N. German et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1368–1373
1373
Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc.
2001, 123, 1004.
31. Reductive amination employed standard conditions using
sodium triacetoxyborohydride. After purification of Boc-
protected intermediates by flash chromatography the Boc
groups were removed as described in Ref. 29 to provide
previously unreported 20 and 21. (20) 1H NMR
(300 MHz, (MeOD) d = 7.32 (m, 2H), 7.13 (m, 4H), 6.68
(dt, J = 1.3, J = 7.2 Hz, 1H), 6.48 (dd, J = 4.2, J = 0.9 Hz,
2H), 3.69 (ddd, J = 1.2 Hz, J = 3.1 Hz, J = 6.6 Hz, 1H),
3.48 (dt, J = 1.5 Hz, J = 13 Hz, 1H), 3.32 (m, 1H), 3.11 (dt,
J = 4.2 Hz, J = 12.7 Hz, 1H), 3.02–2.84 (m, 3H), 2.74 (dt,
J = 4.6 Hz, J = 11.0 Hz, 1H), 2.37 (m, 1H), 2.01 (m,
2H).13C NMR (75 MHz, (MeOD) d = 30.64, 38.49, 43,
43.10, 44.49, 112.64, 115.25, 117.14, 128.92, 138.16,
147.57, 160.42, 163.66. HRMS (ESI): calcd for (M+H+);
285.1722, found; 285.1723. (21) 1H NMR (300 MHz,
(acetone-d6) d = 7.10 (m, 2H), 6.65 (m, 3H), 3.67 (d, J = 12
Hz, 1H), 3.54 (d, J = 12.7 Hz, 1H), 3.18 (dd, J = 2.3,
J = 6.6 Hz, 2H), 3.09 (m, 1H), 2.94 (t, J = 12 Hz, 1H), 2.31
(m, 1H), 1.77–2.12 (m, 7H), 1.43(m, 1H).13C NMR
(75 MHz, (CDCl3) d = 30.64, 38.49, 43, 43.10, 44.49,
112.64, 115.25, 117.14, 128.92, 138.16, 147.57, 160.42,
163.66. HRMS (ESI): calcd for (M+H+); 191.1504, found;
191.1514.
28. 3-Aryloxymethyl piperidines 12–17 were synthesized
from mesylates 10 and 11 using conditions for mesylate
displacement and Boc removal as previously described
(Johnson et al., see Ref. 27). Characterization of
previously described 12, 13, and 14 by NMR and Mass.
Spec. confirmed structure. For unreported derivatives
15–17: (15) 1H NMR (300 MHz, (CDCl3) d = 7.21 (d,
J = 8.4 Hz), 7.06 (dd, J = 2.0, J = 4 Hz, 1H), 7.00 (d,
J = 2.0 Hz, 1H), 3.99 (ddd, J = 4.0, J = 6.0, J = 9 Hz,
2H), 3.51 (m, 2H), 2.91 (m, 2H), 2.5 (m, 1H), 1.99
(m,3H), 1,62 (m, 2H), 1.20 (m, 2H). 13C NMR
(75 MHz, (CDCl3) d = 21.70, 25.43, 33.69, 44.07, 46.26,
70.60, 116.79, 120.63, 122.23, 124.96, 131.16, 154.38.
HRMS (ESI): calcd for (M+H+); 307.0005, found;
306.9976. (16) 1H NMR (300 MHz, (CDCl3) d = 7.20
(m, 4H), 7.0 (m, 3 H), 6.74 (d, J = 1.5 Hz, 1H), 4.83 (bs,
1H), 3.68 (m, 4H), 3.23 (m, 1H), 3.00 (m, 2H), 2.52 (m,
1H), 2.13 (m, 2H). 13C NMR (75 MHz, (dmso-d6)
d = 30.57, 38.87, 44.15, 46.30, 68.87, 115.96, 116.25,
117.29, 120.93, 121.41, 125.12, 129.42, 129.49, 129.52,
131.72, 138.73, 143.81, 154.61, 159.96, 163.20. HRMS
(ESI): calcd for (M+H+) 401.0224, found; 401.0194. (17)
1H NMR (300 MHz, (CDCl3) d = 6.68 (d, J = 8.1 Hz,
1H), 6.44 (s, 1H), 6.26 (d, J = 8 Hz, 1H), 5.91 (s, 2H),
3.79 (m, 2H), 3.52(m, 2H), 2.87 (m, 2H), 2.36 (m, 1H),
1.89 (m, 3H). 13C NMR (75 MHz, (CDCl3) d = 21.78,
25.32, 33.86, 44.74, 47.12, 60.45, 70.31, 98.05, 101.22,
105.54, 107.93, 142.06, 148.31, 153.88. HRMS (ESI):
calcd for (M+H+); 236.1208, found; 236.1248.
29. For previously unreported thioethers 8 and 9: Bu3P
(96 lL, 0.38 mmol) was added to a stirred solution of 6
or 7 (0.12/0.14 mmol) in pyridine (3 mL) containing (PhS)2
(91 mg, 0.42 mmol). After 24 hr at rt the mixture was
poured onto stirred crushed ice. Extraction with ethyl
acetate was followed by washing with 10% HCL, 25%
NaOH, then brine. After separation of product by flash
chromatography (1:4 Ethyl Acetate/Hexanes), product
was dissolved in dichloromethane (5 mL) and treated with
p-toluenethiol (1 equiv)/trifluoroacetic acid (0.5 mL). After
5 h the mixture was concentrated by evaporation, washed
with hexanes (5 · 20 mL) and solids dried to give 8 (80%)
and 9 (85%). (8) 1H NMR (300 MHz, (CDCl3) d = 7.2 (m,
5H), 7.03 (m, 4H), 3.86 (d, J = 12 Hz, 1H), 3.53 (d,
J = 12 Hz, 1H), 3.02 (q, J = 9.6, J = 13.2 Hz, 1H), 2.87 (m,
2H), 2.64 (dt, J = 4.2 Hz, J = 11 Hz, 1H), 2.43 (m, 2H),
2.03 (m, 2H). )13C NMR (75 MHz, (CDCl3) d = 30.75,
35.88, 38.78, 44.52, 44.95, 47.91, 115.92, 127.08, 128.88,
130.62, 134.73, 136.708. (9) 1H NMR (300 MHz, (CDCl3)
d = 7.31 (m, 5H), 3.62 (d, J = 11.4 Hz, 1H), 3.43 (d,
J = 12 Hz, 1H), 2.88 (m, 3H), 2.70 (t, J = 12 Hz, 1H), 1.93
(m, 4H), 1.31 (m, 1H)13C NMR (75 MHz, (CDCl3)
d = 21.81, 28.48, 33.43, 37.94, 44.23, 48.11, 126.88,
129.17, 130.21, 135.27.
32. Wittig salt 22 was synthesized in four steps from 5-bromo-
2-chlorobenzoic acid and has been previously reported,
see; Plater, M. J. J. Chem. Soc. Perkin Trans. I 1997, 19,
2903.
33. Standard Witting olefination procedures using NaH in
DMSO at 60ꢁC followed by work-up and flash chroma-
tography (1:6, AcOEt:Hexane) afforded the Boc-protected
intermediates, which were subjected to Boc removal as
described in Ref.29 to provide previously unreported 23
and 24. (23)1H NMR (300 MHz, (CDCl3) d = 7.45 (d,
J = 14.4 Hz, 1H), 7.23 (m, 3H), 7.10 (d, J = 8.5 H), 6.94 (t,
J = 8.5, J = 10 Hz, 2H), 6.39 (d, J = 18.6 Hz, 1H), 6.00
(dd, J = 9 Hz, J = 16 Hz, 1H), 13C NMR (75 MHz,
(DMSO-d6) d = 30.57, 44.14, 46.30, 68.87, 115.96,
116.25, 117.29, 120.93, 121.40, 125.12, 129.52, 131.72,
138.66, 138.73, 1143.81, 154.61, 159.60 (JCF = 210 Hz).
HRMS (ESI): calcd for (M+H+); 396.0275, found;
396.0772. 24: 1H NMR (300 MHz, (DMSO-d6) d = 9.06
(br s, 1H), 7.87 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.40 (d,
J = 8.4 Hz, 1H), 6.65 (d, J = 15.9 Hz, 1H), 6.42 (dd, J = 6,
J = 15.9 Hz, 1H), 3.24 (m, 2H), 2.75 (m, 3H), 1.83 (m,
2H), 1.44 (q, J = 10 Hz, 1H). 13C NMR (75 MHz,
(DMSO-d6) d = 21.74, 28.34, 36.76, 43.38, 47.38, 120.94,
124.82, 129.80, 131.30, 131.93, 132.10, 136.29, 137.06.
HRMS (ESI): calcd for (M+H+); 303.0056, found;
303.0026.
34. Inhibition of NorA-mediated efflux of EtBr in S. aureus
strain K2361, which overexpresses the NorA efflux pump
system, and inhibition of MepA-mediated efflux of EtBr in
S. aureus strain K2886, which overexpresses the MepA
efflux pump system, was performed as previously
described; see Kaatz, G. W.; Seo, S. M.; OBrien, L.;
Wahiduzzaman, M.; Foster, T. J. Antimicrob. Agents
Chemother. 2000, 44, 1404, Experiments were performed
in duplicate, and the results were expressed as mean total
efflux over a 5 min time course.
30. Oxidation of primary alcohols 6 and 7 to previously
unreported aldehyde 18 and known 19 employed Parikh–
Doering conditions as previously described for Boc-
´
protected hydroxymethyl pyrrolidines, see; Wallen, E. A.
A.; Christiaans, J. A. M.; Saario, S. M.; Forsberg, M. M.;
Vena¨la¨inen, J. I.; Paso, H. M.; Ma¨nnisto¨, P. T.; Gynther,
J. Bioorg. Med. Chem. 2002, 10, 2199, For 18:1H NMR
(300 MHz, (CDCl3) d = 9.47 (s, 1H), 7.18 (m, 2H), 6.97
(m, 2H), 4.39 (m, 1H), 2.21 (m,1H), 2.82 (m, 4H), 1.84 (m,
1H), 1.70 (dt, J = 12 Hz, J = 4 Hz, 1H), 1.48 (s, 9H). 13C
NMR (75 MHz, (CDCl3) d = 28.49, 33.72, 41.02, 43.88,
53.81, 80.21, 115.92, 128.90, 154.55, 160.18, 163.43,
202.35.
35. MIC and combination studies to evaluate lowering of
antibiotic MIC by EPIs against the various strains were
performed as previously reported in Ref. 26 and as
described in (a) Smith, E. C.; Kaatz, G. W.; Seo, S. M.;
Wareham, N.; Williamson, E. M.; Gibbons, S. Antimicrob.
Agents Chemother. 2007, 51, 4480; (b) Eliopoulos, G. M.;
Moellering, Jr. R. C. In Antibiotics in laboratory medicine,
Lorian, V. Ed.; Williams and Wilkins, Baltimore, Md,
1991; Antimicrobial combinations, pp. 432–492.