1742
R. G. Lovey et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1739–1742
afford 6.0 g (34%) of 13.5 Use of CuI gave similar results and
by-product distributions.
300MHz) d 8.32 (s, 1H), 8.25 (s, 1H), 7.83 (s, 1H), 7.49 (d, 2H,
J=9 Hz), 7.45–7.2 (m, 2H), 7.10 (d, 2H, J=9 Hz), 7.02
(m+half AB q, Án=8Hz, 3H total), 6.92 (half AB q,
Án=8Hz, 2H), 4.52 (s, 2H), 4.31 (m, 1H), 3.91 (m, 2H), 3.32
(m, 4H), 3.19 (m, 4H), 2.12 (m, 1H), 1.86 (m, 1H), 1.48 (m, 1H).
7. Base-catalyzed cyclization produced the same products, but
also more oligomeric by-product and lower yields.
8. (a) Heeres, J.; Hendrickx, R.; Van Cutsem, J. J. Med.
Chem. 1983, 26, 611. (b) Heeres, J.; Hendrickx, R.; Van Cut-
sem, J. J. Med. Chem. 1984, 27, 894.
9. Procedure: A mixture of 10 g (30 mmol) of 22b, 13.5 mL
(77 mmol) of diisopropylethylamine, and 200 mL of dry DMF
was treated with 11 mL (63 mmol) of MEM–chloride, and the
mixture was stirred for 24 h. The mixture was filtered, the fil-
trate was evaporated, the residue was treated with 300 mL of
cold MeOH and 300 mL of cold 6 N HCl, the solution was
stirred for 3 h, and then evaporated. The residue was chroma-
tographed (silica gel, 3:7 acetone–CH2Cl2) to afford 7.5 g
(67%) of 24.6 SEM-chloride could be substituted for MEM–
chloride with equal results.
10. Procedure: A mixture of 1.5 g (3.5 mmol) of 17, and 1.25 g
(3.8 mmol) of Cs2CO3 in 50 mL of dry DMF was stirred for
0.75 h. To the mixture was added 1.5 g (2.9 mmol) of 24, it was
stirred at 80 ꢁC for 18 h, then quenched in aqueous 5%
KH2PO4, extracted with EtOAc, evaporated, and the residue
was chromatographed (silica gel, 3:7 acetone–CH2Cl2) to
afford 1.44 g (58%) of 25.6
11. Minimum inhibitory concentrations were determined in
Sabouraud dextrose broth at pH 5.7 for Candida species and
dermatophytes, and in Eagle’s minimum essential medium at
pH 7.0 for Candida species. The MIC was defined as the low-
est concentration of test compound at which fungal growth
was completely inhibited when cultures were examined
visually in 96-well microtiter plates. Test compounds were
dissolved in DMSO or ethanol, serially diluted in growth
medium, inoculated with microorganism (ꢄ104/cc for SDB,
and 5ꢅ102/cc for EMEM), and incubated at 37 ꢁC in a CO2
environment for EMEM, and at 27 ꢁC for SDB. Growth MIC
was determined at 48 h for Candida species and at 72 h for
dermatophytes. All microorganisms used were from in-house
collections derived from clinical isolates. Confer: Lovey, R.
G.; Elliott, A. J.; Kaminski, J. J.; Loebenberg, D.; Parmegiani,
R. M.; Rane, D. F.; Girijavallabhan, V. M.; Pike, R. E.;
Guzik, H.; Antonacci, B.; Tomaine, T. Y. J. Med. Chem. 1992,
35, 4221.
5. This and subsequent compounds were examined for che-
mical homogeneity >97% by reverse-phase HPLC and TLC,
and chiral composition where applicable by HPLC on a chir-
alcel1 OD column with an appropriate EtOH–hexane eluant.
They were characterized by consistent mass spectra and PMR
spectra, and comparison to authentic samples1 where avail-
able. Selective analytical data are given in ref 6.
6. Data for selected compounds. 10: mp 162–163 ꢁC; [a]D21
+4.40ꢁ (c 1, CH2Cl2); H NMR (CDCl3, 200 MHz) d 8.19 (s,
1
1H), 7.82 (s, 1H), 7.64 (s, 1H), 7.45 (m, 3H), 7.1–6.8 (m, 8H),
4.63 (half AB q, Án=14 Hz, 1H), 4.40 (half AB q, Án=14 Hz,
1H), 4.39 (m, 1H), 4.08 (m, 1H), 3.90 (m, 2H), 3.38 (m, 4H),
3.22 (m, 4H), 2.54 (m, 1H), 2.38 (m, 1H), 2.0–1.5 (m, 6H), 0.89
(t, J=7.2 Hz, 9H). 11: mp 146–148 ꢁC; [a]D21 ꢀ8.59 (c 1,
CHCl3). 13: mp 80–81 ꢁC; [a]D21 ꢀ83.9ꢁ (c 1.4, CH2Cl2); 1H
NMR (CDCl3, 200 MHz) d 7.90 (s, 1H), 7.83 (s, 1H), 7.47 (m,
1H), 6.78 (m, 2H), 5.75 (m, 1H), 4.95 (m, 2H), 4.79 (half AB q,
Án=14 Hz, 1H), 4.46 (half AB q, Án=14 Hz, 1H), 2.14 (m,
2H), 1.82 (m, 2H). 14: mp 86–92 ꢁC; [a]D21 ꢀ62.7ꢁ (c 1.1,
1
CH2Cl2); H NMR (CDCl3, 200 MHz) d 7.94, (d, J=3.0 Hz,
1H), 7.83 (s, 1H), 7.47 (m, 1H), 6.77 (m, 2H), 4.74 (half AB q,
Án=14 Hz, 1H), 4.47 (half AB q, Án=14 Hz, 1H), 2.88 (m,
1H), 2.71 (m, 1H), 2.42 (m, 1H), 2.20 (m, 1H), 2.0–1.6 (m,
2H), 1.49 (q, J=5.6 Hz, 1H). 18: mp 150–151 ꢁC; [a]D21 ꢀ11.8ꢁ
(c 1, CHCl3); 1H NMR (CDCl3, 300 MHz) d 8.07 (s, 1H), 7.82
(s, 1H), 7.73 (m, 4H), 7.32 (m, 1H), 6.80 (m, 2H), 4.59 (half
AB q, Án=14 Hz, 1H), 4.39 (half AB q, Án=14 Hz, 1H), 4.3–
3.95 (m, 3H), 2.6 (m, 1H), 2.3 (m, 1H), 1.65 (m, 2H). 17: mp
21
113 ꢁC; [a]D ꢀ9.1ꢁ (c 1, CHCl3); H NMR (CDCl3, 300 MHz)
d 8.11, 7.78 (m, 5H), 7.28 (m, 2H), 6.80 (m, 2H), 4.53 (half AB
q, Án=15 Hz, 1H), 4.41 (half AB q, Án=15 Hz, 1H), 4.24 (m,
1H), 4.00 (m, 2H), 2.48 (m, 1H), 2.26 (m, 1H), 1.82 (m, 1H),
1
1
1.31 (m, 1H). 24: H NMR (CDCl3, 200 MHz) d 7.64 (s, 1H),
7.38 (half AB q, Án=9 Hz, 2H), 7.01 (half AB q, Án=9 Hz,
2H), 6.89 (half AB q, Án=8 Hz2H), 6.74 (half AB q,
Án=8 Hz, 2H), 5.31 (s, 2H), 3.72 (m, 2H), 3.58 (m, 2H), 3.4
(s+m, 7H), 3.20 (m, 4H). 25: 1H NMR (DMSO-d6, 300 MHz)
d 8.39 (s, 1H), 8.30 (s, 1H), 7.82 (s, 1H), 7.48 (d, J=9 Hz, 2H),
7.45–7.2 (m, 2H), 7.10 (d, J=9 Hz, 2H), 7.1–6.85 (m+half AB
q, Án=8 Hz, 3H total), 6.90 (half AB q, Án=8 Hz, 2H), 5.13
(s, 2H), 4.52 (s, 2H), 4.30 (m, 1H), 3.92 (m, 2H), 3.64 (m, 2H),
3.44 (m, 2H), 3.2 (m, 4H), 3.22 (s, 3H), 3.18 (m, 4H), 2.13 (m,
1H), 1.83 (m, 1H), 1.46 (m, 1H). 27: 1H NMR (DMSO-d6,