8818
C. M. Athanassopoulos et al. / Tetrahedron Letters 45 (2004) 8815–8818
Weinheim, pp 272–280, and references cited therein; (c) graphy (FCC) on Merck (230–400 mesh) silica gel. For
Zepik, H. H.; Benner, S. A. J. Org. Chem. 1999, 64, 8080–
8083; (d) Baker, T. J.; Luedtke, N. W.; Tor, Y.; Goodman,
M. J. Org. Chem. 2000, 65, 9054–9058.
eluents see Table 1.
27. These aromatic polyamines were obtained as follows: To a
solution of 5mmol of aromatic diamine (12 or 13) in dry
DMF (5mL) was added Et3N (15mmol) and Trt-bAla-
OSu24b (10.5mmol) and the resulting mixture was heated
to 60°C for 15–20h and then triturated with 40mL
CHCl3. A first crop of the product was collected by
filtration, following washing with ice-cold CHCl3 (60mL)
and Et2O (30mL). Concentration of the CHCl3 filtrates to
one third of the volume, overnight refrigeration and
filtration gave a second crop of pure bisamide 14a or 15a
(yields: 63–65%). Treatment of 2mmol of bisamide 14a or
15a with LiAlH4 (10mmol) in refluxing anhydrous THF
(20mL) for 36h (14a) or 3days (15a), followed by
routine work-up24b and FCC purification with EtOAc/
PhMe (95:5) as eluent, gave pure PAs 14b (68%) and 15b
(57%).
6. Ishikawa, T.; Isobe, T. Chem. Eur. J. 2002, 8, 552–557.
7. Belmont, P.; Jourdan, M.; Demeunynck, M.; Constant,
J.-F.; Garcia, J.; Lhomme, J. J. Med. Chem. 1999, 42,
5153–5159.
8. Pallan, P. S.; Ganesh, K. N. Biochem. Biophys. Res.
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9. Karigiannis, G.; Papaioannou, D. Eur. J. Org. Chem.
2000, 1841–1863.
10. Mitchinson, A.; Golding, B. T.; Griffin, R. J.; OÕSullivan,
M. C. J. Chem. Soc., Chem. Commun. 1994, 2613–2614,
and references cited therein.
11. Chesnov, S.; Bigler, L.; Hesse, M. Helv. Chim. Acta 2000,
83, 3295–3305.
12. Frederic, M.; Scherman, D.; Byk, G. Tetrahedron Lett.
2000, 41, 675–679.
13. Dardonville, C.; Brun, R. J. Med. Chem. 2004, 47, 2296–
2307.
14. Bergeron, R. J.; McManis, J. S. J. Org. Chem. 1987, 52,
1700–1703.
15. Benn, M. H.; Shustov, G.; Shustova, L.; Majak, W.; Bai,
Y.; Fairey, N. A. J. Agric. Food Chem. 1996, 44, 2779–
2781.
16. Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J.
Org. Chem. 1998, 63, 3804–3805.
17. Yong, Y. F.; Kowalski, J. A.; Thoen, J. C.; Lipton, M. A.
Tetrahedron Lett. 1999, 40, 53–56.
18. Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677–
7680.
19. Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem.
1997, 62, 1540–1542; Recently, a polymer-supported
Mukaiyama reagent was reported: Convers, E.; Tye, H.;
Whittaker, M. Tetrahedron Lett. 2004, 45, 3401–3404.
20. The use of a polymeric carbodiimide to potentiate
guanylation has been recently reported: Guisado, O.;
Martinez, S.; Pastor, J. Tetrahedron Lett. 2002, 43, 7105–
7109.
21. Feichtinger, K.; Sings, H. L.; Baker, T. J.; Matthews, K.;
Goodman, M. J. Org. Chem. 1998, 63, 8432–8439.
22. Baker, T. J.; Goodman, M. Synthesis 1999, 1423–1426.
23. Vassis, S.; Govaris, I.; Voyatzi, K.; Mamos, P.; Papa-
ioannou, D. Tetrahedron Lett. 2002, 43, 2597–2600.
24. (a) Mamos, P.; Karigiannis, G.; Athanassopoulos, C.;
Bichta, S.; Kalpaxis, D.; Papaioannou, D. Tetrahedron
Lett. 1995, 36, 5187–5190; (b) Tsiakopoulos, N.; Dam-
ianakos, C.; Karigiannis, G.; Vahliotis, D.; Papaioannou,
D.; Sindona, G. Arkivoc. 2002(13), 79–104.
28. (a) Karigiannis, G.; Mamos, P.; Balayiannis, G.; Katsou-
lis, I.; Papaioannou, D. Tetrahedron Lett. 1998, 39, 5117–
5130; (b) Vassis, S.; Karigiannis, G.; Balayiannis, G.;
Militsopoulou, M.; Mamos, P.; Francis, G. W.; Papa-
ioannou, D. Tetrahedron Lett. 2001, 42, 1579–1582.
29. Characterization of representative products: 6d: foam; Rf
(PhMe/EtOAc = 7:3) 0.76; FT-IR: 3430, 1746, 1630, and
1604cmꢀ1
;
ESI-MS (m/z): 872.13 (M + H+), 630.09
(M + H+–Trt), 242.94 (Trt+); HR-MS (m/z): Found
872.5118 (M+ + 1), C56H66N5O4 requires M+ + 1 =
872.5109; H NMR (400MHz, CDCl3): d 9.85 (1H, br s,
1
BocNH), 7.45, 7.25, and 7.15 (30H, three m, Ph–H),
3.54 and 3.30 (4H, two unresolved m, CH2–
C(@NBoc)NHBoc), 2.10 (4H, unresolved t, TrtNHCH2),
1.74 (4H, unresolved quint., CH2–CH2–CH2), 1.41 (18H,
s, C–CH3) ppm; 13C NMR (100MHz CDCl3): d 155.6,
146.1, 128.6, 127.8, 125.3, 71.2, 48.2, 46.0, 43.4, 40.7, 31.2,
28.6, and 25.4ppm.
14b: foam; Rf (PhMe/EtOAc = 7:3) 0.68; FT-IR: 3398,
3303, and 1612cmꢀ1; ESI-MS (m/z): 797.19 (M+H+),
243.14 (Trt+); HR-MS (m/z): Found 797.4570 (M+ + 1),
C57H57N4 requires M+ + 1 = 797.4583; 1H NMR
(400MHz, CDCl3): d 7.45, 7.24, and 7.15 (30H, three m,
Ph–H), 6.97 (4H, d, J 8.3Hz, Ar–H), 6.51 (4H, d, J 8.4Hz,
Ar–H), 3.76 (2H, s, Ar–CH2-Ar), 3.18 (4H, t, J 6.6Hz,
ArN-CH2), 2.34 (4H, s, NH), 2.25 (4H, t, J 6.5Hz,
TrtNHCH2), 1.74 (4H, quint., J 6.5Hz, CH2–CH2–CH2)
ppm; 13C NMR (100MHz CDCl3): d 146.0, 128.2, 127.8,
126.3, 146.5, 130. 9, 129.6, 113.0, 71.1, 42.8, 41.8, 40.1, and
30.4ppm.
14c: foam; Rf (PhMe/EtOAc = 7:3) 0.61; FT-IR: 3270,
1765, 1634, and 1591cmꢀ1
; ESI-MS (m/z): 1282.53
25. Iwanowicz, E. J.; Poss, M. A.; Lin, J. Synth. Commun.
1993, 23, 1443–1445.
(M + H+), 1040.06 (M + H+–Trt), 243.13 (Trt+); HR-MS
(m/z): Found 1281.7124 (M+ + 1), C79H93N8O8 requires
M+ + 1 = 1281.7116; 1H NMR (400MHz, CDCl3): d 9.51
(2H, br s, BocNH), 7.44, 7.23 and 7.13 (30H, three m, Ph–
H), 7.00 (4H, d, J 8.4Hz, Ar–H), 6.90 (4H, d, J 8.4Hz,
Ar–H), 4.07 (4H, t, J 6.8Hz, ArN–CH2), 3.82(2H, s, Ar–
CH2–Ar), 2.35 (2H, s, TrtNH), 2.10 (4H, t, J 6.0Hz,
TrtNHCH2), 1.70 (4H, quint., J 6. 4Hz, CH2–CH2–CH2),
1.36 and 1.14 (36H, br s, C–CH3) ppm; 13C NMR
(100MHz CDCl3): d 154.7, 146.3, 140.5, 138.5, 129.2,
128.7, 127.7, 126.2, 126.0, 71.1, 40.7, 40.1, 29.7, 28.2, and
27.9ppm.
26. Typical guanylation: To an ice-cold solution of PA/PAC
(1mmol), DBTU [1.2mmol per secondary amino group
(p.sag)] and Et3N (1.2mmolp.sag) in anhydrous CH2Cl2
(10mL) was added MR (1.2mmol p.sag) and the resulting
mixture was stirred at 0°C for 10min and at 25°C for the
time indicated in Table 1. The solvent was evaporated and
the residue was taken up in EtOAc. Washing twice with
water, followed by drying (Na2SO4) and evaporation left
an oily residue, from which the guanylated compounds
were obtained pure by routine flash column chromato-