Professional Documents
Culture Documents
Green Synthesis of r,β-and β,β-Dipeptides under Solvent-Free Conditions
Green Synthesis of r,β-and β,β-Dipeptides under Solvent-Free Conditions
org/joc
ejuarist@cinvestav.mx
Received June 19, 2010
DOI: 10.1021/jo101159a Published on Web 09/27/2010 J. Org. Chem. 2010, 75, 7107–7111 7107
r 2010 American Chemical Society
JOC Article Hern
andez and Juaristi
N-Boc-L-Carnosine-OMe, a protected derivative of natural Boc-β-Ala-L-Val-OMe (3b). (25 mg, 82%) as a gummy solid.
R,β-dipeptide L-carnosine, was prepared in high yield. [R]25D = þ12.0 (c 1.6, CHCl3). (FT-IR/ATR cm-1) νmax 3321,
Research toward the synthesis of other unnatural dipep- 2968, 2933, 1736, 1693, 1655. 1H NMR (500 MHz, CDCl3) δ
tides and evaluation of its potential organocatalytic activity 6.15 (1H, br, Val-NH), 5.18 (1H, br-s, β-Ala-NH), 4.53 (1H, m,
is already in progress in our laboratory. (CHCO2)), 3.73 (3H, s, OCH3), 3.40 (2H, m, CH2NBoc), 2.45
(2H, m, CH2CdO), 2.15 (1H, m, (CH)), 1.41 (9H, s, t-Bu), 0.92
(3H, d, CH3, J = 6.8 Hz), 0.89 (3H, d, CH3, J = 6.8 Hz) ppm.
Experimental Section 13
C NMR (125 MHz, CDCl3) δ 176.6, 171.8, 156.2, 79.3, 57.2,
52.2, 36.8, 36.2, 31.1, 28.4, 19.0, 17.9 ppm. HR-ESI-TOF
General Procedure for the Synthesis of the UNCAs Derived Calculated for C14H27N2O5 [M þ H]þ: 303.1914. Found:
from β-Amino Acids. To a cooled (-20 °C) solution of DMF 303.1921 (2.1 ppm error).
(1.18 mL, 15.3 mmol) in freshly distilled acetonitrile (7.5 mL) Boc-β-Ala-L-Leu-OMe (3c). (28 mg, 88%) as a white solid.
was added dropwise oxalyl chloride (1.34 mL, 15.3 mmol). After mp = 50-52 °C. [R]25D = þ5.5 (c 0.1, CHCl3). (FT-IR/ATR
30 min of stirring at -20 °C, a cooled solution (-20 °C) of N- cm-1) νmax 3347, 2960, 2932, 1752, 1691, 1648. 1H NMR (500
Bis-Boc-β-alanine (740 mg, 2.56 mmol) and pyridine (207 μL, MHz, CDCl3) δ 6.35 (1H, br, Leu-NH), 5.24 (1H, br-s, β-Ala-
2.56 mmol) in acetonitrile (4.5 mL) was added dropwise. The NH), 4.56 (1H, m, (CHCO2)), 3.68 (3H, s, OCH3), 3.36 (2H, m,
solution was stirred at -20 °C for 2 h and after that allowed to CH2NBoc), 2.41 (2H, m, CH2CdO), 1.65-1.55 (2H, m, CH2i-
warm to room temperature (over 1 h) and stirred for a further Bu), 1.54-1.44 (1H, m, CHi-Bu), 1.38 (9H, s, t-Bu), 0.89 (6H, d,
4 h. The reaction was quenched by pouring onto ice and the CH3i-Bu, J = 6.0 Hz) ppm. 13C NMR (125 MHz, CDCl3) δ
product extracted into AcOEt (3 30 mL). The combined 173.5, 171.5, 156.1, 77.4, 52.3, 50.7, 41.3, 36.7, 36.1, 28.4, 24.9,
organics were washed with NaHCO3 solution (pH 8) and brine 22.8, 21.9 ppm. HR-ESI-TOF Calculated for C15H29N2O5 [M þ
(50 mL). The organic phases were dried (MgSO4) and evapo- H]þ: 317.2070. Found: 317.2075 (1.2 ppm error).
rated under vacuum to give a yellowish oil; recrystallization Boc-β-Ala-L-Phe-OMe (3d). (29 mg, 83%) as a white solid.
from ethyl acetate gave the respective UNCA 1a-c. mp = 89-91 °C. [R]25D = þ52.0 (c 1.0, CHCl3). (FT-IR/ATR
3-tert-Butyloxycarbonyl-4,5-dihydro-1,3-oxazine-2,6-dione cm-1) νmax 3320, 2976, 2931, 1735, 1691, 1654. 1H NMR (500
(N-Boc-β-alanine-N-carboxyanhydride), 1a. 320 mg (58%) of MHz, CDCl3) δ 7.31-7.20 (3H, m, H-Ar), 7.11-7.08 (2H, d,
white crystals, mp = 122-124 °C. (FT-IR/ATR cm-1) νmax Horto-Ar, J = 7.0 Hz), 6.04 (1H, br, Phe-NH), 5.10 (1H, br-s, β-
2985, 2939, 1824, 1790, 1739. 1H NMR (500 MHz, CDCl3) δ Ala-NH), 4.88 (1H, m, CH), 3.74 (3H, s, OCH3), 3.36 (2H, m,
3.90 (2H, t, CH2N, J = 6.6 Hz), 2.87 (2H, m, CH2CO), 1.54 (9H, CH2NBoc), 3.16, (1H, dd, CH2Ph, J = 6.3, 13.8 Hz), 3.07 (1H, dd,
s, t-Bu) ppm. 13C NMR (125 MHz, CDCl3) δ 163.7, 150.5, 144.5, CH2Ph, J = 5.7, 13.8 Hz), 2.38 (2H, t, CH2CdO, J = 5.5 Hz), 1.44
85.7, 39.2, 29.5, 27.7 ppm. (9H, s, t-Bu) ppm. 13C NMR (125 MHz, CDCl3) δ 172.0, 171.2,
(S )-3-tert-Butyloxycarbonyl-4-phenyl-4,5-dihydro-1,3-ox- 156.1, 135.8, 129.3, 128.7, 127.3, 79.4, 53.2, 52.5, 38.0, 36.6, 36.2,
azine-2,6-dione ((S )-N-Boc-β3-hPhg-N- carboxyanhydride) 1b. 28.5 ppm. HR-ESI-TOF Calculated for C18H27N2O5 [M þ H]þ:
208 mg (60%) of white crystals. 1H NMR (500 MHz, CDCl3) δ 351.1914. Found: 351.1923 (2.4 ppm error).
7.41-7.33 (3H, m, ArH), 7.22-7.20 (2H, m, ArH), 5.62 (1H, m, Boc-β-Ala-L-Ile-OMe (3e). (25.2 mg, 80%) as a gummy solid.
CH-Ph), 3.23 (1H, dd, J = 16.4, J = 6.4 Hz, CH2), 3.13 (1H, [R]25D = þ5.0 (c 0.7, CHCl3). (FT-IR/ATR cm-1) νmax 3345,
dd, J = 16.4, J = 6.4 Hz, CH2), 1.48 (9H, s, t-Bu) ppm. 13C 2958, 1755, 1689, 1651. 1H NMR (500 MHz, CDCl3) δ 6.05 (1H,
NMR (125 MHz, CDCl3) δ 162.7, 150.3, 144.8, 137.1, 129.6, br, Ile-NH), 5.17 (1H, br-s, β-Ala-NH), 4.58 (1H, m, NCH), 3.74
129.1, 125.2, 86.0, 53.6, 36.8, 27.9 ppm. (3H, s, OCH3), 3.42-3.39 (2H, m, CH2NBoc), 2.47-2.44, (2H,
(S )-3-tert-Butyloxycarbonyl-4-carboxymethyl-4,5-dihydro-1,3- m, CH2CdO), 1.90-1.80 (1H, m, CH), 1.47-1.37 (1H, m,
oxazine-2,6-dione ((S )-N-Boc-β3-chg-(CO2CH3)-N-carboxyanhy- CH2CH3), 1.22-1.12, (1H, m, CH2CH3), 1.43 (9H, s, t-Bu),
dride), 1c. 250 mg (62%) as a gummy solid. 1H NMR (500 MHz, 0.86-0.96 (6H, m, 2CH3) ppm. 13C NMR (125 MHz, CDCl3)
CDCl3) δ 4.55 (1H, dd, J = 8.0, J = 2.6 Hz, CH-CO2CH3), δ 172.5, 171.5, 156.2, 79.4, 56.5, 52.3, 38.0, 36.8, 36.4, 28.5, 25.4,
3.66 (3H, s, -OCH3), 3.20 (1H, dd, J = 19.4, J = 8.0 Hz, CH2), 15.6, 11.7 ppm. HR-ESI-TOF Calculated for C15H29N2O5 [M þ
2.92 (1H, dd, J = 19.4, J = 2.6 Hz, CH2), 1.53 (9H, s, t-Bu) ppm. H]þ: 317.2070. Found: 317.2076 (1.6 ppm error).
13
C NMR (125 MHz, CDCl3) δ 169.2, 148.1, 147.1, 118.3, 85.9, Boc-β-Ala-Gly-OMe (3f). (23 mg, 88%) as a liquid. (FT-IR/
58.5, 53.0, 35.8, 28.0 ppm. (FT-IR/ATR cm-1) νmax 2982, 1833, ATR cm-1) νmax 3316, 2957, 1743, 1688, 1656. 1H NMR (500
1805, 1738. HR-ESI-TOF: Calculated for C9H10N7O5Na MHz, CDCl3) δ 6.49 (1H, br, gly-NH), 5.25 (1H, br-s, β-Ala-
[MþNa]þ: 296.0737. Found: 296.0741 (1.0 ppm error). NH), 4.01 (2H, d, CH2CO2, J = 5.37 Hz), 3.73 (3H, s, OCH3),
General Procedure for the Coupling of UNCAs 1 with Ami- 3.38 (2H, q, CH2NBoc, J = 6.0 Hz), 2.45 (2H, t, CH2CdO, J =
noester Hydrochloride 2. A mixture of UNCA 1 (0.1 mmol), 5.8 Hz), 1.39 (9H, s, t-Bu) ppm. 13C NMR (125 MHz, CDCl3) δ
aminoester hydrochloride 2 (0.1 mmol), and NaHCO3 (0.15 mmol) 172.0, 170.5, 156.2, 79.4, 52.5, 41.2, 36.6, 36.1, 28.5 ppm. HR-
was vigorously milled for 2 h at 3800 rpm in a digital Mixer/ ESI-TOF Calculated for C11H21N2O5 [M þ H]þ: 261.1444.
Amalgamator used with a reactor made of Nylamid (cylinder, 25 Found: 261.1447 (0.7 ppm error).
mm long and with a diameter 10 mm) containing one stainless steel Boc-β-Ala-β-Ala-OMe (3g). (28.5 mg, 96%) as a white solid.
ball with a 5 mm diameter. The solid residue (or the melted mixture) mp = 77-78 °C. (FT-IR/ATR cm-1) νmax 3357, 3288, 2972,
was dissolved in AcOEt and washed with brine. The organic phase 1732, 1683, 1643. 1H NMR (500 MHz, CDCl3) δ 6.19 (1H, br, β-
was dried over MgSO4 and concentrated to yield the dipeptide. Ala-NH), 5.16 (1H, br-s, β-Ala-BocNH), 3.69 (3H, s, OCH3),
Boc-β-Ala-L-Ala-OMe (3a). (24 mg, 88%) as a white solid. mp 3.51 (2H, q, CH2NBoc, J = 6.1 Hz), 3.38 (2H, q, CH2CdO, J =
= 78-80 °C. [R]25D = þ55.0 (c 0.1, CHCl3). (FT-IR/ATR 6.1 Hz), 2.53 (2H, t, CH2NHCO, J = 6.1 Hz), 2.36 (2H, t,
cm-1) νmax 3356, 3321, 2983, 1745, 1682, 1648. 1H NMR (500 CH2CO2, J = 5.9 Hz), 1.41 (9H, s, t-Bu) ppm. 13C NMR (125
MHz, CDCl3) δ 6.30 (1H, br, Ala-NH), 5.19 (1H, br-s, β-Ala- MHz, CDCl3) δ 173.0, 171.6, 156.2, 79.3, 51.9, 36.7, 36.2, 34.9,
NH), 4.55 (1H, q, CH, J = 7.2 Hz), 3.73 (3H, s, OCH3), 3.38 33.9, 28.4 ppm. HR-ESI-TOF Calculated for C12H23N2O5 [M þ
(2H, m, CH2NBoc), 2.41 (2H, t, CH2CdO, J = 5.8 Hz), 1.40 H]þ: 275.1601. Found: 275.1609 (2.7 ppm error).
(9H, s, t-Bu), 1.38 (3H, d, CH3, J = 7.1 Hz) ppm. 13C NMR (125 Boc-β-Ala-(S )-β3-hPhg-OMe (3h). (32 mg, 91%) as a white
MHz, CDCl3) δ 173.5, 171.2, 156.1, 79.3, 52.9, 48.1, 36.6, 36.1, solid. mp = 82-84 °C. [R]25D = -47.0 (c 1.5, CHCl3). (FT-IR/
28.4, 18.3 ppm. HR-ESI-TOF Calculated for C12H23N2O5 [M þ ATR cm-1) νmax 3369, 3336, 2976, 2927, 1736, 1678, 1645. 1H NMR
H]þ: 275.1601. Found: 275.1609 (2.7 ppm error). (500 MHz, CDCl3) δ 7.33-7.24 (5H, m, H-Ar), 6.80 (1H, br,