M. R. Linder et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4140–4143
4143
(acetone-d6) 300 MHz d 8.26 (s, 1H), 8.18 (s, 1H), 8.08
(s, 1H), 5.57 (d, J = 4.6 Hz, 1H), 5.15 (s, 2H), 4.93 (dd,
J1 = J2 = 6.9 Hz, 1H), 4.24 (d, J = 9.4 Hz, 1H), 3.94 (br s,
1H), 3.74 (s, 1H), 3.06 (dd, J1 = 15.5 Hz, J2 = 6.7 Hz, 1H),
2.95–2.80 (m, 3H), 1.94 (m, 1H), 1.83–1.67, 1.62–1.47,
1.41–1.30 (3m, 9H), 1.45 (s, 9H), 1.20–1.11 (m, 1H), 1.00
(s, 3H), 0.94 (s, 3H), 0.85 (s, 3H); 13C NMR (acetone-d6)
75 MHz d 201.5, 159.9, 156.3, 150.3, 148.7, 133.6, 133.2,
129.1, 128.1, 123.3, 107.3, 90.0, 79.8, 71.1, 54.9, 50.6, 53.0,
49.3, 48.3, 41.1, 41.0, 40.8, 33.4, 28.6, 27.3, 26.1, 21.0, 20.4,
tiomeric excesses, and W. Dindorf from the University
of Mainz for elemental analyses, S. Gawlowska for the
performance of in vitro Cryptosporidium assays, and
U. Deutsch for the performance of toxicity studies.
Supplementary data
Supplementary data associated with this article can be
21.2,
19.1,
15.2;
MS
(API-ES)
m/z:
414
20
[MꢀC5H9O2ꢀC12H19O2+H]+; de > 99%; mp: 132 ꢂC;½aꢂD
+71 (c 0.5, DMF). Compound (2R,3S)-1: colorless solid.
1H NMR (DMSO-d6) 300 MHz d 8.23 (s, 1H), 8.22 (s,
1H), 8.15 (s, 1H), 4.98 (s, 2H), 4.75 (d, J = 5.8 Hz, 1H),
2.96 (m, 2H), 2.78 (d, J = 11.5 Hz, 1H), 2.63, (ddd,
J1 = 12.3 Hz, J2 = 8.9 Hz, J3 = 3.6 Hz, 1H), 2.43 (dd,
J1 = 15.5 Hz, J2 = 8.9 Hz, 1H), 2.33 (dd, J1 = 11.8 Hz,
J2 = 2.3 Hz, 1H), 2.09 (br s, 1H), 1.88 (d, J = 11.5 Hz, 1H),
1.56 (d, J = 12.5 Hz, 1H), 1.33 (m, 1H), 1.19 (m, 1H); 13C
NMR (DMSO-d6) 75 MHz d: 203.5, 158.6, 149.7, 147.3,
132.4, 131.7, 128.3, 126.9, 121.8, 70.7, 60.1, 54.8, 45.6,
References and notes
1. Pines, M.; Vlodavsky, I.; Nagler, A. Drug Dev. Res. 2000,
50, 371.
2. Nowak, R. A. Drug Discov. Today: Therap. Strat. 2004, 1,
237.
3. Peregrine, A. S. Vet. Parasitol. 1994, 54, 223.
4. Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kin,
H.-S.; Wataya, Y. J. Org. Chem. 1999, 64, 6833.
5. Agranat, I.; Caner, H.; Caldwell, J. Nature Rev. Drug
Disc. 2002, 1, 753.
20
43.7, 34.2, 25.8; ee > 99%; mp: 170 ꢂC (decomp.); ½aꢂD
+9.4 (c 0.5, DMF); Anal. (C16H17BrClN3O3) C, H, N.
Compound (2S,3R)-1: colorless solid.1H NMR and 13C
NMR as for (2R,3S)-1; ee > 99%; mp: 160 ꢂC (decomp.);
6. Jolly, J.; Rizzi, P.; Grandadam, J. A. U.S. Patent,
4,252,947, 1977.
20
½aꢂD ꢀ10 (c 0.5, DMF); Anal. (C16H17BrClN3O3) C, H, N.
7. Oalmann, C. J.; Richard, J.; Bockovich, N. Abstracts of
Papers, 232nd National Meeting of the American Chem-
ical Society, San Francisco, CA, United States, Sept 10–
14, 2006; American Chemical Society: Washington, DC,
2006; ORGN-071.
Compound (2R,3S)-1, lactate: colorless solid.1H NMR
(DMSO-d6) 300 MHz d 8.25 (s, 1H), 8.23 (s, 1H), 8.17 (s,
1H), 5.00 (s, 2H), 3.94 (q, J = 6.8 Hz, 1H), 3.08 (ddd,
J1 = 9.9 Hz, J2 = J3 = 4.4 Hz, 1H), 3.02 (dd, J1 = 15.9 Hz,
J2 = 4.0 Hz, 1H), 2.86 (d = J = 12.4 Hz, 1H), 2.76 (ddd,
J1 = 8.4 Hz, J2 = J3 = 3.8 Hz, 1H), 2.54 (dd, J1 = 15.8 Hz,
J2 = 8.3 Hz, 1H), 2.45 (dd, J1 = 11.7 Hz, J2 = 2.6 Hz, 1H),
1.90 (m, 1H), 1.61 (m, 1H), 1.42–1.23 (m, 2H), 1.20 (d,
J = 6.9 Hz, 3H); 13C NMR (DMSO-d6) 75 MHz d 202.8,
176.8, 158.7, 149.7, 147.3, 132.4, 131.7, 128.3, 126.9, 121.8,
69.8, 66.1, 59.1, 54.7, 44.9, 42.6, 33.4, 24.5, 20.7; MS (API-
ES) m/z 414 [M+H]+; ee > 99%; mp: 161 ꢂC (decom-
8. (rac)-1 was obtained from Intervet-internal sources.
9. Noe, C. R. Chem. Ber. 1982, 115, 1591.
10. Compound (rac)-3: pale brown solid. H NMR (CDCl3)
1
300 MHz d 8.30 (s, 1H), 8.05 (s, 1H), 8.04 (s, 1H), 5.08 (d,
J = 17.5 Hz, 1H), 4.95 (d, J = 17.5 Hz, 1H), 4.66 (m, 1H),
3.93 (s, 1H), 3.88 (s, 1H), 2.95 (t, J = 11.7 Hz, 1H), 2.80 (d.
J = 4.0 Hz, 1H), 2.77 (s, 1H), 2.75–2.70 (m, 1H), 1.91–1.64
(m, 3H), 1.43 (s, 10H); 13C NMR (CDCl3) 75 MHz d
199.5, 159.5, 156.3, 148.2, 146.8, 133.6, 132.5, 129.6, 127.6,
121.8, 80.7, 67.5, 54.5, 53.8, 40.7, 39.7, 28.4, 26.3, 19.0; MS
(API-ES) m/z: 414 [MꢀC5H9O2+H]+. Compound
(2R,3S)-4: colorless solid. 1H NMR (acetone-d6)
400 MHz d 8.24 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 5.48
(d, J = 5.0 Hz, 1H), 5.20 (d, J = 18.5 Hz, 1H), 5.08 (d,
J = 18.5 Hz, 1H), 4.91 (s, 1H), 4.45 (d, J = 8.1 Hz, 1H),
3.91 (d, J = 11.9 Hz, 1H), 3.74 (s, 1H), 3.00–2.78 (m, 4H),
1.90 (ddd, J1 = 13.2 Hz, J2 = 6.8 Hz, J3 = 5.2 Hz, 1H),
1.78–1.47, 1.40–1.37 (2m, 9H), 1.43 (s, 9H), 1.18–1.11 (m,
1H), 1.00 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H); 13C NMR
(acetone-d6) 75 MHz d 201.1, 159.8, 156.1, 150.3, 148.7,
133.5, 133.1, 129.1, 128.1, 123.2, 109.0, 89.7, 79.8, 72.1,
54.5, 53.7, 53.1, 49.2, 48.4, 41.1, 41.0, 39.7, 33.5, 28.7, 27.3,
24.5, 21.0, 20.1, 21.2, 19.1, 15.2; MS (API-ES) m/z: 414
20
p.);½aꢂD +11.8 (c 0.5, DMF). Compound (2S,3R)-1,
lactate: colorless solid.[1]H NMR and 13C NMR as for
20
(2R,3S)-1, lactate; ee > 99%; mp: 163 ꢂC (decomp.); ½aꢂD
ꢀ11.0 (c 0.5, DMF) Determination of lactate content on a
Metrohm 761 Compact Ion Chromatograph: Metrosep A
Supp 5 (150 · 4.0 mm, 5 lm), NaHCO3 (1 mM)/Na2CO3
(3.2 mM), flow 0.7 ml/min.
11. Crystallographic data (excluding structure factors) for
the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as sup-
plementary publication numbers CCDC612821. Copies
of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
12. Najdrowski, M.; Heckeroth, A. R.; Wackwitz, C.; Gaw-
lowska, S.; Mackenstedt, U.; Kliemt, D.; Daugschies, A.
Parasitol. Res. 2007, 101, 161.
20
[MꢀC5H9O2ꢀC12H19O2+H]+; de > 99%; mp: 151 ꢂC; ½aꢂD
+40 (c 0.5, DMF). Compound (2S,3R)-4: 1H NMR