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H. H. M. Abdu-Allah et al.
PAPER
acid are assigned ‘b’. High-resolution mass spectrometry (HRMS)
was performed with a Bruker Daltonics micrOTOF (ESI-TOF)
mass spectrometer. The multivalent ligand 13 was analyzed using a
quadrupole ion trap mass spectrometer (QIT-MS) coupled with an
electrospray interface (Bruker Esquire 3000 plus, Bruker Daltonik
GmbH, Bremen, Germany). TLC analysis was carried out on Merck
TLC glass plates (silica gel 60 F254) and compounds were visualized
by exposure to UV light and/or by charring with 10% H2SO4 in
EtOH. Flash column chromatography on silica gel (Fuji Silysia Co.,
80 and 300 mesh) or Sephadex® (Pharmacia LH-20) was performed
with the solvent systems (v/v) specified. The quantity of silica gel
was usually estimated as 100- to 150-fold weight of the sample to
be charged. Reversed-phase silica gel (Wakogel® 50 C18) was pur-
chased from Wako Pure Chemical Industries, Ltd. HPLC grade H2O
and MeOH (Wako) were used for purification of the final com-
pounds. Solvent systems for chromatography are specified in v/v.
All evaporations and concentrations were carried out under reduced
pressure.
1H NMR (400 MHz, CDCl3): d = 7.98 (d, J = 2.0 Hz, 3 H, ArH),
7.58 (br s, 3 H, 3 OH), 7.45 (dd, J = 8.2, 2.0 Hz, 3 H, ArH), 7.10 (d,
J = 8.2 Hz, 3 H, ArH), 3.45 (m, 9 H, ArCH2CO + NHCH2), 3.10 (m,
8 H, NHCH2, NH2).
HRMS: m/z [M + H]+ calcd for C29H30N7O12: 656.1952; found:
656.1952.
3,4,5-Tris{2-[2-(2-azidoethoxy)ethoxy]ethoxy}-N-{1,1,1-tris[(4-
hydroxy-3-nitrophenyl)acetamidomethyl]methyl}benzamide
(8)
A soln of acid 727,28 (179.6 mg, 0.28 mmol) in anhyd CH2Cl2 (3 mL)
was cooled to 0 °C. To this mixture was added HOBt (42.5 mg, 0.28
mmol) and EDCl (53.5 mg, 0.28 mmol) at 0 °C and the mixture was
stirred for 30 min. To this was added amine 6 (113 mg, 0.172 mmol)
while stirring, and the reaction mixture was warmed to r.t. Stirring
was continued for 24 h under argon. Then, the mixture was diluted
with CH2Cl2 (20 mL), washed with brine (3 × 15 mL), dried
(Na2SO4) and concentrated under reduced pressure. Purification of
the residue by silica gel chromatography (0.5–1% MeOH in CHCl3)
afforded 8 as an orange-colored solid; yield: 165 mg (75%).
1,1,1-Tris(azidomethyl)-N-(tert-butoxycarbonyl)methylamine
(2)
A soln of tris(azidomethyl)methylamine23 (1; 7.20 g, 36.66 mmol)
in EtOH (100 mL) was added to a soln of Boc2O (8 g, 36.66 mmol)
in EtOH (100 mL). The reaction mixture was stirred at r.t. for 8 h,
then concentrated to dryness to provide a white solid which was re-
crystallized (H2O) to give 2; yield: 9.77 g (90%).
IR (KBr): 2106 (azide), 1680 (amidic carbonyl), 1530 and 1245
cm–1 (nitro).
1H NMR (400 MHz, CDCl3): d = 8.02 (d, J = 2.0 Hz, 3 H, ArH),
7.53–7.45 (m, 6 H, 3 OH + 3 ArH), 7.10 (d, J = 8.2 Hz, 3 H, ArH),
6.95 (s, 2 H, H of gallic residue), 4.23–4.13 (m, 7 H, 3 CH2N3,
CONH), 3.89–3.55 (m, 33 H, 3 ArCH2CO + 3 NHCH2, 12 CH2O),
3.40–3.36 (m, 12 H, 3 NHCH2, 3 CH2O).
HRMS: m/z [M + Na]+ calcd for C53H66N16O22Na: 1301.4435;
found: 1301.4435.
1H NMR (400 MHz, CDCl3): d = 4.70 (br s, 1 H, NH), 3.62 (s, 6 H,
3 CH2), 1.45 (s, 9 H, 3 CH3).
1,1,1-Tris(aminomethyl)-N-(tert-butoxycarbonyl)methylamine
(3)
A round-bottom flask equipped with a stirrer bar was charged with
triazide 2 (1.50 g, 5.06 mmol), EtOH (100 mL) and 10% Pd/C (1 g).
The resulting mixture was stirred under H2 at r.t. for 8 h; then, the
mixture was filtered through Celite® and the filtrate was concentrat-
ed to give triamine 3 as a colorless oil; yield: 1.07 g (97%).
1H NMR (400 MHz, CDCl3): d = 5.68 (br s, 1 H, NH), 2.89 (br s, 6
H, NH2), 2.84 (s, 6 H, CH2), 1.43 (s, 9 H, 3 CH3).
Phenyl (Methyl 5-(Acetoxyacetamido)-4,7,8-tri-O-acetyl-9-azi-
do-3,5,9-trideoxy-d-glycero-a-D-galacto-2-nonulopyranosy-
lonate)-(2→6)-4-O-acetyl-2,3-di-O-benzoyl-1-thio-b-D-galacto-
pyranoside (10)
To a mixture of anhyd ZnI2 (0.85 g, 2.7 mmol, 5 equiv) and Bu4NI
(0.6 g, 1.62 mmol, 3 equiv) was added a soln of compound 919 (0.57
g, 0.54 mmol) in DCE (10 mL) followed by PhSSiMe3 (0.9 mL, 5.4
mmol, 10 equiv). The mixture was stirred at 60 °C for 36 h until no
starting material remained by TLC analysis (MeOH–CHCl3, 2:98).
The reaction mixture was cooled, diluted with CH2Cl2 (30 mL),
washed with H2O (30 mL) and dried. The crude product, obtained
after solvent removal, was acetylated with Ac2O–pyridine (1:1, 8
mL) in the presence of DMAP. After completion of the reaction, a
few drops of H2O were added. The reaction mixture was concentrat-
ed in vacuo and extracted with CHCl3 (50 mL), washed with dil.
HCl (50 mL) and brine (50 mL). The organic extract was dried
(Na2SO4) and then evaporated. The residue was purified by column
chromatography (MeOH–CHCl3, 0.75:99.25) to give 10; yield: 0.49
g (87%).
N-(tert-Butoxycarbonyl)-1,1,1-tris[(4-hydroxy-3-nitrophe-
nyl)acetamidomethyl]methylamine (5)
To a soln of triamine 3 (100 mg, 0.46 mmol) in MeOH (15 mL) was
added succinimido (4-hydroxy-3-nitrophenyl)acetate26 (4; 487 mg,
1.65 mmol). The solution was kept basic with the addition of Et3N
and stirred at r.t. for 36 h. The volatiles were evaporated and the res-
idue was purified by silica gel column chromatography (MeOH–
CHCl3, 2:98) to afford 5 as an orange-colored solid; yield: 268 mg
(77.5%).
1H NMR (400 MHz, CDCl3): d = 8.00 (d, J = 1.8 Hz, 3 H, ArH),
7.51 (dd, J = 8.3, 1.8 Hz, 3 H, ArH), 7.43 (br s, 3 H, 3 OH), 7.10 (d,
J = 8.3 Hz, 3 H, ArH), 5.55 (br s, 1 H, NHCOO), 3.54 (s, 6 H,
ArCH2CO), 3.45 (t, J = 6.2 Hz, 3 H, NHCH2), 3.28 (d, J = 6.2 Hz,
6 H, NHCH2), 1.32 (s, 9 H, 3 CH3).
Rf = 0.2 (MeOH–CHCl3, 1:99).
1H NMR (600 MHz, CDCl3): d = 7.97 (d, J = 7.5 Hz, 2 H, ArH),
7.85 (d, J = 7.5 Hz, 2 H, ArH), 7.57–7.31 (m, 11 H, ArH), 5.88 (d,
J = 13.1 Hz, 1 H, NH), 5.72–5.69 (m, 2 H, H2a, H4a), 5.46 (br d,
J = 10.3 Hz, 1 H, H3a), 5.35 (m, 1 H, H8b), 5.26 (d, J = 7.5 Hz, 1 H,
H7b), 5.07 (d, J = 10.3 Hz, 1 H, H1a), 4.93 (m, 1 H, H4b), 4.61 (d,
J = 15.4 Hz, 1 H, AcOCH2CO), 4.29 (d, J = 15.4 Hz, 1 H,
AcOCH2CO), 4.17–4.09 (m, 3 H, H6a¢, H5b, H6b), 3.94–3.91 (m, 1 H,
H5a), 3.82 (s, 3 H, COOCH3), 3.74 (br d, J = 13.7 Hz, 1 H, H6a¢¢),
3.50 (br q, 1 H, H9b¢), 3.33 (br q, 1 H, H9b¢¢), 2.60 (br d, J = 12.2 Hz,
1 H, H3b-eq), 2.24–2.02 (m, 15 H, 5 OAc), 1.97 (t, J = 12.4 Hz, 1 H,
H3b-ax).
HRMS: m/z [M + Na]+ calcd for C33H37N7O14Na: 778.2296; found:
778.2296.
1,1,1-Tris[(4-hydroxy-3-nitrophenyl)acetamidomethyl]methyl-
amine (6)
A TFA–H2O mixture (3:1, 2 mL) was added to a soln of 5 (250 mg,
0.33 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred for
8 h, then treated with 1 M Na2CO3 (5 mL); the aqueous phase was
extracted with CH2Cl2 (5 × 5 mL). The combined organic layers
were dried (MgSO4), filtered and then evaporated to dryness to give
6 as an orange-colored solid; yield: 206 mg (95%).
13C NMR (150 MHz, CDCl3): d = 171.0, 170.5, 169.9, 169.6, 167.8,
167.6, 165.3, 133.3, 133.0, 132.3, 129.8, 129.6, 129.5, 129.3, 128.9,
128.8, 128.4, 128.3, 127.9, 99.0, 86.5, 73.0, 72.9, 69.9, 68.0, 67.9,
67.8, 67.7, 62.7, 53.0, 51.0, 49.3, 38.0, 29.6, 21.0, 20.7, 20.6, 20.5.
Synthesis 2011, No. 18, 2968–2974 © Thieme Stuttgart · New York