Synthesis and biological evaluation of 10,11-dihydrodictyostatin, a potent analogue of the marine anticancer agent dictyostatin

Article abstract of DOI:10.1021/np070547s

By employing a diverted total synthesis strategy with late-stage intermediates, 10,11-dihydrodictyostatin (5) was prepared and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the NCI/ADR Taxol-resistant cell line. This novel dictyostatin analogue was found to retain potent antimitotic activity, with a comparable profile to discodermolide and Taxol, functioning by microtubule stabilization and G2/M arrest. These SAR studies provide further insight into the interaction between dictyostatin (1) and its tubulin target.

Full text of DOI:10.1021/np070547s

364
J. Nat. Prod. 2008, 71, 364–369
Synthesis and Biological Evaluation of 10,11-Dihydrodictyostatin, a Potent Analogue of the
Marine Anticancer Agent Dictyostatin§
Ian Paterson,*,† Nicola M. Gardner,† Karine G. Poullennec,† and Amy E. Wright‡
UniVersity Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, U.K., and Harbor Branch Oceanographic Institution,
5600 US 1 North, Ft. Pierce, Florida 34946
ReceiVed October 1, 2007
By employing a diverted total synthesis strategy with late-stage intermediates, 10,11-dihydrodictyostatin (5) was prepared
and evaluated in Vitro for growth inhibition against a range of human cancer cell lines, including the NCI/ADR Taxol-
resistant cell line. This novel dictyostatin analogue was found to retain potent antimitotic activity, with a comparable
profile to discodermolide and Taxol, functioning by microtubule stabilization and G2/M arrest. These SAR studies
provide further insight into the interaction between dictyostatin (1) and its tubulin target.
In 1994, Pettit et al. reported the isolation of the novel
22-membered macrolide dictyostatin (1, Figure 1) from a marine
sponge of the genus Spongia collected in the Republic of Maldives,
which also proved to be an important natural source of the
spongistatins.1a Initial biological evaluation of dictyostatin revealed
it to be a potent antimitotic agent, but a more in-depth study was
impeded by the low isolation yield (1.35 mg from ca. 400 kg of
sponges). At the time, a complete assignment of stereochemistry
was not achieved,1 thwarting further development for almost a
b
decade until its reisolation by Wright and co-workers2 from a deep-
sea sponge of the family Corallistidae, collected off the coast of
Jamaica. With this newly available sample, a conclusive stereo-
chemical assignment for dictyostatin was disclosed by us in 2004,
based on extensive NMR experiments using Murata’s J-based
configuration analysis and molecular modeling.3 This structure was
confirmed soon after through two concurrent total syntheses,
reported independently by ourselves4a and the Curran group,4b,c
and more recently by Phillips4d and Ramachandran.4e There has
been an upsurge in biological interest in dictyostatin with its
identification as a microtubule-stabilizing agent,2,5 promoting it into
the elite ranks of Taxol (2), epothilone B (3), and discodermolide
(4), along with several other natural products.6 Dictyostatin potently
inhibits cancer cell growth in Vitro at low nanomolar concentrations,
which is maintained against Taxol-resistant cell lines, and is
generally more active than discodermolide and also binds to the
taxoid binding site on ꢀ-tubulin.2,5 Efforts continue toward the goal
of developing a scalable synthesis to provide the larger quantities
of dictyostatin required for preclinical evaluation of this promising
anticancer agent, as well as analogue studies, pursued by the Curran
Figure 1. Structures of dictyostatin, Taxol, epothilone B, and
discodermolide and overlay of global minima structures of dicty-
group and ourselves,7 to help define the minimum pharmacophore
and enable structural simplification.
ostatin and discodermolide.
The macrocyclic polyketide dictyostatin shows close structural
and stereochemical homology, having the same configuration at
of novel dictyostatin congeners. Herein, we report the synthesis of
10,11-dihydrodictyostatin (5, Figure 2) and provide preliminary
biological data, including growth inhibition against human cancer
cell lines, indicating that it represents a potent new analogue of
10 out of its 11 stereocenters, with the open-chain discodermolide
(4), an extensively studied anticancer agent,8 isolated initially from
another Caribbean sponge (Discodermia dissoluta), that was
advanced into clinical trials.9 These similarities are underscored
dictyostatin.
by the convincing overlay of their preferred solution conformations
(Figure 1)4a and permit the pre-existing library of discodermolide
Results and Discussion
analogues,7,8 together with the recently determined bioactive
Our initial premise for targeting the 10,11-dihydro analogue of
conformation of discodermolide,10 to be used as tools in the design
dictyostatin was the availability of SAR data for a series of reduced
derivatives 6, 7, and 8 of discodermolide obtained semisynthetically
§ Dedicated to Dr. G. Robert Pettit of Arizona State University for his
by catalytic hydrogenation, as reported by Gunasekera et al. (Figure
2).8 Although not prepared directly, the retention of biological
pioneering work on bioactive natural products.
* To whom correspondence should be addressed. Tel: +44-1223-336407.
Fax: +44-1223-336362. E-mail: ip100@cam.ac.uk.
† University Chemical Laboratory.
a
activity in the corresponding 8,9-dihydro analogue of discoder-
molide was presumed from consideration of the available IC50 data
(P-388 leukemia cell line) reported for these saturated derivatives.
‡ Harbor Branch Oceanographic Institution.
10.1021/np070547s CCC: $40.75
2008 American Chemical Society and American Society of Pharmacognosy
Published on Web 12/15/2007

Biological EValuation of 10,11-Dihydrodictyostatin
Journal of Natural Products, 2008, Vol. 71, No. 3 365
Scheme 2. Preparation of C4-C26 Advanced Intermediate
Figure 2. Structures of 10,11-dihydrodictyostatin and related
hydrogenated derivatives 6, 7, and 8 of discodermolide.
Scheme 1. Retrosynthetic Analysis of 10,11-Dihydrodictyostatin
between the known C11-C26 aldehyde 124a and the C10-C16
phosphonate 137a to afford the (Z)-enone 11 predominantly (78%,
5:1 Z:E). As anticipated, conjugate reduction of both the (E) and
(Z)-enones proceeded smoothly using freshly prepared Stryker’s
reagent13 ([Ph3PCuH]6) and gave the desired ketone 14 (68%).
Subsequent oxidative PMB ether cleavage of 14 with DDQ was
followed by an Evans-Saksena reduction14 of the resulting
ꢀ-hydroxy ketone 15 with NaBH(OAc)3 to provide 1,3-anti diol
16, with a useful level of control over the C9 configuration (84%,
10:1 dr). Interestingly, the diastereoselectivity of this transformation
is increased relative to the same reaction carried out on the
corresponding ꢀ-hydroxy (Z)-enone derived from 11 (3:1 dr).
At this stage, we now needed to complete the 26-carbon
dictyostatin backbone and perform the macrocyclization (Scheme
3). First, treatment of 1,3-diol 16 with (MeO)2CMe2 in the presence
of catalytic PPTS gave the acetonide 9 (90%). A Stille coupling
using copper(I) thiophene-2-carboxylate15 (CuTC) of the vinyl
iodide 9 with the stannane 10 and in situ TIPS cleavage (KF) then
gave the corresponding acid 17 (73%) in readiness for macrolac-
tonization. Using the previously employed Yamaguchi protocol,4a,7a
the macrolactone 18 was isolated (without any apparent Z to E
isomerization of the dienoate) in 60% yield and submitted to global
deprotection using HF ·pyridine to generate the targeted 10,11-
Notably, the presence of the C13-C14 alkene, but not the C8-C9
alkene or terminal 1,3-diene, appears to be critical for maintaining
biological activity in discodermolide. In the dictyostatin structure,
this Z-trisubstituted alkene is not present and instead there is a
methyl-bearing stereocenter at C16 that is considered important for
retaining antiproliferative activity against Taxol-resistant cell lines.7
a
This led us to propose that saturation solely of the C10-C11 (Z)-
alkene in dictyostatin might lead to a useful structural simplification
without adversely affecting the cytotoxicity profile. From a
pragmatic standpoint, it was attractive to employ a diverted total
synthesis strategy11 to access this novel analogue by suitable
manipulation of advanced intermediates employed previously.4a,7
a
As outlined retrosynthetically in Scheme 1, conjugate reduction of
the highly functionalized enone 11 and subsequent 1,3-anti reduc-
tion of the derived ꢀ-hydroxy ketone might provide ready access
to a pivotal 10,11-dihydro intermediate, 9, thus enabling completion
of the desired analogue 5 by Stille coupling with the vinyl stannane
10 and macrolactonization, as employed in our earlier dictyostatin
total synthesis.4a
Preparation of the advanced C16-C26 enone 11 (Scheme 2) was
first achieved by an HWE fragment coupling, based on extension
of the Still-Gennari variant12a used in our discodermolide work,12
b

366 Journal of Natural Products, 2008, Vol. 71, No. 3
Paterson et al.
Scheme 3. Completion of the Synthesis of
10,11-Dihydrodictyostatin
compound 5 was shown to act in an analogous fashion to
dictyostatin, through a mechanism of microtubule stabilization,
causing both an accumulation of cells at the G2/M phase (Figure
3a) and formation of characteristic dense intracellular microtubule
bundles (Figure 3b).
From these results, we conclude that the Z-configured C10-C11
olefin does not contribute significantly to the cytotoxicity of
dictyostatin and hence to maintaining the bioactive conformation
of the 22-membered macrolide. However, in the NCI/ADR cell
line, where the overexpression of a P-glycoprotein efflux pump
in the cell membrane gives rise to its observed resistance to Taxol,
the 10Z-unsaturation must play an important role in maintaining
the mechanism through which dictyostatin can bypass the pump.
These results are consistent with the conclusions made from the
corresponding set of saturated discodermolide analogues9 and
further reinforce the similarities observed between these two
microtubule-stabilizing agents.
In conclusion, we have designed and accessed by total synthesis
the novel dictyostatin analogue 5 with a cytotoxicity profile
comparable to that of discodermolide and Taxol. Taken together
with information gained from other analogue studies,7 this further
increases our understanding of the SAR of dictyostatin with its
tubulin target and represents further progress toward the goal of
synthesizing a simplified analogue with a cytotoxicity profile
comparable to that of the parent natural product.
Experimental Section
Biological Assays. Cytotoxicity assays were conducted using a
standard MTT-based protocol as described previously.16 Cell cycle and
immunofluorescence imaging of PANC-1 cells were conducted as per
protocols described previously.2
General Experimental Procedures. 1H and 13C NMR spectra were
recorded in CDCl3 or C6D6 on a Bruker Avance TXI 700, BB-ATM,
TCI-ATM, and DRX-400. IR spectra were measured on a Perkin-Elmer
Spectrum One (FT-IR) spectrophotometer. HRMS were obtained from
the EPSRC Mass Spectrometry Service (Swansea, UK) using a
Micromass Q-TOF or Bruker Bioapex FT-ICR spectrometer. Optical
rotations were recorded on a Perkin-Elmer 241 polarimeter, and [R]D
values are given in 10-1 deg cm2 g-1 at a concentration c (g/100 mL).
Preparative HPLC on a Daicel CHIRALCEL OD HPLC column (250
mm, 10 Å, flow 1 mL/min) used IPA/hexane (gradients) as solvent,
with UV absorption detetction at 254 nm. Analytical TLC was carried
out on Merck Kieselgel 60 F254 plates with visualization using UV (254
nm), potassium permanganate, and/or PMA/Ce(SO4)2 dip. Flash column
chromatography was carried out on Merck Kieselgel 60 (230–440 mesh)
under a positive pressure. Solvents were redistilled prior to use.
Reagents were used as received unless stated otherwise.
Table 1. Cytotoxicity of Dictyostatin (1), Taxol (2), Dis-
codermolide (4), and 10,11-Dihydrodictyostatin (5) in Cultured
Human Cancer Cell Lines as Determined by MTT Metabolism
Following 72 h Exposure to the Test Agent
IC50/nMa
AsPC-1
compound (pancreatic)
DLD-1
(colon)
PANC-1
(pancreatic) (Taxol-resistant)
NCI/ADR
1
2
4
5
9.0 ((5.6) 0.8 ((3.8) 3.4 ((0.2)
9.8 ((1.5)
1000 ((140)
160 ((34)
(4E,6R,7S,10Z,12S,13R,14S,16S,19R,20R,21S,22S,20Z)-13,19-Bis-
(tert-butyldimethylsilyloxy)-21-hydroxy-4-iodo-7-(p-methoxybenzy-
loxy)-6,12,14,16,20,22-hexamethyltricosa-4,10,23,25-tetraen-9-one (11).
To a mixture of 18-crown-6 (908 mg, 3.43 mmol) and K2CO3 (142
mg, 1.03 mmol) in toluene (16 mL) and HMPA (1.6 mL) at 0 °C was
added via cannula a solution of aldehyde 124a (200 mg, 0.343 mmol)
20 ((23)
98 ((34)
43 ((9.4)
11 ((1)
29 ((8)
10 ((1.5)
7 ((2)
59 ((34)
18 ((0.7)
300 ((190)
a Values are ( standard deviation (in parentheses) from a minimum
of four separate experiments.
and phosphonate 137 (326 mg, 0.515 mmol) in toluene (16 mL) and
a
HMPA (1.6 mL). After 5 days stirring at 0 °C, the reaction was
quenched by the addition of saturated aqueous NH4Cl (20 mL), and
the phases were separated. The aqueous layer was extracted with CH2Cl2
(3 × 20 mL), dried (MgSO4), and concentrated in Vacuo. Flash
chromatography (5% EtOAc/hexane) afforded (Z)-enone 11 (212 mg,
dihydrodictyostatin (5) in 85% yield, purified by HPLC prior to
biological evaluation.
Biological Evaluation. The cell growth inhibitory activity of
10,11-dihydrodictyostatin was evaluated in Vitro and measured
relative to dictyostatin itself, Taxol and discodermolide against four
human cancer cell lines: AsPC-1 (pancreatic), DLD-1 (colon),
PANC-1 (pancreatic), and NCI-ADR (Taxol-resistant) (Table 1).
Across the range of Taxol-sensitive cancer cell lines (ASP-1, DLD-
1, PANC-1), the synthesized dictyostatin analogue 5 displayed a
low nanomolar level of cytotoxicity similar to that of Taxol and
was found to be 2–3 times more active than discodermolide, with
a corresponding 5–12-fold drop in activity relative to dictyostatin
itself. In common with discodermolide, however, 10,11-dihydro-
dictyostatin’s activity was significantly reduced upon a switch to
the Taxol-resistant NCI/ADR line. In a separate series of incubatory
experiments performed on the PANC-1 cell line, the dihydro
65%) and its isomeric (E)-enone (26 mg, 13%) as yellow oils: [R]20
D
-23.8 (c 0.21, CHCl3); IR (liquid film)/cm-1 2956, 2929, 2856, 1690,
1
1610, 1514, 1461; H NMR (500 MHz, CDCl3) δH 7.21 (2H, d, J )
8.5 Hz, H-Ar), 6.84 (2H, d, J ) 8.4 Hz, H-Ar), 6.62 (1H, app dt, J )
10.8, 16.6 Hz, H-25), 6.49 (1H, dd, J ) 8.7, 14.5 Hz, H-11), 6.32 (1H,
dd, J ) 9.9, 11.4 Hz, H-5), 6.10-6.06 (2H, m, H-4, H-24), 6.02 (1H,
d, J ) 14.5 Hz, H-10), 5.40 (1H, app t, J ) 10.3 Hz, H-23), 5.20 (1H,
dd, J ) 1.6, 16.9 Hz, H-26a), 5.11 (1H, d, J ) 10.1 Hz, H-26b), 4.50
and 4.38 (2H, AB system, J ) 11.0 Hz, OCH2Ar), 3.88 (1H, app dt, J
) 4.9, 6.6 Hz, H-7), 3.78 (3H, s, ArOCH3), 3.76-3.70 (2H, m, H-6,
H-13), 3.48 (1H, app t, J ) 3.2 Hz, H-19), 3.45 (1H, dd, J ) 2.3, 7.3
Hz, H-21), 2.78 (1H, app qnd, J ) 6.5, 9.8 Hz, H-22), 2.70 (1H, dd,
J ) 6.9 Hz, 16.6 Hz, H-8a), 2.51 (1H, dd, J ) 5.2, 16.5 Hz, H-8b),

Biological EValuation of 10,11-Dihydrodictyostatin
Journal of Natural Products, 2008, Vol. 71, No. 3 367
Figure 3. (a) Cell cycle analysis by flow cytometry of PANC-1 cells incubated for 24 h with 0.05% methanol (vehicle control), 100 nM
10,11-dihydrodictyostatin, or 100 nM dictyostatin. Histograms represent samples of approximately 1 × 104 cells per test and are plotted as
cell number (y-axis) vs fluorescence intensity (x-axis). Both 10,11-dihydrodictyostatin and 100 nM dictyostatin show an accumulation of
cells at the G2/M phase. (b) Immunofluorescence images of PANC-1 cells stained with anti-a-tubulin (green) and propidium iodide (red)
and observed by confocal microscopy. Cells were exposed to 0.05% methanol (vehicle control), 100 nM 10,11-dihydrodictyostatin, or 100
nM dictyostatin. Both 10,11-dihydrodictyostatin and 100 nM dictyostatin show dense microtubule bundles characteristic of microtubule-
polymerizing and -stabilizing agents.
2.45–2.38 (1H, m, H-12), 2.32 (1H, br s, OH), 1.70–1.65 (1H, m, H-20),
1.65–1.52 (3H, m, H-14, H-15a, H-18a), 1.41–1.20 (5H, m, H-15b,
H-16, H2-17, H-18b), 1.03 (3H, d, J ) 6.9 Hz, CH3-12), 1.00 (3H, d,
J ) 7.0 Hz, CH3-6), 0.94 (3H, d, J ) 6.6 Hz, CH3-22), 0.91–0.86
(21H, m, SiC(CH3)3 × 2, CH3-20), 0.82 (6H, app t, J ) 6.6 Hz, CH3-
14, CH3-16), 0.07 (3H, s, Si(CH3)), 0.06 (6H, s, Si(CH3) v 2), 0.05
(3H, s, Si(CH3)); 13C NMR (125 MHz, CDCl3) δC 199.3, 159.2, 152.5,
147.8, 135.4, 132.3, 130.5, 129.9, 129.4, 125.2, 117.7, 113.7, 79.8,
76.8, 75.8, 72.2, 55.3, 46.7, 44.6, 41.3, 41.0, 37.6, 36.4, 36.1, 35.9,
32.1, 31.31, 31.29, 30.6, 26.2, 26.0, 20.5, 19.1, 18.4, 18.1, 17.7, 15.8,
15.6, 6.8, -3.6, -3.7, -4.2, -4.4; HRMS (ESI+) calcd for
C49H85IO6Si2Na [M + Na]+ 975.4832, found 975.4833; Rf 0.46 (10%
EtOAc/hexane).
1.88–1.71 (3H, m, H-14, H-18a, H-20), 1.71–1.62 (1H, m, H-18b),
1.61–1.41 (5H, m, H-11a, H-12, H-16, H2-17), 1.39–1.27 (2H, m,
H-11b, H-15a), 1.20–1.13 (1H, m, H-15b), 1.11 (3H, d, J ) 6.6 Hz,
CH3-14), 1.05 (9H, s, SiC(CH3)3), 1.02 (9H, s, SiC(CH3)3), 0.99 (9H,
app d, J ) 6.9 Hz, CH3-16, CH3-20, CH3-22), 0.85 (3H, d, J ) 6.9
Hz, CH3-12), 0.83 (3H, d, J ) 6.9 Hz, CH3-6), 0.18 (3H, s, Si(CH3)),
0.16 (6H, s, Si(CH3) × 2), 0.13 (3H, s, Si(CH3)); 13C NMR (125 MHz,
C6D6) δC 207.8, 159.7, 148.1, 135.1, 132.8, 131.1, 130.6, 129.6, 117.9,
114.0, 79.9, 77.8, 76.1, 76.0, 75.6, 72.5, 54.7, 45.0, 44.6, 43.8, 42.4,
39.5, 38.1, 36.6, 33.3, 32.3, 32.2, 30.9, 27.1, 26.5, 26.2, 20.5, 18.8,
18.3, 17.9, 16.5, 15.4, 15.1, 8.6, -3.40, -3.44, -3.6, -4.3; HRMS
(ES+) calcd for C49H91IO6Si2N [M + NH4]+ 972.5424, found 972.5426;
Rf 0.26 (15% EtOAc/hexane).
(4E,6R,7S,12S,13S,14S,16S,19R,20R,21S,22S,23Z)-13,19-Bis(tert-
butyldimethylsilyloxy)-21-hydroxy-4-iodo-7-(p-methoxybenzyloxy)-
6,12,14,16,20,22-hexamethyltricosa-4,23,25-trien-9-one (14). To a
solution of enone 11 (73 mg, 0.077 mmol) at rt in deoxygenated toluene
(2 mL) and water (5 µL) was added [Ph3PCuH]6 (45 mg, 0.031 mmol).
After stirring for 2 h, the reaction mixture was concentrated in Vacuo,
and flash chromatography (7% EtOAc/hexane) afforded ketone 14 (54
(4E,6R,7S,12S,13S,14S,16S,19R,20R,21S,22S,23Z)-13,19-Bis(tert-
butyldimethylsilyloxy)-7,21-dihydroxy-4-iodo-6,12,14,16,20,22-hex-
amethyltricosa-4,23,25-trien-9-one (15). To a solution of PMB ether
14 (50 mg, 0.052 mmol) in CH2Cl2 (1.6 mL) and pH 7 buffer (160
µL) at 0 °C was added DDQ (142 mg, 0.624 mmol). After 30 min, the
reaction mixture was diluted with pH 7 buffer (5 mL) and CH2Cl2 (5
mL) and warmed to rt, and the phases were separated. The aqueous
phase was extracted with CH2Cl2 (3 × 4 mL), dried (MgSO4), and
concentrated in Vacuo. Flash chromatography (15% EtOAc/hexane)
mg, 73%) as a colorless oil: [R]20 +11.7 (c 0.99, CHCl3); IR (liquid
D
film)/cm-1 2956, 2929, 2857, 1713, 1612, 1514, 1462; H NMR (500
1
MHz, C6D6) δH 7.21 (2H, d, J ) 8.7 Hz, H-Ar), 6.80 (2H, d, J ) 8.6
Hz, H-Ar), 6.72 (1H, app dt, J ) 10.6, 17.3 Hz, H-25), 6.49 (1H, dd,
J ) 8.4, 14.5 Hz, H-5), 6.09 (1H, app t, J ) 11.0 Hz, H-24), 5.79 (1H,
dd, J ) 0.9, 14.5 Hz, H-4), 5.45 (1H, app t, J ) 10.6 Hz, H-23), 5.15
(1H, dd, J ) 1.8, 17.0 Hz, H-26a), 5.06 (1H, d, J ) 10.1 Hz, H-26b),
4.39 and 4.29 (2H, AB system, J ) 11.0 Hz, OCH2Ar), 3.90 (1H, app
q, J ) 5.1 Hz, H-19), 3.87 (1H, app sep, J ) 3.7 Hz, H-7), 3.54 (1H,
dd, J ) 4.1, 6.5 Hz, H-21), 3.40 (1H, dd, J ) 2.3, 5.6 Hz, H-13), 3.31
(3H, s, ArOCH3), 2.89 (1H, app qnd, J ) 6.7, 10.1 Hz, H-22), 2.42
(1H, dd, J ) 7.7, 16.4 Hz, H-8a), 2.25–2.12 (2H, m, H-6, H-10a),
2.08 (1H, dd, J ) 4.6, 16.6 Hz, H-8b), 2.04–1.95 (1H, m, H-10b),
afforded alcohol 15 (40 mg, 90%) as a colorless oil: [R]20 -18.7(c
D
0.65, CHCl3); IR (liquid film)/cm-1 3464, 2956, 2929, 2857, 1709, 1602,
1461; 1H NMR (500 MHz, C6D6) δH 6.72 (1H, app dt, J ) 11.4, 17.1
Hz, H-25), 6.54 (1H, dd, J ) 8.6, 14.6 Hz, H-5), 6.10 (1H, app t, J )
11.1 Hz, H-24), 5.76 (1H, dd, J ) 0.9, 14.6 Hz, H-4), 5.45 (1H, app
t, J ) 10.5 Hz, H-23), 5.16 (1H, dd, J ) 1.8, 16.8 Hz, H-26a), 5.06
(1H, d, J ) 10.0 Hz, H-26b), 3.89 (1H, app q, J ) 5.9 Hz, H-19), 3.72
(1H, br d, J ) 9.8 Hz, H-7), 3.54 (1H, br t, J ) 5.5 Hz, H-21), 3.37
(1H, dd, J ) 3.2, 5.6 Hz, H-13), 2.93–2.85 (2H, m, H-22, OH), 2.14
(1H, dd, J ) 10.0, 17.2 Hz, H-8a), 2.09–2.01 (1H, m, H-10a), 1.97–1.89
(2H, m, H-10b, H-15a), 1.87–1.73 (5H, m, H-6, H-8b, H-14, H-18a,

368 Journal of Natural Products, 2008, Vol. 71, No. 3
Paterson et al.
H-20), 1.71–1.62 (1H, m, H-18b), 1.61–1.50 (4H, m, H-11a, H-12,
H-16, H-17a), 1.49–1.42 (1H, m, H-17b), 1.29–1.21 (1H, m, H-11b),
1.19–1.14 (1H, m, H-15b), 1.11 (3H, d, J ) 6.9 Hz, CH3-14), 1.06
(9H, s, SiC(CH3)3), 1.01 (9H, s, SiC(CH3)3), 1.02–0.98 (9H, m, CH3-
16, CH3-20, CH3-22), 0.85 (3H, d, J ) 6.9 Hz, CH3-12), 0.83 (3H, d,
J ) 6.9 Hz, CH3-6), 0.17 (3H, s, Si(CH3)), 0.16 (6H, s, Si(CH3) × 2),
0.13 (3H, s, Si(CH3)); 13C NMR (125 MHz, C6D6) δC 210.6, 147.9,
135.0, 132.7, 130.6, 117.9, 80.1, 76.0, 75.9, 75.6, 70.1, 46.6, 46.1, 43.6,
41.7, 39.5, 37.7, 36.5, 33.4, 32.2, 32.1, 30.9, 26.7, 26.5, 26.2, 20.6,
18.8, 18.3, 17.9, 16.6, 15.8, 15.5, 8.7, -3.4, -3.6, -4.3; HRMS (ESI+)
calcd for C41H80IO5Si2 [M + H]+ 835.4583, found 835.4591; Rf 0.62
(20% EtOAc/hexane).
6,12,14,16,20,22-hexamethyl-23,25-dienyl-2,4-dienoic acid (17). To
a deoxygenated solution (freeze–thaw) of iodide 9 (7.8 mg, 8.9 µmol) and
stannane 10 (18 mg, 36 µmol) in NMP (450 µL) at rt was added CuTC
(17 mg, 89 µmol). After stirring for 16 h, the reaction was quenched by
the addition of NH4Cl (1 mL). The phases were separated, the aqueous
layer was extracted with CH2Cl2 (3 × 2 mL), and the combined organic
extracts were dried (MgSO4) and concentrated in Vacuo. The crude product
was redissolved in THF (300 µL) and MeOH (150 µL), and to it at rt was
added KF (10 mg, 176 µmol). The reaction mixture was stirred for 4 h,
before quenching with saturated aqueous NH4Cl (1 mL). Again, the phases
were separated, the aqueous phase was extracted with CH2Cl2 (3 × 5 mL),
and the combined organic extracts were dried (MgSO4) and concentrated
in Vacuo. Flash chromatography (5% EtOAc/hexane f 20% EtOAc/
(4E,6R,7S,9R,12S,13S,14S,16S,19R,20R,21S,22S,23Z)-13,19-Bis-
(tert-butyldimethylsilyloxy)-4-iodo-6,12,14,16,20,22-hexamethyltri-
cosa-4,23,25-triene-7,9,21-triol (16). To a solution of NaBH(OAc)3
(16 mg, 0.078 mmol) in THF (750 µL) at 0 °C was added via cannula
a solution of alcohol 15 (13 mg, 0.016 mmol) in THF (750 µL) and
AcOH (30 µL). After warming to rt, the reaction mixture was stirred
for 3 h before quenching with saturated aqueous NaHCO3 (1 mL)
and Na+/K+ tartrate solution (2 mL). This biphasic mixture was stirred
vigorously for 1 h before the phase separation and extraction of the
aqueous phase with CH2Cl2 (3 × 4 mL). The combined organic extracts
were dried (Na2SO4), concentrated in Vacuo, and purified using flash
chromatography (10% EtOAc/hexane) to afford anti-alcohol 16 (9.5
mg, 74%) and its isomeric syn-alcohol (1.3 mg, 10%) as colorless oils:
[R]20D -10.9 (c 0.48, CHCl3); IR (liquid film)/cm-1 3407, 2956, 2929,
hexane) afforded acid 17 (5.3 mg, 73%) as a colorless oil: [R]20 -33.2
D
(c 0.27, CHCl3); IR (liquid film)/cm-1 2956, 2928, 2856, 1692, 1636, 1601,
1461, 1378; 1H NMR (500 MHz, C6D6) δH 7.72 (1H, dd, J ) 11.9, 15.4
Hz, H-4), 6.72 (1H, app dt, J ) 10.6, 17.2 Hz, H-25), 6.31 (1H, app t, J
) 11.4 Hz, H-3), 6.09 (1H, app t, J ) 11.3 Hz, H-24), 6.05 (1H, dd, J )
8.0, 15.0 Hz, H-5), 5.54 (1H, d, J ) 11.1 Hz, H-2), 5.44 (1H, app t, J )
10.3 Hz, H-23), 5.15 (1H, d, J ) 16.9 Hz, H-26a), 5.06 (1H, d, J ) 9.9
Hz, H-26b), 3.92–3.87 (1H, m, H-19), 3.73–3.66 (1H, m, H-9), 3.66–3.60
(1H, m, H-7), 3.57–3.52 (1H, m, H-21), 3.41 (1H, dd, J ) 2.3, 6.2 Hz,
H-13), 2.89 (1H, app qnd, J ) 7.0, 10.0 Hz, H-22), 2.24–2.17 (1H, m,
H-6), 1.96–1.12 (16H, m, H2-8, H2-10, H2-11, H-12, H-14, H2-15, H-16,
H2-17, H2-18, H-20), 1.41 (3H, s, OC(CH3)), 1.37 (3H, s, OC(CH3)), 1.11
(3H, d, J ) 6.7 Hz, CH3-20), 1.07 (9H, s, SiC(CH3)3), 1.02 (9H, s,
SiC(CH3)3), 1.02–0.95 (15H, m, CH3-6, CH3-12, CH3-14, CH3-16, CH3-
22), 0.16 (6H, s, Si(CH3) × 2), 0.16 (3H, s, Si(CH3)), 0.14 (3H, s, Si(CH3));
13C NMR (125 MHz, C6D6) δC 148.1, 147.4, 135.0, 132.7, 130.7, 118.0,
100.4, 79.7, 76.2, 75.7, 70.1, 67.4, 43.9, 42.0, 39.4, 38.8, 37.0, 36.5, 34.8,
33.0, 32.32, 32.26, 30.8, 30.2, 29.8, 28.3, 27.4, 26.5, 26.2, 20.3, 18.8, 18.3,
17.9, 16.6, 16.2, 15.3, 14.3, 13.9, 8.5, 1.4, -3.37, -3.40, -3.6, -4.3;
HRMS (ESI+) calcd for C47H89O7Si2 [M + H]+ 821.6141, found 821.6139;
Rf 0.67 (20% EtOAc/hexane).
1
2857, 1468, 1378; H NMR (500 MHz, C6D6) δH 6.72 (1H, app dt, J
) 10.5, 17.1 Hz, H-25), 6.46 (1H, dd, J ) 8.7, 14.5 Hz, H-5), 6.10
(1H, app t, J ) 11.1 Hz, H-24), 5.77 (1H, dd, J ) 0.7, 14.4 Hz, H-4),
5.44 (1H, app t, J ) 10.5 Hz, H-23), 5.16 (1H, dd, J ) 1.8, 16.8 Hz,
H-26a), 5.07 (1H, d, J ) 10.4 Hz, H-26b), 3.91–3.86 (1H, m, H-19),
3.73–3.67 (1H, m, H-9), 3.56–3.52 (1H, m, H-21), 3.51–3.48 (1H, m,
H-7), 3.43 (1H, dd, J ) 2.9, 5.5 Hz, H-13), 3.39–3.35 (1H, m, OH),
2.89 (1H, app qnd, J ) 6.7, 9.9 Hz, H-22), 2.01–1.14 (17H, m, H-6,
H2-8, H2-10, H2-11, H-12, H-14, H2-15, H-16, H2-17, H2-18, H-20),
1.11 (3H, d, J ) 7.0 Hz, CH3-20), 1.07 (9H, s, Si(CH3)3), 1.03 (3H, d,
J ) 6.7 Hz, CH3-6), 1.02 (9H, s, Si(CH3)3), 1.01–0.96 (9H, m, CH3-
12, CH3-16, CH3-22), 0.77 (3H, d, J ) 7.0 Hz, CH3-14), 0.17 (3H, s,
Si(CH3)), 0.16 (6H, s, Si(CH3) × 2), 0.13 (3H, s, Si(CH3)); 13C NMR
(125 MHz, C6D6) δC 148.4, 135.1, 132.7, 130.6, 118.0, 80.1, 76.06,
76.02, 75.5, 71.3, 69.7, 47.1, 43.9, 40.3, 39.6, 39.0, 36.5, 36.0, 33.2,
32.2, 32.1, 30.9, 29.8, 26.5, 26.2, 26.1, 20.6, 18.8, 18.3, 17.9, 16.8,
15.7, 8.7, -3.37, -3.43, -3.6, -4.3; HRMS (ESI+) calcd for
C41H82IO5Si2 [M + H]+ 837.4740, found 837.4745; Rf 0.46 (30%
EtOAc/hexane).
Protected Macrolactone 18. To a solution of acid 17 (2.7 mg, 3.3
µmol) in toluene (250 µL) at rt was added Et3N (10 µL of a 0.88 M solution
in toluene, 8.6 µmol), then 2,4,6-trichlorobenzoyl chloride (10 µL of a
0.87 M solution in toluene, 5.9 µmol). After 3 h, with observation of
complete mixed anhydride formation (Rf ) 0.34, 15% EtOAc/hexane),
the reaction mixture was diluted with toluene (5 mL) and DMAP (39 µL,
0.082 M solution in toluene, 3.3 µmol) was added. After stirring for 36 h,
the reaction mixture was filtered through a plug of silica, eluting with Et2O,
and concentrated in Vacuo. Flash chromatography (100% hexane to 5%
EtOAc) afforded macrolactone 18 (1.6 mg, 60%) as a colorless oil: [R]20
D
-3.0 (c 0.29, CHCl3); IR (liquid film)/cm-1 2956, 2930, 2857, 1707, 1640,
1462, 1379; 1H NMR (500 MHz, C6D6) δH 7.53 (1H, dd, J ) 11.1, 15.3
Hz, H-4), 6.73 (1H, app dt, J ) 10.6, 16.6 Hz, H-25), 6.25 (1H, app t, J
) 11.3 Hz, H-3), 6.15 (1H, app t, J ) 11.0 Hz, H-24), 5.80 (1H, dd, J )
7.1, 15.5 Hz, H-5), 6.57 (1H, d, J ) 11.4 Hz, H-2), 5.67–5.61 (1H, m,
H-23), 5.59 (1H, app t, J ) 5.8 Hz, H-21), 5.19 (1H, d, J ) 16.4 Hz,
H-26a), 5.09 (1H, d, J ) 10.0 Hz, H-26b), 3.90 (1H, ddd, J ) 2.8, 6.0,
9.2 Hz, H-7), 3.82–3.76 (1H, m, H-9), 3.76–3.71 (1H, m, H-19), 3.47 (1H,
app t, J ) 3.2 Hz, H-13), 3.21–3.13 (1H, m, H–22), 2.42–2.34 (1H, m,
H-6), 2.04–1.97 (1H, m, H-20), 1.83–1.67 (5H, m, H-8a, H-10a, H-12,
H-14, H-18a), 1.65–1.49 (3H, m, H-8b, H-10b, H-16), 1.45–1.23 (12H,
m, H2-11, H2-15, H2-17, OC(CH3) × 2), 1.14 (3H, d, J ) 6.9 Hz, CH3-6),
1.11 (3H, d, J ) 6.9 Hz, CH3-20), 1.09 (3H, d, J ) 6.7 Hz, CH3-22), 1.07
(3H, d, J ) 6.9 Hz, CH3-12 or 14), 1.05 (9H, s, SiC(CH3)3), 1.04 (9H, s,
SiC(CH3)3), 1.00 (3H, d, J ) 6.6 Hz, CH3-12 or 14), 0.95 (3H, d, J ) 6.6
Hz, CH3-16), 0.151 (3H, s, Si(CH3)), 0.148 (3H, s, Si(CH3)), 0.13 (3H, s,
Si(CH3)), 0.12 (3H, s, Si(CH3)); 13C NMR (C6D6, 125 MHz) δC 171.4,
165.9, 144.7, 134.0, 132.4, 130.4, 127.5, 118.3, 118.2, 100.3, 79.7, 74.3,
69.0, 68.0, 66.8, 44.9, 41.2, 40.2, 39.4, 34.5, 34.1, 32.1, 30.9, 30.4, 28.1,
26.3, 26.24, 26.15, 25.1, 25.0, 20.4, 18.6, 18.4, 18.1, 16.3, 16.2, 10.3, -3.6,
-3.7, -4.0, -4.2; HRMS (ES+) calcd for C47H86O6Si2Na [M + Na]+
825.5828, found 825.5866; Rf 0.29 (4% EtOAc/hexane).
(4E,6S,7S,9R,12R,13S,14S,16S,19S,20S,21S,22S,23Z)-13,19-Bis(tert-
butyldimethylsilyloxy)-(2,2-dimethyl)-7,9-dioxan-4-iodo-
6,12,14,16,20,22-hexamethyltricosa-4,23,25-triene-21-ol (9). To a
solution of triol 16 (21.8 mg, 0.026 mmol) in 2,2-dimethoxypropane
(3 mL) was added a crystal of PPTS. After 2 h, the reaction mixture
was concentrated in Vacuo, and flash chromatography (15% EtOAc/
hexane) afforded acetonide 9 (20.5 mg, 90%) as a colorless oil: [R]20
D
-26.1 (c 0.39, CHCl3); IR (liquid film)/cm-1 2955, 2930, 2857, 1462,
1379; 1H NMR (500 MHz, C6D6) δH 6.72 (1H, app dt, J ) 11.0, 17.1
Hz, H-25), 6.63 (1H, dd, J ) 8.1, 14.4 Hz, H-5), 6.08 (1H, app t, J )
11.0 Hz, H-24), 5.81 (1H, d, J ) 14.6 Hz, H-4), 5.42 (1H, app t, J )
10.4 Hz, H-23), 5.15 (1H, d, J ) 16.9 Hz, H-26a), 5.05 (1H, d, J )
10.3 Hz, H-26b), 3.92–3.88 (1H, m, H-19), 3.67–3.60 (1H, m, H-9),
3.54–3.47 (2H, m, H-7, H-21), 3.40 (1H, dd, J ) 2.1, 6.0 Hz, H-13),
2.88 (1H, app qnd, J ) 6.7, 10.2 Hz, H-22), 2.01–1.93 (1H, m, H-6),
1.91–1.14 (16H, m, H2-8, H2-10, H2-11, H-12, H-14, H2-15, H-16, H2-
17, H2-18, H-20), 1.33 (3H, s, OC(CH3)), 1.31 (3H, s, OC(CH3)), 1.11
(3H, d, J ) 7.1 Hz, CH3-20), 1.07 (9H, s, SiC(CH3)3), 1.02 (9H, s,
SiC(CH3)3), 1.02 (6H, m, CH3-14, CH3-16), 0.98 (3H, d, J ) 7.0 Hz,
CH3-22), 0.96 (3H, d, J ) 7.0 Hz, CH3-12), 0.80 (3H, d, J ) 7.0 Hz,
CH3-6), 0.162 (3H, s, Si(CH3)), 0.157 (3H, s, Si(CH3)), 0.15 (3H, s,
Si(CH3)), 0.14 (3H, s, Si(CH3)); 13C NMR (125 MHz, C6D6) δC 148.5,
135.1, 132.7, 130.7, 118.0, 100.4, 79.8, 76.1, 75.7, 75.6, 69.4, 67.4,
45.2, 43.9, 39.3, 38.8, 36.63, 36.56, 34.8, 33.0, 32.32, 32.26, 30.9, 29.8,
26.5, 26.2, 24.7, 24.6, 20.3, 18.8, 18.3, 17.8, 16.6, 15.3, 15.2, 8.5, -3.3,
-3.4, -3.6, -4.3; HRMS (ESI+) calcd for C44H89IO5Si2N [M + NH4]+
894.5318, found 894.5313; Rf 0.84 (30% EtOAc/hexane).
10,11-Dihydrodictyostatin (5). To a solution of macrolactone 18
(3.2 mg, 4.0 µmol) in THF (408 µL) at 0 °C was added HF ·pyridine
(87 µL). After slow warming to rt, the reaction mixture was stirred for
48 h. The reaction was diluted with EtOAc (1 mL) and subsequently
quenched by the addition of saturated NaHCO3 (1 mL) after cooling
to 0 °C. The phases were then separated, the aqueous phase was
extracted with EtOAc (3 × 3 mL), and the combined organic extracts
were dried (Na2SO4) and concentrated in Vacuo. Initial flash chroma-
tography (100% EtOAc) afforded 10,11-dihydrodictyostatin 5 (1.8 mg,
(2Z,4E,6S,7S,9R,12R,13S,14S,16S,19S,20S,21S,22S,23Z)-13,19-
Bis(tert-butyldimethylsilyloxy)-(2,2-dimethyl)-7,9-dioxan-21-hydroxy-

Biological EValuation of 10,11-Dihydrodictyostatin
Journal of Natural Products, 2008, Vol. 71, No. 3 369
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85%) as a white solid, which was further subject to HPLC (10% IPA/
hexane) purification: [R]20 +5.6 (c 0.16, CHCl3); IR (liquid film)/
D
cm-1 3370, 2924, 2853, 1684, 1637, 1601, 1455; 1H NMR (500 MHz,
C6D6) δH 7.50 (1H, dd, J ) 11.0, 15.8 Hz, H-4), 6.58 (1H, app dt, J )
10.5, 16.9 Hz, H-25), 6.20 (1H, app t, J ) 11.1 Hz, H-3), 5.97 (1H,
app t, J ) 10.9 Hz, H-24), 5.78 (1H, dd, J ) 7.3, 15.7 Hz, H-5), 5.57
(1H, d, J ) 11.5 Hz, H-2), 5.39 (1H, app t, J ) 10.5 Hz, H-23), 5.23
(1H, dd, J ) 4.4, 7.2 Hz, H-21), 5.10 (1H, dd, J ) 1.2, 16.3 Hz, H-26a),
5.01 (1H, br d, J ) 10.2 Hz, H-26b), 3.93 (1H, app q, J ) 5.6 Hz,
H-7), 3.76 (1H, app qn, J ) 6.2 Hz, H-9), 3.56–3.52 (1H, m, H-19),
3.23 (1H, dd, J ) 3.7, 7.1 Hz, H-13), 2.99 (1H, app qnd, J ) 6.7, 10.2
Hz, H-22), 2.37–2.30 (1H, m, H-6), 2.28–2.21 (1H, br s, OH), 2.17–2.09
(2H, m, OH × 2), 1.83–1.67 (4H, m, H-12, H-14, H-20, OH), 1.66–1.52
(6H, m, H2-8, H-10a, H-15a, H-16, H-18a), 1.45–1.18 (7H, m, H-10b,
H2-11, H-15b, H2-17, H-18b), 1.03 (3H, d, J ) 7.1 Hz, CH3-20), 1.01
(3H, d, J ) 7.0 Hz, CH3-6), 0.99 (3H, d, J ) 6.4 Hz, CH3-14), 0.91
(3H, d, J ) 6.5 Hz, CH3-16), 0.88 (3H, d, J ) 6.7 Hz, CH3-22), 0.85
(3H, d, J ) 6.7 Hz, CH3-12); 13C NMR (125 MHz, C6D6) δC 166.8 (C,
C-1), 146.7 (CH, C-5), 144.7 (CH, C-3), 134.1 (CH, C-23), 132.5 (CH,
C-25), 130.4 (CH, C-24), 127.6 (CH, C-4), 118.0 (CH2, C-26), 117.1
(CH, C-2), 78.1 (CH, C-21), 76.5 (CH, C-13), 72.8 (CH, C-19), 71.6
(CH, C-7), 70.2 (CH, C-9), 42.9 (CH, C-6), 40.6 (CH, C-20), 38.5
(CH2, C-8), 35.4 (CH, C-12), 35.3 (CH, C-22), 33.8 (CH2, C-10), 32.8
(CH2, C-11), 32.7 (CH2, C-18), 32.4 (CH, C-14), 29.5 (CH, C-16),
27.6 (CH2, C-17), 25.4 (CH2, C-15), 21.3 (CH3, C-16), 17.6 (CH3,
C-22), 16.6 (CH3, C-12), 15.8 (CH3, C-6), 15.1 (CH3, C-14), 9.3 (CH3,
C-20); HRMS (ES+) calcd for C32H54O6Na [M + Na]+ 557.3813, found
557.3818; Rf 0.52 (100% EtOAc); tR 18 min (10% IPA/hexane).
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Acknowledgment. NIH grant No. CA-93455 provided financial
support for the biological assays, and general project support was
provided by the EPSRC, AstraZeneca, and the EC (Marie Curie
Fellowship to K.G.P.). We thank Dr. J. Leonard (AstraZeneca) for
helpful discussions, Dr. S. Mickel (Novartis) for provision of chemicals,
Ms. P. Linley for cytotoxicity assays, Dr. R. Isbrucker and Ms. T. Pitts
for cell cycle and immunofluorescence assays, and R. Paton (Cam-
bridge) for molecular modeling assistance.
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Supporting Information Available: Copies of NMR spectra for
new compounds reported. This material is available free of charge via
the Internet at http://pubs.acs.org.
References and Notes
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J. Chem. Soc., Chem. Commun. 1994, 9, 1111. (b) Pettit, G. R.;
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NP070547S