Synthetic ansamycins prepared by a ring-expanding Claisen rearrangement. Synthesis and biological evaluation of ring and conformational analogues of the Hsp90 molecular chaperone inhibitor geldanamycin

Article abstract of DOI:10.1039/b615378j

A series of ansa-quinones has been prepared by chemical synthesis, and evaluated by biological techniques. Thus, 19-membered ansa-lactams, simplified analogues of the naturally occurring Hsp90 molecular chaperone inhibitor geldanamycin, were obtained by concise routes, the key steps being the combination of a ring-closing metathesis to give a 17-membered ring followed by Claisen rearrangement to effect ring expansion. The methodology was also used to prepare an "unnatural" 18-membered ring analogue. In ATPase enzyme assays, the synthetic ansa-quinones were weak inhibitors of Hsp90. The Royal Society of Chemistry 2007.

Full text of DOI:10.1039/b615378j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthetic ansamycins prepared by a ring-expanding Claisen rearrangement.
Synthesis and biological evaluation of ring and conformational analogues of
the Hsp90 molecular chaperone inhibitor geldanamycin†
Christopher S. P. McErlean,a Nicolas Proisy,a Christopher J. Davis,b Nicola A. Boland,b Swee Y. Sharp,c
Kathy Boxall,c Alexandra M. Z. Slawin,d Paul Workmanc and Christopher J. Moody*a
Received 23rd October 2006, Accepted 4th December 2006
First published as an Advance Article on the web 4th January 2007
DOI: 10.1039/b615378j
A series of ansa-quinones has been prepared by chemical synthesis, and evaluated by biological
techniques. Thus, 19-membered ansa-lactams, simplified analogues of the naturally occurring Hsp90
molecular chaperone inhibitor geldanamycin, were obtained by concise routes, the key steps being the
combination of a ring-closing metathesis to give a 17-membered ring followed by Claisen rearrangement
to effect ring expansion. The methodology was also used to prepare an “unnatural” 18-membered ring
analogue. In ATPase enzyme assays, the synthetic ansa-quinones were weak inhibitors of Hsp90.
dihydroxyphenyl)pyrazoles,30 as in CCT018159 5a,31,32 G3130 5b,33
Introduction
and VER-49009 5c,34,35 whilst another group contains the 1-aryl-
2-naphthol moiety as in compound 636 (Fig. 1). Of the above
The ATP-dependent molecular chaperone heat shock protein 90
(Hsp90) is one of the most abundant proteins in eukaryotic cells.
It plays a major role in regulating the stabilization, activation and
degradation of a range of so-called client proteins,1–3 including
Hsp90 inhibitors, radicicol 2 (also known as monorden), is the
most potent in vitro,37 although it has little or no activity in vivo.38,39
Geldanamycin 1a, a member of the ansamycin class of antibi-
otics, was isolated from Streptomyces hygroscopicus var. geldanus
several key proteins involved in cell cycle regulation and signal
in 1970,40 and its structure determined by Rinehart and co-
workers.41 The ansamycins as a class display a range of biological
activities, and a number of analogues of geldanamycin derived
from the natural product have been synthesized and evaluated.42,43
Although initial studies focused on geldanamycin’s ability to lower
cellular levels of the oncogene erbB-2, it was the report in 1994
that geldanamycin was a potent inhibitor of Hsp90 that sparked
interest in this natural product,44 and following this discovery, a
number of geldanamycin analogues have been evaluated as Hsp90
inhibitors. For the most part, these are semi-synthetic derivatives
derived by functionalization of the natural product, primarily
at the 17-position,45–48 and include linked geldanamycin dimers
designed to modulate Hsp90 dimerization.49 Variations on the 7-
carbamate are also known.50 Conjugates with steroids,51,52 a kinase
inhibitor,53 and the monoclonal antibody HerceptinTM54 have also
been investigated, as have a small range of “unnatural” analogues
derived by genetic engineering of the Streptomyces hygroscopicus
strain.55,56 Finally, given the in vitro potency of radicicol as
an inhibitor of Hsp90, a number of compounds incorporating
features of both geldanamycin and radicicol have been prepared
and evaluated. These chimeric structures are known as radamide,
radester and radanamycin.57–60
As a result of these efforts, a derivative of geldanamycin, 17-
allylamino-17-desmethoxygeldanamycin (17-AAG) 1b, is the first-
in-class inhibitor of Hsp90 to enter phase II clinical trial.61–64
The fact that the (more soluble) derivative 17-DMAG 1c is
also undergoing evaluation,65 coupled with recent studies on the
time-dependent binding of geldanamycin to Hsp90,66 and the
suggestion that it may be the hydroquinone form of 17-AAG that
is more active,67–70 highlights the intense interest in this class of
compound.71
transduction. These client proteins also include a number of
known over-expressed or mutant oncogenic proteins such as C-
RAF, B-RAF, ERBB2, AKT, telomerase and p53, many of which
are associated with the six hallmarks of cancer.4,5 Consequently,
inhibition of Hsp90 will disrupt multiple cancer causing pathways
simultaneously. Not surprisingly, therefore, Hsp90 has become an
attractive target for novel cancer therapeutic agents, and has been
the subject of several recent reviews.4,6–14
Most inhibitors of Hsp90 block the ATP-binding site, a
conserved pocket in the N-terminal domain,15–18 and it is dis-
ruption of ATP binding (and subsequent hydrolysis) that leads
to proteasomal degradation of client proteins.19 Known inhibitors
include the natural products geldanamycin 1a and radicicol 2, both
of which have been co-crystallized with the yeast protein and their
bound structures determined by X-ray crystallography,17 and in
solution by NMR spectroscopy.20 In view of the intense interest
in Hsp90, several synthetic inhibitors have been developed. Many
of these are ATP mimics and are based on the purine framework
as exemplified by PU3 3a and PU24FC1 3b, and the related aryl-
and heteroaryl-sulfanyl compound PU-H58 4.21–29 However, other
families of inhibitors are now emerging, in particular the 3-(2,4-
aSchool of Chemistry, University of Nottingham, University Park, Notting-
ham, UK NG7 2RD. E-mail: c.j.moody@nottingham.ac.uk
bDepartment of Chemistry, University of Exeter, Stocker Road, Exeter, UK
EX4 4QD
cCancer Research UK Centre for Cancer Therapeutics, The Institute of
Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey,
UK SM2 5NG
dSchool of Chemistry, University of St. Andrews, Fife, Scotland, UK KY16
9ST
† Electronic supplementary information (ESI) available: Experimental
details of the syntheses. See DOI: 10.1039/b615378j
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achieved by Andrus et al.,72,73 the molecule is too complex to
contemplate a drug development programme based around the
total synthesis of novel derivatives. However, the de novo synthesis
of simpler derivatives is a realistic proposition. Therefore in
continuation of our interest in analogues of natural products
as Hsp90 inhibitors,74 we undertook the design and chemical
synthesis of a series of ansa-quinones as simple analogues of
geldanamycin, and their biological evaluation. The results of this
integrated chemistry–biology approach are described herein.
Results and discussion
The starting point for our work was a consideration of the detailed
structure of geldanamycin 1a bound in the ATP-pocket in the N-
terminal domain of yeast Hsp90,17 and of 17-DMAG 1c in the
corresponding binding site in the human protein.75 The important
features of the binding to the yeast protein are shown in Fig. 2(c),
which shows the key role played by the C-7 carbamate that is
involved in hydrogen-bonding interactions with Gly83, Thr171,
Asp79 and Leu34. The C-11 hydroxyl group forms a hydrogen
bond to Lys44 whilst the quinone oxygen interacts with Lys98.
The macrocyclic amide bond is involved in hydrogen-bonding
interactions with Gly123 and Phe124, but, critically, appears to
have to undergo trans to cis isomerization to allow the antibiotic
to adopt the tightly folded conformation within the protein.76
It is clear from the above analysis that any simplified ana-
logues of geldanamycin should retain the key structural features
adumbrated above, i.e. the ansa-quinone macrolactam motif
with appropriately positioned hydroxyl and carbamate groups on
the periphery. These criteria could be met by a much simpler
compound, which lacks the five methyl and methoxy groups
which adorn the natural ansa-chain, and is therefore much more
amenable to synthesis. Such a compound 7b (Fig. 2(b)), which
is simplified further by removal of the C-11 hydroxyl and C-14
methyl groups, was shown by molecular modelling to be able
to adopt the required folded conformation whilst retaining all
the remaining hydrogen-bonds (Fig. 2(d)). The conformation of
analogue 7b is slightly rigidified by the presence of the trans-alkene
bond at C13–C14. Although the simplified analogue 7b retains the
19-membered ring ansa-quinone structure of the natural product
with the key carbamate functionality at C-7, the corresponding
compounds with the carbamate at C-8, and with an “unnatural”
18-membered ring should also bind to the enzyme. The synthesis
of a range of such simplified geldanamycin derivatives is described
herein.77,78
The ansamycin antibiotics are usually synthesized by a route
that involves formation of the amide bond to access the macro-
cycle, and until recently alternative approaches were rarely con-
sidered. However, the advent of reliable catalysts for ring closing
metathesis (RCM) has rendered this reaction highly suitable for
macrocycle construction,79 and the method has recently been
used by others for the synthesis of geldanamycin analogues.80–83
However, the novel feature of our route is the combination of
the RCM reaction (to form a 17-membered macrocycle) with the
Claisen rearrangement (which results in ring expansion to the 19-
membered ansa-ring). Preliminary studies have demonstrated the
feasibility of such a new use of the Claisen rearrangement.77
In order to establish the required methodology, the synthesis
of two very simple ansa-quinones 16a and 16b was carried
Fig. 1 Structures of Hsp90 inhibitors.
Whilst the success to date with 17-AAG validates the potential
of geldanamycin analogues as potential chemotherapeutic agents,
the range of semi-synthetic analogues that can be readily accessed
by chemical manipulation of natural material is severely limited.
Likewise, although the total synthesis of geldanamycin has been
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Fig. 2 (a) Structure of geldanamycin 1a; (b) structure of the simplified analogue 7b; (c) geldanamycin bound in ATP-site of yeast Hsp90 (from X-ray
crystal structure PDB ID 1A4H15†); (d) molecular modelling derived structure of analogue 7b bound in ATP-site of yeast Hsp90.
out initially (Scheme 1). Thus 2-methyldodeca-1,11-dien-3-ol 8,
prepared by addition of isopropenylmagnesium bromide to 9-
decenal, underwent Mitsunobu reaction with 2-nitrophenol to give
9a. Reduction of the nitro group with indium metal,84 followed
by DCC-mediated coupling to 4-pentenoic acid gave the RCM–
Claisen substrate 11a. Treatment of triene 11a with Grubbs’
catalyst [benzylidene bis(tricyclohexylphosphine) dichlororuthe-
nium] gave the 17-membered macrocycle 12a in good yield, with
179–180 ◦C), then an additional complication ensued, namely the
formation of benzoxazoles 15 by cyclodehydration of the phenolic
amide. Finally oxidation of the phenol 14a using Fremy’s salt
(potassium nitrosodisulfonate) gave the ansa-quinone 16a (as a
mixture of alkene isomers). The synthetic sequence was repeated
starting from 5-methoxy-2-nitrophenol to give the 17-methoxy-
ansa-quinone 16b as shown in Scheme 1.
Unsurprisingly, the ansa-quinones 16 lacking the critical car-
bamate functionality at C-7 showed no activity as inhibitors
of Hsp90 (data given later), and therefore our RCM–Claisen
methodology was adapted for the synthesis of quinones bearing a
carbamate at appropriate positions on the ansa-chain (Schemes 2
and 3). The synthesis was initially carried out in the racemic series,
and started from the known 7,7-dimethoxyheptanal 17, obtained
by ozonolysis of cycloheptene under Schreiber’s conditions.86,87
Addition of allylmagnesium chloride was followed by protection
of the resulting alcohol as its tert-butyldiphenylsilyl ether 19a.
Deprotection of the dimethyl acetal gave the corresponding alde-
hyde that was immediately reacted with isopropenylmagnesium
bromide to give the methyl substituted 12-carbon chain 20a as a
mixture of diastereomers. No attempt was made to separate the
diastereomers since the second stereocentre is eventually lost in the
Claisen rearrangement. Mitsunobu reaction of alcohol 20a with 5-
methoxy-2-nitrophenol gave the nitrophenyl ether 21a, reduction
of which with indium–acetic acid in THF gave the aniline 22a.
Initially the aniline 22a was coupled to (E)-2-methyl-2,4-
pentadienoic acid, prepared by Wittig reaction of acrolein with
(carboethoxyethylidene)triphenylphosphorane followed by ester
=
reaction occurring at the less hindered terminal CH CH2 bond.
Unfortunately, however, the macrolactam 12a was formed as a
1 : 1 mixture of cis-and trans-isomers at the 4,5-double bond.
Hydrogenation gave a single characterizable tetrahydro derivative
13a in excellent yield.
The Claisen rearrangement of allyl ether 12a was effected
by heating in boiling xylenes (bp 138–141 ◦C) and gave the
ring expanded 19-membered ansa-lactam 14a in 66% yield as a
mixture of isomers. As far as we are aware this transformation
of an n-membered 1,2-bridged macrocycle into an ansa-bridged
(n + 2)-membered ring represents a new use for the Claisen
rearrangement. Since the Claisen rearrangement itself can result
in a mixture of isomers at the newly formed 13,14-double bond,
the reaction was carried out in the presence of sodium carbonate,
conditions which are reported to favour the formation of the (E)-
alkene.85 However, due to the complexity of the 1H NMR spectrum
of 14a, we were unable to determine precisely the number of
isomers present, although it appeared to be a mixture of two
major components (2.5 : 1). If the Claisen rearrangement was
conducted at a higher temperature in 1,2-dichlorobenzene (bp
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Scheme 1
hydrolysis,88,89 using DCC, but this proved unsatisfactory and
therefore the corresponding acid chloride was used to obtain
the desired amide 23a. Ring-closing metathesis of 23a resulted in
formation of the desired 17-membered lactam 24a in good yield,
but as a mixture of isomers. The aromatic Claisen rearrangement
of allyl aryl ethers is ideally suited to microwave conditions, and
reaction times are shortened dramatically.90–100 Therefore, heating
lactam 24a in xylene under microwave irradiation effected the
Claisen rearrangement to give the ring-expanded ansa-lactam 25a.
Deprotection of the silyl ether with fluoride gave the 7-hydroxy
ansa-lactam 26a which after crystallization was obtained as a
single (E,Z,E)-isomer at the 2,3-, 4,5- and 13,14-double bonds
respectively, the structure being confirmed by X-ray crystallogra-
phy (Fig. 3).‡ Two points are noteworthy: firstly the deprotection
of the silyl ether was surprisingly difficult and probably reflects the
hindered nature of the 7-position as a consequence of the folded
Fig. 3 X-Ray crystal structure of ansa-lactam 26a.
conformation of the ansa-chain. Secondly, notwithstanding the
fact that the ansa-lactam 26a could be obtained as single isomer,
‡ CCDC reference numbers 624769. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b615378j
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Scheme 2
the facile (E/Z)-isomerization of, presumably, the 13,14-double
bond was a constant problem.
Indeed following oxidation of the phenol 26a with Fremy’s salt
the ansa-quinone 27a was obtained as a ca. 6 : 1 mixture of
isomers. Finally, the C-7 carbamate was introduced by reaction
of the alcohol 27a with sodium cyanate and trifluoroacetic acid
(TFA) in dichloromethane101 to give the ansa-quinone carbamate
7a (Scheme 2).
With a route to the C-7 substituted ansa-quinone success-
fully established, the sequence was repeated to obtain chiral
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Scheme 3
non-racemic material. Thus 7,7-dimethoxyheptanal 17 was sub-
jected to Brown’s chiral allylation methodology102,103 to give the
(S)-homoallylic alcohol (S)-18 in good yield. Analysis of the
corresponding benzoate ester by HPLC on a chiral stationary
phase established the enantiomeric excess of (S)-18 as 93%. Pro-
tection of the alcohol with the more labile tert-butyldimethylsilyl
group, deprotection of the acetal, and addition of vinylmagnesium
bromide gave the 12-carbon side chain 20b as a mixture of
diastereomers. The methyl group at the eventual 14-position was
omitted in this series of compounds in an attempt to prevent the
facile isomerization of the 13,14-double bond. Mitsunobu reac-
tion, nitro reduction and coupling to 2-methyl-2,4-pentadienoic
acid proceeded as before, albeit with some minor modifications,
to give the RCM-substrate 23b. Cyclization of 23b mediated by
Grubbs’ catalyst gave the 17-membered lactam 24b as a mixture
of diastereomers, Claisen rearrangement of which, again under
microwave irradiation, gave the ansa-lactam 25b as a single isomer.
Deprotection, oxidation and installation of the carbamate then
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gave the desired ansa-quinone carbamate 7b (Scheme 2). The
assignment of E,Z-geometry to the 2,3- and 4,5-alkenes was
confirmed by NOE experiments.
at 7.27 ppm (dH) and 77.1 ppm (dC), and are accurate to 0.01 ppm
and 0.10 ppm respectively. In reporting the NMR data for
mixtures of diastereoisomers, signals arising from the major and
minor isomers are reported separately if possible; in the 1H NMR,
the integration of signals is consistent within each isomer, e.g. a
methyl group is reported as 3 H for both isomers even though the
peaks are unequal in area when the ratio of isomers is >1 : 1.
In the 13C NMR spectra, signals corresponding to CH, CH2, or
CH3 groups are assigned from DEPT. Mass spectra (CI and EI)
were obtained from EPSRC national mass spectrometry centre,
Swansea or on an Agilent 6890 series GC and Micromass GCT.
Although the ansa-quinones 7 are simplified analogues of gel-
danamycin they still share the 19-membered ring structure of the
natural product with a carbamate positioned at C-7 on the ansa-
chain. However, our synthetic route is sufficiently flexible to allow
the preparation of “unnatural” analogues. Therefore the ansa-
quinones 37a containingan 18-membered ring, and 37b containing
a 19-membered ring but with the carbamate at C-8 on the ansa-
chain were also prepared starting from 6,6-dimethoxyhexanal
28104 as shown in Scheme 3. The chemistry proceeded as before,
although again problems of isomerization of the alkene resulting
from Claisen rearrangement were encountered.
The novel compounds were evaluated in the malachite green
assay for Hsp90 ATPase activity,105 and for their ability to inhibit
the growth of HCT116 human colon cancer cells using the
colorimetric sulforhodamine B (SRB) assay;106 the results are
shown in Table 1. It is immediately apparent that these “stripped
down” analogues of geldanamycin exhibit only weak activity as
inhibitors of Hsp90, notwithstanding the fact that molecular
modelling suggested that such compounds should bind to the
enzyme’s ATP-site. Presumably the structures have been simplified
too much, with the loss of the C-11 hydroxyl hydrogen bond being
most likely responsible for their poor potency as Hsp90 inhibitors.
Interestingly, inhibition of cell growth was seen at 25–40 lM,
presumably due to alternative mechanisms.
Lactam
24a. N-[2-(9-tert-Butyldiphenylsiloxy-2-methyl-
dodeca-1,11-dien-3-yloxy)-2-methoxyphenyl]-2-methylpenta-2,4-
dienamide 23a (0.35 g, 0.53 mmol) in anhydrous dichloromethane
(100 mL) was slowly added to a solution of Grubbs’ catalyst
(0.13 g, 0.16 mmol, 30 mol%) in anhydrous dichloromethane
(952 mL) under reflux. The mixture was heated under reflux
for 24 h then concentrated in vacuo. The crude product was
purified twice by flash chromatography on silica, eluting with
ethyl acetate and light petroleum (1 : 9) to give the title compound
as a colourless sticky solid (0.27 g, 81%) as a mixture of three
isomers (Found: MH+, 638.3663. C40H51NO4Si + H requires
638.3665); mmax (film)/cm−1 3426, 3063, 2935, 2853, 1665, 1593,
1516, 1484, 1048; dH (400 MHz; CDCl3) mixture of isomers
8.34–8.27 (1 H, m, ArH), 8.02 (1 H, s, NH), 8.00 (1 H, s,
NH), 7.73–7.71 (4 H, m, ArH), 7.47–7.38 (6 H, m, ArH),
=
=
In summary, a versatile route to simplified analogues of the nat-
urally occurring ansa-quinone geldanamycin has been developed.
The route involves a ring-closing metathesis to give a 17-membered
ring followed by Claisen rearrangement to effect ring expansion.
Biological evaluation of these novel analogues showed that they
were poor inhibitors of Hsp90. Studies involving the synthesis of
further geldanamycin analogues, in particular those containing a
C-11 hydroxyl group, are in progress.
6.90 (1 H, d, J 11.1, CMe CHCH CH), 6.87 (1 H, d, J, 10.8,
=
=
CMe CHCH CH), 6.52–6.39 (2 H, m, ArH), 6.32 (1 H, t, J 11.1,
=
=
=
=
CMe CHCH CH), 6.25–6.17 (1 H, m, CMe CHCH CH),
=
=
6.07–5.97 (1 H, m, CMe CHCH CH), 5.89–5.84 (1 H, m,
=
=
=
=
CMe CHCH CH), 5.69–5.62 (1 H, m, CMe CHCH CH),
=
=
4.98 (2 H, s, MeC CH2), 4.97 (2 H, s, MeC CH2), 4.92 (2 H, s,
=
=
MeC CH2), 4.90 (2 H, s, MeC CH2), 4.55–4.45 (1 H, m,
ArOCH), 3.97–3.91 (1 H, m, CHOTBDPS), 3.77 (3 H, s, OMe),
3.76 (3 H, s, OMe), 2.69–2.22 (2 H, m, CH2), 2.09 (3 H, s, Me),
2.07 (3 H, s, Me), 2.02 (3 H, s, Me), 2.01 (3 H, s, Me), 1.74 (3 H, s,
Me), 1.68–1.42 (8 H, m, 4 × CH2), 1.11 (9 H, s, t-Bu), 1.10
(9 H, s, t-Bu), 1.09 (9 H, s, t-Bu); dC (100 MHz; CDCl3) mixture
of isomers 168.6 (C), 168.23 (C), 168.2 (C), 156.0 (C), 155.9 (C),
155.63 (C), 155.6 (C), 148.1 (C), 148.0 (C), 147.4 (C), 143.9 (C),
143.6 (C), 143.1 (C), 142.3 (C), 138.1 (CH), 137.8 (CH), 135.94
(CH), 135.9 (CH), 135.87 (CH), 135.2 (C), 134.9 (C), 134.4 (C),
134.32 (C), 134.3 (C), 134.25 (C), 134.2 (C), 133.2 (CH), 132.9
(C), 132.85 (C), 132.7 (CH), 132.2 (CH), 132.1 (CH), 129.7 (CH),
129.68 (CH), 129.6 (CH), 127.64 (CH), 127.61 (CH), 127.6 (CH),
126.9 (CH), 126.8 (CH), 125.7 (CH), 125.5 (CH), 125.3 (CH),
125.2 (CH), 122.4 (C), 122.3 (C), 121.7 (C), 121.6 (C), 120.4 (CH),
120.2 (CH), 118.7 (CH), 118.6 (CH), 112.6 (CH2), 112.5 (CH2),
112.2 (CH2), 112.1 (CH2), 103.9 (CH), 103.8 (CH), 103.7 (CH),
103.68 (CH), 101.2 (CH), 101.0 (CH), 100.8 (CH), 100.77 (CH),
82.3 (CH), 82.2 (CH), 81.9 (CH), 81.4 (CH), 72.8 (CH), 72.6
(CH), 72.1 (CH), 71.8 (CH), 55.4 (Me), 55.42 (Me), 41.9 (CH2),
41.7 (CH2), 37.6 (CH2), 36.9 (CH2), 35.7 (CH2), 35.2 (CH2), 34.9
(CH2), 34.4 (CH2), 34.3 (CH2), 34.26 (CH2), 33.5 (CH2), 29.4
(CH2), 29.1 (CH2), 28.5 (CH2), 28.1 (CH2), 27.2 (CH2), 27.1 (CH),
26.9 (CH), 26.0 (CH2), 25.5 (CH2), 25.4 (CH2), 25.1 (CH2), 24.9
(CH2), 24.7 (CH2), 24.4 (CH2), 24.1 (CH2), 22.7 (Me), 19.4 (C),
19.39 (C), 19.3 (C), 19.2 (C), 18.9 (Me), 18.5 (Me), 18.3 (Me), 18.2
Experimental section
Chemistry
General. Commercially available reagents and solvents were
used throughout without further purification. Indium powder
was ∼100 mesh purchased from Aldrich. ‘Light petroleum’ refers
to the fraction that boils between 40 ◦C and 60 ◦C. Microwave
reactions were carried out in a CEM DiscoverTM 300 W microwave.
Analytical thin layer chromatography was carried out using
aluminium backed plates coated with Merck Kieselgel 60 GF254.
Developed plates were visualized under ultra-violet light (254
nm) and/or potassium permanganate, ethanolic anisaldehyde,
or ninhydrin dip. Flash chromatography was carried out using
Merck Kieselgel 60 H silica. Fully characterized compounds were
chromatographically homogeneous.
IR spectra were recorded on a Nicolet Magna 550 spectrometer
with internal calibration. Spectra were recorded as potassium
bromide discs, as solutions in CHCl3, or as films between sodium
chloride plates. NMR spectra were recorded on a Bruker AM
300 or Bruker Advance DRX 400 spectrometer at the frequencies
stated. Chemical shifts are recorded in ppm and J values in Hz.
Chemical shift values are referenced against residual chloroform
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Table 1 Inhibition of yeast Hsp90 by novel ansa-quinones
Compound
Structure
ATPase assay IC50/lM
SRB assay IC50/lMa
Geldanamycin 1a
>4.8
>0.067
17-AAG 1b
>8.7
>0.099
16a
16b
27a
>100
>100
>100
26
28
32
7a
>50
32
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Table 1 (cont.)
Compound
Structure
ATPase assay IC50/lM
>100
SRB assay IC50/lMa
7b
40
36a
37a
36b
>100
>100
>100
nd
nd
nd
37b
>100
nd
a nd = not determined.
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(Me), 13.5 (Me), 13.49 (Me), 13.4 (Me), 13.3 (Me), 11.5 (Me);
m/z (CI) 638 (MH+, 93%), 620 (20), 580 (25), 560 (47), 422 (28),
382 (100), 297 (24), 239 (37), 199 (57), 179 (53).
˚
k = 0.71073 A). The data were collected at T = 125(2) K, 6794
reflections were measured on a Bruker SMART CCD diffrac-
tometer equipped with an Oxford Cryostream low-temperature
device (x-scan, 0.3◦/frame) yielding 3816 unique data (Rmerg
0.0133). Conventional R = 0.0681 for 3131 reflections with I ≥
2r, GOF = 1.032. Final wR2 = 0.0834 for all data (278 refined
parameters). The hydroxy hydrogen atoms were refined subject to
=
Claisen rearrangement of lactam 24a to ansa-lactam 25a. Lac-
tam 24a (0.395 g, 0.620 mmol) was dissolved in xylene (4 mL) in
a sealed tube. The mixture was heated at 150 ◦C for 40 min in
a microwave reactor (300 W). The crude product was purified by
flash chromatography on silica, eluting with ethyl acetate and light
petroleum (3 : 7) to give the title compound as a colourless sticky
oil (0.225 g, 57%) (Found: MH+, 638.3675. C40H51NO4Si + H
requires 638.3665); mmax (film)/cm−1 3421, 2935, 2863, 1650, 1583,
1521, 1491; dH (300 MHz; CDCl3) 8.20 (1 H, d, J 8.9, ArH), 8.08
(1 H, s, NH), 7.73–7.69 (4 H, m, ArH), 7.44–7.37 (6 H, m, ArH),
˚
a tight distance constraint. (O–H −0.980(1) A). The largest peak
−3
˚
in the residual map is 1.515 e A , near C(15).‡
Oxidation of ansa-lactam 26a to ansa-quinone 27a. Ansa-
lactam 26a (0.052 g, 0.130 mmol) was dissolved in acetone (30 mL)
and Fremy’s salt (0.140 g, 0.520 mmol) in sodium dihydrogen
phosphate buffer (15 mL) was added. The mixture was stirred
for 2 h, then diluted with ethyl acetate (60 mL) and washed with
water (2 × 20 mL), brine (20 mL), dried (MgSO4), filtered and
evaporated in vacuo. The crude product was purified by flash
chromatography on silica, eluting with ethyl acetate and light
petroleum (1 : 4) to give the title compound as an orange oil
(0.040 g, 74%) as a mixture of isomers (Found: MH+, 414.2294.
C24H31NO5 + H requires 414.2280); mmax (film)/cm−1 3360, 2925,
2853, 1680, 1650, 1598, 1511; dH (300 MHz; CDCl3) major isomer
8.73 (1 H, br, NH), 7.25 (1 H, s, quinone-H), 7.04 (1 H, d, J 11.3,
=
=
6.83 (1 H, d, J 11.1, CMe CHCH CH), 6.52–6.49 (2 H, m, ArH,
=
=
OH), 6.25 (1 H, t, J 11.0, CMe CHCH CH), 5.73 (1 H, q, J 8.3,
=
=
=
CMe CHCH CH), 5.59 (1 H, t, J 6.2, ArCH2CMe CHCH2),
3.84–3.77 (1 H, m, CHOTBDPS), 3.81 (3 H, s, OMe), 3.52 (2 H, q,
J 15.4, ArCH2), 2.52–2.25 (2 H, m, CH2), 2.11–2.00 (5 H, m, Me,
CH2), 1.59 (3 H, s, Me), 1.55–1.44 (2 H, m, CH2), 1.34–1.26 (4 H,
m, 2 × CH2), 1.08 (11 H, br, t-Bu, CH2); OH not observed; dC
(75 MHz; CDCl3) 168.5 (C), 154.0 (C), 145.9 (C), 136.8 (C), 134.8
(C), 134.6 (C), 134.5 (CH), 129.9 (CH), 128.7 (CH), 127.9 (CH),
127.87 (CH), 126.4 (CH), 125.6 (CH), 121.7 (C), 117.7 (CH), 112.8
(C), 103.1 (CH), 73.8 (CH), 56.4 (Me), 38.5 (CH2), 36.6 (CH2), 34.6
(CH2), 30.1 (CH2), 29.0 (CH2), 27.7 (CH2), 27.5 (Me), 26.3 (CH2),
19.9 (C), 16.0 (Me), 13.3 (Me); m/z (CI) 638 (MH+, 88%), 620
(37), 580 (32), 560 (53), 382 (100), 199 (32), 179 (23).
=
=
=
=
CMe CHCH CH), 6.45 (1 H, t, J 11.0, CMe CHCH CH),
=
=
6.06 (1 H, q, J 9.4, CMe CHCH CH), 5.23 (1 H, td, J 7.4,
=
1.1, ArCH2CMe CH), 4.10 (3 H, s, OMe), 3.85–3.76 (1 H, m,
CHOH), 3.15 (2 H, s, ArCH2), 2.52–2.44 (1 H, m, CHOH), 2.40–
2.25 (1 H, m, CHOH), 2.03–1.97 (5 H, m, Me, CH2), 1.63–1.55
(7 H, m, Me, 2 × CH2), 1.43–1.20 (4 H, m, 2 × CH2); OH not
observed; minor isomer 8.89 (1 H, br, NH), 7.26 (1 H, s, quinone-
Ansa-lactam 26a. Ansa-lactam 25a (0.126 g, 0.200 mmol) was
dissolved in anhydrous THF (3 mL) and tetra-n-butylammonium
fluoride (1 M in THF; 0.50 mL, 0.50 mmol) was added. The
mixture was stirred under an atmosphere of nitrogen at room
temperature for 24 h, then quenched by the addition of saturated
ammonium chloride solution (3 mL). The mixture was then
extracted with ethyl acetate (3 × 10 mL), th extracts combined,
washed with water (3 × 10 mL), brine (10 mL), dried (MgSO4),
filtered and evaporated in vacuo. The crude product was purified
by flash chromatography on silica, eluting with ethyl acetate and
light petroleum (1 : 4) to give the ti◦tle compound as a colourless
solid (0.050 g, 63%); mp 185–187 C (Found: MH+, 400.2485.
C24H33NO4 + H requires 400.2488); mmax (KBr)/cm−1 3406, 2929,
2856, 1652, 1645, 1616, 1558, 1539, 1520, 1507; dH (400 MHz;
CDCl3) 8.22 (1 H, d, J 9.0, ArH), 8.17 (1 H, br, NH), 6.99 (1 H,
=
=
H), 7.04 (1 H, d, J 11.3, CMe CHCH CH), 6.45 (1 H, t, J 11.0,
=
=
=
=
CMe CHCH CH), 6.06 (1 H, q, J 9.4, CMe CHCH CH),
=
5.09 (1 H, t, J 5.5, ArCH2CMe CH), 4.13 (3 H, s, OMe), 3.85–
3.76 (1 H, m, CHOH), 3.15 (2 H, s, ArCH2), 2.52–2.44 (1 H,
m, CHOH), 2.40–2.25 (1 H, m, CHOH), 2.03–1.97 (5 H, m, Me,
CH2), 1.63–1.55 (7 H, m, Me, 2 × CH2), 1.43–1.20 (4 H, m, 2 ×
CH2); OH not observed; dC (100 MHz; CDCl3) major isomer 184.2
(C), 183.1 (C), 168.7 (C), 156.7 (C), 138.3 (C), 135.8 (CH), 132.4
(C), 130.6 (C), 129.4 (CH), 127.9 (CH), 126.1 (C), 126.0 (CH),
111.4 (CH), 71.9 (CH), 61.7 (Me), 38.2 (CH2), 35.9 (CH2), 33.3
(CH2), 29.5 (CH2), 28.9 (CH2), 27.6 (CH2), 25.6 (CH2), 15.8 (Me),
12.5 (Me); minor isomer 184.2 (C), 183.1 (C), 168.7 (C), 156.7 (C),
138.3 (C), 135.9 (CH), 132.4 (C), 130.6 (C), 129.0 (CH), 128.8
(CH), 126.1 (C), 126.0 (CH), 111.3 (CH), 71.89 (CH), 61.7 (Me),
37.5 (CH2), 35.6 (CH2), 33.3 (CH2), 29.4 (CH2), 28.5 (CH2), 27.1
(CH2), 24.6 (CH2), 24.4 (Me), 12.5 (Me); m/z (CI) 414 (MH+, 5%),
285 (13), 257 (12), 111 (16), 107 (19), 101 (20), 91 (63), 85 (31), 69
(23), 57 (26).
=
=
d, J 11.4, CMe CHCH CH), 6.57 (1 H, s, ArOH), 6.50 (1 H, d,
=
=
J 9.0, ArH), 6.48 (1 H, t, J 11.6, CMe CHCH CH), 6.44 (1 H,
=
=
br, OH), 5.95 (1 H, q, J 8.3, CMe CHCH CH), 5.65 (1 H, t, J
=
7.1, ArCH2CMe CH), 3.81 (3 H, s, OMe), 3.53 (2 H, q, J 15.4,
ArCH2), 2.53–2.52 (1 H, m, CHOH), 2.15–2.14 (2 H, m, CH2),
2.03 (3 H, s, Me), 1.58 (3 H, s, Me), 1.57–1.26 (10 H, m, 5 × CH2);
dC (100 MHz; CDCl3) 167.9 (C), 153.7 (C), 145.6 (C), 136.6 (C),
134.9 (C), 132.8 (CH), 128.6 (CH), 126.8 (CH), 125.8 (CH), 121.2
(C), 117.4 (CH), 112.4 (C), 102.8 (CH), 71.8 (CH), 56.0 (Me), 38.0
(CH2), 36.3 (CH2), 34.4 (CH2), 29.4 (CH2), 29.1 (CH2), 27.6 (CH2),
25.7 (CH2), 15.5 (Me), 12.9 (Me); m/z (CI) 400 (MH+, 100%), 382
(18).
Ansa-quinone carbamate 7a. Ansa-quinone 27a (0.040 g,
0.097 mmol) was dissolved in dichloromethane (6 mL). Sodium
cyanate (0.151 g, 2.33 mmol) and TFA (0.180 mL, 0.266 g,
2.33 mmol) were then added at 0 ◦C. The mixture was then
stirred slowly at room temperature for 17 h, before quenching with
sodium hydrogen carbonate solution (5%; 10 mL). The mixture
was then extracted with ethyl acetate (3 × 20 mL), the extracts
combined and washed with brine (20 mL), dried (MgSO4), filtered
and evaporated in vacuo. The crude product was purified by flash
chromatography on silica, eluting with ethyl acetate and light
Crystal data for 26a. C24H33NO4, M = 399.51, triclinic, space
¯
˚
group P1, a = 8.8832(12), b = 10.3813(15), c = 12.0879(17) A,
◦
3
˚
a = 81.631(2), b = 81.670(2), c = 78.225(2) , U = 1072.0(3) A ,
F(000) = 432, Z = 2, Dc = 1.238 Mg m−3, l = 0.083 mm−1(Mo–Ka,
540 | Org. Biomol. Chem., 2007, 5, 531–546
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The Royal Society of Chemistry 2007
©

View Article Online
petroleum (2 : 3) to give the title compound as a sticky, orange
oil (0.016 g, 36%) as a mixture of isomers (5 : 2) (Found: MH+,
457.2354. C25H32N2O6 + H requires 457.2338); mmax (film)/cm−1
3473, 3359, 2925, 2858, 1733, 1716, 1695, 1653, 1597, 1557, 1506;
dH (400 MHz; CDCl3) major isomer 8.66 (1 H, s, NH), 7.28 (1 H,
was subjected to microwave irradiation at 300 W and 180 ◦C for
50 min. After solvent evaporation, flash chromatography using
ether and light petroleum (3 : 17) gave the title compound as a
yellow oil (34 mg, 58%); [a]3D2 +2.15 (c 1.86, CHCl3) (Found: MH+,
500.3174. C29H45NO4Si + H requires 500.3196); mmax (CHCl3)/cm−1
3426, 3019, 2930, 1656, 1524, 1265; dH (300 MHz; CDCl3) 8.13
(1 H, d, J 9.0, ArH), 8.11 (1 H, br s, NH), 6.90 (1 H, d, J 12.0,
=
=
d, J 1.3, quinone-H), 7.07 (1 H, d, J 11.4, CMe CHCH CH),
=
=
6.42 (1 H, t, J 10.8, CMe CHCH CH), 5.99–5.92 (1 H, m,
=
=
=
=
=
CMe CH CH CH), 5.28 (1 H, t, J 7.2, ArCH2CMe CH), 4.99–
4.94 (2 H, m, OCONH2), 4.15 (3 H, s, OMe), 3.28–3.14 (2 H, m,
ArCH2), 2.70–2.61 (1 H, m, CHOCONH2), 2.27–2.23 (2 H, m,
CH2CHOCONH2), 2.04–1.98 (5 H, m, Me, CH2), 1.82–1.76 (2 H,
m, CH2), 1.72–1.66 (2 H, m, CH2), 1.57 (3 H, s, Me), 1.55–1.45
(2 H, m, CH2), 1.36–1.25 (2 H, m, CH2); minor isomer 8.89 (1 H,
s, NH), 7.27 (1 H, d, J 1.3, quinone-H), 7.10 (1 H, d, J 13.2,
CMe CHCH CH), 6.43 (1 H, d, J 9.0, ArH), 6.33 (1 H, t, J
=
=
12.0, CMe CHCH CH), 6.31 (1 H, s, OH), 5.86–5.75 (2 H,
=
=
=
m, CMe CHCH CHCH2, ArCH2CH CH), 5.67–5.61 (1 H,
m, ArCH2CH CH), 3.75 (3 H, s, OMe), 3.74–3.70 (1 H, m,
CHOTBS), 3.51 (1 H, dd, J 15.0, 6.0, ArCHHCH CH), 3.43
(1 H, dd, J 15.0, 6.0, ArCHHCH CH), 2.45–2.24 (2 H, m,
=
=
=
=
CH(OTBS)CH2), 2.20–2.06 (2 H, m, ArCH2CH CHCH2), 1.98
=
=
=
=
Me CHCH CH), 6.45 (1 H, t, J 10.8, CMe CHCH CH), 5.13
(3 H, s, Me),1.48–1.17 (8 H, m, 4 × CH2), 0.84 (9 H, s, t-Bu), 0.00
(6 H, s, Me); dC (75 MHz; CDCl3) 168.6 (C), 153.4 (C), 145.7 (C),
135.5 (CH), 134.9 (C), 134.6 (CH), 129.8 (CH), 126.7 (CH), 125.8
(CH), 121.9 (C), 117.8 (CH), 113.1 (C), 103.2 (CH), 72.8 (CH),
56.3 (Me), 38.8 (CH2), 37.1 (CH2), 32.5 (CH2), 29.9 (CH2), 29.1
(CH2), 27.6 (CH2), 26.36 (CH2), 26.31 (Me), 18.5 (C), 13.3 (Me),
−3.8 (Me).
Ansa-lactam 26b. Ansa-lactam 25b (18 mg, 0.036 mmol) was
dissolved in THF (1 mL) and tetra-n-butylammonium fluoride
(1 M in THF; 180 lL, 0.18 mmol) was added and the solution was
stirred at room temperature for 5.5 h. Solvent evaporation gave
a brown oil which was subjected to flash chromatography using
ether and light petroleum (3 : 1) which gave the title compound
as an amorphous, off-white solid (7.7 mg, 55%); mp 173–178 ◦C;
[a]3D2 +13 (c 0.77, CHCl3) (Found: MH+, 386.2297. C23H31NO4 +
H requires 386.2331); mmax (CHCl3)/cm−1 3428, 3020, 2929, 1646,
1524, 1266; dH (300 MHz; CDCl3) 8.21 (1 H, d, J 9.0, ArH), 8.17
=
(1 H, t, J 6.7, ArCH2CMe CH), 4.16 (3 H, s, OMe), 2.56–2.51
(1 H, m, CHOCONH2), 2.38–2.34 (2 H, m, CH2CHOCONH2),
1.63 (3 H, s, Me); dC (100 MHz; CDCl3) major isomer 184.1 (C),
183.6 (C), 169.0 (C), 157.0 (C), 156.9 (C), 138.2 (C), 134.7 (CH),
132.8 (C), 130.4 (C), 129.6 (CH), 128.0 (CH), 126.09 (CH), 125.66
(C), 111.3 (CH), 74.1 (CH), 61.8 (Me), 34.2 (CH2), 33.2 (CH2),
32.99 (CH2), 30.0 (CH2), 29.7 (CH2), 28.0 (CH2), 25.2 (CH2),
15.8 (Me), 12.5 (Me); minor isomer 184.4 (C), 183.57 (C), 168.2
(C), 156.8 (2 × C), 138.0 (C), 134.5 (CH), 132.5 (C), 130.2 (C),
129.1 (CH), 128.8 (CH), 126.1 (CH), 125.7 (C), 111.3 (CH), 74.5
(CH), 61.6 (Me), 33.7 (CH2), 33.0 (CH2), 29.5 (CH2), 28.6 (CH2),
27.6 (CH2), 25.6 (CH2), 24.7 (CH2), 23.6 (Me), 61.6 (Me); 1 C
unobserved; m/z (CI) 457 (MH+, 59%), 416 (100), 398 (80).
Lactam 24b. (3R,9S)- and (3S,9S)-N-[2-(9-(tert-Butyldi-
methylsiloxydodeca-1,11-dien-3-yloxy)-4-methoxyphenyl]-2-
methylpenta-2,4-dienamide 23b (200 mg, 0.379 mmol) was dis-
solved in dichloromethane (76 mL) and Grubbs’ catalyst (62 mg,
0.076 mmol, 20 mol%) was added. The solution was stirred at
reflux for 3 h and then the solvent was removed. Flash chro-
matography using ether and light petroleum (1 : 9) gave the title
compound as a brown oil (156 mg, 82%); [a]3D2 −63 (c 0.63, CHCl3);
mmax (CHCl3)/cm−13430, 3020, 2930, 1655, 1522; dH (300 MHz;
CDCl3) mixture of isomers 8.24–8.17 (1 H, m, ArH), 7.89 (1 H, s,
=
=
(1 H, br s, NH), 6.97 (1 H, d, J 9.0, CMe CHCH CH), 6.52–
=
=
6.45 (2 H, m, ArH, CMe CHCH CH), 6.35 (1 H, s, OH), 5.94
=
=
(1 H, dt, J 9.0, 6.0, CMe CHCH CH), 5.83 (1 H, dt, J 18.0, 6.0,
ArCH2CH CH), 5.62 (1 H, dt, J 18.0, 6.0, ArCH2CH CH),
3.80 (3 H, s, OMe), 3.80–3.76 (1 H, m, CHOH), 3.56 (1 H,
=
=
=
dd, J 15.0, 6.0, ArCH2CH CH), 3.46 (1 H, dd, J 15.0, 6.0,
=
ArCH2CH CH), 2.55–2.46 (1 H, m, CH(OH)CH2), 2.33–2.27
=
=
=
NH), 6.82–6.57 (1 H, m, CMe CHCH CH), 6.41–6.30 (3 H,
(1 H, m, CH(OH)CH2), 2.23–2.04 (3 H, m, ArCH2CH CHCH2
=
=
=
m, ArH, CMe CHCH CH), 5.84–5.73 (2 H, m, CH CH2,
and CHOH), 1.99 (3 H, s, Me), 1.70–1.12 (8 H, m, 4 × CH2);
dC (75 MHz; CDCl3) 168.4 (C), 153.4 (C), 145.7 (C), 135.5 (CH),
135.3 (C), 133.0 (CH), 129.8 (CH), 127.3 (CH), 126.3 (CH), 121.8
(C), 117.8 (CH), 113.0 (C), 103.2 (CH), 72.0 (CH), 56.3 (Me), 38.4
(CH2), 36.8 (CH2), 32.8 (CH2), 31.2 (CH2), 29.6 (CH2), 27.7 (CH2),
26.1 (CH2), 13.3 (Me).
=
=
=
CMe CHCH CH), 5.21–5.12 (2 H, m, CH2 CHCH(O)), 4.70–
4.56 (1 H, m, CH CH2), 3.80–3.72 (1 H, m, CHOTBS), 3.69 and
=
3.68 (3 H, 2 × s, OMe), 2.61–2.40 (1 H, m, CH2CHOTBS), 2.45–
2.08 (1 H, m, CH2CHOTBS), 1.99 and 1.95 (3 H, 2 × s, Me),
1.76–1.15 (10 H, m, 5 × CH2), 0.83 (9 H, s, t-Bu), 0.00 (6 H, s,
Me); dC (75 MHz; CDCl3) mixture of isomers 169.0 (C), 168.9 (C),
168.6 (C), 156.3 (C), 148.3 (C), 147.7 (C), 138.3 (CH), 137.9 (CH),
137.7 (CH), 137.4 (CH), 135.5 (C), 135.1 (C), 133.7 (CH), 133.2
(CH), 132.5 (CH), 127.3 (CH), 126.1 (CH), 125.8 (CH), 122.8 (C),
122.1 (C), 122.0 (C), 120.8 (CH), 117.4 (CH2), 117.2 (CH2), 116.8
(CH2), 116.7 (CH2), 104.1 (CH), 101.9 (CH), 101.7 (CH), 101.4
(CH), 79.7 (CH), 79.2 (CH), 72.4 (CH), 72.1 (CH), 71.5 (CH), 71.3
(CH), 55.8 (Me), 42.5 (CH2), 42.2 (CH2), 36.6 (CH2), 35.8 (CH2),
35.7 (CH2), 35.6 (CH2), 35.4 (CH2), 35.3 (CH2), 30.1 (CH2), 28.3
(CH2), 27.8 (CH2), 26.2 (Me), 24.7 (CH2), 24.5 (CH2), 24.4 (CH2),
24.1 (CH2), 18.5 (C), 13.8 (Me), −4.1 (Me).
Ansa-quinone 27b. Ansa-lactam 26b (14 mg, 0.036 mmol)
was dissolved in acetonitrile (2 mL) and salcomine (2.5 mg,
0.0072 mmol, 20 mol%) was added. The solution was rapidly
stirred overnight open to the atmosphere. After solvent evap-
oration, flash chromatography using ether and light petroleum
(1 : 1) gave the title co◦mpound as an amorphous, orange solid
(11 mg, 73%); mp 48–56 C; [a]3D2 +34 (c 1.0, CHCl3) (Found: MH+,
400.2139. C23H29NO5 + H requires 400.2124); kmax (CH3CN)/nm
(e/dm3 mol−1 cm−1) 206 (e 13400), 295 (e 18200), 362 (e 2500);
mmax (CHCl3)/cm−1 3018, 2929, 1689, 1652, 1498, 1220, 1206; dH
(300 MHz; CDCl3) 8.67 (1 H, s, NH), 7.20 (1 H, s, quinone-H),
=
=
Claisen rearrangement of lactam 24b to ansa-lactam 25b. Lac-
tam 24b (59 mg, 0.12 mmol) was dissolved in xylenes (2.5 mL) and
6.99 (1 H, d, J 12.05, CMe CHCH CH), 6.40 (1 H, dd, J 12.0,
=
=
=
=
9.0, CMe CHCH CH), 6.00 (1 H, q, J 9.0, CMe CHCH CH),
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©

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=
=
=
5.41 (1 H, dt, J 15.0, 6.0, ArCH2CH CH), 5.19 (1 H, dt, J 15.0,
CMe CHCH CH), 6.38–6.23 (2 H, m, ArH), 5.93 (1 H, q,
=
=
=
=
6.0, ArCH2CH CH), 4.03 (3 H, s, OMe), 3.77–3.70 (1 H, m,
J 8.8, CMe CHCH CH), 4.93–4.83 (2 H, m, CMe CH2),
4.51–4.44 (1 H, m, ArOCH), 3.99–3.85 (1 H, m, CHOTBDPS),
3.75 (1.5 H, s, OMe), 3.74 (1.5 H, s, OMe), 2.60–2.03 (2 H, m,
CH(OTBDPS)CH2), 2.03 (3 H, s, Me), 1.70–0.82 (8 H, m, 4 ×
CH2), 1.70 (1.5 H, s, Me), 1.67 (1.5 H, s, Me), 1.03 (9 H, s, t-Bu);
dC (75 MHz; CDCl3) mixture of isomers 167.5 (C), 167.1 (C),
155.71 (C), 155.67 (C), 147.64 (C), 147.61 (C), 142.9 (C), 142.4
(C), 135.99 (CH), 135.93 (CH), 134.9 (CH), 134.5 (C), 134.48
(CH), 134.41 (CH), 134.0 (CH), 133.7 (CH), 133.5 (C), 129.67
(CH), 129.62 (CH), 127.49 (CH), 127.40 (CH), 125.9 (CH), 125.5
(CH), 125.3 (CH), 124.7 (CH), 121.8 (C), 119.5 (CH), 112.1
(CH2), 111.9 (CH2), 103.6 (CH), 103.5 (CH), 100.6 (CH), 100.5
(CH), 81.7 (CH), 81.6 (CH), 73.0 (CH), 72.8 (CH), 55.4 (Me),
36.0 (CH2), 35.7 (CH2), 34.7 (CH2), 34.06 (CH2), 34.00 (CH2),
33.6 (CH2), 27.06 (Me), 27.04 (Me), 26.1 (CH2), 25.1 (CH2), 23.8
(CH2), 22.9 (CH2), 10.4 (C), 19.3 (C), 18.9 (Me), 18.6 (Me), 13.2
(Me), 13.0 (Me); m/z (CI) 624 (MH+, 62%), 606 (100), 529 (17),
368 (64).
=
CHOH), 3.09 (2 H, d, J 6.0, ArCH2CH CH), 2.46–2.37 (1 H,
m, CH(OH)CH2), 2.32–2.22 (1 H, m, CH(OH)CH2), 1.96 (2 H,
d, J 6.0, ArCH2CH CHCH2), 1.92 (3 H, s, Me), 1.60 (1 H, br s,
OH), 1.54–1.48 (4 H, m, 2 × CH2), 1.36–1.18 (4 H, m, 2 × CH2);
dC (75 MHz; CDCl3) 184.6 (C), 183.5 (C), 169.2 (C), 156.6 (C),
138.7 (C), 136.1 (CH), 133.9 (CH), 132.9 (C), 129.9 (CH), 126.7
(C), 126.4 (CH), 125.8 (CH), 111.6 (CH), 72.3 (CH), 62.2 (Me),
38.6 (CH2), 36.2 (CH2), 32.7 (CH2), 29.7 (CH2), 29.0 (CH2), 26.9
(CH2), 26.0 (CH2), 12.8 (Me); m/z (EI) 399 (M+, 9%), 384 (100),
368 (17), 321 (5), 215 (17).
=
Ansa-quinone carbamate 7b. Ansa-quinone 27b (10 mg,
0.025 mmol) was dissolved in dichloromethane (2.5 mL). Sodium
cyanate (40 mg, 0.62 mmol) was added and the mixture was
cooled to 0 ◦C. Trifluoroacetic acid (46 lL, 0.62 mmol) was
added and the reaction mixture was stirred for 15 h at room
temperature before dilution with dichloromethane (10 mL). The
solution was neutralized by the addition of saturated sodium
hydrogen carbonate (10 mL). The layers were separated and the
aqueous phase was extracted with dichloromethane (3 × 10 mL).
The combined organics were dried (Na2SO4) and the solvent
was evaporated. Flash chromatography using ether and light
petroleum (1 : 1) gave the title compound as an amorphous yellow
Claisen rearrangement of lactam 35a. Lactam 35a (0.370 g,
0.59 mmol) was dissolved in xylene (19.5 mL) in a sealed tube.
The mixture was heated at 180 ◦C for 35 min in a microwave
reactor (300 W). The solvent was then removed in vacuo and the
crude product was purified by flash chromatography on silica,
eluting with ethyl acetate and light petroleum (1 : 9) to give the
rearrangement product as a yellow oil (0.312 g, 84%) (Found: MH+,
624.3502. C39H49NO4Si + H requires 624.3509); mmax (film)/cm−1
3427, 3071, 2931, 2857, 1665, 1590, 1523, 1110, 702; dH (300 MHz;
CDCl3) 8.15 (1 H, d, J 8.8, ArH), 8.13 (1 H, s, NH), 7.69–7.64
(4 H, m, ArH), 7.43–7.31 (6 H, m, ArH), 7.07 (1 H, d, J 10.9,
◦
solid (4.7 mg, 43%); mp 128–131 C; [a]3D2 +60 (c 0.10, CHCl3)
(Found: MH+, 443.2200. C24H30N2O6 + H requires 443.2182); kmax
(CH3CN)/nm (e/dm3 mol−1 cm−1) 261 (e 33088), 331 (e 5311); mmax
(CHCl3)/cm−1 3697, 3604, 2927, 2855, 1722, 1649, 1601, 1385; dH
(300 MHz; CDCl3) 8.56 (1 H, s, NH), 7.20 (1 H, s, quinone-H), 6.99
=
=
(1 H, d, J 12.0, CMe CHCH CH), 6.35 (1 H, dd, J 12.0, 9.0,
CMe CHCH CH), 5.89 (1 H, q, J 9.0, CMe CHCH CH),
=
=
=
=
=
=
CMe CHCH CH), 6.55 (1 H, s, OH), 6.49 (1 H, d, J 8.8, ArH),
=
=
=
5.40 (1 H, dt, J 15.0, 6.0, ArCH2CH CH), 5.30–5.15 (3 H, m,
6.26 (1 H, t, J 11.3, CMe CHCH CH), 5.89 (1 H, q, J 10.1,
=
=
=
=
ArCH2CH CH, OCONH2), 4.92–4.86 (1 H, m, CHOCONH2),
CMe CHCH CH), 5.45 (1 H, t, J 7.1, CMe CHCH2), 3.91–
3.82 (1 H, m, CHOTBDPS), 3.80 (3 H, s, OMe), 3.50 (2 H, s,
ArCH2), 2.51–2.26 (2 H, m, CH(OTBDPS)CH2), 2.12–0.80 (8 H,
m, 4 × CH2), 1.99 (3 H, s, Me), 1.53 (3 H, s, Me), 1.02 (9 H, s,
t-Bu); dC (75 MHz; CDCl3) 168.9 (C), 153.6 (C), 145.9 (C), 136.5
(C), 136.0 (CH), 135.3 (CH), 134.7 (C), 133.4 (C), 129.5 (CH),
128.3 (CH), 127.6 (CH), 127.3 (CH), 125.1 (CH), 121.2 (C), 117.7
(CH), 112.3 (C), 102.6 (CH), 73.7 (CH), 55.9 (Me), 38.8 (CH2),
34.8 (CH2), 34.1 (CH2), 29.1 (CH2), 28.0 (CH2), 27.0 (Me), 23.9
(CH2), 19.4 (C), 15.7 (Me), 12.4 (Me); some peaks are ‘doubled’
due to the presence of diastereomers; m/z (CI) 624 (MH+, 100%),
546 (40), 368 (88), 350 (21).
=
4.08 (3 H, s, MeO), 3.20–3.14 (1 H, m, ArCH2CH CH), 2.97
=
(1 H, dd, J 15.0, 9.0, ArCH2CH CH), 2.65–2.53 (1 H, m,
CH(OCONH2)CH2), 2.20–2.12 (1 H, m, CH(OCONH2)CH2),
=
1.97–1.91 (2 H, m, ArCH2CH CHCH2), 1.91 (3 H, s, Me), 1.76–
1.23 (8 H, m, 4 × CH2); dC (75 MHz; CDCl3) 184.3 (C), 183.9 (C),
169.4 (C), 156.8 (C), 156.5 (C), 138.6 (C), 135.0 (CH), 134.1 (CH),
133.3 (C), 130.1 (CH), 126.5 (CH), 126.2 (C), 125.4 (CH), 111.6
(CH), 74.4 (CH), 62.3 (Me), 34.4 (CH2), 33.4 (CH2), 33.1 (CH2),
30.1 (CH2), 29.8 (CH2), 26.9 (CH2), 25.6 (CH2), 12.8 (Me).
Lactam 35a. N-[2-(8-tert-Butyldiphenylsiloxy-2-methylun-
deca-1,10-dien-3-yloxy)-4-methoxyphenyl]-2-methylpenta-2,4-di-
enamide 34a (0.200 g, 0.30 mmol) in anhydrous dichloromethane
(56 mL) was slowly added to a solution of Grubbs’ catalyst
(0.075 g, 0.09 mmol, 30 mol%), in anhydrous dichloromethane
(550 mL) under reflux. The mixture was heated under reflux
for 24 h then concentrated in vacuo. The crude product was
purified by flash chromatography on silica, eluting with ethyl
acetate and light petroleum (1 : 9) to give the title compound as
a dark oil (0.188 g, 98%) as a 1 : 1 mixture of diastereoisomers
(Found: MH+, 624.3504. C39H49NO4Si + H requires 624.3509);
mmax (film)/cm−1 3431, 3070, 2932, 2856, 1659, 1615, 1522, 1110,
702; dH (300 MHz; CDCl3) mixture of isomers 8.47–8.43 (1 H,
2 × d, J 8.8, ArH), 8.11 (0.5 H, s, NH), 7.99 (0.5 H, s, NH),
7.67–7.62 (4 H, m, ArH), 7.37–7.28 (6 H, m, ArH), 6.72
Ansa-lactam 36a. The above ansa-lactam (0.187 g, 0.30 mmol)
was dissolved in anhydrous THF (4.5 mL) and tetra-n-
butylammonium fluoride (1 M in THF; 0.74 mL, 0.74 mmol)
was added dropwise. The mixture was then stirred under reflux
for 12 h, before being cooled to room temperature. The mixture
was then acidified with saturated ammonium chloride solution
extracted with ethyl acetate (3 × 15 mL), combined, washed with
brine (30 mL), dried (MgSO4), filtered and evaporated in vacuo.
The crude product was purified by flash chromatography on silica,
eluting with ethyl acetate and light petroleum (4 : 1) to give the title
compound as a colourless solid (0.093 g, 80%) as a 1 : 5 : 63 mixture
of three diasteroisomers; mp 172–175 ◦C (from ethyl acetate
and light petroleum) (Found: MH+, 386.2325. C23H31NO4
H requires 386.2331); mmax (KBr)/cm−1 3414, 2925, 2852, 1640,
+
=
=
(1 H, t, J 11.3, CMe CHCH CH), 6.45 (1 H, dt, J 2.6 7.3,
542 | Org. Biomol. Chem., 2007, 5, 531–546
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
=
=
1531; dH (300 MHz; CDCl3) mixture of isomers 8.22 (1 H, s, NH),
6.42 (1 H, t, J 10.9, CMe CHCH CH), 5.98 (1 H, q, J 10.2,
=
=
=
=
=
8.02 (1 H, d, J 8.8, ArH), 7.15 (1 H, d, J 15.4, CMe CHCH CH),
CMe CHCH CH), 5.25 (1 H, t, J 6.4, CMe CHCH2), 5.02–
4.63 (2 H, m, OCONH2), 4.12 (3 H, s, OMe), 3.24–3.11 (2 H, m,
ArCH2), 2.67–2.55 (1 H, m, CHOCONH2), 2.42–2.28 (2 H, m,
CH(OCONH2)CH2), 1.96 (3 H, s, Me), 1.53 (3 H, s, Me), 2.11–
0.82 (8 H, m, 4 × CH2); minor isomer 8.40 (1 H, s, NH), 7.40
=
=
6.69 (1 H, s, OH), 6.53–6.46 (2 H, m, ArH, CMe CHCH CH),
=
=
5.97 (1 H, q, J 13.8, CMe CHCH CH), 5.56 (1 H, t, J 7.8,
CMe CHCH2), 3.80 (3 H, s, OMe), 3.80–3.73 (1 H, m, CHOH),
=
3.52 (2 H, s, ArCH2), 2.44–2.37 (2 H, m, CH(OH)CH2), 2.03
(3 H, s, Me), 1.52 (3 H, s, Me), 2.22–1.23 (8 H, m, 4 × CH2), 1.77
(1 H, br s, OH); dC (75 MHz; CDCl3) mixture of isomers 168.7
(C), 153.7 (C), 145.9 (C), 136.9 (C), 134.5 (C), 133.7 (CH), 128.3
(CH), 127.0 (CH), 126.4 (CH), 121.2 (C), 117.6 (CH), 112.3 (C),
102.7 (CH), 71.7 (CH), 55.9 (Me), 38.1 (CH2), 34.4 (CH2), 34.2
(CH2), 29.2 (CH2), 27.7 (CH2), 23.5 (CH2), 15.7 (Me), 12.5 (Me);
some peaks are ‘doubled’ due to the presence of diastereomers, but
peaks due to minor isomer are very small; m/z (CI) 386 (MH+,
100%), 350 (43).
=
(1 H, s, ArH), 5.14 (1 H, t, J 7.3, CMe CHCH2), (3 H, s, OMe),
1.99 (3 H, s, Me), 1.57 (3 H, s, Me); dC (75 MHz; CDCl3) mixture
of isomers; peaks due to major isomer reported 184.1 (C), 183.6 (C),
168.9 (C), 156.65 (C), 156.60 (C), 138.6 (C), 135.2 (CH), 132.0 (C),
130.8 (CH) 130.1 (C), 128.5 (CH), 125.9 (C), 125.7 (CH), 110.5
(CH), 73.7 (CH), 61.7 (Me), 35.3 (CH2), 33.0 (CH2), 31.4 (CH2),
29.7 (CH2), 27.1 (Me), 22.3 (CH2), 15.8 (Me), 12.1 (CH2); m/z
(CI) 443 (MH+, 25%), 400 (83), 382 (100), 368 (18).
Lactam
35b. N-[2-(8-tert-Butyldiphenylsiloxy-2-methyl-
Oxidation of ansa-lactam 36a. Ansa-lactam 36a (0.093 g,
0.24 mmol) was dissolved in acetone (55 mL) and Fremy’s salt
(0.260 g, 0.96 mmol) in sodium dihydrogen phosphate buffer
(28 mL) was added. The mixture was stirred for 2 h, then diluted
with ethyl acetate (100 mL), and washed with water (2 × 30 mL),
brine (30 mL), dried (MgSO4), filtered and evaporated in vacuo.
The crude product was purified by flash chromatography on silica,
eluting with ethyl acetate and light petroleum (1 : 4) to give the
quinone as an orange oil (0.066 g, 70%) as a 1 : 10 mixture
of diastereoisomers (Found: MH+, 400.2134. C23H29NO5 + H
requires 400.2124); mmax (film)/cm−1 3421, 3359, 2929, 2856, 1687,
1650, 1601, 1498, 703; dH (300 MHz; CDCl3) major isomer 8.79
(1 H, s, NH), 7.25 (1 H, s, quinone-H), 7.10 (1 H, d, J 11.5,
dodeca-1,11-dien-3-yloxy)-4-methoxyphenyl]-2-methylpenta-2,4-
dienamide 34b (0.159 g, 0.24 mmol) in anhydrous dichloromethane
(45 mL) was slowly added to a solution of Grubbs’ catalyst
(0.059 g, 0.07 mmol, 30 mol%), in anhydrous dichloromethane
(425 mL) under reflux. The mixture was heated under reflux for
24 h then concentrated in vacuo. The crude product was purified
by flash chromatography on silica, eluting with ethyl acetate and
light petroleum (1 : 9) to give the title compound as a dark oil
(0.147 g, 96%) as 1 : 1 mixture of diastereoisomers (Found: MH+,
638.3655. C40H51NO4Si + H requires 638.3665); mmax (film)/cm−1
3434, 3070, 2934, 2857, 1665, 1615, 1520, 1110, 702; dH (300 MHz;
CDCl3) mixture of isomers 8.40–8.29 (1 H, m, ArH), 8.02 (0.5 H, s,
NH), 8.05 (0.5 H, s, NH), 7.67–7.65 (4 H, m, ArH), 7.41–7.32 (6 H,
=
=
=
=
=
=
CMe CHCH CH), 6.49 (1 H, t, J 10.8, CMe CHCH CH),
m, ArH), 6.48–6.45 (1 H, m, CMe CHCH CH), 6.44–6.38
=
=
=
=
6.11 (1 H, q, J 8.1, CMe CHCH CH), 5.27 (1 H, t, J 6.4,
(2 H, m, ArH), 6.26–6.22 (1 H, m, CMe CHCH CH), 5.80–5.45
=
=
=
=
CMe CHCH2), 4.11 (3 H, s, OMe), 3.80–3.74 (1 H, m, CHOH),
(1 H, m, CMe CHCH CH), 4.95–4.93 (2 H, m, MeC CH2),
4.42–4.36 (1 H, m, ArOCH), 3.81–3.73 (1 H, m, CHOTBDPS),
3.74 (1.5 H, s, OMe), 3.73 (1.5 H, s, OMe), 2.18 (3 H, s, Me), 1.68
(1.5 H, s, Me), 1.67 (1.5 H, s, Me), 1.04 (9 H, s, t-Bu), 2.18–0.87
(12 H, 6 × CH2); dC (75 MHz; CDCl3) mixture of isomers 168.17
(C), 168.03 (C), 155.73 (C), 155.68 (C), 147.7 (C), 147.5 (C), 144.1
(C), 143.8 (C), 137.2 (CH), 137.0 (CH), 135.8 (CH), 134.45 (C),
134.39 (C), 129.52 (CH), 127.49 (CH), 124.86 (CH), 124.75 (C),
123.73 (CH), 123.60 (CH), 121.74 (C), 121.71 (C), 119.85 (CH),
119.75 (CH), 112.4 (CH2), 112.2 (CH2), 103.58 (CH), 103.54
(CH), 100.70 (CH), 100.62 (CH), 82.50 (CH), 82.44 (CH), 72.2
(CH), 71.4 (CH), 55.3 (Me), 35.9 (CH2), 35.0 (CH2), 34.8 (CH2),
34.7 (CH2), 27.00 (Me), 26.95 (Me), 26.1 (CH2), 24.8 (CH2), 24.5
(CH2), 23.9 (CH2), 22.8 (CH2), 19.32 (C), 19.29 (CH), 17.9 (Me),
17.7 (Me), 13.29 (Me), 13.22 (Me); m/z (CI) 638 (MH+, 77%),
620 (65), 386 (100), 300 (83).
3.21–3.14 (2 H, m, ArCH2), 2.43–2.10 (2 H, m, CH(OH)CH2),
1.99 (3 H, s, Me), 1.69 (1 H, s, OH), 1.54 (3 H, s, Me), 2.07–
0.88 (8 H, m, 4 × CH2); minor isomer 8.43 (1 H, s, NH), 7.19
=
(1 H, s, ArH), 5.12–5.08 (1 H, m, CMe CHCH2), 4.14 (3 H, s,
OMe); dC (75 MHz; CDCl3) mixture of isomers 184.1 (C), 183.1
(C), 168.9 (C), 156.5 (C), 138.5 (C), 136.6 (CH), 132.0 (C), 130.7
(C), 129.9 (CH), 128.5 (CH), 125.9 (C), 125.6 (CH), 110.6 (CH),
72.0 (CH), 61.6 (Me), 38.8 (CH2), 34.3 (CH2), 33.1 (CH2), 29.8
(CH2), 27.3 (Me), 23.0 (CH2), 15.7 (Me), 12.1 (Me); m/z (CI) 400
(MH+, 100%), 384 (22), 368 (12).
Ansa-quinone carbamate 37a. The above ansa-quinone
(0.038 g, 0.09 mmol) was dissolved in dichloromethane (6 mL).
Sodium cyanate (0.154 g, 2.37 mmol) and trifluoroacetic acid
(183 ll, 2.37 mmol) were then added at 0 ◦C. The mixture was
stirred slowly at room temperature for 4.5 h, before the solution
was diluted with dichloromethane (100 mL) and quenched with
a sodium hydrogen carbonate solution (5%; 80 mL). The mixture
was then extracted with ethyl acetate (3 × 100 mL), the extracts
combined andwashedwith brine (100mL), dried(MgSO4), filtered
and evaporated in vacuo. The crude product was purified by flash
chromatography on silica, eluting with ethyl acetate and light
petroleum (3 : 7) to give the title compound as a orange oil (0.020 g,
47%) as a 1 : 2.2 : 3.4 : 12.8 mixture of four diastereoisomers
(Found: MH+, 443.2177. C24H30N2O6 + H requires 443.2182);
mmax (film)/cm−1 3478, 3361, 2925, 2855, 1693, 1651, 1600, 1503,
701; dH (300 MHz; CDCl3) major isomer 8.74 (1 H, s, NH), 7.26
Claisen rearrangement of lactam 35b. Lactam 35b (0.156 g,
0.24 mmol) was dissolved in xylene (7 mL) in a sealed tube.
The mixture was heated at 180 ◦C for 35 min in a microwave
reactor (300 W). The solvent was then removed in vacuo and the
crude product was purified by flash chromatography on silica,
eluting with ethyl acetate and light petroleum (1 : 9) to give the
rearrangement product as a red oil (0.085 g, 54%) as a mixture
of diastereoisomers (Found: MH+, 638.3672. C40H51NO4Si +
H requires 638.3665); mmax (film)/cm−1 3428, 3070, 2932, 2857,
1662, 1590, 1525, 1110, 703; dH (300 MHz; CDCl3) mixture of
isomers 8.20 (1 H, d, J 9.0, ArH), 8.15 (1 H, s, NH), 7.71–7.62
(4 H, m, ArH), 7.45–7.29 (6 H, m, ArH), 6.87 (1 H, d, J 11.3,
=
=
(1 H, s, quinone-H), 7.07 (1 H, d, J 11.5, CMe CHCH CH),
This journal is The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 531–546 | 543
©

View Article Online
=
=
CMe CHCH CH), 6.48 (1 H, d, J 9.0, ArH), 6.44 (1 H, s, OH),
OH, 6 × CH2); minor isomer 8.84 (1 H, s, NH), 7.27 (1 H, d, J 11.3,
=
=
=
=
6.22 (1 H, t, J 11.1, CMe CHCH CH), 5.75 (1 H, q, J 10.3,
CMe CHCH CH), 7.16 (1 H, s, quinone-H), 5.10 (1 H, t, J 6.8,
=
=
=
=
CMe CHCH CH), 5.48 (1 H, t, J 6.8, CMe CHCH2), 3.79
(3 H, s, OMe), 3.66 (1 H, q, J 4.7, CHOTBDPS), 3.48–3.46 (2 H,
m, ArCH2), 2.25–0.82 (12 H, m, 6 × CH2), 2.00 (3 H, s, Me), 1.55
(3 H, s, Me), 1.05 (9 H, s, t-Bu); dC (75 MHz; CDCl3) mixture of
isomers 167.9 (C), 153.4 (C), 145.4 (C), 137.0 (CH), 136.2 (CH),
135.8 (CH), 134.3 (C), 133.8 (C), 129.5 (CH), 128.1 (CH), 127.4
(CH), 125.9 (CH), 124.2 (CH), 121.3 (C), 117.1 (CH), 112.2 (C),
102.8 (CH), 73.6 (CH), 55.9 (Me), 37.3 (CH2), 35.8 (CH2), 34.1
(CH2), 29.8 (CH2), 27.8 (CH2), 27.0 (Me), 24.2 (CH2), 23.8 (CH2),
19.3 (C), 15.7 (Me), 12.7 (Me); m/z (CI) 638 (MH+, 56%), 620
(100), 542 (26), 382 (32).
CMe CHCH2), 4.18 (3 H, s, OMe); dC (75 MHz; CDCl3) mixture
of isomers 184.1 (C), 183.9 (C), 168.5 (C), 156.9 (C), 139.7 (C),
138.7 (CH), 134.7 (C), 131.4 (C), 129.9 (CH), 127.7 (CH), 125.8
(C), 124.6 (CH), 111.5 (CH), 70.6 (CH), 61.7 (Me), 37.1 (CH2),
36.4 (CH2), 33.4 (CH2), 28.9 (CH2), 27.1 (CH2), 23.8 (CH2), 23.6
(CH2), 15.7 (Me), 12.3 (Me); m/z (CI) 414 (MH+, 100%), 396 (54).
Ansa-quinone carbamate 37b. The above ansa-quinone
(0.014 g, 0.038 mmol) was dissolved in dichloromethane (2.1 mL).
Sodium cyanate (0.055 g, 0.84 mmol) and trifluoroacetic acid
◦
(0.096 g, 0.84 mmol) were then added at 0 C. The mixture was
stirred slowly at room temperature for 3 h, before quenching with
sodium hydrogen carbonate solution (5%; 20 mL). The mixture
was then extracted with ethyl acetate (3 × 30 mL), combined
and washed with brine (50 mL), dried (MgSO4), filtered and
evaporated in vacuo. The crude product was purified by flash
chromatography on silica, eluting with ethyl acetate and light
petroleum (1 : 4) to give the title compound as a orange oil
(0.009 g, 58%) as a 1 : 6 mixture of diastereoisomers (Found: MH+,
457.2329. C25H32N2O6 + H requires 457.2338); mmax (film)/cm−1
3465, 3365, 2929, 2858, 1691, 1650, 1590, 1503; dH (300 MHz;
CDCl3) major isomer 8.81 (1 H, s, NH), 7.29 (1 H, s, quinone-
Ansa-lactam 36b. The above ansa-lactam (0.168 g, 0.26 mmol)
was dissolved in anhydrous THF (4 mL) and tetra-n-
butylammonium fluoride (1 M in THF; 0.65 mL, 0.65 mmol)
was added dropwise. The mixture was then stirred under reflux for
12 h, before being cooled to room temperature. The mixture was
acidified with saturated ammonium chloride solution extracted
with ethyl acetate (3 × 15 mL), the extracts combined, washed
with brine (20 mL), dried (MgSO4), filtered and evaporated in
vacuo. The crude product was purified by flash chromatography
on silica, eluting with ethyl acetate and light petroleum (4 : 1) to
give the title compound as a colourless solid (0.085 g, 80%) as a
=
=
H), 7.08–6.99 (1 H, m, CMe CHCH CH), 6.35–6.28 (1 H, m,
◦
mixture of diastereoisomers; mp 194-196 C (from ethyl acetate
=
=
=
=
CMe CHCH CH), 6.02–5.89 (1 H, m, CMe CHCH CH),
and light petroleum) (Found: MH+, 400.2476. C24H33NO4
+
=
5.18–5.09 (1 H, m, CMe CHCH2), 4.59 (2 H, s, CONH2), 4.12
H requires 400.2488); mmax (film)/cm−1 3468, 3401, 2925, 2853,
1652, 1590, 1525; dH (300 MHz; CDCl3) mixture of isomers 8.20
(1 H, d, J 9.0, ArH), 8.17 (1 H, s, NH), 7.06 (1 H, d, J 11.3,
(3 H, s, OMe), 3.24–3.12 (2 H, m, ArCH2), 1.98 (3 H, s, Me), 2.42–
2.20 (3 H, m, CH2, CH(OCONH2)), 1.58 (3 H, s, Me), 2.05–0.85
(10 H, m, 5 × CH2); minor isomer 8.91 (1 H, s, NH), 7.47 (1 H,
s, quinone-H), 2.04 (3 H, s, Me), 1.58 (3 H, s, Me); dC (75 MHz;
CDCl3) mixture of isomers 184.1 (C), 183.9 (C), 168.5 (C), 156.9
(C), 139.7 (C), 138.7 (CH), 132.1 (C), 131.1 (C), 129.9 (CH), 128.3
(C), 127.7 (CH), 125.8 (C), 124.6 (CH), 111.5 (CH), 70.6 (CH),
61.7 (Me), 37.1 (CH2), 36.4 (CH2), 33.4 (CH2), 28.9 (CH2), 27.1
(CH2), 23.8 (CH2), 23.6 (CH2), 15.7 (Me), 12.3 (Me); m/z (CI) 457
(MH+, 16%), 416 (100), 398 (28), 285 (28).
=
=
CMe CHCH CH), 6.65 (1 H, s, OH), 6.49 (1 H, d, J 9.0, ArH),
=
=
6.33 (1 H, t, J 10.9, CMe CHCH CH), 5.93 (1 H, q, J 8.5,
=
=
=
CMe CHCH CH), 5.62 (1 H, t, J 7.2, CMe CHCH2), 3.80
(3 H, s, OMe), 3.64–3.56 (1 H, m, CHOH), 3.52 (2 H, s, ArCH2),
=
2.36–2.33 (2 H, m, CH2), 2.17–2.15 (2 H, m, MeC CHCH2), 2.01
(3 H, s, Me), 1.59 (3 H, s, Me), 1.82 (1 H, s, OH), 1.70–0.85 (8 H,
m, 4 × CH2); dC (75 MHz; CDCl3) mixture of isomers 168.0 (C),
153.6 (C), 145.5 (C), 136.8 (C), 133.6 (CH), 134.0 (C), 128.4 (CH),
126.1 (CH), 124.8 (CH), 121.1 (C), 117.5 (CH), 112.3 (C), 102.7
(CH), 72.4 (CH), 55.9 (Me), 38.0 (CH2), 36.7 (CH2), 34.3 (CH2),
29.3 (CH2), 27.4 (CH2), 24.7 (CH2), 24.5 (CH2), 15.6 (Me), 12.8
(Me); m/z (CI) 400 (MH+, 100%), 382 (45).
Molecular modelling
Molecular modelling was carried out in conjunction with Stephen
Connelly (University of Exeter) using the Dock function in MOE
(MOE 2004.03, Chemical Computing Group Inc, Cambridge,
UK). In MOE-Dock, the configuration space includes all orien-
tations and conformations of the ligand such that all of its atoms
are inside the docking box.
Oxidation of ansa-lactam 36b. Ansa-lactam 36b (0.029 g,
0.07 mmol) was dissolved in acetone (16 mL) and Fremy’s salt
(0.063 g, 0.29 mmol) in sodium dihydrogen phosphate buffer
(8 mL) was added. The mixture was stirred for 2 h, diluted with
ethyl acetate (30 mL). The organic layer was washed with water
(2 × 10 mL), brine (10 mL), dried (MgSO4), filtered and evaporated
in vacuo. The crude product was purified by flash chromatography
on silica, eluting with ethyl acetate and light petroleum (1 : 4) to
give the quinone as an orange oil (0.019 g, 63%) as a 1 : 8.5 mixture
of diastereoisomers (Found: MH+, 414.2293. C24H31NO5 + H
requires 414.2293); mmax (film)/cm−1 3362, 2928, 2855, 1684,
1651, 1600, 1504; dH (300 MHz; CDCl3) major isomer 8.80
Biology
Malachite green assay. A colourimetric assay for the release
of inorganic phosphate upon hydrolysis of ATP was used to
determine the potency of Hsp90 inhibitors against the enzyme.
It is based on the formation of phosphomolybdate complex and
subsequent reaction with malachite green.105
=
=
(1 H, s, NH), 7.38 (1 H, d, J 11.1, CMe CHCH CH), 7.35 (1 H,
Growth inhibition assay. The colorimetric sulforhodamine B
assay (SRB) was used to measure growth inhibition studies as
described previously.106 The IC50 was calculated as the drug
concentration that inhibits cell growth by 50% compared with
control growth.
=
=
s, quinone-H), 6.32 (1 H, t, J 10.7, CMe CHCH CH), 6.05 (1 H,
=
=
=
q, J 8.6, CMe CHCH CH), 5.25 (1 H, t, J 7.2, CMe CHCH2),
4.12 (3 H, s, OMe), 3.64–3.60 (1 H, m, CHOH), 3.19–3.13 (2 H, m,
ArCH2), 1.97 (3 H, s, Me), 1.52 (3 H, s, Me), 2.42–0.85 (13 H, m,
544 | Org. Biomol. Chem., 2007, 5, 531–546
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Pearl, G. W. Aherne, E. McDonald and P. Workman, Bioorg. Med.
Chem. Lett., 2005, 15, 3338.
Acknowledgements
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This work was supported by Cancer Research UK [CUK] grant
numbers C215/A3535 (CJM) and CA309/A2187 (PW). PW is a
Cancer Research UK Life Fellow. We thank Stephen Connelly
(University of Exeter) for help with molecular modelling, the
EPSRC Mass Spectrometry Centre at Swansea, and the EPSRC
Chemical Database Service at Daresbury.107
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