T. S. Cooper et al. / Tetrahedron Letters 47 (2006) 2241–2243
2243
O
O
HO
HO
O
O
O
O
O
O
OTf
O
b
a
CHO
N
OBn
OBn
Boc
OBn
18
19
20
˚
Scheme 5. Reagents and conditions: (a) 2-tributylstannyl-3-formylfuran, Pd(Ph3P)2Cl2 DMF, 60 °C, 1 h; (b) (i) allylamine, NaBH(OAc)3, 4 A sieves,
CH2Cl2, rt, 2 h, (ii) Boc2O, CH2Cl2, 3 h, (iii) 48% KOH/DMSO, 65 °C, 1 h.
structure–activity relationships (SAR) will be discussed
in future publications.
R
R
O
O
O
OH
OH
Y
Y
X
X
a, b
N
N
Acknowledgements
H
Boc
HO
BnO
O
This work was supported by Cancer Research UK
[CUK] programme Grant number C309/A2187. P.W.
is a Cancer Research UK Life Fellow. We thank
Dr. Amin Mirza and Dr. Bernard Nutley, for their assis-
tance with NMR and mass spectrometry.
21 X = NH, Y = (CH2)2
22 X = O, Y see Table 1
23 X = NH, Y = (CH2)2
24 X = O, Y see Table 1
Scheme 6. Reagents and conditions: (a) Cl2Ru@CHPh(PCy)3
0.1 equiv, CH2Cl2, reflux, 2 h; (b) BCl3, CH2Cl2 (30–35%).
References and notes
1. Roe, S. M.; Prodromou, C.; O’Brien, R.; Ladbury, J. E.;
Piper, P. W.; Pearl, L. H. J. Med. Chem. 1999, 42, 260–
266.
2. Workman, P. Cancer Lett. 2004, 26, 149–157.
3. Banerji, U.; O’Donnell, A.; Scurr, M.; Pacey, S.; Staple-
ton, S.; Asad, Y.; Simmons, L.; Maloney, A.; Raynaud,
F.; Campbell, M.; Walton, M.; Lakhani, S.; Kaye, S.;
Workman, P.; Judson, I. J. Clin. Oncol. 2005, 23, 4152–
4161.
4. Cheung, K.-M.; Matthews, T.; James, K.; Rowlands, M.;
Boxall, K.; Sharp, S.; Maloney, A.; Roe, S. M.; Prodro-
mou, C.; Pearl, L.; Aherne, G. W.; McDonald, E.;
Workman, P. Bioorg. Med. Chem. Lett. 2005, 15, 3338–
3343.
5. Dymock, B.; Barril, X.; Brough, P.; Cansfield, J.; Massey,
A.; McDonald, E.; Hubbard, R.; Surgenor, A.; Roughley,
S.; Webb, P.; Workman, P.; Wright, L.; Drysdale, M.
J. Med. Chem. 2005, 48, 4212–4215.
6. Atrash, B.; Cooper, T. S.; Sheldrake, P.; Workman, P.;
McDonald, E. Tetrahedron Lett. 2006, 47, preceding
paper, doi:10.1016/j.tetlet.2006.01.116.
7. Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 28, 446.
8. Dushin, R. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1992,
114, 655.
9. Alternative sets of radicicol analogues have also been
prepared. See Refs. 10 and 11.
Table 1.
X
Y
R
Ring size
Cyclisation
yield (%)
21
NH
O
O
O
O
(CH2)2
Bond
CH2
CH2
(CH2)2
CH2O
H
H
H
Me
H
15
13
14
14
15
15
56
60
64
83
62
79
22a
22b
22c
22d
22e
O
H
of resorcinol functionality.9–11 Cyclisation to form 13-
to 15-membered rings using ring-closing metathesis gen-
erally gave better yields of macrocyclic products than
the lactonisation methods described in the previous
letter.
The compounds were designed to have a topology
resembling radicicol but with replacement of the unde-
sirable epoxide and dienone functionality and introduc-
tion of amine and amide functional groups to provide
potential sites for molecular recognition and for solubili-
sation. Six of these compounds are modest inhibitors
(IC50 range 12–56 lM) of the ATPase activity of
HSP90, and offer potential as starting points for the
development of anti-cancer drugs. Assay details and
10. Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413.
11. Moulin, E.; Zoete, V.; Barluenga, S.; Karplus, M.;
Winssinger, N. J. Am. Chem. Soc. 2005, 127, 6999–7004.