1
766
Vol. 55, No. 12
1
ꢂ
madzu RF5300 spectrophotometer. H-NMR spectra were obtained on a (MꢂNa) .
4
00 MHz Bruker DPX-400 spectrometer using tetramethylsilane in CDCl3,
2,2ꢀ-Bis[3,6,9-tris(tert-butoxycarbonyl)-3,6,9-triazanonyl]-4,4ꢀ-bithia-
zole (11a) and 2,2ꢀ-bis[3,7,11-tris(tert-butoxycarbonyl)-3,7,11-triazaun-
and 4,4-dimethyl-4-silapentane-sulfonic acid sodium salt in D O, as internal
2
references. MALDI-TOF-MS analysis was conducted using a Kratos Kom- decyl]-4,4ꢀ-bithiazole (11b) General Procedure: To a stirred solution of 9
pact MALDI IV instrument. A saturated solution of 2,5-dihydroxybenzoic
(10 mmol) in dry EtOH (100 ml), 1,4-dibromobutane-2,3-dione (10, 1.22 g,
acid in a 1 : 1 mixture of water and acetonitrile containing 1% trifluoroacetic
5.0 mmol) was added in one portion at room temperature. The mixture was
acid was used as the matrix. The instrument was calibrated externally with a heated at 60 °C for 5 h with stirring, then the organic solvent was removed
C60/70 mixture.
under reduced pressure. A mixture of EtOAc (100 ml) and aqueous NaOH
N,Nꢀ,Nꢁ-Tris(tert-butoxycarbonyl)-N-(2-cyanoethyl)diethylenetri- (2.0 mol/l, 30 ml) was poured onto the residue and the organic layer was sep-
amine (6a) and N,Nꢀ,Nꢁ-Tris(tert-butoxycarbonyl)-N-(2-cyanoethyl)- arated, washed twice with brine (30 ml), and dried over anhydrous Na SO .
2
4
dipropylenetriamine (6b) General Procedure: Acrylonitrile (2.65 g,
The solvent was removed in vacuo to give a crude product, which was puri-
fied by silica gel flash column chromatography with EtOAc–hexane (1 : 1).
11a: Yield: 3.7 g (73%), colorless microcrystals (acetone), mp 123—
50 mmol) was added dropwise to liquid dialkylenetriamine (5, 500 mmol) at
5
°C over a period of 30 min with stirring. The mixture was stirred for an ad-
ꢃ1
1
ditional 30 min and excess dialkylenetriamine was removed under reduced 124 °C. IR (KBr) cm : 3388, 3192, 1184. H-NMR (CDCl ) d: 1.43 (18H,
pressure to give crude N-(2-cyanoethyl)dialkylenetriamine, which was used s), 1.46 (36H, s), 3.15—3.70 (24H, m), 7.55, 7.70 (2H, each s). MALDI-
3
ꢂ
in the next step without purification. Boc O (33 g, 150 mmol) was added in TOF-MS m/z: 1050 (MꢂNa) . Anal. Calcd for C H N O S : C, 56.12; H,
2
48 82
8
12
2
small portions to a stirred solution of the residue in a mixture of tetrahydro-
furan (THF, 200 ml) and an aqueous NaOH (4.0 mol/l, 40 ml), and the mix-
ture was stirred for 5 h at room temperature. After the organic solvent was 1692. H-NMR (CDCl ) d: 1.43 (18H, each s), 1.45 (36H, each s), 3.09—
removed under reduced pressure, ethyl acetate (EtOAc, 400 ml) was poured 3.61 (32H, m), 5.30 (1H, br s), 7.63 (2H, s). MALDI-TOF-MS m/z: 1106
8.05; N, 10.91. Found: C, 56.08; H, 7.98; N, 10.94.
ꢃ1
11b: Yield: 3.3 g (60%), amorphous solid. IR (KBr) cm : 3368, 3212,
1
3
ꢂ
into the residual aqueous suspension. The organic layer was separated, (MꢂNa) .
washed twice with brine (50 ml), and then dried over anhydrous Na SO .
2,2ꢀ-Bis(3,6,9-triazanonyl)-4,4ꢀ-bithiazole Hexahydrochloride (3a) and
2
4
The organic solvent was removed in vacuo to yield a colorless waxy solid, 2,2ꢀ-Bis(3,7,11-triazaundecyl)-4,4ꢀ-bithiazole Hexahydrochloride (3b)
which was purified by silica gel flash column chromatography with General Procedure: To a solution of 11 (2.0 mmol) in dry dioxane (10 ml),
EtOAc–hexane (1 : 1).
HCl in dioxane (4.0 mol/l, 10 ml) was added at room temperature and the
mixture was stirred overnight. The obtained precipitate was collected by
suction filtration and purified by recrystallization.
6
a: Yield 20 g (87%), colorless prisms (ether), mp 99—100 °C. IR (KBr)
ꢃ1
1
cm : 3360, 2244, 1682. H-NMR (CDCl ) d: 1.43 (9H, s) 1.47 (18H, s),
.53—2.67 (2H, m), 3.22—3.54 (10H, m), 4.65—5.15 (1H, m). MALDI-
3
2
3a: Yield: 1.2 g (93%), colorless plates (MeOH : H Oꢄ4 : 1), mp 257—
2
ꢂ
ꢃ1
1
TOF-MS m/z: 479 (MꢂNa) . Anal. Calcd for C H N O : C, 57.87; H, 262 °C (dec.). IR (KBr) cm : 3488—2944. H-NMR (D O) d: 3.42—3.72
2
2
40
4
6
2
ꢂ
8
.83; N, 12.27. Found: C, 57.63; H, 8.92; N, 12.23.
(16H, m), 3.61 (8H, m), 7.90 (2H, s). MALDI-TOF-MS m/z: 449 (MꢂNa) .
ꢃ1
6
b: Yield 22 g (92%), amorphous solid. IR (KBr) cm : 3368, 2252, Anal. Calcd for C H N S ·6HCl: C, 33.50; H, 6.25; N, 17.36. Found: C,
18 34 8 2
1
1
692. H-NMR (CDCl ) d: 1.44, 1.46, 1.47 (27H, each s), 1.63—1.66 (4H, 33.67; H, 6.30; N, 17.30.
m), 1.78 (2H, q, Jꢄ7.3 Hz), 2.63 (2H, q, Jꢄ7.3 Hz), 3.09—3.29 (8H, m),
3
3b: Yield; 1.26 g (90%), colorless plates (MeOH : H Oꢄ4 : 1), mp 263—
2
ꢂ
ꢃ1
1
4.65—5.10 (2H, m). MALDI-TOF-MS m/z: 507 (MꢂNa) .
268 °C (dec.). IR (KBr) cm : 3200—2952. H-NMR (D O) d: 2.11—2.21
2
N,Nꢀ,Nꢁ-Tris(tert-butoxycarbonyl)diethylenetriamine-N-propi- (4H, m), 3.11—3.62 (8H, m), 3.55—3.62 (8H, m), 7.88 (2H, s). MALDI-
onamide (7a) and N,Nꢀ,Nꢁ-Tris(tert-butoxycarbonyl)dipropylenetri- TOF-MS m/z: 505 (MꢂNa) . Anal. Calcd for C H N S ·6HCl: C, 37.67;
ꢂ
2
2
42
8 2
amine-N-propionamide (7b) General Procedure: An aqueous hydrogen H, 6.90; N, 15.97. Found: C, 37.50; H, 6.87; N, 15.73.
peroxide solution (30%, 50 ml) was added dropwise to a stirred suspension
of 6 (30 mmol) in a mixture of aqueous NaOH (2.0 mol/l, 50 ml) and EtOH
2,2ꢀ-Bis{2-[3,6-bis(tert-butoxycarbonyl)-3,6-diazahexanoyl]amino-
ethyl}-4,4ꢀ-bithiazole (13) N,Nꢀ-Dicyclohexylcarbodiimide (DCC, 1.03 g,
(200 ml) over a period of 1 h while the temperature was maintained at 5 °C 5.0 mmol) was added to a stirred solution of 3,6-di(Boc)-3,6-diazahexanoic
or less. The mixture was heated at 60 °C for 1 d with stirring, then the solu-
tion was concentrated to 1/3 the original volume in vacuo. The obtained pre-
acid (12, 1.6 g, 5.0 mmol) and 1-hydroxybenzotriazole (HOBT, 0.68 g,
5.0 mmol) in dry N,Nꢀ-dimethylformamide (DMF, 20 ml) at room tempera-
cipitate was collected by suction filtration and washed with ice cold water, ture, the mixture was stirred for 1 h, then 1b (0.65 g, 2.0 mmol) and diiso-
then purified by silica gel flash column chromatography with EtOAc–hexane propylethylamine (0.65 g, 5.0 mmol) at room temperature were added with
(3 : 1).
stirring. After the mixture was stirred overnight at room temperature, the ob-
7
a: Yield: 9.1 g (64%), colorless microcrystals (EtOAc), mp 143—144 °C.
tained precipitate was filtered and the filtrate was concentrated in vacuo to
ꢃ1
1
IR (KBr) cm : 3408, 1704, 1676. H-NMR (CDCl ) d: 1.44, 1.46, 1.47 give an oily residue. A mixture of EtOAc (100 ml) and aqueous NaOH
27H, each s), 2.51 (2H, br s), 3.20—3.60 (10H, m), 4.65—5.15 (1H, m). (1.0 mol/l, 20 ml) was poured onto the residue and the organic layer was sep-
MALDI-TOF-MS m/z: 497 (MꢂNa) . Anal. Calcd for C H N O : C,
3
(
ꢂ
arated, washed twice with 10% citric acid solution (30 ml) and brine (30 ml),
2
2
42
4
7
5
5.68; H, 8.92; N, 11.81. Found: C, 55.64; H, 9.15; N, 11.64.
and dried over anhydrous Na SO . The solvent was removed in vacuo to give
a crude product, which was purified by silica gel flash column chromatogra-
2
4
ꢃ1
1
7b: Yield: 8.3 g (55%), amorphous solid. IR (KBr) cm : 3356, 1676. H-
NMR (CDCl ) d: 1.46 (27H, s), 1.61—1.77 (4H, m), 2.51 (2H, br s), 3.09— phy with acetone–hexane (1 : 1). Yield: 1.3 g (76%), colorless microcrystals
3
ꢃ1
3
.21 (8H, m), 3.50 (2H, t, Jꢄ6.7 Hz), 5.31—5.51 (1H, br s). MALDI-TOF-
MS m/z: 525 (MꢂNa)
N,Nꢀ,Nꢁ-Tris(tert-butoxycarbonyl)diethylenetriamine-N-propi- (4H, m), 3.76 (4H, q, Jꢄ6.0 Hz), 5.35 (2H, br s), 7.00 (2H, br s), 7.69 (2H,
onthioamide (9a) and N,Nꢀ,Nꢁ-Tris(tert-butoxycarbonyl)trimethylenetri- s). MALDI-TOF-MS m/z: 877 (MꢂNa) . Anal. Calcd for C H N O S :
(acetone : hexaneꢄ5 : 1), mp 139—140 °C. IR (KBr) cm : 3388, 1702,
ꢂ
1
.
1680. H-NMR (CDCl ) d: 1.42 (36H, s), 3.20—3.30 (8H, m), 3.33—3.40
3
ꢂ
3
8
62
8
10 2
amine-N-propionthioamide (9b) General Procedure: To a stirred suspen- C, 53.38; H, 7.31; N, 13.10. Found: C, 53.47; H, 7.24; N, 13.13.
sion of 7 (10 mmol) in dry 1,2-dimethoxyethane (DME, 100 ml), Lawesson’s
reagent (8, 2.6 g, 6.5 mmol) was added in portions at room temperature.
After the reaction mixture was heated at 60 °C for 4 h with stirring, the or-
2,2ꢀ-Bis[2-(3,6-diazahexanoyl)aminoethyl]-4,4ꢀ-bithiazole Tetrahy-
drochloride (4a) Following the general procedure described above for the
preparation of 3b, HCl in dioxane (4.0 mol/l, 10 ml) was added dropwise to a
ganic solvent was removed under reduced pressure. A mixture of EtOAc solution of 13 (855 mg, 1.0 mmol) in dioxane (10 ml) at room temperature
200 ml) and aqueous NaOH (2.0 mol/l, 50 ml) was poured onto the residue
and the mixture was stirred overnight to give a crude product, which was pu-
(
and the organic layer was separated, washed twice with brine (30 ml), then rified by recrystallization. Yield 509 mg (85%), colorless microcrystals
ꢃ1
dried over anhydrous Na SO . The solvent was removed in vacuo to give a (MeOH : H Oꢄ9 : 1), mp 248—250 °C (dec.). IR (KBr) cm : 3456—2940,
2
4
2
1
crude product, which was purified by silica gel flash column chromatogra- 1670. H-NMR (D O) d: 3.33 (4H, t, Jꢄ6.6 Hz), 3.40—3.55 (8H, m), 3.72
2
phy with EtOAc–hexane (2 : 1).
a: Yield: 3.4 g (70%), colorless microcrystals (ether : hexaneꢄ5 : 1), mp
(4H, t, Jꢄ6.6 Hz), 3.98 (4H, s), 7.79 (2H, s). MALDI-TOF-MS m/z: 455
ꢂ ꢂ
9
(MꢂH) , 477 (MꢂNa) . Anal. Calcd for C H N O S ·4HCl: C, 36.01; H,
18 30 8 2 2
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1
1
1
47—148 °C. IR (KBr) cm : 3384, 1682. H-NMR (CDCl ) d: 1.44, 1.46, 5.71; N, 18.66. Found: C, 35.85; H, 5.60; N, 18.66.
3
.47 (27H, each s), 3.01 (2H, br s), 3.20—3.65 (10H, m), 4.65—5.15 (1H,
2,2ꢀ-Bis{3-(tert-butoxycarbonyl)-6-[N-(tert-butoxycarbonyl)glycyl]-
3,6-diazahexyl}-4,4ꢀ-bithiazole (15) Following the procedure described
above for the preparation of 13, the condensation of 2a (1.94 g, 4.0 mmol)
ꢂ
m). MALDI-TOF-MS m/z: 513 (MꢂNa) . Anal. Calcd for C H N O S: C,
2
2
42
4
6
5
3.85; H, 8.63; N, 11.42. Found: C, 53.62; H, 8.69; N, 11.40.
9
ꢃ1
1
b: Yield: 3.2 g (61%), amorphous solid. IR (KBr) cm : 3336, 1682. H- with N-Boc glycine (14, 1.4 g, 8 mmol) using DCC (2.0 g, 9.0 mmol) as a de-
NMR (CDCl ) d: 1.46 (27H, s), 1.59—1.83 (4H, m), 3.00—3.11 (10H, m), hydration agent were carried out in the presence of HOBT (1.35 g, 10 mmol)
3
3
.58 (2H, t, Jꢄ6.6 Hz), 4.78—5.25 (1H, br s). MALDI-TOF-MS m/z: 541 and diisopropylethylamine (2.58 g, 20 mmol) in dry DMF (30 ml) at room