Hz, 1H), 5.23 (d, J 9.2 Hz, 1H), 7.12 – 7.53 (m, 10H), 7.93 (br s, 1H); δC (101 MHz,
CD3OD) 17.3, 26.1, 27.5, 30.1, 31.3, 35.2, 36.9, 43.1, 51.3, 62.5, 79.3, 127.0, 129.5, 129.6, 129.7, 130.0, 130.7,
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