I. Paterson, O. Delgado / Tetrahedron Letters 44 (2003) 8877–8882
8881
Acknowledgements
7. A 20,000 step Monte Carlo search was performed for the
structures 1, 3 and 4 using the AMBER force field, together
with the generalised Born/surface area (CB/SA) water
solvent model. Mohamadi, F.; Richards, N. G. J.; Guida,
W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.;
Hendrickson, T.; Still, W. C. J. Comp. Chem. 1990, 11, 440.
8. In each case, we found several discrete families of low energy
conformations, as anticipated from the results of Snyder
and co-workers. For conformational studies on discoder-
molide, see: (a) Monteagudo, E.; Cicero, D. O.; Cornett,
B.; Myles D. C.; Snyder, J. P. J. Am. Chem. Soc. 2001, 123,
6929; (b) Smith, A. B., III; La Marche, M. J.; Falcone-Hin-
dley, M. Org. Lett. 2001, 3, 695.
We thank the EC (Network HPRN-CT-200-0018),
Gobierno de Canarias, Cambridge European Trust and
Novartis Pharma AG for support, and Professor J.
Vilarrasa and Oriol Pineda (University of Barcelona)
for helpful discussions over the modelling studies.
References
1. For recent reviews, see: (a) Paterson, I.; Florence, G. J. Eur.
J. Org. Chem. 2003, 2193; (b) Kalesse, M. ChemBioChem
2000, 1, 171.
2. Isolation and structure determination: Gunasekera, S. P.;
Gunasekera, M.; Longley, R. E.; Schulte, G. K. J. Org.
Chem. 1990, 55, 4912. Additions and corrections: J. Org.
Chem. 1991, 56, 1346.
9. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.;
Piancatelli, G. J. Org. Chem. 1997, 62, 6974.
10. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
11. Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
12. (a) Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann,
R. C.; McClure, C. K.; Norcross, R. D. Tetrahedron 1990,
46, 4663; (b) Paterson, I.; Oballa, R. M.; Norcross, R. D.
Tetrahedron Lett. 1996, 37, 8581.
3. For biological studies, see: (a) ter Haar, E.; Kowalski, R.
J.; Hamel, E.; Lin, C. M.; Longley, R. E.; Gunasekera, S.
P.; Rosenkranz, H. S.; Day, B. W. Biochemistry 1996, 35,
243; (b) Schreiber, S. L.; Chen, J.; Hung, D. T. Chem. Biol.
1996, 3, 287; (c) Kowalski, R. J.; Giannakakou, P.;
Gunasekera, S. P.; Longley, R. E.; Day, B. W.; Hamel, E.
Mol. Pharmacol. 1997, 52, 613; (d) Balachandran, R.; ter
Haar, E.; Welsh, M. J.; Grant, S. G.; Day, B. W.
Anti-Cancer Drugs 1998, 9, 67; (e) Martello, M. A.;
McDaid, H. M.; Regl, D. L.; Yang, C. H.; Meng, D.; Pettus,
T. R. R.; Kaufman, M. D.; Arimoto, H.; Danishefsky, S.
J.; Smith, A. B., III; Horwitz, S. B. Clin. Cancer Res. 2000,
6, 1978; (f) Kar, S.; Florence, G. J.; Paterson, I.; Amos,
L. A. FEBS Letters 2003, 539, 34.
4. Kinder, F. R.; Bair, K. W.; Chen, W. C.; Florence, G.;
Francavilla, C.; Geng, P.; Gunasekera, S.; Lassota, P. T.;
Longley, R. E.; Palermo, M. G.; Paterson, I.; Pomponi, S.;
Ramsay, T. M.; Rogers, L.; Sabio, M.; Sereinig, N.;
Sorenson, E.; Wang, R. M.; Wright, A.; Guo, Q. Abstracts
of Papers, 224th National Meeting of the American
Chemical Society, Boston, MA, August 18–22, 2002;
236-MEDI, Part 2; ACS, Washington, DC, 2002.
5. (a) Paterson, I.; Florence, G. J. Tetrahedron Lett. 2000, 41,
6935; (b) Nerenberg, J. B.; Hung, D. T.; Schreiber, S. L.
J. Am. Chem. Soc. 1996, 118, 11054; (c) Martello, L. A.;
LaMarche, M. J.; He, L.; Beauchamp, T. J.; Smith, A. B.;
Horwitz, S. B. Chem. Biol. 2001, 8, 843; (d) Gunasekera,
S. P.; Longley, R. E.; Isbrucker, R. A. J. Nat. Prod. 2001,
64, 171; (e) Gunasekera, S. P.; Paul, G. K.; Longley, R.
E.; Isbrucker, R. A.; Pomponi, S. A. J. Nat. Prod. 2002,
65, 1643; (f) Gunasekera, S. P.; Longley, R. E.; Isbrucker,
R. A. J. Nat. Prod. 2002, 65, 1830; (g) Shin, Y.; Choy, N.;
Turner, T. R.; Balachandran, R.; Madiraju, C.; Day, B. W.;
Curran, D. P. Org. Lett. 2002, 4, 4443; (h) Choy, N.; Shin,
Y.; Nguyen, P. Q.; Curran, D. P.; Balachandran, R.;
Madiraju, C.; Day, B. W. J. Med. Chem. 2003, 46, 2846;
(i) Minguez, J. M.; Kim, S.-Y.; Giulano, K. A.; Balachan-
dran, R.; Madiraju, C.; Day, B. W.; Curran, D. P. Biorg.
Med. Chem. 2003, 11, 3335.
13. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am.
Chem. Soc. 1988, 110, 3560.
14. All new compounds gave spectroscopic data in agreement
with the structures indicated. Analogue 3 had 1H NMR (500
MHz, CDCl3) lH 6.61 (1H, ddd, J=16.8, 10.8, 10.4 Hz,
H23), 6.04 (1H, app t, J=11.0 Hz, H22), 5.53 (1H, dd,
J=11.0, 8.0 Hz, H8), 5.41 (1H, dd, J=10.7, 10.5 Hz, H9),
5.34 (1H, dd, J=10.4, 10.3 Hz, H21), 5.24 (2H, m, H13,
H24A), 5.13 (1H, d, J=10.3 Hz, H24B), 4.74 (1H, ddd,
J=10.3, 8.0, 3.4 Hz, H7), 4.70–4.58 (4H, m, H5, H19,
CONH2), 3.82 (1H, br d, J=11.0 Hz, H25A), 3.73 (1H, dd,
J=3.8, 3.8 Hz, H3), 3.58–3.54 (2H, m, H17, H25B), 3.20 (1H,
dd, J=6.8, 4.3 Hz, H11), 3.00 (1H, ddq, J=10.1, 6.8, 6.8
Hz, H20), 2.78 (1H, ddq, J=9.7, 6.7, 6.7 Hz, H10), 2.66 (1H,
qd, J=7.1, 4.4 Hz, H2), 2.63–2.56 (1H, m, H12), 2.14–1.87
(8H, m, H4, H6A, H15A, H15B, H18, 3×OH), 1.78–1.61 (5H,
m obs, H6B, 14-Me, OH), 1.33 (3H, d, J=7.3 Hz, 2-Me),
1.08 (3H, d, J=7.1 Hz, 4-Me), 1.05–0.99 (9H, d, 10-Me,
18-Me, 20-Me), 0.97 (3H, d, J=7.0 Hz, 12-Me); 13C NMR
(125 MHz, CDCl3) lC 173.8, 157.3, 134.5, 133.3, 132.9,
132.5, 132.0, 130.6, 130.1, 118.2, 79.5, 79.0, 73.2, 64.3, 43.1,
40.9, 39.1, 37.7, 36.2, 35.7, 35.3, 35.1, 31.2, 31.1, 30.9, 29.7,
23.3, 18.3, 17.5, 15.6, 15.3, 12.6, 8.4; HRMS (ES+) calcd
for C33H55NO9Na [M+Na]+ 615.3775, found 615.3765.
Analogue 4 had 1H NMR (500 MHz, CDCl3) lH 6.62 (1H,
ddd, J=16.9, 10.8, 10.5 Hz, H23), 6.03 (1H, app t, J=11.0
Hz, H22), 5.53 (1H, dd, J=11.1, 7.7 Hz, H8), 5.44 (1H, dd,
J=10.7, 10.3 Hz, H9), 5.29 (1H, dd, J=10.6, 10.4 Hz, H21),
5.21 (1H, dd, J=16.8, 1.2 Hz, H24A), 5.15–5.09 (2H, m, H13,
H24B), 4.73 (1H, ddd, J=8.3, 8.3, 3.2 Hz, H7), 4.65–4.59
(2H, m, H5, H19), 4.58 (2H, br s, CONH2), 4.53 (1H, dd,
J=7.9, 6.1 Hz, H25A), 4.25–4.21 (2H, m, H17, H25B), 3.74
(1H, dd, J=4.1, 3.9 Hz, H3), 3.19 (1H, dd, J=6.6, 5.2 Hz,
H11), 2.98 (1H, ddq, J=9.0, 6.9, 6.9 Hz, H20), 2.81–2.65
(3H, m, H2, H10, H16), 2.63 (1H, ddq, J=10.1, 6.9, 6.9 Hz,
H12), 2.46 (1H, dd, J=13.7, 10.6 Hz, H15A), 2.36 (1H, dd,
J=13.8, 5.0 Hz, H15B), 2.22–2.00 (4H, m, H4, 3×OH), 1.86
(1H, ddq, J=13.5, 6.8, 3.4 Hz, H18), 1.73 (1H, ddd, J=14.4,
9.4, 2.4, H6A), 1.72 (1H, ddd, J=14.2, 10.7, 3.3 Hz, H6B),
1.62 (3H, s, 14-Me), 1.33 (3H, d, J=7.2 Hz, 2-Me), 1.09
(3H, d, J=6.9 Hz, 18-Me), 1.05 (3H, d, J=6.9 Hz, 10-Me),
1.04–1.00 (6H, m, 4-Me, 20-Me), 0.97 (3H, d, J=6.8 Hz,
12-Me); 13C NMR (125 MHz, CDCl3) lC 173.7, 156.6,
6. (a) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.
Angew. Chem. Int. Ed. 2000, 39, 377; (b) Paterson, I.;
Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, S. J. Am.
Chem. Soc 2001, 123, 9535; (c) Paterson, I.; Delgado, O.;
Florence, G. J.; Lyothier, I.; Scott, J.; Sereinig, N. Org. Lett.
2003, 5, 35.