Synthesis of Enantiomeric Aminoalkylcarbamoylphosphonates and Their Evaluation
9
(c 1.99, CH3OH); mp 105–108°C; NMR (CDCl3) 31P,
δ -4.00 ppm; 1H, δ 1.19–1.29 (m, 12H), 2.87–2.97
(m, 2H), 3.34–3.55 (m, 2H), 3.63–3.77 (m, 1H),
4.60–4.77 (m, 2H), 4.99 (s, 2H), 5.75 (d, 1H, J = 7.2
Hz), 5.85 (t, 1H, J = 6.0 Hz), 6.89–7.03 (m, 4H),
7.12–7.20 (m, 2H), 7.21–7.29 (m, 4H), 7.30–7.38 (m,
2H), 7.63–7.75 (m, 3H); IR (neat) ν 3335, 3177, 2985,
column purified (silica gel, 5% MeOH in EtOAc)
to provide (S)-2-(benzyloxycarbonylamino)-3-(4-
phenoxybenzenesulfonamido)propanol, (1.38
3
g, 76% yield) as colorless solid. [α]D = +4.56 (c
0.98, CH3OH); mp. 86–89°C; NMR (CDCl3) 1H, δ
2.66–2.75 (m, 1H), 3.04–3.20 (m, 2H), 3.60–3.92 (m,
3H), 5.05 (s, 2H), 5.44–5.53 (m, 2H), 6.96–7.10 (m,
4H), 7.19–7.27 (m, 1H), 7.29–7.36 (m, 5H), 7.37–7.46
(m, 2H), 7.75 (d, 2H, J = 9.0 Hz); 13C(CDCl3): δ 43.4,
51.9, 61.9, 66.9, 117.7, 120.3, 125.0, 127.9, 128.2,
128.5, 129.1, 130.2, 133.0, 136.1, 155.0, 156.6, 161.6;
1719, 1649 cm−1 13C(CDCl3) δ 23.5, 23.6, 23.7, 23.7,
;
39.9 (d, J = 7.5 Hz), 43.5, 50.7, 66.7, 73.9 (d, J = 6.0
Hz), 117.5, 120.1, 124.8, 127.8, 128.0, 128.4, 129.0,
130.1, 133.4, 136.1, 155.0, 156.2, 161.3, 167.9 (d, J =
226.3 Hz); MS-ES (m/z): 648 (M + 1).
IR (neat) ν 3368, 3295, 3059, 1704 cm−1
.
(R)-2-(Benzyloxycarbonylamino)-3-(4-phenoxy
benzenesulfonamido)propyl Azide (4). To so-
(R)-N-[2-Amino-3-(4-phenoxybenzenesulfona-
mido)propyl]carbamoyl Phosphonic Acid (6). To
a stirred solution of (R)-benzyl 1-(diisopropy-
lphosphonoformamido)-3-(4-phenoxyphenylsul-
fonamido)prop-2-ylcarbamate (0.13 g, 0.2 mmol)
in CHCl3 (2 mL), TMSBr (0.26 mL, 2.0 mmol) was
added dropwise. The reaction mixture was stirred for
12 h at 50°C. Then two portions of 5 equiv of TMSBr
were added to the reaction mixture at an interval of
24 h. After completion of the reaction, the solvent
was evaporated. Methanol was added to the reaction
mixture and stirred at RT for 1 h. Solvents were
evaporated, and the required (R)-N-[2-amino-3-
(4-phenoxyphenylsulfonamido)propyl]carbamoyl-
phosphonic acid 6 (0.055 g, 64% yield) solidified to
a white solid by adding EtOH, mp 220–235°C; NMR
a
lution of (S)-2-(benzyloxycarbonylamino)-3-(4-
phenoxybenzenesulfonamido) -propanol (0.45 g, 1.0
mmol) in toluene (10 mL), PPh3 (0.28 g, 1.1 mmol)
was added and the mixture was stirred at RT for 5
min. After adding hydrazoic acid (1.25 M in toluene,
1.04 mL, 1.3 mmol), DiEthylAzoDicarboxylate
(DEAD) (0.17 mL, 1.1 mmol) was added dropwise.
The reaction mixture was stirred at RT for 30
min and filtered, and solvent was evaporated.
The crude residue was chromatographed (silica
gel, 30% EtOAc in n-hexane) to afford (R)-2-
(benzyloxycarbonylamino)-3-(4-phenoxybenzene
sulfonamido)-propyl azide 4 (0.29 g, 60% yield) as
low melting solid. NMR (CDCl3) 1H, δ 2.85–3.10 (m,
2H), 3.35–3.55 (m, 2H), 3.70–3.85 (m, 1H), 5.01 (s,
2H), 5.10 (t, 1H, J = 6.0 Hz), 5.22 (d, 1H, J = 9.0 Hz),
6.90–7.03 (m, 4H), 7.12–7.20 (m, 2H), 7.23–7.30 (m,
4H), 7.31–7.38 (m, 2H), 7.69 (d, 2H, J = 9.0 Hz);
[α]D = +1.00 (c 1.99, CH3OH); 13C(CDCl3): δ 44.1,
50.1, 51.7, 67.1, 117.6, 120.3, 125.0, 128.0, 128.2,
128.5, 129.2, 130.2, 132.9, 136.0, 155.0, 156.1, 161.7;
1
(D2O + NaHCO3) 31P, δ –1.17 ppm; H, δ 2.56–2.78
(m, 2H), 2.88–3.12 (m, 2H), 3.32–3.46 (m, 1H),
6.80–6.90 (m, 4H), 6.96–7.05 (m, 1H), 7.13–7.24
(m, 2H), 7.52 (dd, 2H, J = 9.0, 2.4 Hz); Sodium
salt MS-ES (m/z): 474 (M + 1). Anal. Calcd. For
2C16H20N3O7PS + 3H2O: C, 42.11, H, 5.08, N, 9.21.
Found: C, 41.85, H, 4.89, N, 9.05.
IR (neat) ν 3296, 2101, 1699 cm−1
.
Diisopropyl (R)-N-[2-(Benzyloxycarbonylamino)-
3-(4-phenoxybenzenesulfonami-do)propyl]carbamoy
lphosphonate (5). Trimethylphosphine [0.93 mL
(R)-4-Phenoxy-N-((1-tritylaziridin-2-yl)methyl)
benzenesulfonamide (7). To
a
solution of
(S)-3-(4-phenoxybenzenesulfonamido)-2-(tritylami
no)propanol (1.80 g, 3.2 mmol) in toluene (30 mL),
PPh3 (0.923 g, 3.52 mmol) was added and the
mixture was stirred at RT for 5 min. After adding
hydrazoic acid (0.62 M in toluene, 5.66 mL, 3.52
mmol), DEAD (0.55 mL, 3.52 mmol) was added
dropwise. The reaction mixture was stirred at RT for
30 min and filtered, and the solvent was evaporated.
The crude residue was chromatographed (silica gel,
30% EtOAc in n-hexane) to afford (R)-4-phenoxy-N-
((1-tritylaziridin-2-yl)methyl)benzenesulfonamide 7
(1.31 g, 75% yield) as white solid. mp. 85–87°C. NMR
(CDCl3) 1H, δ 1.02 (d, 1H, J = 6.3 Hz), 1.38–1.46 (m,
1H), 1.74 (d, 1H, J = 3.0 Hz), 3.14–3.34 (m, 2H), 4.78
(t, 1H, J = 5.1 Hz), 7.02–7.14 (m, 4H), 7.20–7.29 (m,
(1.0
dropwise to
M
solution), 0.933 mmol] was added
stirred solution of (R)-2-
a
(benzyloxycarbonylamino)-3-(4-phenoxybenzenesul
fonam-ido)propyl azide (0.15 g, 0.31 mmol) in
dry CH2Cl2 (1.0 mL). The reaction mixture was
stirred at RT for 1.5 h under nitrogen atmo-
sphere. NPPF-iPr (0.15 g, 0.46 mmol) was added
to the reaction mixture and stirred for one more
hour at RT. The solvent was evaporated, and the
crude residue was column purified (silica gel,
80% EtOAc/n-hexane) to afford diisopropyl (R)-
N-[2-(benzyloxycarbonylamino)-3-(4-phenoxyben-
zenesulfonamido)propyl]carbamoylphosphonate 5
(0.165 g, 82% yield) as colorless solid. [α]D = +7.50
Heteroatom Chemistry DOI 10.1002/hc