Synthesis of resorcinylic macrocycles related to radicicol via ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2006.01.117

Novel resorcinylic macrolides, for example, 17, 24, were prepared via ring-closing metathesis as analogues of the HSP90 inhibitor radicicol.

Full text of DOI:10.1016/j.tetlet.2006.01.117

Tetrahedron Letters 47 (2006) 2241–2243
Synthesis of resorcinylic macrocycles related to radicicol via
ring-closing metathesis
Tracey S. Cooper, Butrus Atrash, Peter Sheldrake,
Paul Workman and Edward McDonald*
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton,
Surrey SM2 5NG, UK
Received 21 November 2005; revised 4 January 2006; accepted 18 January 2006
Available online 10 February 2006
Abstract—Novel resorcinylic macrolides, for example, 17, 24, were prepared via ring-closing metathesis as analogues of the HSP90
inhibitor radicicol.
Ó 2006 Elsevier Ltd. All rights reserved.
Radicicol 1, is reported to inhibit the ATPase activity of
the chaperone protein HSP90 with KD = 19 nM.1 Sev-
eral oncogenic proteins are clients for HSP90 and are
down-regulated when HSP90 is blocked.2 There is there-
fore much current interest in developing inhibitors of
HSP90 as drugs for cancer treatment.3 Towards that
end we have recently reported the discovery4 by high
throughput screening (HTS) of the novel pyrazole inhibi-
tor 2, and of potent inhibitors5 based on this structure.
is to extend the diversity of our biological screening
collection by preparing drug-like compounds related
to natural products.
A prototype 14-membered macrocyclic amine 7 was pre-
pared from four fragments as outlined in Scheme 1.
There is considerable scope for varying the substitution
patterns in both phenyl rings, or replacing these by
heterocycles; for varying ring size; and for introducing
substituents by starting with appropriate aliphatic
fragments. If compounds are found to show activity in
biological screening assays the basic nitrogen allows
the formation of water-soluble salts and is an additional
site for the preparation of analogues.
H
O
Et
O
O
O
HO
H
O
HO
O
N
HO
Cl
Me
To effect the synthesis of 7, phenol 3 and alcohol 4 were
converted to ether 8 under Mitsunobu conditions. Suzu-
ki coupling of 8 with boronic acid 5 was followed by
reductive amination with 6. Boc-protection afforded cyc-
lisation precursor 9 and the RCM cyclisation step to 7
N
OH
H
2
1
In the preceding letter,6 we described the development of
short modular synthetic routes to macrocyclic com-
pounds related to radicicol, based on lactone formation
as the cyclisation step. Because yields were modest we
have since explored ring-closing metathesis7 (RCM) as
an alternative strategy for preparing collections of
drug-like compounds related to radicicol. One objective
OH
HO
I
4
3
O
B(OH)2
CHO
N
H2N
H
7
6
5
*
Corresponding author. Tel.: +44 0208 722 4294; fax: +44 0208 722
4047; e-mail: ted.mcdonald@icr.ac.uk
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.117

2242
T. S. Cooper et al. / Tetrahedron Letters 47 (2006) 2241–2243
H
H
N
a
O
N
O
3 +
4
a
O
O
HO
O
I
HO
O
n
( )n
N
R
O
( )n
N
O
8
b
R
OBn
OBn
R
16a,b,c
15a,b,c
O
c,d
7
N
H
10
N
H
N
Ring Yield
size
14
O
Boc
9
%
b
17a
17b
H
H
1
2
60
56
64
HO
O
( )n
N
O
Scheme 2. Reagents and conditions: (a) DEAD, PPh3, THF, rt (90%);
(b) (i) 2-formylbenzene boronic acid 5, Pd(PPh3)4, Cs2CO3, DMF, 12 h
(50%), (ii) allylamine 6, NaBH(OAc)3, CH2Cl2, rt 16 h (65%), (iii)
Boc2O (90%); (c) Cl2Ru@CHPh(PCy3)2 0.1 equiv, CH2Cl2, reflux, 10 h
(90%); (d) 1:1 TFA–CH2Cl2, rt, 30 min (90%).
15
R
17c Me 1 14
OH
Scheme 4. Reagents and conditions: (a) Cl2Ru@CHPh(PCy)3
0.1 equiv, CH2Cl2, reflux, 2 h, 56–64%; (b) H2/Pd–C, EtOH, 24 h,
100%.
gave an encouragingly high yield of 90%. Impressively,
RCM cyclisation of the analogous precursor from 4-
formylbenzene boronic acid gave the para-cyclophane
10 in 88% yield (Scheme 2).
These compounds underwent RCM to give 16-mem-
bered ether lactams 13a,b with cyclisation yields of
85% and 62%, respectively. Catalytic hydrogenation
effected deprotection and simultaneous alkene reduction
to resorcinols 14a,b.
When our studies on resorcinylic pyrazole inhibitors of
HSP90 (discovered by high throughput screening)
revealed that protein–phenol interactions contribute
strongly to binding and inhibitory activity4 we turned
our attention to the synthesis of radicicol mimetics
incorporating a resorcinol functionality. To provide a
template suitable for elaboration to resorcinol-fused
macrocycles 2,4,6-trihydroxybenzoic acid was reacted
with acetone in trifluoroacetic acid/trifluoroacetic anhy-
dride to give the benzodioxinone8 followed by selective
protection of the 4-hydroxy group by Mitsunobu reac-
tion with benzyl alcohol. The free phenolic OH of 11
was converted into an alkene–ether via a second Mitsu-
nobu reaction with dec-l-en-10-ol. Hydrolysis of the lac-
tone protecting group and subsequent reaction with
allylamine or N-methyl allylamine afforded the amide
cyclisation precursors 12a and 12b (Scheme 3).
Macrocycles 16a–c and 17a–c incorporating additional
polar functionality were prepared from the dienes 15a–c
(Scheme 4). Dienes 15 were prepared from 11 by Mit-
sunobu reaction with an N-Boc-protected hydroxyamine,
opening of the dioxinone ring, condensation with allyl-
amine, removal of the Boc-protecting group and amide
formation with pent-4-enoic acid.
Finally, a small collection of furanyl macrocycles was
prepared. These compounds have structural features in
common with both radicicol and the resorcinylic pyra-
zole series of HSP90 inhibitors, for example, 2, and
incorporate a basic nitrogen atom to enhance aqueous
solubility via salt formation, and to allow optimisation
of properties by N-substitution.
Protected resorcinol 11 was converted to triflate 18
(using triflic anhydride in pyridine–dichloromethane)
and palladium-catalysed arylation using 2-tributylstann-
yl-3-formylfuran gave aldehyde 19. Reductive amina-
tion followed by Boc-protection and alkaline
hydrolysis of the dioxinone afforded the phenolic acid
20 (Scheme 5).
R
O
O
O
N
O
OH
a
HO
O
( )3
12a, R = H
12b, R = Me
OBn
OBn
O
11
b
Acid 20 was converted to amide 21 and to the set of
esters 22a–e, and each precursor was cyclised by RCM
using Cl2Ru@CHPh(PCy3)2 in CH2Cl2 (Scheme 6).
Yields are reported in Table 1.
R
N
R
N
O
c
HO
O
HO
O
( )3
( )3
Simultaneous removal of both benzyl and Boc-protect-
ing groups was achieved by treatment with BCl3 to
afford olefinic resorcinols 23 and 24a–e. The
corresponding saturated macrocycles were obtained by
hydrogenation.
OH
OBn
14a,b
13a,b
Scheme 3. Reagents and conditions: (a) (i) Dec-1-en-10-ol, DEAD,
PPh3, THF, 90%, (ii) 48% KOH–DMSO 1:1, 65 °C, 1 h, (iii)
RNHCH2CH@CH2, EDC, HOBt, CH2Cl2, 3 h, 85–90%; (b)
Cl2Ru@CHPh(PCy)3 0.1 equiv, CH2Cl2, reflux, 2 h; (c) H2/Pd–C,
EtOH, 24 h, 100%.
In summary, we have developed short routes to a variety
of macrocyclic lactones and lactams with incorporation

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
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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.