OCH2CH3), 3.54 (1H, dd, J 5.0, 1.5, ArCH), 3.32 (1H, s,
EtOC(O)CHCH), 3.15 (1H, dd, J 5.0, 3.5, EtOC(O)CH), 2.78
(1H, d, J 1.5, ArCHCH), 1.79 (1H, d, J 9.0, CHCHHCH),
1.52 (1H, ddd, J 9.0, 3.5, 1.5, CHCHHꢀCH), 1.20 (3H, t, J 7.0,
OCH2CH3); dC (120 MHz, CDCl3) 173.97, 145.00, 138.66, 135.19,
134.94, 134.29, 133.74, 132.54, 131.47, 129.19, 128.09, 127.05,
126.61, 60.32, 50.13, 49.94, 46.55, 46.48, 45.73, 14.23; HRMS
(M + H)+ found 385.1041, C22H22O2SCl requires 385.1029, D ppm
+3.1.
m, EtOC(O)CHCH, ArCHCH), 2.55 (2H, m, NCH2CH2NH),
2.48 (1H, d, J 9.5, EtOC(O)CHCHCHHꢀN), 2.34 (1H, d, J, 9.5,
ArCHCHCHHꢀN), 2.14–2.08 (1H, m, EtOC(O)CHCHCHHꢀN),
1.88 (1H, d, J 10.5, ArCHCHCHHꢀN), 1.83 (1H, s, CHCHHꢀCH),
1.49 (1H, d, J 11.5, CHCHHꢀCH), 1.20 (3H, t, J 7.0, OCH2CH3);
dC (100 MHz; CDCl3) 173.89, 155.23, 148.49, 137.17, 136.34,
135.14, 132.94, 131.67, 129.52, 129.07, 128.87, 127.05, 126.53,
126.29, 112.10, 60.65, 57.11, 56.72, 54.36, 54.28, 45.28, 43.93,
40.24, 39.03, 37.28, 14.37; mp 50–52 ◦C (ether–40 : 60 petrol).
(1S*,5R*,6S*,7R*)-7-[2-(4-Chloro-phenylsulfanyl)-phenyl]-3-[2-
(4-nitrophenylamino)-ethyl]-2-aza-bi-cyclo[3.2.1]octane-6-
carboxylic acid (gemmacin B, (13))
(1R*,2S*,3R*,4S*,5S*,6R*)-3-[2-(4-Chloro-phenylsulfanyl)-
phenyl]-5,6-dihydroxy-bicyclo-[2.2.1]heptane-2-carboxylic acid
ethyl ester (4)
To a solution of the ethyl ester 5 (119 mg, 0.21 mmol) in THF
(1.75 ml) was added 1 M potassium hydroxide solution (5.25 ml,
6 : 1 methanol–water). The reaction was heated at 50 ◦C overnight
then acidified with HCl and extracted with chloroform. The
organic layer was reduced in vacuo and the crude product purified
by flash column chromatography to give the title compound as a
yellow solid (65.7 mg, 58%).
To a solution of 3 (5.3 g, 13.8 mmol) in acetone (200 ml) and water
(20 ml) was added NMO (3.2 g, 27.6 mmol) and osmium tetroxide
(2.5 mol% solution in pentane; 0.1 ml). The reaction was stirred
for four hours until complete by TLC and then quenched with
saturated sodium sulfite solution (200 ml). The aqueous layer was
extracted with ethyl acetate (2 × 300 ml) and the organic layer was
dried (MgSO4) and solvent removed in vacuo. The crude product
was purified by flash column chromatography to yield the title
compound as a white foam (5.30 g, 92%).
Rf 0.14 (SiO2, 10 : 1 CH2Cl2–methanol) mmax (neat) 3311,
−1
=
2941, 1706, 1600 (C O), 1473, 1303, 1184, 1109, 1091 cm ;
dH (500 MHz; MeOD) 7.97 (2H, d, J 9.5, ArH), 7.43 (1H, d,
J 7.5, ArH), 7.34 (1H, t, J 7.5, ArH), 7.30 (1H, dd, J 7.5,
1.0, ArH), 7.16 (1H, td, J 7.5, 1.0, ArH), 7.10 (2H, d, J 8.5,
ArH), 6.83 (2H, d, J 8.5, ArH), 6.73 (2H, d, J 9.0, ArH),
4.36 (1H, d, J 6.0, ArCH), 3.40–3.34 (1H, m, NCH2CHHꢀNH),
3.31 (1H, t, J 5.0, HOC(O)CH), 3.26 (1H, m, NCH2CHH’NH),
Rf 0.27 (SiO2, 4 : 1 ether–40 : 60 petrol); mmax (neat) 3359
−1
=
(OH), 2976, 1725 (C O), 1474, 1176, 1091, 1031 cm ; dH
(400 MHz; CDCl3) 7.29–7.22 (5H, m, ArH), 7.18–7.12 (3H,
m, ArH), 4.07 (2H, q, J 7.0, OCH2CH3), 4.03 (1H, d, J 6.0,
EtOC(O)CHCHCHOH), 3.96 (1H, d, J 6.0, ArCHCHCHOH),
3.54 (1H, d, J 5.5, ArCH), 2.97 (1H, dd, J 6.5, 4.5, EtOC(O)CH),
2.75 (2H, br s, OH), 2.59 (1H, d, J 2.5, EtOC(O)CHCH), 2.13
(1H, s, ArCHCH), 1.93 (1H, dd, J 11.0, 2.5, CHCHHCH), 1.63
(1H, dt, J 11.0, 1.5, CHCHHꢀCH), 1.20 (3H, t, J 7.0, OCH2CH3);
dC (100 MHz; CDCl3) 172.88, 144.73, 135.02, 134.42, 133.84,
132.67, 131.38, 129.28, 128.17, 127.31, 126.29, 73.82, 70.36, 60.81,
51.40, 49.90, 47.24, 42.67, 31.61, 14.16; HRMS (M + Na)+ found
441.0885, C22H23O4SClNa requires 441.0903, D ppm −4.1.
3.18 (1H, d,
m, HOC(O)CHCHCHHꢀN, NCH2CHHꢀNH), 2.79–2.73 (2H,
m, ArCHCHCHHꢀN, ArCHCH), 2.46 (1H, d,
11.0,
J
11.0, ArCHCHCHHꢀN), 2.96–2.85 (3H,
J
HOC(O)CHCHCHHꢀN), 2.12–2.08 (1H, m, CHCHHꢀCH), 1.97
(1H, br s, HOC(O)CHCH), 1.65 (1H, d, J 12.0, CHCHHꢀCH);
dC (125 MHz; MeOD) 179.36, 155.41, 148.75, 138.67, 137.51,
135.88, 134.44, 133.19, 131.72, 130.35, 130.16, 128.46, 127.67,
127.19, 112.64, 58.84, 58.36, 56.84, 55.85, 48.53, 44.86, 40.62,
39.35, 36.83; HRMS (M + Na)+ found 538.1538, C28H28N3O4SCl
requires 538.1567, D ppm 3.2; mp 90–92 ◦C.
(1S*,5R*,6S*,7R*)-7-[2-(4-Chloro-phenylsulfanyl)-phenyl]-3-[2-(4-
nitrophenylamino-ethyl]-3-aza-bi-cyclo[3.2.1]octane-6-carboxlic
acid ethyl ester (5, where R = CH2CH2NH-p-C6H5NO2)
Acknowledgements
To a solution of 4 (310 mg, 0.74 mmol) in THF–water (1 : 1, 60 ml)
was added sodium periodate (285 mg, 1.33 mmol) at 0 ◦C. The
reaction was stirred for 3 hours then extracted with chloroform.
The organic layer was dried and the solvent was removed in vacuo.
The crude product was dissolved in dry DCE (35 ml) and N-(4-
nitrophenyl)ethane-1,2-diamine (134 mg, 0.74 mmol) was added.
The reaction was stirred at room temperature for 1 hour then
sodium triacetoxyborohydride (314 mg, 1.48 mmol) was added
and the reaction stirred overnight. The reaction was poured into
water and extracted with chloroform to give the title compound
as a yellow solid (142.8 mg, 34%).
We acknowledge the EPSRC, BBSRC, MRC and the Augustus
and Harry Newman Foundation for generous support. We also
acknowledge the EPSRC National Mass Spectrometry Service
Centre, Swansea, for providing mass spectrometric data.
Notes and references
1 For recent reviews on antibacterials see: (a) D. J. Payne, M. N. Gwynn,
D. J. Holmes and D. L. Pompliano, Nat. Rev. Drug Discovery, 2007, 6,
29–40; (b) F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand and D.
Habich, Angew. Chem., Int. Ed., 2006, 45, 5072–5129.
2 For a discussion of drug discovery see: (a) A. Sewing, T. Winchester,
P. Carnell, D. Hampton and W. Keighley, Drug Discovery Today, 2008,
13, 227–233; (b) A. Bender, D. Bojanic, J. W. Davies, T. J. Crisman, D.
Mikhailov, J. Scheiber, J. L. Jenkins, Z. Deng, W. A. G. Hill, M. Popov,
E. Jacoby and M. Glick, Curr. Opin. Drug Discovery Dev., 2008, 11,
327–337; (c) D. J. Diller, Curr. Opin. Drug Discovery Dev., 2008, 11,
346–355.
Rf 0.38 (SiO2, 2 : 1 ether–40 : 60 petrol) mmax (neat) 3334, 2926,
−1
=
1718 (C O), 1600, 1473, 1302, 1183, 1108 cm ; dH (400 MHz;
CDCl3) 8.05 (2H, d, J 9.0, ArH), 7.38 (1H, d, J 8.0, ArH), 7.33
(1H, d, J 4.0, H11, ArH), 7.19–7.13 (1H, m, ArH), 7.08 (2H, d, J
8.5, ArH), 6.75–6.69 (3H, m, ArH), 6.22 (1H, br s, NH), 4.55 (1H,
d, J 6.0, ArCH), 4.18–4.05 (2H, m, OCH2CH3), 3.25 (1H, t, J 6.0,
EtOC(O)CH), 3.08–3.00 (2H, m, NCH2CH2NH), 2.78–2.71 (2H,
3 G. L. Thomas, R. J. Spandl, F. G. Glansdorp, M. Welch, A. Bender,
J. Cockfield, J. A. Lindsey, C. Bryant, D. F. J. Brown, O. Loiseleur, H.
2980 | Org. Biomol. Chem., 2008, 6, 2978–2981
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