LETTER
Synthesis of a New Chiral Polyamine Template
1877
(11) Benoiton, N. L.; Kuroda, K.; Chen, F. M. F. Int. J. Peptide
Protein Res. 1980, 15, 475-479. Wünsch, E.; Drees, F. Chem.
Ber. 1966, 99, 110-120.
(12) Bellasio, E.; Gallo, G. Farmaco, Ed. Sci. 1970, 25, 295-304;
Chem. Abstr. 1970, 72, 132598. Bellasio, E.; Pagani, G.;
Ripamonti, A.; Testa, E. Farmaco, Ed. Sci. 1965, 20, 428-445;
Chem. Abstr. 1965, 63, 9945.
(13) Appel, R. Angew. Chem. Int. Ed. Engl. 1975, 14, 801-812.
(14) Procedure for the preparation of 3S,7R-bis-[(tert-
butoxycarbonyl)amino]-2-keto-1,5-diazabicyclo[3.3.0]octane
(5): To an ice cooled solution of 4 (1.0g, 2.7 mmol) in dry THF
(10mL) a solution of BH3 in THF (1M, 7.6mL) was slowly
added. The resulting mixture was stirred at r.t. for 16h and
cooled to 0 °C before the addition of MeOH (4mL) and HCl
in dioxane (4M, 2.5mL). After stirring for 7h at r.t. and
cooling with an ice bath, a solution of Na2CO3 (2M, 2mL) and
di-tert-butyldicarbonate (1.25g, 5.7mmol) were successively
added. To the resulting mixture a solution of Na2CO3 (2M,
8.0mL) was slowly added. The resulting suspension was
stirred at r.t. overnight, filtered and the filtrate was
H2O 1:1) to afford 9, (310mg, 77%).1H NMR (H2O/10% D2O,
ppm, d):8.21 (d, 1H, J = 6.1 Hz), 4.54 (dd, 1H, J = 10.5 and
2.9 Hz), 3.76, 3.74 (2s+m, 9H), 3.57 (d, 2H, J = 7.16 Hz), 3.26
(dd, 1H, J = 14.0 and 6.1 Hz), 3.22 (dd, 1H, J = 12.47 and 1.7
Hz), 2.92 (m, 2H), 2.87 (q, 2H, J = 7.2 Hz), 1.17 (t, 3H, J = 7.2
Hz).13C NMR (D2O, ppm, d):171.95, 159.52, 158.54, 54.27,
53.61, 53.51, 52.45, 49.69, 49.60, 43.29, 42.43, 42.39, 9.48.
MS (ESI, H2O/CH3CN 1:1): m/z 162 (M+2H)2+, 323 (M+H)+.
[a]20D:-12° (H2O).
(19) Iddon, B.; Lim, B. L. J. Chem. Soc., Perkin Trans 1 1983, 3,
271-277.
(20) Breslow, R.; Hunt, J. T.; Smiley, R.; Tarnowski, T. J. Am.
Chem. Soc. 1983, 105, 5337-5342.
(21) Kirk, K. L. J. Heterocycl. Chem. 1985, 22, 57-59.
(22) Roberts, J. L.; Borromeo, P. S.; Poulter, C. D. Tetrahedron
Lett. 1977, 1621-1624.
(23) Sato, F.; Oguro, K.; Watanabe, H.; Sato, M. Tetrahedron Lett.
1980, 21, 2869-2872.
(24) Smith, J. G.; Dibble, P. W.; Sandborn, R. E. J. Org. Chem.
1986, 51, 3762-3768.
concentrated. The resulting crude (1.15g) was purified by
flash chromatography (70%CH3CN/1%MeOH/CH2Cl2) to
afford 4b (0.575g, 60%): mp 209-210 °C (recrystallization
from i-PrOH). 1H NMR (CDCl3, ppm, d):5.97 (br s, 1H, NH),
5.89 (d, J = 5.9 Hz, 1H, NH), 4.60 (br s, 1H), 4.52 (dd,
J = 15.3 and 8.2 Hz, 1H), 3.73-3.64 (m, 2H), 3.39 (m, 1H),
3.20 (br s, 1H), 2.96 (br s, 1H), 2.58 (br s, 1H), 1.39 and 1.38
(2 s, 9 H, t-Bu). 13C NMR (CDCl3, ppm, d):165.6, 155.4,
155.1, 80.2, 79.7, 60.7, 57.7, 54.6, 52.3, 47.0, 28.2. MS
(FAB): m/z 356 (M), 301, 245, 158, 57. Anal. Calcd for
C16H28N4O5 (356.43): C, 53.92; H, 7.92; N, 15.72. Found: C,
54.02; H, 7.81; N, 15.75. [a]20D:28° (CDCl3)
(25) Mander L. N.; Sethi, S. P. Tetrahedron lett. 1983, 24, 5425-
5428.
(26) Procedure for the preparation of 2-(1-tritylimidazolyl)acetal-
dehyde (10):1-Trityl-2-methylimidazole (11) was prepared as
described in the literature.21 To a -78 °C cooled solution of 1-
trityl-2-methylimidazole (mp 219-221 °C (EtOAc/ hexanes);
lit. 217-219 °C) (2g, 6.2mmol) in dry THF (60mL) n-BuLi
(1.6mol/L, 4mL) was added dropwise. After stirring for 50min
at -78 °C, freshly distilled HCO2Et (2.4mL, 31mmol) was
quickly added. The color of the reaction mixture changed from
red to pale yellow. After stirring for 15min at -78 °C, citric
acid (5%, 20mL) was added. The layers were separated, the
organic phase was diluted with EtOAc (50mL), dried
(Na2SO4), filtered and evaporated. The resulting solid was
triturated with hexanes (70mL) and EtOAc (5mL) to give
1.89g of a white solid (10, 87%, mp 103-118 °C) of enough
quality for the next reaction. 1H NMR (DMSO-d6, ppm, d):
enol 7.32 (m, Ar, 9H), 7.19 (m, Ar and H-imidazole, 7H), 6.62
(d, J = 1.4 Hz, H-imidazole, 1H), 6.57 (d, J = 6.1 Hz, CHO,
1H), 4.41 (d, J = 6.1 Hz, CH-imidazole, 1H). 13C NMR
(DMSO-d6, ppm, d):151.1, 148.9, 141.7, 129.4, 129.3, 128.5,
128.3, 128.1, 123.2, 119.3, 92.2, 74.7. MS (FAB): m/z 506,
353 (M+1), 243, 165.
(15) Procedure for the preparation of 6 and 7: To a suspension of 5
(0.44g, 1.25 mmol) in i-PrOH (14mL) a slurry of Raney nickel
(aprox. 3g, FLUKA 83440, previously washed 2 times with i-
PrOH) in i-PrOH (2mL) was added. The resulting mixture was
stirred at 50 °C for 1 h (followed by TLC), cooled and filtered
through celite. The crude product was purified by flash
chromatography (SiO2,TBME/Hexanes, 2:1) to give a white
solid (7, 0.33g, 92%): m. p. 218-220 °C. 1H NMR (CDCl3,
ppm, d):7.28 (br s, 1H, NH), 5.62 (d, J = 6.2 Hz, 2H, NH),
4.62 (m, 1H), 3.97 (m, 1H), 3.74 (br s, 1H), 3.29 (dd, J = 12.2
and 4.5 Hz, 2H), 2.72 (dd, J = 14.4 and 3.7 Hz, 1H), 2.70 (t,
J = 11.6 Hz, 1H), 2.46 (m, 1H), 1.45 and 1.43 (2 s, 9 H, t-Bu).
13C NMR (CDCl3, ppm, d):176.0, 155.2, 155.1, 79.8, 79.7,
55.0, 52.9, 51.7, 50.8, 43.7, 28.5, 28.3. MS (FAB): m/z 359
(M+1), 303, 247, 57. Compound 7 was prepared according to
the same procedure, using ethanol as solvent.
(27) deBenneville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950,
72, 3073-3075. Marshall, J. A.;Johnson, W. S. J. Org. Chem.
1963, 28, 421-423. Ketcha, D. M.; Lieurance, B. A.
Tetrahedron Lett. 1989, 30, 6833-6836.
(28) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem.
(16) Ainsworth, C. J. Am. Chem. Soc. 1956, 78, 1635-1636.
(17) Kneeland, D. M.; Ariga, K.; Lynch, V. M.; Huang, C.-Y.;
Anslyn, E. V. J. Am. Chem. Soc. 1993, 115, 10042, 10055.
Muche, M.-S.; Göbel, M. W. Angew. Chem. Int. Ed. Engl.
1996, 35, 2126-2129. Metzger, A.; Lynch, V. M.; Anslyn, E.
V. Angew. Chem., Int. Ed. Engl. 1997, 36, 862-864.
(18) Procedure for the preparation of 3S, 7R-bis(4,5-dihydro-1H-
imidazol-2ylamino)-5-ethyl-2-keto-1,5-diazacyclooctane
hydrochloride (9): To a solution of 8 (300mg, 1.02mmol) in
5.5mL of DMF, triethylamine (440ml, 3.20mmol) was added
under argon. After stirring for 10 min the solution was filtered
and 4,5-dihydro-1H-imidazole-2-sulfonic acid
1997, 62, 1540-1542.
(29) Procedure for the preparation of 3,7-S-diguanidino-5-[2‘-
(imidazolyl)ethyl]-2-keto-1,5-diazacyclooctane
hydrochloride (1): compounds 6 (400mg, 1.12mmol) and 10
(790mg, 2.23mmol) were dissolved in CHCl3/EtOH 3:1
(10mL). The mixture was stirred for 3h under argon at r.t.
NaBH3CN (207mg, 2.8mmol) was added followed by the
slow addition of AcOH (2mL). After 3h the solution was
basified with sat. aq NaHCO3 and extracted with CH2Cl2. The
organic layers were dried (Na2SO4) and evaporated. Column
chromatography (SiO2, 2% MeOH/CH2Cl2) afforded 758mg
(95%) of 12. Compound 12 was dissolved in dry CH2Cl2 and
4M HCl in dioxane. After 2h stirring at 0 °C, the solvent was
evaporated, the white residue 13 was dried under high vacuum
and used without further purification. To a suspension of 13
(1.35g) and di-tert-butoxycarbonylthiourea (1.75g,
6.33mmol) in dry THF (21mL) was added Et3N (2.2mL) and
EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride, 1.21g, 6.33mmol). After 3h stirring under
argon at r.t., the mixture was washed three times with water,
dried (MgSO4) and evaporated. Column chromatography
(290mg,1.94mmol, dissolved in 8mL of DMF) was added
over 4h using a syringe pump. The mixture was stirred for 48h
at r.t. under argon. The resulting precipitate was collected by
filtration and washed with ether. The crude product was
adsorbed on a cation exchange column (Sephadex CM C-25,
3 x 10cm) and eluted with a salt gradient (0.1M-0.5M
NH4OAc). The product fractions were collected and
lyophilized. The acetate was converted to the chloride by
anion exchange (Dowex 1X8, Cl- form, Fluka, eluent CH3CN/
Synlett 1999, No. 12, 1875–1878 ISSN 0936-5214 © Thieme Stuttgart · New York