Z.S. Al-Taie, J.M. Anderson, L. Bischoff et al.
Tetrahedron xxx (xxxx) xxx
(CDCl3) (mixture of rotamers) 178.5, 161.2/158.9/156.5/156.0/155.6/
153.8 (3 ꢂ C), 137.5/136.5/136.2/136.0/134.5 (2 ꢂ C), 129.6/129.3/
128.8/128.7/128.7/128.6/128.4/128.3/128.2/128.2/127.1/127.1
(10 ꢂ CH) 127.1/127.0/126.5, 81.4/80.4/79.4, 68.5/67.8/67.3, 58.6/
56.9/56.2, 38.5/38.0/37.6, 28.4/28.3; nmax 3395, 3350, 3271, 3059,
3033, 2985, 2956, 1708, 1684, 1620, 1543, 1511, 1439, 1378, 1316,
1294, 1252, 1201 cm-1; MS (ESI) m/z 441.2 (100, [MþH]þ); HRMS
(ESI) found 441.2134, C23H29N4Oþ5 ([MþH]þ), requires 441.2132.
(ESI) found 402.2348, C17H32N5Oþ6 ([MþH]þ) requires 402.2347.
Dibenzyl
oxopropane-1,2-diyl))dicarbamate 8b.
Method B: N-Cbz- -alanine 11b (0.93 g, 4.16 mmol, 2.2 equiv.);
((2S,2′S)-((iminomethylene)bis(azanediyl))bis(1-
L
DMF (5 mL); CDI (0.92 g, 5.7 mmol, 3.0 equiv.); 2 h; guanidine
hydrochloride (0.18 g, 1.88 mmol, 1.0 equiv.); DMF (5 mL); NaH
(60%, 0.07 g, 1.75 mmol, 0.93 equiv.); 24 h; 2 d; column chroma-
tography (90e100% Et2O in hexane) gave 8b (0.71 g, 1.51 mmol) in
80% yield as a white solid. Rf 0.33 (Et2O); ½a D
ꢃ
27 -22.7 (CHCl3, c ¼ 1.0);
Benzyl (S)-(1-(3-(tert-butyloxycarbonyl)guanidino)-1-oxo-3-
phenylpropan-2-yl)carbamate 7g.
Mp 90e93 ꢀC; dH (CDCl3) (mixture of rotamers), 7.83 (1H, br s,
3 ꢂ NH), 7.27e7.39 (10H, m, 2 ꢂ Ph), 5.57e5.72 (2H, br m, 2 ꢂ NH),
5.13 (2H, d, J 12.3 Hz, 2 ꢂ CH), 5.08 (2H, d, J 12.3 Hz, 2 ꢂ CH),
4.29e4.41/4.14e4.29 (2H, m/m, 2 ꢂ CH), 1.42/1.40 (6H, 2 ꢂ d, J
7.0 Hz, 2 ꢂ Me); dC (CDCl3) 176.0, 158.6, 156.0, 136.2, 128.7, 128.4,
128.3, 67.3, 52.8,18.6; nmax 3338, 3031, 2977, 1693, 1643, 1605, 1508,
1213 cm-1; MS (ESI) m/z 470.2 (100, [MþH]þ), HRMS (ESI) found
470.2040, C23H28N5O6þ ([MþH]þ) requires 470.2034.
Method A: N-Cbz- -phenylalanine 11d (1.00 g, 3.34 mmol, 1.0
L
equiv.); DMF (15 mL); CDI (0.60 g, 3.74 mmol, 1.12 equiv.); 30 min;
N-Boc-guanidine 10b (0.59 g, 4.14 mmol, 1.24 equiv.); DMF (15 mL);
3 d, rt. Extraction with EtOAc; washed HCl (0.1 M, 50 mL), NaHCO3
(aq. sat. 50 mL) and brine (2 ꢂ 50 mL); column chromatography
(50% Et2O in hexane) gave 7g (1.23 g, 2.79 mmol) in 84% yield as a
white solid. Rf 0.23 (50% Et2O in hexane); ½a D21
ꢃ
-32.2 (CHCl3,
c ¼ 1.54); Mp 123e125 ꢀC; dH (CDCl3) (mixture of rotamers) 8.75
(3H, br s, 3 ꢂ NH), 7.02e7.40 (10H, m, 2 ꢂ Ph), 5.60e5.71/5.58 (1H,
m/d, J 6.6 Hz, NH), 4.96e5.10 (2H, m, CH2), 4.57e4.65/4.37e4.51
(1H, 2 ꢂ m, CH), 2.92e3.22/3.12/3.26 (2H, m/dd/dd, J 13.6, 5.0/13.6,
5.2 Hz, 2 x CH) 1.47 (9H, s, 3 ꢂ Me); dC (CDCl3) (mixture of rotamers)
182.6, 159.0, 155.7, 154.3, 136.7, 136.5. 129.6/128.5/128.4/128.2/
126.8 (10 x CH), 83.7, 66.8/67.0, 58.1/59.0, 38.4/39.5, 28.0; nmax
3378, 3031, 2977, 1721, 1641, 1542, 1497, 1145, 1081 cm-1; MS (ESI)
m/z 441.2 (100%, [MþH]þ); HRMS (ESI) found 441.2136, C23H29N4O5þ
([MþH]þ), requires 441.2133.
Di-tert-butyl
bis(1-oxo-3-phenylpropane-1,2-diyl))dicarbamate 8c.
Method B: N-Boc- -phenylalanine 11c (1.10 g, 4.15 mmol, 2.2
((2S,2′S)-((iminomethylene)bis(azanediyl))
L
equiv); DMF (5 mL); CDI (0.92 g, 5.66 mmol, 3.0 equiv); 2 h; gua-
nidine hydrochloride (0.19 g, 1.99 mmol, 1.0 equiv); DMF (5 mL);
NaH (60%, 0.07 g, 1.75 mmol, 0.9 equiv.); 2 d; column chromatog-
raphy (35% Et2O in hexane) gave 8c (0.78 g, 1.40 mmol) in 80% yield
as a white solid. Rf 0.48 (70% Et2O in hexane); ½a D27
ꢃ
-21.4 (CHCl3,
c ¼ 1.0); Mp 83e86 ꢀC; dH (mixture of rotamers) 9.71 (3H, br s,
3 ꢂ NH), 7.09e7.33 (10H, m, 2 ꢂ Ph), 5.46e5.74/5.23e5.46 (2H,
2 ꢂ m, 2 ꢂ NH), 4.40e4.62/4.19e4.40 (2H, 2 ꢂ m, 2 ꢂ CH),
2.95e3.24 (4H, m, 2 ꢂ CH2), 1.38 (18H, s, 6 ꢂ Me); dC (mixture of
rotamers) 178.6, 158.3, 155.6, 136.4, 129.4, 128.6, 127.0, 80.6/80.3,
59.3/57.4, 38.7/38.1, 28.4; nmax 3368, 3008, 2977, 2932, 1689, 1645,
1604, 1496 cm-1; MS (ESI) m/z 554.3 (100, [MþH]þ), HRMS (ESI)
found 554.2982, C29H40N5Oþ6 ([MþH]þ) requires 554.2973.
Benzyl
phenylpropan-2-yl)carbamate 7h.
Method A: N-Cbz- -phenylalanine 11d (1.00 g, 3.34 mmol, 1.0
(S)-(1-(3-(benzyloxycarbonyl)guanidino)-1-oxo-3-
L
equiv.); DMF (15 mL), 0 ꢀC; CDI (0.70 g, 4.98 mmol, 1.49 equiv.);
30 min; N-Cbz-guanidine 10a (0.70 g, 3.67 mmol, 1.10 equiv.); DMF
(15 mL); 3 d, rt; 2 d, 40 ꢀC. Extraction with EtOAc (3 ꢂ 50 mL);
washed with HCl (0.1 M, 50 mL), NaHCO3 (aq. sat. 50 mL) and brine
(2 ꢂ 50 mL); column chromatography (45% Et2O in hexane) gave 7h
(0.30 g, 0.63 mmol) in 19% as a white solid. Rf 0.35 (70% Et2O in
Dibenzyl
oxo-3-phenylpropane-1,2-diyl))dicarbamate 8d.
Method B: N-Cbz- -phenylalanine 11d (1.24 g, 4.15 mmol, 2.2
((2S,2′S)-((iminomethylene)bis(azanediyl))bis(1-
hexane); ½a 2D5
ꢃ
-19.6ꢀ (CHCl3, c ¼ 1.0); Mp 83e86 ꢀC; dH (CDCl3)
L
(mixture of rotamers) 8.80 (3H, br s, 3 ꢂ NH), 6.85e7.31 (15H, m,
3 ꢂ Ph), 7.33e7.50/5.48e5.59 (1H, br s/m, NH), 5.01 (2H, s, CH2),
4.74e5.07 (2H, m, 2 ꢂ CH), 4.62e4.74/4.16e4.32 (1H, 2 ꢂ m, CH),
2.62e3.11 (2H, m, CH2); dC (CDCl3) (mixture of rotamers) 177.9,
160.2, 158.9/158.7, 156.7/155.9, 136.6, 136.2/136.0, 135.8/135.6,
129.3,128.6,128.6,128.5, 128.3,128.2,128.2,128.1, 127.9, 127.1, 127.0
(15 ꢂ CH), 67.4, 67.1, 58.4/57.3, 38.1/38.0/37.7; nmax 3390, 3338,
3278, 3063, 3031, 2962, 1687, 1664, 1630, 1523, 1497, 1268, 1111,
1087 cm-1; MS (ESI) m/z 475.2 (100, [MþH]þ); HRMS (ESI) , found
475.1977, C26H27N4O5þ [MþH]þ), requires 475.1976.
equiv); DMF (5 mL); CDI (0.92 g, 5.70 mmol, 3.0 equiv); 0 ꢀC,
90 min; guanidine hydrochloride (0.18 g, 1.88 mmol, 1.0 equiv);
DMF (5 mL); NaH (60%, 73.0 mg, 1.83 mmol, 0.97 equiv.), ; 4 d;
column chromatography (50% Et2O in hexane) gave 8d (0.55 g,
0.89 mmol) in 49% yield as a white solid. Rf 0.26 (70% Et2O in
hexane); ½a 2D8
ꢃ
-12.8 (CHCl3, c ¼ 1.0); Mp 150e152 ꢀC; dH (CDCl3)
(mixture of rotamers) 9.07 (3H, br s, 3 ꢂ NH), 6.76e7.38 (20H, m,
4 ꢂ Ph), 5.52e5.87 (2H, m, 2 ꢂ NH), 4.91e5.14 (4H, m, 2 ꢂ CH2),
4.52e4.91/4.29e4.50 (2H, 2 ꢂ m, 2 ꢂ CH), 2.75e3.20 (4H, m,
2 ꢂ CH2); dC (mixture of rotamers) 178.4, 158.4/158.3, 156.2/156.1,
136.2, 136.0, 129.5, 129.4, 128.7, 128.6, 128.6, 128.3128.2, 127.1, 67.3/
66.8, 59.0/57.8, 39.3/38.1; nmax 3351, 3063, 3030, 2952, 1689, 1644,
1604, 1496, 1212 cm-1; MS (ESI) m/z 622.3 (100, [MþH]þ), HRMS
(ESI) found 622.2660, C35H36N5Oþ6 ([MþH]þ) requires 622.2667.
Di-tert-butyl
bis(1-oxopropane-1,2-diyl))dicarbamate 8a.
Method B: N-Boc- -alanine 11a (1.78 g, 9.4 mmol, 2.2 equiv);
((2S,2′S)-((iminomethylene)bis(azanediyl))
L
DMF (5 mL); CDI (2.04 g, 12.7 mmol, 3.0 equiv); 0 ꢀC, 90 min;
guanidine hydrochloride (0.41 g, 4.3 mmol, 1.0 equiv); DMF (5 mL);
NaH (60%, 0.16 g, 4.0 mmol, 0.93 equiv.), 24 h; 5 d; freeze dried then
column chromatography (60% Et2O in hexane) gave 8a (1.05 g,
2.6 mmol) in 65% yield as a white solid. Rf 0.30 (75% Et2Oin hex-
Catalysed reactions of 2-hydroxy-1,4-napthoquinone 2 with
b-nitrostyrene 3.
2-Hydroxy-1,4-napthoquinone 2 (100 mg, 0.574 mmol) and the
required catalyst (0.04e0.1 equiv.) were dissolved in the requisite
ane); ½a 2D1
ꢃ
-30 (CHCl3, c ¼ 1.0); Mp 76e78 ꢀC; dH (CDCl3) (mixture of
solvent and cooled to the required temperature (ꢁ20 to 0 ꢀC).
b-
rotamers) 9.18 (3H, br s, 3 ꢂ NH), 5.40e5.56/5.30e5.40 (2H, 2 ꢂ m,
2 ꢂ NH), 4.19e4.36/3.96e4.19 (2H, 2 ꢂ m, 2 ꢂ CH), 1.43 (18H, s,
6 ꢂ Me), 1.38 (6H, d, J 6.8 Hz, 2 ꢂ Me); dC (CDCl3) 180.1, 158.7, 155.6,
80.3, 52.3, 28.4, 18.6; nmax 3245, 3219, 3001, 2977, 2932, 1690, 1644,
1603, 1509, 1247; cm-1; MS (ESI) m/z 402.2 (100, [MþH]þ); HRMS
Nitrostyrene 3 (128.5 mg, 0.861 mmol, 1.5 equiv) was then added
and the mixture stirred for the required time and temperature.
Reaction progress was determined by sampling and determination
by 1H NMR. On completion the solvent was evaporated to give a
deep red residue which was purified by column chromatography
7