Design and total synthesis of unnatural analogues of the sub-nanomolar SERCA inhibitor thapsigargin

Article abstract of DOI:10.1039/b702481a

Thapsigargin is a densely oxygenated guaianolide which displays potent sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) binding affinities. The total syntheses of designed unnatural analogues of this important natural product are described. This

Full text of DOI:10.1039/b702481a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Design and total synthesis of unnatural analogues of the sub-nanomolar
SERCA inhibitor thapsigargin†
Stephen P. Andrews,a Malcolm M. Tait,a,b Matthew Balla and Steven V. Ley*a
Received 15th February 2007, Accepted 7th March 2007
First published as an Advance Article on the web 23rd March 2007
DOI: 10.1039/b702481a
Thapsigargin is a densely oxygenated guaianolide which displays potent sarco/endoplasmic reticulum
Ca2+ ATPase (SERCA) binding affinities. The total syntheses of designed unnatural analogues of this
important natural product are described. This article constitutes the chemical synthesis behind an
ongoing project. Rational modifications have been made to the lactone region of thapsigargin in order
to obtain derivatives for future structure–activity relationship studies.
For example, modification of the C-7/11 diol functionality of
thapsigargin afforded acetates 2 and 3, which exhibit SERCA
binding affinities of the same order of magnitude as thapsigargin
(Table 1). Ether 4 and lactol 5 display even higher potencies,
Introduction
Thapsigargin (1) is a potent and selective inhibitor of sarco/
endoplasmic reticulum Ca2+ ATPases (SERCAs).1,2 As such, thap-
sigargin is capable of severely unbalancing cellular Ca2+ concen-
trations,3 often leading to disrupted cell function and growth,4
and apoptosis of the affected cell.5 Significantly, this has led to the
development of a thapsigargin-derived prodrug for the treatment
of prostate cancer. When tested in vivo, the prodrug was selectively
cytotoxic to prostate tumours, whilst displaying minimal host
toxicity.6
which are almost as great as that of the natural product.10,13
Another important discovery was that other members of the
thapsigargin family are highly active, including nortrilobolide (6),
which is equipotent with thapsigargin, despite lacking the large
octanoate group at C-2.9a Of further significance is the observation
that another C-2 deoxygenated compound (7, also obtained by
total synthesis), which lacks the internal C-4/5 olefin moiety of
the thapsigargins, is ten times more potent than thapsigargin.9e
Conversely, analogues of thapsigargin with epimerised C-3 or
C-8 stereogenic centres have been shown to possess lower SERCA
inhibition properties by factors of 438 and 3124, respectively.10
We have previously reported the synthesis of some unnatural
analogues of thapsigargin.9e,12 In this article, we describe the
chemical synthesis of our most recent generation of targets.
Following the recent publication of the first total synthesis of
thapsigargin,7,8 and with a growing understanding of its structure–
activity relationship (SAR), highly active analogues of the natural
product with simplified structures are increasingly within reach
of the synthetic chemist.9 Furthermore, owing to the difficulties
in cultivating Thapsia (from which thapsigargin is harvested in
relatively small quantities), total synthesis appears attractive as a
means of obtaining thapsigargin and related analogues.10
Results and discussion
Existing SAR
Target analogues
Chemical transformations of natural samples of thapsigargin
have previously provided analogues with modified peripheral
functionality.10 Stereocentres of the natural product have also been
epimerised, and together, these studies have provided valuable
SAR data. However, there are very few literature examples
of analogues in which the core structure of the molecule has
been significantly modified, or which have been prepared by
total synthesis.9e,11,12 Upon analysing literature SAR data it also
becomes apparent that very few analogues have been prepared in
which the lactone region of thapsigargin has been modified, but
of those that have been tested, many exhibit exceptional levels of
SERCA inhibition.
To address the issue of obtaining simplified analogues of thapsi-
gargin by total synthesis, we sought to prepare a complimentary set
of compounds from known common intermediate 12 (Scheme 1).
It was anticipated that this group of analogues (8, 9, 10 and 11)
would reveal key SAR data concerning the importance of the
rigidity of the lactone ring, as well as the necessity for hydrogen
bond donors/acceptors at this site of the pharmacophore. These
particular molecules were chosen, in part, for their availability
from common intermediate 12. However, we aimed to retain high
activity in these analogues, so all targets would incorporate the
key features discussed above: they would retain the C-3 and C-8
stereochemistry of the natural product, but would lack oxygen at
C-2 and be saturated at C-4/5.14
aUniversity Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW,
UK. E-mail: svl1000@cam.ac.uk; Web: http://leygroup.ch.cam.ac.uk;
Fax: +44 (0)1223 336442; Tel: +44 (0)1223 336398
Synthesis of butenolide analogue 8
bGI Medicinal Chemistry, Neurology and GI CEDD, GlaxoSmithKline, New
During our work on the total synthesis of thapsigargin, we
developed a route capable of generating large quantities of 12
as a single diastereomer.8,15 By modifying our existing method for
generating the lactone of thapsigargin from this intermediate, we
Frontiers Science Park (North), Third Avenue, Harlow, Essex, CM19 5AW,
UK
† Electronic supplementary information (ESI) available: Additional exper-
imental information and spectra. See DOI: 10.1039/b702481a
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Table 1 Relative potencies of thapsigargin (1) and related analogues
Scheme 1 Possible generation of target analogues 8, 9, 10 and 11 from common intermediate 12.
anticipated that butenolide 16 would be available from 12 in four
steps via a tethered Horner–Wadsworth–Emmons reaction, and
that subsequent installation of the peripheral ester moieties would
proceed in an analogous fashion to those in our natural product
synthesis.
To this end, protection of the free C-8 hydroxyl of 12 as a
methoxymethyl acetal,16 and selective cleavage of the TES group
with HF·pyridine at room temperature, generated alcohol 14
(Scheme 2). Construction of the butenolide proceeded by first teth-
ering the requisite phosphonate to O-6, and then performing the
intramolecular olefination.17 The hydroxyl at C-3 was unmasked
by treatment of silyl ether 16 with HF·pyridine, and then in-
verted with a two-step protocol involving oxidation with catalytic
amounts of TPAP,18 and stereoselective reduction of the resulting
ketone (18) with sodium borohydride (d.r. = 3 : 1).19 Separation of
the epimeric alcohols was not possible at this stage, so they were
carried through the next two steps as a mixture. Methanolysis
of the methoxymethyl acetals under acidic conditions, and then
selective acylation20 afforded 22 as a single diastereomer (64% after
separation of the C-3 epimeric angelates by flash chromatography,
theoretical maximum yield = 75%). Finally, installation of the
acetate group at O-10 furnished the desired analogue 8, in a total
of 11 steps from common intermediate 12.
Synthesis of analogue 9
We aimed to remove the C-7 oxygenation of 13 by forming
a xanthate at this position, and then performing a Barton–
McCombie deoxygenation reaction.21 Reduction of ketone 13
proceeded with excellent facial selectivity, affording alcohol 23 as
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Scheme 2 Synthesis of analogue 8. Reagents and conditions: a) MOM-Cl, Hu¨nig’s base, DMAP, CH2Cl2, rt, 16 h; b) HF·pyridine, pyridine, THF, rt,
25 min, 96% over two steps; c) EDCI, HO2CCH(Me)P(O)(OEt)2, CH2Cl2, rt, 13 h, 90%; d) NaH, THF, reflux, 20 min; e) HF·pyridine, THF, pyridine,
rt, 7 days, 77%; f) TPAP, NMO, 4 A MS, rt, 30 min, 91%; g) NaBH4, MeOH, −30 ◦C, 1 h (d.r. = 3 : 1, R:S); h) angelic acid, 2,4,6-tricholorobenzoyl
˚
chloride, Et3N, PhMe, 75 ◦C, 2 days, 85% over two steps (d.r. = 3 : 1, R:S); i) HCl, MeOH, 40 ◦C, 3 h 45 min, quantitative (d.r. = 3 : 1, R:S); j) butyric
anhydride, DMAP, CH2Cl2, rt, 1 h, separation of C-3 isomers, 64%; k) isopropenyl acetate, p-TsOH, CH2Cl2, rt, 16 h, 99%.
a single diastereomer (d.r. >19 : 1), but it was necessary to perform
and quench the reaction at 0 ◦C in order to suppress migration of
the neighbouring TES group (Scheme 3). However, when 23 was
treated with carbon disulfide and NaHMDS, migration of the TES
group was again observed, and a mixture of the two regioisomeric
xanthates 24 and 25 was isolated.22
three steps, with no observed migration of the SEM group.21
Cleavage of the MOM and SEM acetals from 29 was possible
with magnesium bromide diethyl etherate and butane thiol, or
with HCl/methanol.25 Treatment of the resulting triol (30) with
butyric anhydride afforded a 2 : 1 mixture of desired butanoate 32
and the bis-acylated compound 31. Double acetylation of diol 32
afforded silyl ether 33 which was deprotected and inverted at C-3
(similarly to 16 in Scheme 2, but now with a significantly higher
facial selectivity (d.r. >19 : 1) for the ketone reduction). Finally,
esterification of the free alcohol under conditions developed for
the total synthesis of thapsigargin7 afforded the desired bicyclic
analogue 9 in 92% yield.
Towards the synthesis of analogue 10
Intermediate 12 was protected at O-8 as the corresponding SEM
acetal (38, Scheme 5).23 Owing to the high levels of oxygenation
in target molecule 10, we intended to install the requisite acetyl
functionalities at O-6 and O-10 early, in order to circumvent the
further need for protecting groups at these positions. However,
deprotection of 38 at O-6 and O-10 caused the formation of
unwanted lactol derivatives such as 39.26
Scheme 3 TES migrations under xanthate-forming conditions (R =
TBDPS). Reagents and conditions: a) NaBH4, THF, 0 ◦C, 5.5 h, 91%,
(d.r. >19 : 1); b) CS2, THF, −78 ◦C, 30 min, then NaHMDS, 1 h, then
MeI, 1.5 h to rt, 13 h.
In order to prevent the formation of such lactols, it was
ultimately necessary to mask the C-7 ketone. Thus, formation of
the exo-methylene functionality (40),27 required for later dihydrox-
ylation, served to achieve this goal. However, by performing the
olefination reaction on this particular substrate, in which bulky
protecting groups flanked the ketone, the yield was somewhat
compromised.28 Dihydroxylation of 40 was performed with Sharp-
less’ biphasic conditions,29 and it was found that the reaction
proceeded in good yield and with excellent facial selectivity to
afford the desired diol 41. However, it was felt that the extra
oxygenation at C-7/11 should be installed later in the synthesis to
simplify protecting group strategies, so we focused our attention
on installing the C-6 and C-10 acetates on 40.
To overcome the problem of migration of the triethylsilyl group,
it was necessary to replace it with a more robust protecting group
at O-6, and the 2-(trimethylsilyl)ethoxymethyl (SEM) group was
chosen for this purpose (Scheme 4).23,24 Treatment of 14 with
SEMCl and Hu¨nig’s base afforded 26, which could be successfully
reduced and converted to the corresponding xanthate (28). Treat-
ment of the xanthate with tributyltin hydride and AIBN effected
the deoxygenation, affording a 71% isolated yield of 29 over the
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Scheme 4 Synthesis of analogue 9. Reagents and conditions: a) SEM-Cl, Hu¨nig’s base, DMAP, CH2Cl2, rt, 15 h, 80%; b) NaBH4, THF, 0 ◦C, 2 h then
rt, 20 h, 92%, (d.r. >19 : 1); c) CS2, THF, −78 ◦C, 30 min then NaHMDS, 1.5 h, then MeI, 1.5 h, 98%; d) Bu3SnH, catalytic AIBN, PhMe, 110 ◦C, 3 h,
79%; e) K2CO3, n-BuSH, MgBr2·Et2O, Et2O, rt, 45 min, 85%; f) HCl, MeOH, 40 ◦C, 2 h, 92%; g) butyric anhydride, DMAP, CH2Cl2, rt, 3 h, 57% 32,
˚
30% 31; h) p-TsOH, isopropenyl acetate, rt, 16 h, 87%; i) TBAF, THF, rt, 15.5 h, 75%; j) catalytic TPAP, NMO, 4 A MS, CH2Cl2, rt, 30 min, 93%; k)
NaBH4, MeOH, −30 ◦C, 1 h, 88%, (d.r. >19 : 1); l) 37, NaHCO3, PhMe, 80 ◦C, 18.5 h, 92%.
C-3 inversion of 44 proceeded smoothly, providing alcohol 46 as
a single diastereomer (d.r. >19 : 1). Angeloylation of 46 under
the conditions used for lactone 19 resulted in decomposition,20
and the formation of a complex mixture of products.30 However,
application of our milder angeloylation conditions to the remain-
ing portion of alcohol 467 effected clean conversion to the desired
angelate 47 in 96% isolated yield.
Double acetal deprotection of 47, followed by selective acylation
of the secondary hydroxyl with butyric anhydride, and then acety-
lation of the remaining alcohol (49), afforded olefin 11. However,
dihydroxylation of a sample of 11 using the same conditions that
had successfully generated 41 resulted in decomposition of the
molecule.
Scheme 5 Formation of lactol derivative 39, and dihydroxylation of 40
Conclusions
(R = TBDPS). Reagents and conditions: a) SEMCl, Hu¨nig’s base, DMAP,
˚
CH2Cl2, rt, 18 h, quantitative; b) Amberlyst-15, MeOH, 4 A MS, rt, 4 h,
Thapsigargin is a valuable compound which is routinely used
for studying cell physiology. Prodrug derivatives of the natural
product have shown potential in the development of a treatment
for prostate cancer. However, thapsigargin is in relatively short
supply as its natural source (Thapsia) cannot be cultivated—
the demand for material must therefore be met by the synthetic
chemist. In the continuing search for a greater understanding of
this intriguing pharmacophore, numerous analogues have been
prepared by derivatising the natural product, and they have
been used for comparative binding studies. However, there have
57%; c) 2.0 eq. PPh3+CH3 Br−, 1.9 eq. KHMDS, THF, −78 ◦C to rt over
45 min, 34%; d) OsO4, K3Fe(CN)6, MeSO2NH2, quinuclidine, K2CO3,
t-BuOH, H2O, rt, 3 days, 81% (d.r. >19 : 1).
Synthesis of analogue 11
Application of the Amberlyst-15 deprotection conditions to 40
cleanly removed the TES group, but did not cleave the MOM
acetal on this substrate (Scheme 6). Nonetheless, acetylation of
42 with acetic anhydride generated 43, and silyl deprotection and
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˚
Scheme 6 Synthesis of analogue 11. Reagents and conditions: a) Amberlyst-15, 4 A MS, MeOH, rt, 16 h, 76%; b) Ac2O, DMAP, pyridine, CH2Cl2, rt,
˚
18 h, 91%; c) TBAF, THF, rt 12 h, 88%; d) TPAP, NMO, 4 A MS, CH2Cl2, 1 h, rt, 67%; or DMP, NaHCO3, CH2Cl2, rt, 30 min, 80%; e) NaBH4, MeOH,
◦C, 2 h, 74%; f) PhMe, NaHCO3, 37, 80 ◦C, 22 h, 96%; g) HCl, MeOH, 40 ◦C, 30 min; h) butyric anhydride, DMAP, CH2Cl2; i) isopropenyl acetate,
0
p-TsOH, CH2Cl2, rt, 18 h, 42% over three steps.
been few attempts to greatly simplify the parent structure for
this purpose. In this article, we have demonstrated the utility
of total synthesis in the generation of analogues with modified
carbon skeletons by preparing analogues 8, 9 and 11. This work
constitutes the chemical synthesis behind an ongoing project; our
efforts to generate further synthetic analogues of this important
natural product are continuing in order to improve the current
understanding of its SAR. The results of other analogue syntheses,
and the biological evaluation of all of these compounds, will be
reported in due course.
were recorded on a Bruker DPX-400 spectrometer operating at
400 MHz, a Bruker Avance 500 spectrometer with dual cryoprobe
operating at 500 MHz, or a Bruker DRX-600 spectrometer
operating at 600 MHz, as stated with each experiment. Samples
were either dissolved in CDCl3 and the residual protic solvent
calibrated to 7.27 ppm, or in CD3OD and the residual solvent
calibrated to 3.31 ppm (as stated). Signals are quoted in ppm
to the nearest 0.01 ppm and multiplicities (J) are recorded in
Hertz (Hz). 13C NMR spectra were recorded on a Bruker DPX-
400 spectrometer operating at 100 MHz, a Bruker Avance 500
spectrometer with dual cryoprobe operating at 125 MHz, or a
Bruker DRX-600 spectrometer operating at 150 MHz (as stated).
Samples were either dissolved in CDCl3 and the solvent calibrated
to 77.0 ppm, or in CD3OD and the residual solvent calibrated to
49.0 ppm (as stated). Signals are quoted in ppm to the nearest
0.1 ppm. COSY, HMQC, HMBC and DEPT experiments were
used to aid the assignment of NMR signals.
High-resolution mass spectrometry was conducted using a
Kratos Concept spectrometer or Waters Micromass LCT Premier
spetrometer using EI or ESI ionisation techniques. Optical rota-
tions were recorded on a Perkin–Elmer 343 digital polarimeter at
25 ◦C with a path length of 10 cm, using a sodium lamp (589 nm)
as the light source, and are reported in 10−1 deg cm2 g−1 (concen-
tration, c, in g per 100 mL). Infrared spectra of sample films were
recorded by a Perkin–Elmer Spectrum One spectrometer equipped
with an attenuated total reflectance sampler. Melting points are
uncorrected and were measured with Reichert hot-stage apparatus
using BDH microscopic slides.
Experimental
Representative experimental procedures are supplied here. All
other procedures for reactions featured in this article (including
compounds referenced in the footnotes) can be found in the ESI†,
along with 1H and 13C spectra for each compound.
All non-aqueous reactions were performed in oven-dried
(200 ◦C) glassware under an argon atmosphere; synthetic interme-
diates were dried in vacuo before use. All reagents were obtained
from commercial sources and used as supplied unless otherwise
stated. Molecular sieves were dried at 200 ◦C before use, and
Amberlyst-15 resin was washed thoroughly with methanol and
dichloromethane and dried in vacuo before use. Solvents used were
of reagent grade and were distilled before use: tetrahydrofuran
and diethylether over calcium hydride and lithium aluminium
hydride; dichloromethane, toluene, methanol and acetonitrile
over calcium hydride. Petrol or petroleum ether (PE) refers to
the fraction distilled between 40 and 60 ◦C; anhydrous N,N-
dimethylformamide and acetone were sourced commercially and
used as supplied.
Phosphonate 15
EDCI (450 mg, 2.35 mmol) was added to a solution of hydroxy ke-
tone 14 (446 mg, 782 lmol) and 2-(diethoxy-phosphoryl)propionic
acid (247 mg, 1.17 mmol) in CH2Cl2 (15 mL). The mixture was
stirred at room temperature for 13 h, then quenched with saturated
sodium bicarbonate solution (70 mL) and extracted with EtOAc
(3 × 70 mL). The combined organic phases were washed with brine
Flash column chromatography was performed with Merck 60
Kieselgel (230–400 mesh). Thin layer chromatography (TLC) was
performed with Merck 60 F254 silica gel plates and viewed under
UV radiation (254 nm) or by staining with acidic aqueous ammo-
nium molybdate(IV) and heating as necessary. All 1H NMR spectra
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(100 mL), dried (MgSO4) and concentrated in vacuo. The crude
product was filtered through a pad of silica, eluting with EtOAc–
PE 4 : 1, to furnish the phosphonate as a colourless oil and as a
1 : 1 mixture C-11 epimers (539 mg, 90%); (Note: assignments A
and B do not refer to the two epimers specifically); dH (600 MHz;
CDCl3) 7.65 (8H, m, o-PhA and o-PhB), 7.43 (4H, m, p-PhA and
p-PhB), 7.39 (8H, m, m-PhA and m-PhB), 5.05 (2H, m, H-6A and
H-6B), 4.71 (2H, m, O-10A-CH2O and O-10B-CH2O), 4.62 (2H, m,
129.7 (p-Ph), 129.6 (p-Ph), 127.6 (m-Ph), 127.5 (m-Ph), 126.2 (C-
7), 94.7 (O-8-CH2O), 90.6 (O-10-CH2O), 82.5 (C-6), 77.3 (C-10),
73.3 (C-3), 66.9 (C-8), 55.8 and 55.6 (O-8-CH2OCH3 and O-10-
CH2OCH3), 54.1 (C-5), 46.1 (C-1), 43.7 (C-4), 37.6 (C-9), 37.1
(C-2), 27.7 (C-14), 27.0 (C(CH3)3), 19.3 (C(CH3)3), 15.5 (C-15),
−1
=
9.0 (C-13); mmax (film; cm ) 2932 (C–H), 2857 (C–H), 1756 (C O),
1590w (Ar); [a]D +10.1 (c. 0.495, CHCl3); found (ESI+) [MNa]+
631.3085; C35H48O7SiNa requires M, 631.3067.
ꢀ
ꢀ
O-10A -CH2O and O-10B -CH2O), 4.55 (2H, m, O-8A-CH2O and O-
ꢀ
ꢀ
8B-CH2O), 4.51 (1H, m, O-8A -CH2O and O-8B -CH2O), 4.31 (2H,
m, H-3A and H-3B), 4.19 (2H, m, H-8A and H-8B), 4.14 (4H, m,
EtA and EtB CH2), 3.33 and 3.32 (2 × 6H, s, O-10A-CH2OCH3, O-
10B-CH2OCH3, O-8A-CH2OCH3 and O-8B-CH2OCH3), 3.17 (1H,
m, PCHA), 3.11 (1H, m, PCHB), 2.85 (2H, m, H-1A and H-1B),
2.17–2.07 (6H, m, H-4A, H-5A, H-9A H-4B, H-5B and H-9B), 1.80
Alcohol 17
Two batches of TBDPS ether 16 were treated separately and
combined for workup: a stock solution of HF·pyridine (1.4 mL)
and pyridine (1.2 mL) in THF (3.0 mL) was added to a
stirring solution of crude tert-butyldiphenylsilylether 16 (278 lmol
transferred by mass) in pyridine (4.0 mL) and THF (6.0 mL). The
resulting mixture was stirred at room temperature for 7 days, then
quenched by drop-wise addition of saturated sodium bicarbonate
solution (100 mL) and extracted with Et2O (3 × 50 mL). The
combined organic phases were washed with brine (100 mL), dried
(MgSO4) and evaporated under reduced pressure. The crude oil
was combined with that from a second batch (a reaction of
154 lmol) and chromatographed (SiO2, Et2O–PE 1 : 4, increasing
gradually to 3 : 2 to recover starting material (33 mg, 13%), then
EtOAc–PE 4 : 1) to afford the alcohol as a colourless oil (117 mg,
77%); dH (600 MHz; CDCl3) 4.88 (1H, dd, J 10.0, 5.8, H-8), 4.81
(1H, d, J 10.5, H-6), 4.74 (1H, d, J 7.3, O-10-CH2O), 4.62 (3H,
m, 2 × O-8-CH2O and 1 × O-10-CH2O), 4.39 (1H, m, H-3), 3.37
(3H, s, O-8-CH2OCH3), 3.28 (3H, s, O-10-CH2OCH3), 2.71 (1H,
ddd, J 12.9, 7.1, 6.4, H-1), 2.55 (1H, m, H-4), 2.22 (1H, dd, J
14.5, 5.8, H-9), 2.01 (1H, dd, J 14.5, 10.0, H-9ꢀ), 1.91 (3H, s, H-
13), 1.82 (1H, ddd, J 13.2, 13.0, 6.0, H-2), 1.77 (1H, dd, J 13.2,
6.9, H-2), 1.61 (1H, m, H-5), 1.33 (3H, s, H-14), 1.10 (3H, d,
J 7.4, H-15) (OH signal not observed); dC (150 MHz; CDCl3)
174.2 (C-12), 161.0 (C-11), 126.4 (C-7), 94.7 (O-8-CH2O), 90.5
(O-10-CH2O), 82.9 (C-6), 77.3 (C-10), 72.0 (C-3), 66.8 (C-8), 55.8
(O-8-CH2OCH3), 55.6 (O-10-CH2OCH3), 53.9 (C-5), 46.6 (C-1),
ꢀ
ꢀ
(2H, m, H-9A and H-9B ), 1.51–1.43 (10H, m, H-2A, H-2B, H-
ꢀ
ꢀ
2A , H-2B , PC(CH3)A and PC(CH3)B), 1.31 (6H, m, EtA and EtB
CH2CH3), 1.26 (6H, m, H-15A and H-15B), 1.20 (6H, s, H-14A and
H-14B), 1.08 (18H, s, (C(CH3)3)A and (C(CH3)3)B); dC (150 MHz;
CDCl3) 201.9 (C-7A and C-7B), 169.1 (C-12 C-12B), 135.9 (o-PhA
and o-PhB), 135.8 (o-PhAand o-PhB), 134.6 (ipso-PhA and ipso-
PhB), 133.6 (ipso-PhA and ipso-PhB), 129.68 (p-PhA and p-PhB),
129.68 (p-PhA and p-PhB), 127.61 (m-PhA and m-PhB), 127.56 (m-
PhA and m-PhB), 94.73 and 94.68 (O-8A-CH2O and O-8B-CH2O),
90.63 and 90.60 (O-10A-CH2O and O-10B-CH2O), 78.2 and 77.8
(C-10A and C-10B), 77.7 and 77.2 (C-6A and C-6B), 74.2, 73.96,
73.93 and 73.8 (C-3A, C-3B, C-8A and C-8B), 62.69 and 62.65 (EtA
and EtB OCH2), 55.93, 55.88, 55.70 and 55.62 (O-8A-CH2O, O-
8B-CH2O, O-10A-CH2O and O-10B-CH2O), 48.0 and 47.9 (C-5A
and C-5B), 46.54 and 46.49 (C-1A and C-1B), 44.24 and 44.24 (C-
4Aand C-4B), 39.4 and 38.5 (PCHA and PCHB), 37.6 and 37.4
(C-2A and C-2B), 36.6 and 34.2 (C-9A and C-9B), 30.2 and 29.7
(PC(CH3)A and PC(CH3)B), 27.8 and 27.7 (C-14A and C-14B), 27.0
((C(CH3)3)A and (C(CH3)3)B), 19.4 ((C(CH)3)A and (C(CH)3)B),
16.40 and 16.37 (EtA and EtB OCH2CH3), 15.94 and 15.85 (C-
15A and C-15B); mmax (film; cm−1) 2932 (C–H), 2857 (C–H), 1756
=
=
=
(C O), 1733 (ketone C O), 1257 (P O), 1022 (P–O–C); found
(ESI+) [MNa]+ 785.3447; C39H59O11PSiNa requires M, 785.3462.
43.6 (C-4), 38.0 (C-9), 37.3 (C-2), 27.7 (C-14), 14.5 (C-15), 9.0
−1
=
(C-13); mmax (film; cm ) 3474 (br, O–H), 2935 (C–H), 1749 (C O),
1672w (C C); [a]D +4.00 (c 0.75, CHCl3); found (ESI+) [MNa]+
393.1870; C19H30O7Na requires M, 393.1889.
=
Butenolide 16
A solution of the phosphonate ester 15 (610 mg, 801 lmol) in THF
(30 mL) was treated with NaH (60% dispersion in oil, 33.7 mg,
841 lmol) at rt for 5 min and then refluxed for 20 min. The reaction
was cooled, quenched with ammonium chloride solution (50 mL)
and extracted with Et2O (3 × 50 mL). The combined organic
phases were washed with brine (100 mL), dried (MgSO4) and
concentrated in vacuo. The crude oil was used without further
purification; dH (600 MHz; CDCl3) 7.65 (4H, m, o-Ph), 7.43 (2H,
m, p-Ph), 7.40 (4H, m, m-Ph), 4.84 (1H, dd, J 10.2, 5.9, H-8), 4.72
(1H, d, J 7.2, O-10-CH2O), 4.62 (1H, d, J 10.7, H-6), 4.60–4.55
(3H, m, 2 × O-8-CH2O and 1 × O-10-CH2O), 4.45 (1H, m, H-3),
3.33 (3H, s, O-8-CH2OCH3), 3.28 (3H, s, O-10-CH2OCH3), 2.77
(1H, ddd, J 12.4, 7.4, 6.5, H-1), 2.51 (1H, m, H-4), 2.12 (1H,
dd, J 14.5, 5.9, H-9), 1.88 (3H, s, H-13), 1.82 (1H, dd, J 14.5,
10.2, H-9), 1.60 (2H, m, H-2 and H-5), 1.49 (1H, ddd, J 13.0,
12.9, 6.7, H-2), 1.20 (3H, s, H-14), 1.15 (3H, d, J 7.3, H-15), 1.10
Ketone 18
A stirring mixture of alcohol 17 (115 mg, 311 lmol), NMO
(55.0 mg, 467 lmol), 4 A MS (200 mg) and CH2Cl2 (1.0 mL)
˚
was treated with TPAP (11 mg, 31 lmol). The mixture was stirred
at room temperature for 30 min then filtered, concentrated in vacuo
and purified by column chromatography (SiO2, EtOAc–PE 1 : 1) to
afford the ketone as a colourless oil, 104 mg, 91%; dH (600 MHz;
CDCl3) 4.93 (1H, dd, J 10.6, 6.0, H-8), 4.84 (2H, m, H-6 and
1 × O-10-CH2O), 4.67 (1H, d, J 7.1, O-8-CH2O), 4.65 (1H, d,
J 7.1, O-8-CH2O), 4.63 (1H, d, J 7.4, O-10-CH2O), 3.39 (3H, s,
O-10-CH2OCH3), 3.12 (3H, s, O-8-CH2OCH3), 2.84 (1H, q, J 7.5,
H-4), 2.78 (1H, ddd, J 14.2, 7.1, 7.0, H-1), 2.34 (2H, m, H-2 and
H-9), 2.25 (1H, m, H-2ꢀ), 2.04 (1H, dd, J 14.7, 10.6, H-9ꢀ), 1.98
(1H, dd, J 10.6, 6.3, H-5), 1.95 (3H, s, H-13), 1.34 (3H, s, H-
14), 1.19 (3H, d, J 7.5, H-15); dC (150 MHz; CDCl3) 217.8 (C-3),
173.7 (C-12), 160.5 (C-11), 127.2 (C-7), 95.1 (O-8-CH2O), 90.9
=
(9H, s, C(CH3)3); dC (150 MHz; CDCl3) 174.2 (C O), 161.2 (C-
11), 135.8 (o-Ph), 135.7 (o-Ph), 134.6 (ipso-Ph), 133.7 (ipso-Ph),
1432 | Org. Biomol. Chem., 2007, 5, 1427–1436
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(O-10-CH2O), 80.5 (C-6), 76.7 (C-10), 67.1 (C-8), 56.0 and 55.9
67.3 (C-8), 55.9 and 55.8 (O-8-CH2OCH3 and O-10-CH2OCH3),
(O-8-CH2OCH3 and O-10-CH2OCH3), 51.6 (C-5), 48.4 (C-4), 45.1
53.4 (C-5), 47.4 (C-1), 43.8 (C-4), 37.4 (C-9), 35.0 (C-2), 27.9
=
(C-1), 39.4 (C-2), 37.1 (C-9), 27.8 (C-14), 16.4 (C-15), 9.1 (C-13);
(C-14), 20.6 (C(O)CCH3), 19.3 (C-15), 16.5 (C C(H)CH3), 9.1
−1
=
=
mmax (film; cm ) 2932 (C–H), 1755 (lactone C O), 1742 (acetate
(C-13); mmax (film; CHCl3) 2931 (C–H), 1754 (lactone C O), 1713
+
=
=
=
C O), 1675w (C C); [a]D +48.3 (c 0.555, CHCl3); found (ESI+)
(angelate C O); found (ESI+) [MH] 453.2510; C24H37O8 requires
[MH]+ 369.1929; C19H29O7 requires M, 369.1913.
M, 453.2488.
Alcohols 19
Diols 21
Sodium borohydride (92.3 mg, 2.43 mmol) was added to a solution
of ketone 18 (89.4 mg, 243 lmol) in methanol (1.0 mL) at
−30 ◦C. The resulting mixture was stirred at −30 ◦C for 1 h
then warmed to room temperature, quenched with saturated
ammonium chloride solution (20 mL) and extracted with Et2O
(3 × 20 mL). The combined organic phases were washed with
brine (50 mL), dried (MgSO4) and evaporated under reduced
pressure. The product was determined to be a 3 : 1 (R:S) mixture of
Concentrated HCl (3 drops) was added to a solution of the MOM
ethers 20 (91.0 mg, 201 lmol) in MeOH (2.0 mL). The mixture
was stirred at 40 ◦C for 3 h 45 min, cooled, quenched with
sodium bicarbonate solution (20 mL) and extracted with EtOAc
(3 × 20 mL). The combined organic phases were washed with
brine (50 mL), dried (MgSO4) and concentrated in vacuo. Column
chromatography (SiO2, EtOAc–PE 1 : 1 then 7 : 3) afforded the diol
as a 3 : 1 (R:S) mixture of C-3 epimers (74.6 mg, quantitative).
Major diastereomer (C-3-(R)): dH (600 MHz; CDCl3) 6.08 (1H,
1
C-3 epimers by H NMR and used without further purification.
=
Major diastereomer (C-3-(R)): dH (600 MHz; CDCl3) 5.26 (1H,
d, J 10.6, H-6), 4.89 (1H, dd, J 10.4, 5.8, H-8), 4.76 (1H, d, J
7.3, O-10-CH2O), 4.67 (1H, d, J 7.0, O-8-CH2O), 4.65 (1H, d, J
7.0, O-8-CH2O), 4.59 (1H, d, J 7.3, O-10-CH2O), 3.98 (1H, m,
H-3), 3.39 (3H, s, CH3O), 3.28 (3H, s CꢀH3O) 2.42 (2H, m, H-1
and H-2), 2.23 (2H, m, H-4 and H-9), 2.12 (1H, dd, J 14.4, 10.6,
H-9ꢀ), 1.98 (3H, s, H-13), 1.58 (1H, m, H-2ꢀ), 1.57 (1H, m, H-
5), 1.31 (3H, s, H-14), 1.08 (3H, d, J 7.4, H-15); dC (150 MHz;
CDCl3) 174.4 (C-12), 161.6 (C-11), 126.2 (C-7), 95.0 (O-8-CH2O),
90.7 (O-10-CH2O), 82.4 (C-6), 78.7 (C-3), 77.3 (C-10), 67.2 (C-
8), 55.9 (O-8-CH2OCH3), 55.8 (O-10-CH2OCH3), 53.7 (C-5), 47.4
(C-1), 37.6 (C-9), 37.1 (C-4), 31.9 (C-2), 28.0 (C-14), 19.4 (C-15),
m, C C(H)CH3), 5.43 (2H, m, H-3 and H-6), 4.87 (1H, m, H-8),
2.75 (1H, m, H-4), 2.51 (1H, m, H-1), 2.23 (1H, m, H-5), 2.05
=
(2H, m, H-2 and H-9), 2.00 (3H, m, C C(H)CH3), 1.97 (3H, s,
C(O)CCH3), 1.88 (3H, s, H-13), 1.88 (1H, m, H-9ꢀ), 1.64 (1H,
m, H-2ꢀ), 1.35 (3H, s, H-14), 1.13 (3H, d, J 7.5, H-15) (2 OH
signals not observed); dC (150 MHz; CDCl3) 174.0 (C-12), 167.7
=
(C(O)CCH3), 163.3 (C-7), 138.4 (C C(H)CH3), 127.8 and 127.1
(C-11 and C C(H)CH3), 81.2 (C-6), 80.5 (C-10), 71.8 (C-3), 62.5
(C-8), 53.2 (C-5), 50.8 (C-1), 43.7 (C-4), 40.3 (C-9), 34.9 (C-2), 33.4
(C-14), 15.8 (C(O)CCH3), 15.7 (C C(H)CH3), 9.1 (C-13); mmax
=
=
=
(film; CHCl3) 3429 (OH), 2929 (C-H), 1734 (br, 2 × C O); found
(ESI+) [MNa]+ 387.1800; C20H28O6Na requires M, 387.1784.
9.1 (C-13); mmax (film; cm−1) 3430 (br, O–H), 2918 (C–H), 2850
+
=
=
(C–H), 1750 (C O), 1675w (C C); found (ESI+) [MH]
Butyrate 22
371.2077; C19H31O7 requires M, 371.2070.
Butyric anhydride (36 lL, 220 lmol) was added to a solution
of alcohols 21 (73 mg, 201 lmol) in CH2Cl2 (1.0 mL) followed
by catalytic DMAP. The mixture was stirred for 1 h at room
temperature, then quenched with saturated ammonium chloride
solution (20 mL) and extracted with Et2O (3 × 20 mL). The
combined organic phases were washed with brine (50 mL), dried
(MgSO4) and evaporated under reduced pressure. At this stage,
the C-3 epimers were separable: column chromatography (SiO2,
EtOAc–PE 1 : 4) afforded the R-configured C-3 epimer 22
(46.6 mg, 64%; theoretical maximum yield = 75%); dH (600 MHz;
Angelates 20
2,4,6-Trichlorobenzoyl chloride (380 lL, 2.43 mmol) was added to
a solution of angelic acid (243 mg, 2.43 mmol) in toluene (2.0 mL)
followed by Et3N (338 lL, 2.43 mmol). The mixture was stirred at
room temperature for 2 h then treated with a solution of the crude
alcohols 19 (assume 243 lmol) in toluene (3 mL). The resulting
mixture was stirred at 75 ◦C for 2 days then cooled, quenched with
saturated ammonium chloride solution (20 mL) and extracted with
EtOAc (3 × 20 mL). The combined organic extracts were washed
with brine (50 mL), dried (MgSO4) and concentrated in vacuo.
Column chromatography (SiO2, EtOAc–PE 15 : 85 to 30 : 70)
afforded a 3 : 1 (R:S) mixture of epimeric C-3 alcohols (93.0 mg,
85%) over two steps. Major diastereomer (C-3-(R)): dH (600 MHz;
=
CDCl3) 6.10 (2H, m, H-8 and C C(H)CH3), 5.14 (1H, d, J
11.3, H-6), 4.87 (1H, m, H-3), 2.74 (1H, m, H-4), 2.50 (1H,
ddd, J 13.7, 7.6, 7.0, H-2), 2.29 (3H, m, H-1 and CH2CH2CH3),
2.14 (1H, dd, J 14.0, 10.8, H-9), 2.05 (3H, s, C(O)CCH3), 2.04
ꢀ
=
(1H, m, H-9 ), 2.00 (3H, dd, J 7.2, 1.0, C C(H)CH3), 1.89
(3H, s, H-13), 1.66 (4H, m, H-2ꢀ, H-5 and CH2CH2CH3), 1.35
(3H, s, H-14), 1.14 (3H, d, J 7.5, H-15), 0.96 (3H, t, J 7.4,
CH2CH2CH3) (OH signal not observed); dC (150 MHz; CDCl3)
173.6 (C-12), 172.4 (C(O)CH2), 167.6 (C(O)CCH3), 159.9 (C-7),
=
CDCl3) 6.08 (1H, m, C C(H)CH3), 5.15 (1H, m, H-6), 5.10 (1H,
m, H-3), 4.88 (1H, m, H-8), 4.76 (1H, m, O-10-CH2O), 4.68 (1H, m,
O-8-CH2O), 4.66 (1H, m, O-8-CH2O), 4.58 (1H, m, O-10-CH2O),
3.49 and 3.27 (3H, s, O-8-CH2OCH3 and 3H, s, O-10-CH2OCH3),
=
=
2.68 (1H, m, H-4), 2.50 (1H, m, H-1), 2.37 (1H, m, H-2), 2.24 (1H,
138.3 (C C(H)CH3), 127.67 and 127.64 (C-11 and C C(H)CH3),
81.1 (C-6), 80.0 (C-3), 71.7 (C-10), 64.7 (C-8), 55.0 (C-5), 50.2 (C-
1), 43.6 (C-4), 36.8 (C-9), 36.0 (CH2CH2CH3), 34.7 (C-2), 33.1 (C-
ꢀ
=
m, H-9), 2.04 (1H, m, H-9 ), 1.95 (3H, d, J 7.2, C C(H)CH3),
1.90 (3H, s, H-13), 1.88 (3H, s, C(O)CCH3), 1.82 (1H, m, H-2),
1.67 (1H, m, H-5), 1.26 (3H, s, H-14), 1.13 (3H, d, J 7.5, H-15); dC
(150 MHz; CDCl3) 174.2 (C-12), 169.6 (C(O)CCH3), 161.4 (C-11),
=
14), 20.6 (C C(H)CH3), 19.3 (C-15), 18.4 (CH2CH2CH3), 15.8
(C(O)CCH3), 13.6 (CH2CH2CH3), 9.0 (C-13); mmax (film; cm−1)
=
=
138.3 (C C(H)CH3), 127.6 (C C(H)CH3), 126.5 (C-7), 95.2, (O-
8-CH2O), 90.7 (O-10-CH2O), 81.4 (C-6), 80.1 (C-10), 74.2 (C-3),
3478 (br, O–H), 2967 (C–H), 2927 (C–H), 2876 (C–H), 1757
=
=
=
(lactone C O), 1733 (acetate C O), 1718 (angelate C O),
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1645w (C C); [a]D −56.5 (c 1.08, CHCl3); found (ESI+) [MNa]+
C(CH3)3), 0.94–0.90 (2H, m, SiCH2CH2), 0.01 (9H, s, Si(CH3)3)
[selected NOE contacts: H-5 to H-1, 13.3%; H-5 to H-7, 5.8%
enhancement]; dC (100 MHz; CDCl3) 135.9 (o-Ph), 135.9 (o-Ph),
134.9 (ipso-Ph), 134.2 (ipso-Ph), 129.5 (p-Ph), 127.5 (m-Ph), 127.5
(m-Ph), 96.2 (O-8-CH2O), 95.8 (O-6-CH2O), 90.8 (O-10-CH2O),
79.6 (C-6), 78.0 (C-10), 74.6 (C-3), 74.5 (C-7), 74.4 (C-8), 65.7
(SiCH2CH2), 55.6 (O-10-CH2OCH3), 55.5 (O-8-CH2OCH3), 50.0
(C-5), 46.1 (C-1), 44.1 (C-4), 38.0 (C−2), 37.5 (C-9), 28.0 (C-11),
27.1 (C(CH3)3), 19.5 (C(CH3)3), 18.1 (SiCH2CH2), 15.5 (C-12),
−1.4 (Si(CH3)3); mmax (film; cm−1) 3453w, 2953m, 2893m, 1719w,
1568w, 1463w, 1428m, 1372w, 1249m, 1193m, 1148m, 1103s, 1037s,
917m, 860m, 835m, 741m, 702s; [a]D 22.0 (c 0.30, CHCl3); found
(ESI+) [MNa]+ 725.3875; C38H62O8NaSi2 requires M, 725.3881.
=
457.2207; C24H34O7Na requires M, 457.2202.
Analogue 8
A solution of the alcohol 22 (8.3 mg, 19.1 lmol) in CH2Cl2
(500 lL) was treated with isopropenyl acetate (200 lL, 1.82 mmol)
and catalytic p-TsOH for 16 h at room temperature. The mixture
was then quenched with saturated sodium bicarbonate solution
(20 mL) and extracted with Et2O (3 × 20 mL). The combined
organic phases were washed with brine (40 mL), dried (MgSO4)
and evaporated under reduced pressure. Column chromatography
(SiO2, Et2O–PE 3 : 7 increasingto 1:1)afforded the title compound
as a colourless oil (9.0 mg, 99%); dH (600 MHz; CDCl3) 6.08
=
(1H, qd, J 7.1, 1.0, C C(H)CH3), 5.93 (1H, dd, J 11.0, 5.6,
Xanthate 28
H-8), 5.18 (1H, d, J 9.0, H-6), 4.89 (1H, m, H-3), 3.01 (1H,
ddd, J 13.7, 6.9, 6.8, H-1), 2.71 (1H, m, H-4), 2.53 (2H, m, H-
2 and H-9), 2.27 (2H, t, J 7.3, CH2CH2CH3), 2.19 (1H, dd, J
Carbon disulfide (361 lL, 6.01 mmol) was added to a solution of
alcohol 27 (704 mg, 1.00 mmol) in THF (29 mL) at −78 ◦C. After
stirring at this temperature for 30 min the mixture was treated
dropwise with NaHMDS (1.3 mL of a 1 M solution in THF,
1.30 mmol). The resulting yellow solution was stirred for 1.5 h
then treated with MeI (623 lL, 10.01 mmol) and stirred for a
further 1.5 h. After this time the reaction mixture was quenched at
−78 ◦C with aqueous ammonium chloride (15 mL) then allowed
to warm to room temperature over 40 min. After partitioning
between water (10 mL) and EtOAc (30 mL) the aqueous layer was
extracted with EtOAc (3 × 30 mL). The combined organics were
dried (MgSO4) and concentrated in vacuo to a yellow oil. This was
purified by flash chromatography (SiO2, Et2O–PE, 30:70) to yield
the title compound as a yellow oil, 781 mg, 98%; dH (400 MHz;
CDCl3) 7.68–7.65 (4 H, m, o-Ph), 7.44–7.33 (6 H, m, m-Ph, p-Ph),
6.24 (1 H, dd, J 2.2, 7.2, H-7), 4.83 (1 H, d, J 7.1, O-10-CH2O),
4.74 (1H, d, J 7.1, O-10-CH2O), 4.71 (1H, d, J 7.1, O-8-CH2O),
4.69 (1H, d, J 7.1, O-8-CH2O), 4.59 (1H, d, J 6.9, O-6-CH2O),
4.57 (1H, d, J 6.9, O-6-CH2O), 4.40–4.36 (1H, m, H-8), 4.23–4.22
(1H, m (br), H-3), 3.94 (1H, dd, J 4.4, 7.2, H-6), 3.71–3.58 (2H,
m, SiCH2CH2), 3.43 (3H, s, O-10-CH2OCH3), 3.31 (3H, s, O-8-
CH2OCH3), 2.94 (1H, ddd, J 6.4, 9.8, 13.3, H-1), 2.53 (3H, s,
C(S)SCH3), 2.11–2.05 (1H, m, H-5), 1.98–1.90 (2H, m, H−9),
1.87–1.79 (1H, m, H-4), 1.53 (1H, ddd, J 3.8, 12.7, 12.7, H-2),
1.44 (1H, dd, J 6.4, 11.8, H-2ꢀ), 1.11–1.09 (6H, m, H-11, H-12),
1.08 (9H, s, C(CH3)3), 1.01–0.92 (2H, m, SiCH2CH2), 0.02 (9H, s,
Si(CH3)3); dC (100 MHz; CDCl3) 215.9 (OC(S)), 136.0 (o-Ph),
135.9 (o-Ph), 135.0 (ipso-Ph), 134.1 (ipso-Ph), 129.6 (p-Ph), 129.5
(p−Ph), 127.5 (m-Ph), 127.5 (m-Ph), 95.6 (O-8-CH2O), 94.5 (O-
6-CH2O), 90.9 (O-10-CH2O), 84.3 (C-7), 77.6 (C-10), 74.6 (C-3),
74.1 (C-6), 71.1 (C-8), 65.5 (SiCH2CH2), 55.7 (O-10-CH2OCH3),
55.5 (O-8-CH2OCH3), 49.4 (C−5), 46.3 (C-1), 45.4 (C-4), 38.5 (C-
2), 38.1 (C-9), 28.6 (C-11), 27.1 (C(CH3)3), 19.5 (C(CH3)3), 19.3
(C(S)SCH3), 18.2 (SiCH2CH2), 15.5 (C-12), −1.4 (Si(CH3)3); tmax
(film; cm−1) 3075w, 2948m, 2929m, 2889m, 2857w, 1461w, 1428m,
1373w, 1249m, 1218m, 1187m, 1149m, 1103m, 1040s, 967m, 919m,
860m, 835m, 741m, 703m; [a]D +248.5 (c 1.01, CHCl3); found
(ESI+) [MNa]+ 815.3488; C40H64O8NaSi2S2 requires M, 815.3479.
=
14.1, 11.0, H-9), 2.01 (3H, dd, J 7.1, 1.0, C C(H)CH3), 1.98
(3H, s, C(O)CH3), 1.90, (3H, s, C(O)CCH3), 1.84 (3H, s, H-
13), 1.64 (3H, s, H-14), 1.63 (3H, m, H-2ꢀ and CH2CH2CH3),
1.51 (1H, dd, J 10.8, 6.1, H-5), 1.14 (3H, d, J 7.6, H-15), 0.94
(3H, t, J 7.3, CH2CH2CH3); dC (150 MHz; CDCl3) 173.4 (C-12),
172.0 (C(O)CH2), 169.8 (C(O)CH3), 167.5 (C(O)CCH3), 159.2
=
=
(C-7), 138.6 (C C(H)CH3), 128.1 (C-11), 127.5 (C C(H)CH3),
82.6 (C-10), 81.2 (C-6), 79.7 (C-3), 63.8 (C-8), 52.6 (C-5), 46.1
(C-1), 43.7 (C-4), 35.9 (CH2CH2CH3), 35.3 (C-9), 34.1 (C-2),
27.4 (C-14), 21.9 (C(O)CH3), 20.6 (C(O)CCH3), 19.2 (C-15),
18.4 (CH2CH2CH3), 15.8 (C C(H)CH3), 13.5 (CH2CH2CH3), 8.9
(C-13); mmax (film; cm ) 2966 (C–H), 1761 (lactone C O), 1736
(acetate C O), 1715 (angelate C O), 1649w (C C); [a]D −69.0
(c 0.455, CHCl3); found (ESI+) [MNa]+ 499.2311; C26H36O8Na
requires M, 499.2308.
=
−1
=
=
=
=
Alcohol 27
A◦solution of ketone 26 (764 mg, 1.09 mmol) in THF (24 mL) at
0 C was treated portionwise with sodium borohydride (214 mg,
5.66 mmol). The suspension was stirred at this temperature for 2 h
then warmed to room temperature over 1.5 h. A further portion
of sodium borohydride (86 mg, 2.27 mmol) was added and the
mixture stirred at room temperature for a further 18.5 h, at which
point it was cooled to 0 ◦C and quenched with aqueous ammonium
chloride (20 mL). After warming to room temperature over 30 min,
the solution was extracted with EtOAc (4 × 30 mL), then the
combined organics were dried (MgSO4) and concentrated in vacuo
to a clear oil. This was purified by flash chromatography (SiO2,
Et2O–PE, 1 : 4) to yield the title compound as a clear oil (704 mg,
92%, S:R ratio > 20 : 1); dH (400 MHz; CDCl3) 7.68–7.65 (4 H,
m, o-Ph), 7.44–7.33 (6 H, m, m-Ph, p-Ph), 4.74 (1 H, d, J 7.1,
O-10-CH2O), 4.70 (1 H, d, J 7.2, O-10-CH2O), 4.69 (1 H, d, J 6.8,
O-6-CH2O), 4.68 (1 H, d, J 6.7, O-8-CH2O), 4.63 (1 H, d, J 6.6,
O-8-CH2O), 4.56 (1 H, d, J 6.9, O-6-CH2O), 4.21–4.18 (1 H, m, H-
3), 4.13 (1 H, ddd, J 2.9, 6.0, 11.6, H-8), 4.06 (1 H, ddd, J 3.6, 3.6,
7.4, H-7), 3.69–3.56 (2 H, m, SiCH2CH2), 3.56 (1 H, dd, J 7.1, 7.1,
H-6), 3.38 (3 H, s, O-10-CH2OCH3), 3.34 (3 H, s, O-8-CH2OCH3),
2.86–2.78 (1 H, m, H-1), 2.82 (1 H, d, J 4.1, OH) 2.20–2.12 (1 H,
m, H-4), 1.99 (1 H, ddd, J 6.6, 6.6, 9.0, H-5), 1.90–1.80 (2 H, m,
H-9), 1.57–1.43 (2H, m, H-2), 1.12–1.08 (15H, m, H-11, H-12,
Tris-acetal 29
Bu3SnH (795 lL, 2.95 mmol) and AIBN (10 granules) were added
to a solution of xanthate 28 (781 mg, 0.99 mmol) in degassed
1434 | Org. Biomol. Chem., 2007, 5, 1427–1436
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toluene (43 mL) and the mixture was heated at reflux for 3 h.
After cooling to room temperature the mixture was concentrated
in vacuo, then the residue was partitioned between water (20 mL)
and EtOAc (30 mL). The aqueous layer was extracted with EtOAc
(3 × 30 mL), then the combined organics were dried (MgSO4)
and concentrated in vacuo to a clear oil. This was purified by
flash chromatography (SiO2, Et2O–PE, neat PE then 1 : 10 to 1 :
1) to yield the title compound as a clear oil (535 mg, 79%); dH
(600 MHz; CDCl3) 7.67 (4H, d (br), J 7.6, o-Ph), 7.43–7.34 (6H,
m, m-Ph, p-Ph), 4.74 (1H, d, J 7.6, O-10-CH2O), 4.73 (1H, d, J
7.6, O-10-CH2O), 4.65 (1H, d, J 7.0, O-8-CH2O), 4.62 (1H, d, J
6.8, O-6-CH2O), 4.57 (1H, d, J 6.7, O-6-CH2O), 4.56 (1H, d, J
7.0, O-8-CH2O), 4.23–4.22 (1H, m, H-3), 4.01–3.97 (1H, m, H-8),
3.66–3.55 (2H, m, SiCH2CH2), 3.52 (1H, dd, J 8.3, 8.3, H-6), 3.40
(3H, s, O-10-CH2OCH3), 3.32 (3H, s, O-8-CH2OCH3), 2.87–2.83
(1H, m, H-1), 2.17 (1H, ddd, J 3.7, 9.3, 18.1, H-7), 1.98 (1H, dd,
J 5.9, 14.4, H-9), 1.95–1.86 (2H, m, H-4, H-5), 1.80 (1H, dd, J
5.5, 14.3, H−7ꢀ), 1.56 (1H, dd, J 9.9, 14.4, H-9ꢀ), 1.49 (1H, dd, J
6.5, 12.6, H-2), 1.35 (1H, ddd, J 4.6, 12.9, 12.9, H-2ꢀ), 1.13 (3H,
d, J 6.9, H-12), 1.08 (9H, s, C(CH3)3), 1.07 (3H, s, H-11), 0.92–
0.87 (2H, m, SiCH2CH2), 0.01 (9H, s, Si(CH3)3); dC (150 MHz;
CDCl3) 135.9 (o-Ph), 135.9 (o-Ph), 134.9 (ipso-Ph), 134.1 (ipso-
Ph), 129.5 (p-Ph), 129.5 (p-Ph), 127.5 (m-Ph), 127.5 (m-Ph), 94.7
(O-8-CH2O), 93.2 (O-6-CH2O), 90.9 (O-10-CH2O), 78.1 (C-10),
74.8 (C-6), 74.5 (C-3), 70.6 (C-8), 65.2 (SiCH2CH2), 55.6 (O-10-
CH2OCH3), 55.2 (O-8-CH2OCH3), 52.1 (C-5), 46.1 (C-1), 44.5
(C-4), 40.5 (C-9), 38.4 (C-2), 37.6 (C-7), 28.7 (C-11), 27.1
(C(CH3)3), 19.5 (C(CH3)3), 18.1 (SiCH2CH2), 15.8 (C-12), −1.4
(Si(CH3)3); mmax (film; cm−1) 2953m, 2931m, 2893m, 2304w, 1456m,
1428m, 1373m, 1249m, 1191m, 1145m, 1096m, 1036s, 940m,
918m, 860m, 836m, 741m, 702m, 613m; [a]D +2.2 (c 2.6, CHCl3);
found (ESI+) [MNa]+ 709.3940; C38H62O7NaSi2 requires M,
709.3932.
(C-1), 43.6 (C-4), 38.0 (C-9), 37.9 (C-7), 36.5 (CH2CH2CH3), 34.3
(C-2), 27.5 (C-13), 22.4, 21.3 (O-6-C(O)CH3/O-10-C(O)CH3),
20.6 (O-3-C(O)CCH3), 18.9 (C-14), 18.3 (CH2CH2CH3), 15.8
(C C(H)CH3), 13.7 (CH2CH2CH3); mmax (film; cm−1) 3676m,
=
2972s, 2902m, 1733s, 1647w, 1455m, 1406m, 1394m, 1374m, 1235s,
1177m, 1159m, 1076s, 1067s, 1046s, 946w, 880s; [a]D −46.1 (c 0.38,
CHCl3); found (ESI+) [MNa]+ 489.2442; C25H38O8Na requires M,
489.2464.
Olefin 40
KHMDS (1.43 mL, 716 lmol, 0.5 M in PhMe) was added dropwise
to a stirring suspension of methyltriphenylphosphonium bromide
(269 mg, 754 lmol) in THF (3.0 mL). The resulting yellow mixture
was stirred at rt for 1 h then cooled to −78 ◦C. The ketone
38 (291 mg, 377 lmol) was added dropwise as a solution in
THF (3.0 mL), and the mixture warmed to room temperature
with stirring for 45 min. The reaction was filtered through a pad
of silica, concentrated under reduced pressure, and purified by
column chromatography (SiO2, Et2O–PE 1 : 19) to afford the
title compound as a colourless oil (98.6 mg, 34%); dH (600 MHz;
CDCl3) 7.67 (4 H, m, o-Ph), 7.44 (2 H, p-Ph), 7.38 (4 H, m-Ph),
ꢀ
=
=
5.15 (1H, s, CH), 5.12 (1H, s, C H ), 4.70 (1H, d, J 7.2, O-
10-CH2O), 4.68 (1H, d, J 7.2, O-10-CH2O), 4.67 (1H, d, J 6.9,
O-8-CH2O), 4.51 (1H, d, J 6.9, O-8-CH2O), 4.43 (1H, dd, J 9.5,
6.5, H-8), 4.23 (1H, m, H-3), 3.95 (1H, d, J 7.6, H-6), 3.72 (1H,
ddd, J 16.3, 7.3, 6.9, SiCH2CH2), 3.49 (1H, ddd, J 16.3, 6.9, 6.2,
SiCH2CH2), 3.36 (3H, s, OCH3), 2.81 (1H, ddd, J 12.6, 7.6, 7.1,
H-1), 2.08 (1H, m, H-4), 2.00 (1H, dd, J 14.2, 6.5, H-9), 1.85
(1H, dd, J 12.6, 7.6, H-5), 1.63 (1H, dd, J 14.2, 9.5, H-9ꢀ), 1.47–
1.44 (1H, m, H-2), 1.34 (1H, m, H-2ꢀ) 1.25 (3H, s, H-14), 1.13
(3H, d, J 7.1, H-15), 1.08 (9H, s, (C(CH3)3), 0.98–0.89 (11H, m,
SiCH2CH2 and SiCH2CH3), 0.51 (6H, q, J 8.1, SiCH2CH3), 0.02
(9H, s, Si(CH3)3); dC (150 MHz; CDCl3) 150.1 (C-7), 135.90 (o-
Ph), 135.86 (o-Ph), 134.9 (ipso-Ph), 134.2 (ipso-Ph), 129.50 (p-Ph),
Analogue 9
=
129.47 (p-Ph), 127.4 (m-Ph), 112.3 ( CH2), 91.3 (O-8-CH2O), 90.8
To a solution of alcohol 36 (6.7 mg, 0.0174 mmol) in toluene
(0.5 mL) was added sodium bicarbonate (15 mg, 0.174 mmol) fol-
lowed by (2Z)-2-methyl-2-butenoic 2,4,6-trichlorobenzoic anhy-
dride (2.7 mg, 0.087 mmol) as a solution in toluene (0.66 mL). The
mixture was heated at 80 ◦C for 18.5 h then cooled and quenched
with aqueous sodium bicarbonate (5 mL). After extracting with
EtOAc (4 × 7 mL), the combined organics were dried (MgSO4) and
concentrated in vacuo to a clear oil. This was purified twice by flash
chromatography (SiO2, EtOAc–PE, 1:19to 1:4;then asecond col-
umn: SiO2, EtOAc–PE 1 : 10 then 1 : 4) to yield the title compound
as a clear oil (7.5 mg, 92%); dH (600 MHz; CDCl3) 6.07 (1 H, qd, J
(O-10-CH2O), 78.0 (C-10), 74.2 (C-3), 72. 9 (C-6), 72.7 (C-8), 65.0
(SiCH2CH2), 56.1 (OCH3), 55.5 (C-5), 45.5 (C-1), 43.6 (C-4), 39.9
(C-9), 38.1 (C-2), 29.3 (C-14), 27.0 (C(CH3)3), 19.4 (C(CH3)3),
18.1 (SiCH2CH2), 15.7 (C-15), 6.9 (Si(CH2CH3)3), 4.7 (Si(CH2)3,
−1.4 (Si(CH3)3); mmax (film; cm−1) 2954 (C–H), 2926 (C–H), 1461
(Ar), 1428 (Ar), 835 (Si(CH3)3); [a]D −24.4 (c 0.93, CHCl3); found
(ESI+) [MNa]+ 791.4543; C43H72O6Si3Na requires M, 791.4534.
Diol 41
t
A solution of olefin 40 (22.7 mg, 29.5 lmol) in BuOH (400 lL)
=
1.3, 7.1, C C(H)CH3), 5.14–5.10 (1H, m, H-8), 5.04 (1H, dd (br),
was treated with a biphasic solution of OsO4 (75 lL, 6.0 lmol,
2.5% by weight in tBuOH), K2CO3 (12.0 mg, 88.5 lmol),
K3Fe(CN)6 (29.0 mg, 88.5 lmol), MeSO2NH2 (8.4 mg, 88.5 lmol)
J 9.1, 9.1, H-6), 4.71 (1H, dd, J 7.0, 13.1, H-3), 3.00 (1H, ddd, J 7.5,
7.5, 13.3, H-1), 2.53 (1H, dd, J 6.6, 14.5, H-9), 2.35 (1H, ddd, J 6.9,
6.9, 12.7, H-2), 2.32–2.24 (2H, m, CH2CH2CH3), 2.12–1.87 (5H,
m, H-4, H-5, H-7, H-9ꢀ), 2.04, 2.03 (6H, 2 × s, O-6-C(O)CH3/O-
t
and quinuclidine (3.3 mg, 29.5 lmol) in BuOH–H2O (600 lL,
2 : 1). The resulting mixture was stirred in the dark for 3 days
and quenched by stirring with saturated sodium sulfite solution
(5.0 mL) for 1 h. The mixture was diluted with H2O (10 mL) and
extracted with Et2O (3 × 20 mL). The combined organic phases
were washed with brine (50 mL), dried (MgSO4) and evaporated
under reduced pressure. Column chromatography (SiO2, Et2O–
PE 1 : 9) afforded the diol as a colourless oil (19.2 mg, 81%); C-7
stereochemistry tentatively assigned as (R): weak NOE (<1%)
=
10-C(O)CH3), 1.98 (3H, d (fine splitting), J 7.2, C C(H)CH3),
1.88 (3H, s, C(O)CCH3), 1.66–1.63 (2H, m, CH2CH2CH3), 1.61–
1.52 (1H, m, H-2ꢀ), 1.54 (3H, s, H-13), 1.12 (3H, d, J 7.1, H-14),
0.94 (3H, t, J 7.5, CH2CH2CH3); dC (150 MHz; CDCl3) d 172.9
(O-8-C(O)CH2), 170.1, 170.0 (O-6-C(O)CH3/O-10-C(O)CH3),
168.0 (O-3-C(O)C), 138.1 (C C(H)CH3), 127.8 (C C(H)CH3),
83.6 (C-10), 79.1 (C-3), 71.4 (C-6), 67.4 (C-8), 50.9 (C-5), 45.2
=
=
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observed between H-6 and H-11, NOESY coupling between H-6
and H-11 observed. No NOESY or NOE interaction observed
between H-11 and H-8; dH (600 MHz; CDCl3) 7.67 (4H, m, o-Ph),
7.44 (2H, p-Ph), 7.38 (4H, m-Ph), 4.84 (1H, d, J 7.3, O-10-CH2O),
4.80 (1H, d, J 6.7, O-8-CH2O), 4.71 (1H, d, J 7.3, O-10-CH2O),
4.69 (1H, d, J 6.7, O-8-CH2O), 4.22 (1H, m, H-3), 4.00 (1H, br d,
J 8.6, OH), 3.92 (1H, dd, J 11.0, 2.5, H-8), 3.79 (1H, d, J 10.7,
H-11), 3.74 (1H, dd, J 9.3, 5.7, H-6), 3.63 (3H, m, SiCH2CH2
and H-11ꢀ), 3.47 (3H, s, OCH3), 3.31 (1H, br s, OH), 2.83 (1H, m,
H-1), 2.36 (1H, m, H-5), 2.29 (1H, m, H-4), 1.82 (1H, dd, J 14.7,
11.0, H-9), 1.76 (1H, dd, J 14.7, 2.5, H-9ꢀ), 1.48 (1H, m, H-2), 1.43
(3H, s, H-14), 1.32 (1H, m, H-2ꢀ), 1.11 (3H, d, J 7.0, H-15), 1.08
(9H, s, C(CH3)3), 0.91 (11H, m, SiCH2CH2 and SiCH2CH3), 0.57
(6H, q, J 8.0, SiCH2CH3), −0.10 (9H, s, Si(CH3)3); dC (150 MHz;
CDCl3)135.9 (o-Ph), 135.8 (o-Ph), 135.0 (ipso-Ph), 134.1 (ipso-Ph),
129.5 (p-Ph), 127.52 (m-Ph), 127.46 (m-Ph), 95.9 (O-8-CH2O), 90.6
(O-10-CH2O), 79.6 (C-10), 78.7 (C-7), 77.4 (C-8), 74.9 (C-3),
72.5 (C-6), 65.3 (SiCH2CH2), 64.0 (C-11), 55.6 (OCH3), 48.5
(C-5), 46.7 (C-1), 42.0 (C-4), 38.2 (C-9), 38.0 (C-2), 29.6 (C-
14), 27.1 (C(CH3)3), 19.4 (C(CH3)3), 18.0 (SiCH2CH2), 15.4 (C-
15), 6.7 (Si(CH2CH3)3), 4.3 (Si(CH2CH3)3), −1.5 (Si(CH3)3); mmax
(film; cm−1) 3413 (br, O–H), 2929 (C–H), 1460 (Ar), 1428 (Ar),
822 (Si(CH3)3); [a]D +61.4 (c 0.28, CHCl3); found (ESI+) [MNa]+
825.4572; C43H74O8Si3Na requires M, 825.4589.
2006, 14, 2810; (b) C. M. Jakobsen, S. R. Denmeade, J. T. Isaacs, A.
Gady, C. E. Olsen and S. B. Christensen, J. Med. Chem., 2001, 44,
4696; (c) S. B. Christensen, A. Andersen, H. Kromann, M. Treiman,
B. Tombal, S. Denmeade and J. T. Isaacs, Bioorg.Med. Chem., 1999,
7, 1273; (d) S. B. Christensen, A. Andersen, J. C. J. Poulsen and M.
Treiman, FEBS Lett., 1993, 335, 345; (e) H. Søhoel, T. Liljefors, S. V.
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17973.
10 S. B. Christensen, A. Andersen, U. W. Smitt, D. Deepale and S.
Srivastar, Fortschr. Chem. Org. Naturst., 1997, 71, 129 and references
therein.
11 (a) O. Pedersen, C. Christophersen, L. Brehm and S. B. Christensen,
Acta Chem. Scand., Ser. B, 1985, 39, 375; (b) A. Lauridsen, C. Cornett,
T. Vulpius, P. Moldt and S. B. Christensen, Acta Chem. Scand., 1996,
50, 150.
12 S. V. Ley, A. Antonello, E. P. Balskus, D. T. Booth, S. B. Christensen, E.
Cleator, H. Gold, K. Ho¨genauer, U. Hu¨nger, R. M. Myers, S. F. Oliver,
O. Simic, M. D. Smith, H. Søhoel and A. J. A. Woolford, Proc. Natl.
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and E. Hecker, J. Cancer Res. Clin. Oncol., 1992, 118, 348.
14 O-10-Deacetyl thapsigargin has been shown to be 40 times less potent
than the natural product (see ref. 13a). We therefore chose to retain the
acetate at this position of our analogues.
15 S. F. Oliver, K. Ho¨genauer, O. Simic, A. Antonello, M. D. Smith and
S. V. Ley, Angew. Chem., Int. Ed., 2003, 42, 5996.
16 G. Stork and T. Takahashi, J. Am. Chem. Soc., 1977, 99, 1275.
17 (a) L. Horner, H. Hoffman and H. G. Wippel, Chem. Ber., 1958, 91,
61; (b) W. S. Wadsworth and W. D. Emmons, J. Am. Chem. Soc., 1961,
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Soc., Chem. Commun., 1987, 1625; (b) S. V. Ley, J. Norman, W. P.
Griffith and S. P. Marsden, Synthesis, 1994, 639.
19 For substrate 18, the d.r. of the reduction could not be improved by
using reaction temperature as low as −78 ◦C. The, use of K-selectride
as the reducing agent overturned the observed facial selectivity, and
formed alcohol 17 as the major product (d.r. >19 : 1).
20 B. Hartmann, A. M. Kanazawa, J. P. Depres and A. E. Greene,
Tetrahedron Lett., 1991, 32, 5077.
Acknowledgements
This work was supported by an Insight Faraday CASE award
(SPA), GlaxoSmithKline (MMT), EPSRC (MB) and a Novartis
Fellowship (SVL). The authors also wish to thank Dr Neil Miller
for helpful discussions.
References and notes
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21 D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin Trans. 1,
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22 Attempts to prepare the corresponding C-7 mesylate of 23 and displace
it with hydride were also unsuccessful.
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23 B. H. Lipshutz and J. J. Pegram, Tetrahedron Lett., 1980, 21,
3343.
24 Attempts to conserve the number of synthetic steps by directly installing
the required O-6 acetate functionality on 23 ultimately led to migration
of the acetate group from O-6 to O-7 during subsequent reduction of
the ketone (see ESI† for details of acetate preparation).
3 H. Ali, S. B. Christensen, J. C. Foreman, F. L. Pearce, W. Piotrowski
and O. Thastrup, Br. J. Pharmacol., 1985, 85, 705.
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26 Attempts to deprotect O-10 in the presence of the C-7 ketone on other
substrates, and with 38 under different reaction conditions, also led to
the formation of analogous lactol derivatives.
27 G. Wittig and U. Schollkopf, Chem. Ber., 1954, 97, 1318.
28 Attempts to methylenate 13 proceeded similarly (see ESI† for spectra).
In our hands, other methylenation procedures including Tebbe, Nysted
and Petasis reagents under standard conditions all failed to generate 40.
The use of a microwave-mediated Petasis reaction afforded the desired
product (40) in 21% isolated yield. For a similar reaction, see: M. J.
Gaunt, A. S. Jessiman, P. Orsini, H. R. Tanner, D. F. Hook and S. V.
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Tetrahedron Lett., 1990, 31, 2999.
30 Significant quantities of material were lost during this poor esterifica-
tion reaction, but we were able to isolate the desired product (47, 2.9%)
as well as the corresponding MOM-deprotected derivative (9.1%). The
two analogous C-3 tiglate compounds (in which the angelate esters
had isomerised) were also isolated (3.6% and 4.2%, respectively). See
Experimental section and ESI† for further information.
1436 | Org. Biomol. Chem., 2007, 5, 1427–1436
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The Royal Society of Chemistry 2007
©