1840
G. Giorgioni et al. / Bioorg. Med. Chem. 18 (2010) 1834–1843
5.1.2. (S)-2-(tert-Butoxycarbonylamino)-3-(3,4-dihydroxy
phenyl)-propionic acid (7)
3H, ArH, NH), 5.05 (s, 4H, CH2), 4.08 (m, 1H, CH), 3.95 (m, 2H,
CH2), 3.62 (s, 3H, CH3), 3.0–2.92 (m, 1H, CH2), 2.86–2.58 (m, 1H,
CH2), 1.30 (s, 9H, 3CH3) Anal. (C31H36N2O7) C, H, N. ESIMS: m/z
(MꢀH)ꢀ 547.
To an ice cooled solution of L-DOPA (1 g, 5 mmol) and NEt3
(1.08 mL, 7.5 mmol) in dioxane/water (50%, 20 mL), di-tert-butyl-
dicarbonate (1.2 g, 5.5 mmol) was added portionwise. The result-
ing mixture was stirred for 30 min at 0 °C, then at rt for 18 h.
The solution was concentrated under reduced pressure, then water
(10 mL) and ethyl acetate (10 mL) were added. The aqueous layer
was washed with ethyl acetate, acidified to pH 1 with 1 N HCl,
and back-extracted with ethyl acetate. The organic extracts were
washed with brine, dried over Na2SO4, and evaporated to give
5.1.6. (S)-Methyl 2-(4-(3,4-bis(benzyloxy)benzyl)-2,2-dimethyl-
5-oxoimidazolidin-1-yl)acetate (12a)
A solution of 10 in 10 mL of 3 M hydrogen chloride in methanol
(10 mL) was stirred at room temperature for 30 min. The solvent
was removed under reduced pressure and the residue (11) was dis-
solved in methanol (10 mL). The pH of the solution was adjusted to
8.2 with 2 N NaOH solution in methanol. Acetone (2 mL) was
added, and the mixture stirred at room temperature for 21 h. The
solvent was removed under reduced pressure and the residue puri-
fied by chromatography on silica gel using ethyl acetate as eluant
to afford a colorless oily product. Yield 65%. 1H NMR (DMSO-d6)
d: 7.52–7.25 (m, 10H, ArH), 7.05 (d, 1H, ArH), 6.95 (d, 1H, ArH),
6.76 (dd, 1H, ArH), 5.10 (s, 4H, 2CH2), 3.98 (s, 2H, CH2), 3.65 (s,
3H, CH3), 3.60–3.50 (m, 1H, CH), 3.02–2.95 (m, 1H, CH2), 2.80–
2.55 (m, 2H, CH2, NH), 1.20 (2s, 6H, 3CH3). Anal. (C29H32N2O5) C,
H, N. ESIMS: m/z (MH+) 489.
the protected amino acid, N-Boc-L-DOPA, as a brown oil which
was used in the next step without further purification.
5.1.2.1. Data for (S) enantiomer. Yield 95%. ½a D20
¼ þ12:75 (c 1,
ꢃ
MeOH). 1H NMR (CDCl3): d 7.80 (br s, 1H, COOH); 6.90–6.60 (m,
2H, ArH); 6.50 (d, 1H, ArH); 5.20 (d, 1H, NH); 4.60–4.25 (m, 1H,
CH); 2.90 (s, 2H, CH2); 1.35 (s, 9H. 3CH3) Anal. (C14H19NO6): C, H, N.
5.1.2.2. Data for racemate. Yield 88.5%. 1H NMR (DMSO-d6): d
12.50 (br s, 1H, COOH); 8.70 (br s, 2H, 2OH); 7.00 (d, 1H, ArH);
6.60–6.35 (m, 3H, 2ArH and NH); 4.00–4.85 (m, 1H, CH-N); 2.80–
2.40 (m, 2H, CH2); 1.35 (s, 9H. CH3).
5.1.7. (S)-Methyl 2-(4-(3,4-dihydroxybenzyl)-2,2-dimethyl-5-
oxoimidazolidin-1-yl)acetate (6a)
5.1.3. (S)-Benzy-3-(3,4-bis-benzyloxyphenyl)-2-(tert-butoxy
carbonylamino) propanoate (8)
A mixture of 12a (1.38 g, 2.8 mmol), and 10% palladium on
charcoal (0.140 g), in 25 mL of absolute ethanol (25 mL), under
hydrogen atmosphere (20 psi) was stirred at room temperature
for 5 h. The mixture was filtered and the solvent was evaporated
in vacuo to give a residue purified by column chromatography over
silica gel using ethyl acetate as eluant. The residue was recrystal-
lized from ethanol. Yield 75%. Mp 170–172 °C. 1H NMR (DMSO-
d6): d 8.75–8.65 (2s, 2H, OH), 6.60 (m, 2H, ArH), 6.45 (dd, 1H,
ArH), 3.96 (s, 2H, CH2), 3.72 (s, 3H, CH3), 3.58–3.45 (m, 1H, CH),
2.95–2.86 (m, 1H, CH2), 2.60–2.42 (m, 1H, CH2), 120 (2s, 6H,
2CH3). Anal. (C15H20N2O5) C, H, N. ESIMS: m/z (MH+) 309.
A mixture of S-(7) (2.25 g, 7.6 mmol), K2CO3 (1.66 g, 12 mmol),
and benzyl chloride (4.06 g, 23.7 mmol) in acetone (30 mL) was re-
fluxed for 5 h. The solvent was evaporated under reduced pressure
and the residue was diluted with water and then extracted with
ethyl acetate. The organic extracts were washed with brine, dried
over Na2SO4 and evaporated. The residue was recrystallized from
ethyl acetate/hexane to give the product. Yield 97%. Mp 114–
116 °C. ½a 2D0
ꢃ
¼ þ3:2 (c 1, CHCl3). 1H NMR (CDCl3): d 7.45–7.22 (m,
10H, ArH), 6.78 (d, 1H, ArH), 6.70 (d, 1H, ArH), 6.55 (d, 1H, ArH),
5.05 (s, 2H, CH2), 5.02 (s, 2H, CH2), 5.00 (s, 2H, CH2), 4.95 (d, 1H,
NH), 4.58 (m, 1H, CH), 2.98 (d, 2H, CH2), 1.40 (s, 9H, 3CH3). Anal.
(C35H37NO6,) C, H, N.
5.1.8. (S)-Methyl-2-(4-(3,4-bis(benzyloxy)benzyl)-2,2-diethyl-5-
oxoimidazolidin-1-yl)acetate (12b)
The pH of a solution of 11 hydrochloride (1 g, 2 mmol) in meth-
anol (10 mL) was adjusted to pH 8.2 with 2 N NaOH solution in
methanol. 3-Pentanone (1 mL) was added and the mixture was
stirred for 24 h at room temperature. The solvent was removed un-
der reduced pressure and the residue was purified by column chro-
matography on silica gel using a mixture of n-hexane/ethyl acetate
(80/20, v/v) as eluant. The yellow oil obtained was recrystallized
from ethanol. Yield 95%. Mp 170–172 °C. 1H NMR (DMSO-d6): d
7.55–7.25 (m, 10H, ArH), 6.98–6.86 (m, 2H, ArH), 6.76 (dd, 1H,
ArH), 5.05 (2s, 4H, 2CH2), 3.84 (s, 2H, CH2), 3.76–3.65 (m, 1H,
CH), 3.60 (s, 3H, CH3), 2.96–2.84 (m, 1H, CH2), 2.72–2.55 (m, 1H,
CH2), 2.20 (br s, 1H, NH), 1.60–1.30 (m, 4H, CH2), 1.75–1.65 (2t,
6H, 2CH3). Anal. (C31H36N2O5) C, H, N. ESIMS: m/z (MH+) 517.
5.1.4. (S)-3-3,4-Bis(benzyloxy)phenyl-2-(tert-butoxy carbon
ylamino)propanoic acid (9)
To a suspension of 8 in water/dioxane (8.25%, 55 mL), 1 N NaOH
solution (10 mL) was added dropwise. The mixture was stirred at
room temperature for 24 h. The solution was acidified to pH 1 with
2 N HCl then extracted with ethyl acetate. The organic extracts
were washed with brine, dried over Na2SO4 and evaporated. The
residue was recrystallized from CH2Cl2/n-hexane to give the prod-
uct. Yield 86%. Mp 125–126 °C. 1H NMR (DMSO-d6): d 12.60 (s, 1H,
OH), 7.45–7.22 (m, 10H, ArH), 7.10–6.90 (m, 3H, ArH, NH), 6.76 (d,
1H, ArH), 5.05 (s, 4H, 2CH2), 4.05 (m, 1H, CH), 2.98–2.65 (m, 2H,
2CH2), 1.30 (s, 9H, 3CH3). Anal. (C28H31NO6,) C, H, N.
5.1.5. (S)-Methyl-2-3-(3,4-bis(benzyloxy)phenyl)-2-(tert-butoxy
carbonylamino)propanamido acetate (10)
5.1.9. (S)-Methyl 2-(4-(3,4-dihydroxybenzyl)-2,2-diethyl-5-
oxoimidazolidin-1-yl)acetate (6b)
An ice cooled solution of glycine methyl ester hydrochloride
(0.27 g, 2.1 mmol) and 9 (1 g, 2.1 mmol) in dichloromethane
(20 mL) was treated with NEt3 (0.9 mL, 6.3 mmol), EDCI (0.48 g,
2.5 mmol) and HOBT (0.34 g, 2.5 mmol). The reaction mixture
was stirred at 0 °C for 1 h and then at 25 °C for 17 h. The organic
solution was washed with water (1 ꢂ 5 mL), 2 N HCl solution
(1 ꢂ 5 mL), saturated NaHCO3 (1 ꢂ 5 mL), and then dried on
Na2SO4. The solvent was removed under reduced pressure and
the residue recrystallized from ethyl acetate to give the product.
Yield 75%. Mp 133–135 °C. 1H NMR (DMSO-d6): d 8.38 (t, 1H,
NH), 7.45–7.25 (m, 10H, ArH), 7.05 (s, 1H, ArH), 6.98–6.75 (m,
A mixture of 12b (0.61 g, 1.2 mmol), 10% palladium on charcoal
(0.061 g) in 25 mL of absolute ethanol (11 mL) was stirred under
hydrogen atmosphere (25 psi) at room temperature for 24 h. The
mixture was filtered and the solvent evaporated under reduced
pressure to give a residue that was recrystallized from ethanol.
Yield 72%. Mp 153–155 °C.1H NMR (DMSO-d6): d 9.88–9.65 (2s,
2H, 2OH), 6.65–6.68 (m, 2H, ArH), 6.45 (dd, 1H, ArH), 4.82 (s, 2H,
CH2), 3.70–3.55 (m, 4H, CH, CH3), 2.85–2.86 (m, 1H, CH2), 2.50–
2.42 (m, 1H, CH2), 2.35 (d, 1H, NH), 1.60–1.30 (m, 4H, 2CH2),
1.78–1.40 (2t, 6H, 2CH3). Anal. (C17H24N2O5) C, H, N. ESIMS: m/z
(MH+) 337.