Total synthesis and biological evaluation of potent analogues of dictyostatin: Modification of the C2-C6 dienoate region

Article abstract of DOI:10.1016/j.bmcl.2008.09.109

By exploiting a Still-Gennari olefination of a common C11-C26 aldehyde with a C4-C10 or C1-C10 β-ketophosphonate, three modified C2-C6 region analogues of the 22-membered macrolide dictyostatin were synthesised and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the Taxol-resistant NCI/ADR-Res cell line. 6-Desmethyldictyostatin and 2,3-dihydrodictyostatin displayed potent (low nanomolar) antiproliferative activity, intermediate between dictyostatin and discodermolide, while 2,3,4,5-tetrahydrodictyostatin showed activity comparable to discodermolide. As with dictyostatin, these simplified analogues act through a mechanism of microtubule stabilisation, G2/M arrest and apoptosis.

Full text of DOI:10.1016/j.bmcl.2008.09.109

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6268–6272
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Total synthesis and biological evaluation of potent analogues of dictyostatin:
Modification of the C2–C6 dienoate region
a
b
b
Ian Paterson a, , Nicola M. Gardner , Esther Guzmán , Amy E. Wright
*
a University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
b Harbor Branch Oceanographic Institution at Florida Atlantic University, 5600 US 1 North, Ft. Pierce, FL 34946, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
By exploiting a Still–Gennari olefination of a common C11–C26 aldehyde with a C4–C10 or C1–C10
b-ketophosphonate, three modified C2–C6 region analogues of the 22-membered macrolide dictyostatin
were synthesised and evaluated in vitro for growth inhibition against a range of human cancer cell lines,
including the Taxol-resistant NCI/ADR-Res cell line. 6-Desmethyldictyostatin and 2,3-dihydrodictyostatin
displayed potent (low nanomolar) antiproliferative activity, intermediate between dictyostatin and dis-
codermolide, while 2,3,4,5-tetrahydrodictyostatin showed activity comparable to discodermolide. As
with dictyostatin, these simplified analogues act through a mechanism of microtubule stabilisation,
G2/M arrest and apoptosis.
Received 3 September 2008
Accepted 22 September 2008
Available online 11 October 2008
Keywords:
Total synthesis
Macrolide
Anticancer
Tubulin
Ó 2008 Elsevier Ltd. All rights reserved.
26
The tubulin/microtubule system is an important target in
current cancer chemotherapy.1 TaxolÒ (1, Fig. 1) and its semi-syn-
thetic derivative TaxotereÒ act by stabilising cellular microtubules
and suppressing microtubule dynamics in cell division, and are
widely used in the treatment of breast, ovarian and lung cancers.
Despite the clinical utility of the taxane class of microtubule-stabil-
ising agents, they have limited effectiveness towards multidrug-
resistant cancers, prompting the search for new and improved
antitumour agents.2
Bz
OH
NH
AcO
O
OH
Ph
O
O
HO
O
O
HO
1
O
H
HO
BzO
AcO
OH OH
2: dictyostatin
1:Taxol (paclitaxel)
24
OH
In a similar manner to Taxol, the antimitotic marine macrolide
dictyostatin (2), first reported by Pettit in 1994,3a functions by
microtubule stabilisation and G2/M arrest.3b Upon re-isolation from
a Caribbean deep-sea sponge by Wright and co-workers,3b detailed
NMR analysis enabled us to assign the full stereochemistry.4 Concur-
rent total syntheses by the Paterson5a and Curran groups5b indepen-
dently confirmed this structure, enabling more extensive biological
evaluation of this promising anticancer agent,6 as well as the initia-
tion of SAR studies.7,8 From elegant NMR studies by Jiménez-Barbero
and co-workers,9 the bioactive conformation of dictyostatin bound
to the taxoid binding site on b-tubulin was recently proposed, high-
lighting its similarity to the tubulin-bound 3D structure of the struc-
turally related polyketide discodermolide (3).10
HO
O
O
OH NH2
1
OH
O
O
3: discodermolide
Figure 1. Structures of Taxol, dictyostatin and discodermolide.
To date, a variety of dictyostatin analogues,7,8 together with hy-
brid structures with discodermolide,11,12 have been synthesised
and evaluated for their anticancer properties, leading to an evolv-
ing common pharmacophore model with discodermolide. Herein,
we report the total synthesis and biological evaluation of 6-des-
methyldictyostatin (4, Fig. 2), 2,3-dihydrodictyostatin (5) and
2,3,4,5-tetrahydrodictyostatin (6), incorporating modifications to
the C2–C6 dienoate region of dictyostatin. We disclose that the no-
vel dictyostatin analogues 4, 5 and 6 display potent growth inhib-
itory activity in vitro against a range of human cancer cell lines,
including the Taxol-resistant NCI/ADR-Res cell line. As with dict-
yostatin, these simplified analogues act through a mechanism of
microtubule stabilisation, G2/M arrest and apoptosis.
* Corresponding author. Tel.: +44 4 1223336407.
E-mail address: ip100@cam.ac.uk (I. Paterson).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.09.109

I. Paterson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6268–6272
6269
methyldictyostatin was envisaged to be the preparation of the no-
vel C4–C10 phosphonate 10, lacking a C6 methyl substituent and
having a PMB ether7a at C7 (rather than the TBS ether used
initially5a).
26
OH
OH
HO
HO
O
O
O
O
Preparation of the b-ketophosphonate 10 required for the Still–
Gennari fragment coupling started out from the (S)-epoxide 11
(Scheme 2), which was obtained by a Jacobsen hydrolytic kinetic
resolution reaction.13 A CuCl-catalysed epoxide-opening of 11 with
vinyl magnesium bromide afforded the secondary alcohol 12 in
99% ee. Following PMB ether formation, a sequence of oxidative
olefin cleavage (OsO4, NMO; NaIO4) and Takai olefination14 of the
resulting aldehyde gave the (E)-vinyl iodide 13 (53% from 12). After
TBS ether cleavage (TBAF, AcOH), the resulting alcohol was con-
verted via the carboxylic acid 14 into the acid chloride using the
Ghosez chloroenamine reagent,15 followed by the addition of
(CF3CH2O)2P(O)CH2Li to provide the b-ketophosphonate 10 (60%
from 13).
1
6
2
3
OH OH
OH OH
4: 6-desmethyldictyostatin
5: 2,3-dihydrodictyostatin
16
OH
OH
HO
HO
O
O
O
O
1
2
5
OH OH
6: 2,3,4,5-tetrahydrodictyostatin
OH OH
7: 16-desmethyldictyostatin
As deployed in our dictyostatin total synthesis, we were now
ready to perform the Still–Gennari HWE coupling16 with the
C11–C26 aldehyde 8 (Scheme 3).5a Following treatment of a mix-
ture of phosphonate 10 and aldehyde 8 with K2CO3 (18-crown-6,
PhMe, HMPA), the required (Z)-enone 15 was obtained in an iso-
lated yield of 54% (72%, 3:1 Z:E). Oxidative cleavage (DDQ, pH 7
buffer) of the PMB ether in 15 then released the b-hydroxyketone
in readiness for a hydroxyl-directed reduction. Reduction with
Figure 2. Structures of dictyostatin analogues.
In previous SAR work on dictyostatin, the importance of the C16
methyl substituent was probed through the synthesis of 16-des-
methyldictyostatin (7, Fig. 2).7a,8a Our biological results7a for 7
led us to conclude that the C16 methyl group was both important
in contributing to the low nanomolar levels of cytotoxicity of dict-
yostatin and permitting its circumvention of P-glycoprotein-med-
iated drug resistance. Looking towards achieving further
structural simplifications, it was next proposed to explore the con-
tribution of the C2–C6 dienoate region of dictyostatin to the phar-
macophore by synthesising 6-desmethyldictyostatin (4) to
evaluate its cytotoxicity in a panel of Taxol-sensitive and resistant
cell lines.
Access to the targeted 6-desmethyl analogue 4 was planned by
adapting our existing synthetic strategy for dictyostatin5a as used
for preparing an initial set of analogues7a (Scheme 1). This relies
on a pivotal Still–Gennari HWE fragment coupling with the fully
elaborated C11–C26 aldehyde 8, followed in turn by introduction
of the (2Z,4E)-dienoate by a Stille coupling with stannane 9 and
Yamaguchi macrolactonisation. By pursuing a similar strategy,
the primary modification required to assemble 6-des-
17
NaBH(OAc)3 afforded the expected 1,3-anti diol 16 with moder-
ate selectivity (78%, 80:20 dr). A switch to the Corey–Bakshi–Shi-
bata (R)-oxazoborolidine-mediated reduction18 gave the 1,3-anti
diol 16 (76%, 89:11 dr) with improved levels of diastereoselectivi-
ty. After formation of the acetonide 17 (Me2C(OMe)2, PPTS), a
CuTC-mediated Liebeskind–Stille coupling19 with the vinyl stann-
ane 95a installed the (2Z,4E)-dienoate and a Yamaguchi macrolac-
tonisation20 then gave the 22-membered macrolide 18. Following
global deprotection of 18 with HFꢀpyridine and HPLC purification,
6-desmethyldictyostatin (4) was isolated in 53% yield from 16 in
readiness for biological testing.
The remarkable structural and stereochemical homology be-
tween the C8–C26 region of dictyostatin and the corresponding
MgBr
CuCl, THF (99%)
TBSO
TBSO
O
OH
26
11
12
OH
HO
Yamaguchi
macrolactonisation
1. PMBTCA, cat. Sc(OTf) 3,
THF (90%)
2. cat. OsO4, NMO, THF/H2O
O
O
11
10
1
4
TBSO
6
I
3
Still-Gennari
olefination
OPMB
3. NaIO4, THF/pH 7 buffer
(80% over 2 steps)
4. CHI3, CrCl2, THF/1,4-dioxane
OH OH
Stille coupling
13
4: 6-desmethyldictyostatin
(74%, 5:1 E:Z)
TBS
O
26
1. TBAF, AcOH, THF (90%)
2. Dess-Martin, CH2Cl2 (91%)
O
I
TBSO
OH OPMB
3. NaClO2, NaH2PO4,
t-BuOH/H2O (99%)
11
H
OH
14
8
O
+
epoxide opening
CF3CH2O
NMe2
1
CO2TIPS
CF3CH2O
4
10
4
1.
Cl , CH2Cl2
10
CF3CH2O
Bu3Sn
CF3CH2O
+
P
I
P
I
3
2. LiHMDS, (CF3CH2O)2P(O)CH3,
THF (74% over 2 steps)
O
O
OPMB
O
O
OPMB
9
10
10
Scheme 1. Retrosynthetic analysis of 6-desmethyldictyostatin (4).
Scheme 2. Synthesis of C4–C10 b-ketophosphonate 13.

6270
I. Paterson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6268–6272
8 + 10
K2CO3, 18-crown-6
OH
(72%, 3:1 Z:E)
HO
PhMe/HMPA
Yamaguchi
macrolactonisation
TBS
O
O
O
2
TBSO
Still-Gennari
olefination
5
3
OH OH
OH
I
5: Δ4,5, 2,3-dihydrodictyostatin
6: 2,3,4,5-tetrahydrodictyostatin
O
OPMB
15
TBS
O
1. DDQ, CH2Cl2
2a. NaBH(OAc)3, AcOH, THF
or 2b. (R)-CBS, BH3•THF, THF
(2a. 78% over 2 steps,
80:20 dr)
(2b. 76%, 89:11 dr)
TBSO
TBS
O
H
OH
8
O
TBSO
+
OPMB
OPMB
1
OH
I
CF3CH2O
10
4
CF3CH2O
P
5
O
O
O
OPMB
OR OR
20 (for 6)
16: R = H
17: R–R = CMe2
(MeO)2CMe2,
PPTS (92%)
1
CF3CH2O
1. 11, CuTC, NMP; 2. Cl3(C6H2)COCl, Et3N,
10
CF3CH2O
KF, THF/MeOH
DMAP, PhMe
TBS
O
P
O
OPMB
cross-metathesis
19 (for 5)
TBSO
O
O
OPMB
1
CF3CH2O
10
CF3CH2O
O
O
P
+
18
22
O
O
OPMB
21
(35% over 4 steps)
HF•pyridine, THF
Scheme 4. Retrosynthetic analysis of 2,3-dihydrodictyostatin (5) and 2,3,4,5-
tetrahydrodictyostatin (6).
OH
HO
O
O
building block 19 might arise from a cross-metathesis reaction be-
tween b-ketophosphonate 21 and the olefin 22. This sequence was
viewed as particularly attractive due to its enhanced convergence
and versatility.
OH OH
Starting from the previously reported PMB ether 237a obtained
using a Brown crotylation sequence, treatment with Jones reagent
(CrO3, H2SO4) led to cleavage of the TBS ether and subsequent oxi-
dation of the resulting alcohol to provide the acid 24 in 88% yield
(Scheme 5). Conversion to the acid chloride was now possible
using oxalyl chloride, and addition of (CF3CH2O)2P(O)CH2Li pro-
vided the b-ketophosphonate 21 (65% from 24) in readiness for
the planned cross-metathesis reaction21 with the terminal olefin
22. Only when the Grubbs second-generation Ru catalyst (10 mol
%) was used in the presence of AcOH22 (10 mol %) did this afford
the desired unsaturated phosphonate 19 in high yield (81%, 10:1
E:Z).23 Raney nickel catalysed hydrogenation of alkene 19 then
gave the corresponding saturated phosphonate 20 (89%), as re-
quired for the construction of 2,3,4,5-tetrahydrodictyostatin.
With the two b-ketophosphonates 19 and 20 in hand, the tar-
geted analogues 5 and 6 were then completed in a parallel synthe-
sis sequence (Scheme 6). First the phosphonates were each coupled
with the fully elaborated C11–C26 aldehyde 8 under modified
Still–Gennari olefination conditions,16 providing the corresponding
(Z)-enones, 19 ? 26 (65%) and 20 ? 27 (54%). DDQ-mediated oxi-
dative cleavage of the C1 and C7 PMB ethers then gave the corre-
sponding triols, 26 ? 28 and 27 ? 29. In this situation, the
4: 6-desmethyldictyostatin
Scheme 3. Completion of the synthesis of 6-desmethyldictyostatin (4).
C6–C24 region of discodermolide has previously been exploited in
the design of novel dictyostatin analogues7,8 and hybrid mole-
cules.11 In contrast, the discodermolide structure features a d-lac-
tone in the C1–C5 region, whereas the dictyostatin macrolide
differs in having a (2Z,4E)-dienoate moiety. Hence, it was proposed
to further probe the SAR associated with the unique C1–C5 region
of dictyostatin through the total synthesis of two novel reduced
analogues, 2,3-dihydrodictostatin (5) and 2,3,4,5-tetrahydrodict-
yostatin (6).
In designing a synthetic route to analogues 5 and 6, it was
apparent that removal of the dienoate negated the requirement
for the Stille coupling step and hence the presence of a vinyl iodide
in the b-ketophosphonate fragment. By retaining the Yamaguchi
macrolactonisation and Still–Gennari olefination with the pivotal
aldehyde 8, a unified route was planned to the phosphonates 19
and 20, which differed only in the presence or absence of a D4,5
olefin, as required for the construction of analogues 5 and 6,
respectively (Scheme 4). It was envisaged that the key C1–C10
-

I. Paterson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6268–6272
19 or 20 + 8
6271
TBSO
(5:1 Z:E)
K2CO3, 18-crown-6,
PhMe/HMPA
OPMB
23
TBS
O
CrO3, H2SO4,
Me2CO (88%)
TBSO
O
HO
OR
4
OH OPMB
24
1. (COCl)2, CH2Cl2
5
O
OR
26: R = PMB, Δ4,5 (65%); 27: R = PMB (54%)
28: R = H, Δ4,5 (77%); 29: R = H (84%)
(65% over 2 steps)
DDQ, CH2Cl2
2. (CF3CH2O)2P(O)CH3,
LiHMDS
CF3CH2O
CF3CH2O
P
(R)-CBS, BH3•THF, THF
TBS
O
O
O
OPMB
21
TBSO
OPMB
Grubbs II (10 mol%),
AcOH (10 mol%),
40 oC, CH2Cl2
(81% 10:1 E:Z)
OPMB
HO
OH
22
OH OH
30: Δ4,5 (95%, 88:12 dr); 31 (85%, 89:11 dr))
CF3CH2O
CF3CH2O
P
1. PPTS, (MeO)2CMe2; PPTS,
CH2Cl2/MeOH
2. TEMPO, BAIB, CH2Cl2
3. NaClO2, NaH2PO4, t-BuOH/H2O
O
O
O
OPMB
19
Raney Ni, H2, EtOH
(89%)
TBS
O
OPMB
CF3CH2O
CF3CH2O
TBSO
P
O
OPMB
HO
CO2H
20
Scheme 5. Synthesis of b-ketophosphonates 19 and 20.
O
O
32: Δ4,5 (59%); 33 (97%)
Evans–Saksena hydroxyl-directed reduction proceeded with little
or no stereocontrol. As previously observed, a switch to the CBS
(R)-oxazoboroline-mediated reduction afforded the desired 1,3-
anti diols, 28 ? 30 (95%, 88:12 dr) and 29 ? 31 (85%, 89:11 dr),
with high diastereoselectivity. The 1,3-diols were then trans-
formed into their acetonides, followed by chemoselective oxida-
tion of the primary alcohol (TEMPO/BAIB; NaClO2) to afford the
seco-acids, 30 ? 32 and 31 ? 33. Following macrolactonisation
under Yamaguchi conditions,20 global deprotection and HPLC puri-
fication afforded 2,3-dihydrodictyostatin (4, 39%) and 2,3,4,5-tetra-
hydrodictyostatin (6, 45%) in readiness for biological evaluation.
Biological evaluation. The cell growth inhibitory activities of the
dictyostatin analogues 4, 5 and 6 were evaluated in vitro relative to
Taxol (1), dictyostatin (2), and discodermolide (3) against four can-
cer cell lines: AsPC-1 (pancreatic), DLD-1 (colon), PANC-1 (pancre-
atic) and NCI/ADR-Res (Taxol-resistant ovarian) (Table 1). Drug
resistance is mediated in the NCI/ADR-Res cell line by the overex-
pression of a P-glycoprotein in the cell membrane, facilitating the
removal of the drug agent from the cell.
1. Cl3(C6H2)COCl, Et3N,
DMAP, PhMe
2. HCl, MeOH
OH
HO
O
O
OH OH
5: Δ4,5, 2,3-dihydrodictyostatin (38%)
6: 2,3,4,5-tetrahydrodictyostatin (45%)
Scheme 6. Completion of the synthesis of 2,3-dihydrodictyostatin (5) and 2,3,4,5-
tetrahydrodictyostatin (6).
Table 1
Cytotoxicity of Taxol (1), dictyostatin (2), discodermolide (3)7a and dictyostatin
analogues 4,
5 and 6 in cultured human cancer cells as determined by MTT
Gratifyingly, all three synthetic dictyostatin analogues, 4, 5 and
6, showed low nanomolar antiproliferative activity in both the Tax-
ol-sensitive and resistant cell lines. As anticipated, 6-des-
methyldictyostatin (4) proved to be the most potent of the
analogues studied, and was intermediate between dictyostatin
and discodermolide. This result is consistent with the findings of
the Curran group,8b where 6-epi-dictyostatin was found to be
essentially equipotent to dictyostatin in its antiproliferative activ-
ity against the Taxol-resistant ovarian 1A9/Ptx22 cell line. More-
over, both sets of results suggest that the C6 substituent is
located in a relatively open region of the binding site on b-tubulin,
where it forms no strong interactions.
metabolism following 72 h exposure to the test agent
Compound
IC50 (nM)a
PANC-1
AsPC-1
pancreatic
DLD-1
colon
NCI/ADR-
Res
pancreatic
1
2
3
4
5
6
89 ( 23)
6.2 ( 1.7)
98 ( 34)
56 ( 25)
94 ( 28)
120 ( 25)
22 ( 3.5)
2.2 ( 0.9)
29 ( 8)
8.1 ( 3.8)
22 ( 13)
55 ( 13)
9.9 ( 3.6)
4.2 ( 1.7)
59 ( 34)
17 ( 10)
42 ( 7)
1300 ( 345)
6.6 ( 1.0)
160 ( 34)
43 ( 13)
66 ( 11)
130 ( 66)
64 ( 33)
a Values are standard deviation (in parenthesis) from a minimum of four separate
experiments.

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I. Paterson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6268–6272
Partial saturation of the (2Z,4E)-dienoate in 2,3-dihydrodictyost-
References and notes
atin (5) was found to be well tolerated and led to low nanomolar
antiproliferative activity in both the Taxol-sensitive and resistant
cell lines, again intermediate between dictyostatin and discodermo-
lide. In comparison, 2,3,4,5-tetrahydrodictyostatin (6) showed cell
growth inhibitory activity resembling that of discodermolide. We
attribute this trend to a decreased entropic component of the bind-
ing energy as a result of the greater rotational freedom of the C1–C5
region upon saturation. As a nanomolar level of antiproliferative
activity was still observed for both these analogues, the presence
of the (2Z)-olefin or (4E)-olefin does not appear to be critical. In a
separate series of incubatory experiments performed on the
PANC-1 cell line, the three analogues 4, 5 and 6 were shown to act
in an analogous fashion to dictyostatin, through a mechanism of
microtubule stabilisation, causing both an accumulation of cells at
the G2/M phase and formation of characteristic dense intracellular
microtubule bundles.
In conclusion, we have synthesised three potent new dictyosta-
tin analogues by modification of the C2–C6 dienoate region.
Removal of the C6 methyl substituent, as in 6-desmethyldictyosta-
tin (4), and partial saturation of the (2Z,4E)-dienoate, as in
2,3-dihydrodictyostatin (5), were found to be well tolerated and
led to low nanomolar antiproliferative activity in both the Taxol-
sensitive and resistant cell lines, intermediate between dictyostatin
and discodermolide. Full saturation of the (2Z,4E)-dienoate region,
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NIH Grant No. CA-93455 provided financial support for the bio-
logical assays and general project support was provided by the
EPSRC and AstraZeneca. We thank Prof. John Leonard (AstraZeneca)
for helpful discussions, Ms. Tara Pitts and Ms. Pat Linley (HBOI) for
assisting in our biological evaluation and Dr. Stuart Mickel (Novar-
tis) for the gift of chemicals.
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hydride facilitates olefin isomerisation, preventing the metathesis proceeding.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.09.109.