2444
R. Messer et al.
LETTER
procedure including an additional final washing step with CH2Cl2 (1
mL). The portions carrying compounds 9 and 11 were put aside for
the final cleaving step. The remaining two portions were again sus-
pended in CH2Cl2 (1.5 mL). The material was split into 3 equal frac-
tions. One fraction of each series (containing compounds 10 and 12)
was again saved for final cleavage from the support. The two re-
maining portions of each series were further derivatised as de-
scribed below.
169.2, 157.0, 149.3, 146.0, 143.8, 140.1, 139.6, 129.5, 129.4, 129.1,
128.4, 129.1, 127.9, 123.0, 120.3, 119.0, 115.3, 113.0, 112.2, 106.4,
78.5, 76.0, 71.8, 58.7, 55.7, 43.8, 42.8, 42.0, 41.4, 39.7, 34.3. ESI-
MS (positive mode): 674 [M+ + Na+], 651 [M+], 621, 620. HRMS:
m/z calcd for C33H38N4O10Na: 637.2485; found: 673.2480.
Acknowledgment
Financial support by the Swiss National Foundation (grant 200021-
101861/1) is gratefully acknowledged. We thank L. Moesch for ex-
cellent technical assistance.
Aminolysis of the Lactone
The remaining portions of resin obtained as described above were
treated with an excess of the corresponding amine (20 equiv) in the
presence of 2-hydroxy pyridine (4 equiv) in 0.5 mL THF.
References
Cleavage of the Products from the Supports
(1) Newmann, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod.
2003, 1022.
(2) Messer, R.; Fuhrer, C. A.; Häner, R. Curr. Opin. Chem. Biol.
2005, 259.
(3) (a) Guella, G.; Dini, F.; Pietra, F. Helv. Chim. Acta 1996,
710. (b) Nakatsu, T.; Ravi, B. N.; Faulkner, D. J. Org. Chem.
1981, 2435. (c) Ge, Y.; Kondo, S.; Odagaki, Y.; Katsumura,
S.; Nakatani, K.; Isoe, S. Tetrahedron 1993, 10555. (d) Ge,
Y.; Nakatani, K.; Isoe, S. Bioorg. Med. Chem. Lett. 1993,
1085.
(4) Messer, R.; Schmitz, A.; Moesch, L.; Häner, R. J. Org.
Chem. 2004, 8558.
(5) (a) Pirrung, M. C. Chem. Rev. 1997, 473. (b) Adel, N.;
Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 449.
(6) Schmidt, R. R.; Heermann, D.; Jung, K. J. Liebigs Ann.
Chem. 1974, 1856.
The compounds so obtained were cleaved from the support by five
repetitive treatments with 0.6 mL of a mixture of H2O–TFA–
CH2Cl2 (1:19:80) for 15 min. The thus obtained solutions contain-
ing the products were collected in round-bottom flasks and concen-
trated. The obtained crude materials (purity generally >80%) were
re-dissolved in MeOH and concentrated again before purification
by normal phase HPLC (LiChrospher® Si 60, 10 mm) using isocratic
elution with MeCN.
(2R,2aR,4aS,6S,7aS,7bS)-6-{3-[(Furan-2-carbonyl)amino]phe-
nyl}-2-methoxy-4-oxohexahydro-1,3,7-trioxacyclopenta[cd]in-
dene-7a-carboxylic Acid [(2-Methoxyethyl-carbamoyl)meth-
yl]amide (12)
Yield 6.0 mg (71%). TLC (MeCN): Rf = 0.46; HPLC: tR = 8.55,
l
max = 276 nm. 1H NMR (300 MHz, acetone-d6): d = 9.46 (1 H, br),
7.94–7.90 (1 H,), 7.76–7.75 (1 H, m), 7.69 (1 H, m), 7.73 (1 H, br),
7.37–7.31 (1 H, t, J = 7.9 Hz), 7.24–7.23 (1 H, m), 7.19–7.16 (1 H,
m), 7.10 (1 H, br), 6.66–6.64 (1 H, m), 5.28 (1 H, s), 4.93 (1 H, d,
J = 6.2 Hz), 4.81 (1 H, dd, J = 9.7, 6.5 Hz), 4.01–3.86 (3 H, m), 3.42
(7) Papa, D.; Schwenk, E.; Villani, F.; Klingsberg, E. J. Am.
Chem. Soc. 1948, 3356.
(8) Other conditions and different coupling reagents were tried
but did not result in an improvement of the yields.
(9) In a preliminary experiment, the yield could be improved
using different conditions. Thus, the use of lithium
perchlorate (1.5 M) in MeCN as a catalyst allowed
cyclisation of 5a at a temperature of 50 °C in 50 h.
Compound 6a was isolated in a 55% yield. Further
experiments in this direction are ongoing.
(3 H, s), 3.42–3.34 (5 H, m), 3.24 (3 H, s), 2.44–2.19 (2 H, m). 13
C
NMR (75 MHz, acetone-d6): d = 178.1, 169.6, 169.2, 157.1, 146.0,
143.4, 139.8, 129.7, 122.7, 120.5, 120.4, 119.2, 115.4, 113.0, 107.7,
84.9, 73.4, 71.8, 58.7, 55.9, 43.3, 39.8, 39.0, 36.4, 28.3. ESI-MS
(positive mode): 566 [M+ + Na+], 544 [M+], 512. HRMS: m/z calcd
for C26H29N3O10Na: 566.1750; found: 566.1769.
(10) Sharma, S. K.; Songster, M. F.; Colpitts, T. L.; Hegyes, P.;
Barany, G.; Castellino, F. J. J. Org. Chem. 1993, 58, 4993.
(11) HCTU: N-[(1H-6-chlorobenzotriazol-1-yl)(dimethyl-
amino)methylene]-N-methylmethanaminium hexafluoro-
phosphate N-oxide.
(12) The loading efficiency was determined by UV spectrometric
quantification of the dibenzofulvene–piperidine adduct
formed during deprotection (lmax = 302 nm, e = 7800), see:
Carpino, L. A.; Han, G. Y. J. Org. Chem. 1972, 3404.
(13) Tan, D. S.; Foley, M. A.; Shair, M. D.; Schreiber, S. L. J.
Am. Chem. Soc. 1998, 8565.
(2R,3R,3aS,4S,6S,7aS)-6-{3-[(Furan-2-carbonyl)amino]phe-
nyl}-3-hydroxy-2-methoxyhexahydrofuro[2,3-b]pyran-4,7a-di-
carboxylic Acid 4-Benzylamide 7a-{[(2-methoxyethyl-
carbamoyl)methyl]amide} (15)
Yield 7.0 mg (70%). TLC (EtOAc): Rf = 0.15; HPLC: tR = 8.61,
l
max = 277 nm. 1H NMR (300 MHz, acetone-d6): d = 9.47 (1 H, br),
8.26 (1 H, br), 7.92–7.88 (1 H, m), 7.77 (1 H, m), 7.75–7.74 (1 H,
m), 7.73–7.72 (1 H, m), 7.37–7.18 (9 H, m), 6.65–6.63 (1 H, m),
5.13 (1 H, s), 4.92 (1 H, dd, J = 11.9, 2.3 Hz), 4.49 (2 H, s), 4.28 (1
H, d, J = 6.0 Hz), 3.98–3.82 (2 H, m), 3.38–3.36 (5 H, m), 3.36 (3
H, s), 3.24 (3 H, s), 2.93–2.89 (2 H, m), 2.43–2.31 (1 H, m), 1.88–
1.82 (1 H, m). 13C NMR (75 MHz, acetone-d6): d = 175.0, 169.8,
Synlett 2005, No. 16, 2441–2444 © Thieme Stuttgart · New York