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F.-A. Litty et al.
Paper
Synthesis
13C NMR (75 MHz, CDCl3): δ = 176.5 (CO2H), 168.4 (2 × CO-Pht), 155.6
(CO-Boc), 134.0 (2 × ArCH), 132.0 (2 × ArC), 123.3 (2 × ArCH), 80.3
[C(CH3)3], 53.0 (α-CH), 37.4 (δ-CH2), 29.8 (β-CH2), 28.3 [C(CH3)3], 24.8
(γ-CH2).
MS (ESI): m/z = 541 [M + Na]+, 419 [M – C4H8 – CO2 + H]+, 319 [M – 2 ×
C4H8 – 2 × CO2 + H]+ 263 [M – 3 × C4H8 – 2 × CO2 + H]+.
Anal. Calcd for C27H38N2O8 (518.61): C, 62.53; H, 7.39; N, 5.40. Found:
C, 62.00; H, 7.34; N, 5.49.
MS (ESI): m/z = 725 [2 × M + H]+, 625 [2 × M – C4H8 – CO2 + H]+, 363 [M
+ H]+, 263 [M – C4H8 – CO2 + H]+.
Nα,Nα-Bis(tert-butyloxycarbonyl)-L-ornithine tert-Butyl Ester (5)
Anal. Calcd for C18H22N2O6 (362.38): C, 59.66; H, 6.12; N, 7.73. Found:
C, 59.21; H, 6.15; N, 7.58.
Compound 4 (1.88 g, 3.6 mmol) was dissolved in a mixture of CH2Cl2
and MeOH (1:1, 40 mL). Hydrazine hydrate (2.7 mL, 54 mmol, 15
equiv) was added and the reaction mixture was stirred magnetically
at r.t. After 24 h, the mixture was filtered to remove the precipitated
phthalhydrazide and quenched by adding sat. aq NaHCO3 (30 mL). The
organic phase was separated and the aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic phases were washed
with brine (30 mL), dried (Na2SO4), and concentrated under reduced
pressure. Compound 5 was at this point already pure (TLC) and used
in the following reaction without any purification; yield: 1.27 g
(90%); colorless oil; Rf = 0.37 (CH2Cl2–MeOH–aq NH3, 8.5:1.5:0.5).
1H NMR (300 MHz, CDCl3): δ = 4.72 (dd, 3J = 9.6, 5.2 Hz, 1 H, α-CH),
2.64–2.79 (m, 2 H, δ-CH2), 2.03–2.15 (m, 1 H, β-CH2), 1.80–1.94 (m, 1
H, β-CH2), 1.40–1.56 (m, 2 H, γ-CH2), 1.51 [2 s, 18 H, C(CH3)3], 1.45 [s,
9 H, C(CH3)3], 1.21 (br s, 2 H, NH2).
13C NMR (75 MHz, CDCl3): δ = 169.9 (CO2t-Bu), 152.5 (2 × CO-Boc),
82.7 [2 × C(CH3)3], 81.2 [C(CH3)3], 58.8 (α-CH), 42.0 (δ-CH2), 30.7 (β-
CH2), 28.1 [2 × C(CH3)3], 28.0 [C(CH3)3], 26.6 (γ-CH2).
Nα-(tert-Butyloxycarbonyl)-Nδ-phthalimido-L-ornithinetert-Butyl
Ester (3)19
Compound 2 (1.87 g, 5.2 mmol), benzyltriethylammonium chloride
(1.17 g, 5.2 mmol, 1 equiv), tert-butyl bromide (27 mL, 239 mmol, 46
equiv), and K2CO3 (19 g, 135 mmol, 26 equiv) were added to DMAC
(40 mL). This reaction mixture was heated for 5 h at 55 °C and cooled
to r.t. The salts were filtered and washed with EtOAc (3 × 25 mL). The
filtrate was washed with H2O (3 × 20 mL) and the combined aqueous
phases were extracted with EtOAc (1 × 25 mL). The combined organic
layers were dried (Na2SO4) and the solvent was removed under re-
duced pressure. The crude product was purified by flash column
chromatography (silica gel, cyclohexane–EtOAc, 0–20%); yield: 2.0 g
(93%); colorless oil; Rf = 0.48 (cyclohexane–EtOAc, 2:1). The spectro-
scopic data were in agreement with those reported.19
IR (ATR): 3399, 2978, 1771, 1740, 1694, 1508, 1393, 1150, 718 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.81–7.88 (m, 2 H, ArH), 7.68–7.75 (m,
2 H, ArH), 5.06 (d, 3J = 8.3 Hz, 1 H, NH), 4.14–4.27 (m, 1 H, α-CH), 3.71
(t, 3J = 6.9 Hz, 2 H, δ-CH2), 1.62–1.91 (m, 4 H, β,γ-CH2), 1.45 [s, 9 H,
C(CH3)3], 1.43 [s, 9 H, C(CH3)3].
MS (ESI): m/z = 777 [2 × M + H]+, 389 [M + H]+, 289 [M – C4H8 – CO2 +
H]+.
Anal. Calcd for C19H36N2O6 (388.51): C, 58.74; H, 9.34; N, 7.21. Found:
C, 58.49; H, 9.61; N, 6.91.
13C NMR (75 MHz, CDCl3): δ = 171.6 (CO2t-Bu), 168.3 (2 × CO-Pht),
155.3 (CO-Boc), 133.9 (2 × ArCH), 132.1 (2 × ArC), 123.3 (2 × ArCH),
79.7, 80.3 [2 × C(CH3)3], 53.6 (α-CH), 37.6 (δ-CH2), 30.3 (β-CH2), 28.3
[C(CH3)3], 28.0 [C(CH3)3], 24.5 (γ-CH2).
Nα,Nα-Bis(tert-butyloxycarbonyl)-Nδ-(2-nitrophenylsulfonyl)-L-or-
nithine tert-Butyl Ester (6)
Compound 5 (1.27 g, 3.3 mmol) and 2-nitrosulfonyl chloride (0.95 g,
4.3 mmol, 1.3 equiv) were dissolved in anhydrous CH2Cl2 (60 mL).
Et3N (589 μL, 4.3 mmol, 1.3 equiv) was added and the reaction mix-
ture was stirred magnetically at 0 °C for 30 min and at r.t. for an addi-
tional 2 h. The solvent was removed in vacuo to afford the crude
product. Purification was performed by flash column chromatogra-
phy (silica gel, cyclohexane–EtOAc, 0–25%); yield: 1.46 g (78%); color-
less oil; Rf = 0.69 (cyclohexane–EtOAc, 1:1).
MS (ESI): m/z = 419 [M + H]+, 319 [M – C4H8 – CO2 + H]+, 263 [M – 2 ×
C4H8 – CO2 + H]+.
Anal. Calcd for C22H30N2O6 (418.49): C, 63.14; H, 7.23; N, 6.69. Found:
C, 62.70; H, 7.56; N, 7.12.
Nα,Nα-Bis(tert-Butyloxycarbonyl)-Nδ-phthalimido-L-ornithine
tert-Butyl Ester (4)
IR (ATR): 2978, 1734, 1697, 1554, 1366, 1155, 1130, 851 cm–1
.
Compound 3 (2.0 g, 4.8 mmol), DMAP (61 mg, 0.5 mmol), and di-tert-
butyl dicarbonate (10.9 g, 48 mmol, 10 equiv) were dissolved in anhy-
drous MeCN (25 mL) under an argon atmosphere. This reaction mix-
ture was stirred magnetically until the reaction was completed (TLC).
The mixture was diluted with CH2Cl2 (25 mL) and washed with sat. aq
NaHCO3 (20 mL), H2O (20 mL), and brine (20 mL). The organic phase
was dried (Na2SO4) and concentrated in vacuo. Purification was car-
ried out by flash column chromatography (silica gel, cyclohexane–
EtOAc, 0–20%); yield: 1.9 g (77%); colorless oil; Rf = 0.56 (cyclohex-
ane–EtOAc, 2:1).
1H NMR (300 MHz, CDCl3): δ = 8.10–8.16 (m, 1 H, ArH), 7.82–7.89 (m,
1 H, ArH), 7.69–7.77 (m, 2 H, ArH), 5.35 (t, 3J = 6.2 Hz, 1 H, NH), 4.63
(dd, 3J = 9.0, 5.5 Hz, 1 H, α-CH), 3.12 (q, 3J = 6.7 Hz, 2 H, δ-CH2), 2.02–
2.14 (m, 1 H, β-CH2), 1.78–1.91 (m, 1 H, β-CH2), 1.54–1.67 (m, 2 H, γ-
CH2), 1.49 [2 s, 18 H, C(CH3)3], 1.43 [s, 9 H, C(CH3)3].
13C NMR (75 MHz, CDCl3): δ = 169.4 (CO2t-Bu), 152.5 (2 × CO-Boc),
148.1 (ArC–N), 133.8 (ArC–S), 125.4, 131.1, 132.8, 133.5 (ArCH), 83.0
[2 × C(CH3)3], 81.5 [C(CH3)3], 58.2 (α-CH), 43.5 (δ-CH2), 28.0 [2 ×
C(CH3)3], 27.9 [C(CH3)3], 26.8 (β-CH2), 26.5 (γ-CH2).
IR (ATR): 2978, 1773, 1736, 1711, 1366, 1126, 1026, 719 cm–1
.
MS (ESI): m/z = 596 [M + Na]+, 362 [M – 3 × C4H8 – CO2 + H]+, 318 [M –
1H NMR (300 MHz, CDCl3): δ = 7.82–7.84 (m, 2 H, ArH), 7.69–7.73 (m,
2 H, ArH), 4.78 (dd, 3J = 9.3, 5.1 Hz, 1 H, α-CH), 3.72 (dt, 3J =6.9 Hz, 4J =
1.9 Hz, 2 H, δ-CH2), 2.04–2.16 (m, 1 H, β-CH2), 1.83–1.97 (m, 1 H, β-
CH2), 1.68–1.79 (m, 2 H, γ-CH2), 1.49 [2 s, 18 H, C(CH3)3], 1.43 [s, 9 H,
C(CH3)3].
13C NMR (75 MHz, CDCl3): δ = 169.6 (CO2t-Bu), 168.3 (2 × CO-Pht),
152.4 (2 × CO-Boc), 133.8 (2 × ArCH), 132.2 (2 × ArC), 123.2 (2 ×
ArCH), 82.9 [2 × C(CH3)3], 81.3 [C(CH3)3], 58.4 (α-CH), 37.5 (δ-CH2),
28.0 [2 × C(CH3)3], 27.9 [C(CH3)3], 26.5 (β-CH2), 25.6 (γ-CH2).
3 × C4H8 – 2 × CO2 + H]+.
Nα,Nα-Bis(tert-butyloxycarbonyl)-Nδ-methyl-Nδ-(2-nitrophenyl-
sulfonyl)-L-ornithine tert-Butyl Ester (7)
To a solution of 6 (1.45 g, 2.5 mmol) in DMF (15 mL) were added
K2CO3 (1.05 g, 7.6 mmol, 3 equiv) and MeI (475 μL, 7.6 mmol, 3 equiv).
The reaction mixture was stirred magnetically at r.t. for 6 h. The mix-
ture was quenched by adding 10% aq ammonia (10 mL) and extracted
with CH2Cl2 (3 × 10 mL). The combined organic phases were dried
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 723–729