Total synthesis and biological evaluation of C16 analogs of (-)-dictyostatin

Article abstract of DOI:10.1021/jm061385k

The structure-activity relationship of the crucial C16 region of (-)-dictyostatin was established through total synthesis of analogs followed by detailed biological characterization. A versatile synthetic strategy was used to prepare milligram quantities

Full text of DOI:10.1021/jm061385k

J. Med. Chem. 2007, 50, 2951-2966
2951
Total Synthesis and Biological Evaluation of C16 Analogs of (-)-Dictyostatin
Won-Hyuk Jung,† Cristian Harrison,† Youseung Shin,† Jean-Hugues Fournier,† Raghavan Balachandran,‡ Brianne S. Raccor,†
Rachel P. Sikorski,§ Andreas Vogt,§ Dennis P. Curran,*,† and Billy W. Day*,†,‡
Department of Chemistry, Department of Pharmaceutical Sciences, and Department of Pharmacology, UniVersity of Pittsburgh,
Pittsburgh, PennsylVania 15261
ReceiVed December 1, 2006
The structure-activity relationship of the crucial C16 region of (-)-dictyostatin was established through
total synthesis of analogs followed by detailed biological characterization. A versatile synthetic strategy
was used to prepare milligram quantities of 16-normethyldictyostatin, 16-epi-dictyostatin, and the C16-
normethyl-C15Z isomer. Along the way, a number of other E/Z isomers and epimers were prepared, and a
novel lactone ring contraction to make iso-dictyostatins with 20-membered macrolactones (instead of 22-
membered macrolactones) was discovered. The synthesis of 16-normethyl-15,16-dehydrodictyostatin is the
first of any dictyostatin by a maximally convergent route in which three main fragments are assembled,
coupled in back-to-back steps, and then processed through refunctionalization and macrolactonization. Cell-
based and biochemical evaluations showed 16-normethyl-15,16-dehydrodictyostatin and 16-normethyldic-
tyostatin to be the most potent of the new agents, only 2- and 5-fold less active than (-)-dictyostatin itself.
This data and that from previously generated dictyostatin analogs are combined to produce a picture of the
structure-activity relationships in this series of anticancer agents.
Introduction
The potent anticancer agent (-)-dictyostatin was discovered
over a decade ago,1 but its initial development was stifled
because the full structure was not known and because only small
quantities were available from natural sources.2 A detailed NMR
study suggested it to have the structure 1 (Figure 1),3 sharing
identical configurations at all common stereocenters with the
potent anticancer agent (+)-discodermolide 2. This assignment
was soon confirmed by back-to-back total syntheses,4 which
also provided larger quantities of the natural product for more
detailed characterization. Two additional total syntheses5 and
other studies on fragment synthesis6 testify to the continued high
level of interest in this agent.
Dictyostatin 1 has proven to be somewhat more active than
the (already very active) discodermolide, and it potently inhibits
the binding of radiolabeled paclitaxel, discodermolide, and
epothilone B to microtubules.7 It is also very active against
paclitaxel-resistant cell lines. Accordingly, (-)-dictyostatin is
Figure 1. Structures of dictyostatin 1, discodermolide 2, and key
analogs.
one of the most potent microtubule stabilizing agents discovered
to date, and an increased understanding of the structure-activity
relationship (SAR) of this class of molecules is an important
goal.
chain is important because there are many active analogs of
discodermolide with modifications in this part of the molecule,10
and indeed preliminary work has shown that both analogs and
epimers of dictyostatin in this region of the molecule can be
quite active.11
Known features of the SAR of discodermolide8 provide a
starting point for addressing the SAR of dictyostatin, and the
activities of synthetic analogs and isomers prepared during
structure assignment studies provide additional information.9
With this backdrop, we focused our work on two key portions
of the dictyostatin molecule that differ significantly from
discodermolide: (1) the bottom chain, C1-C9 region; and (2)
the isolated, methyl-bearing stereocenter at C16. The bottom
The isolated stereocenter at C16 of dictyostatin 1 is of special
interest because discodermolide 2 does not have a corresponding
stereocenter; instead, it has a C13-C14 Z-alkene. (Note that
the carbon backbone of dictyostatin is two atoms longer than
that of discodermolide, so C13 and C14 of discodermolide 2
correspond to C15 and C16 of dictyostatin 1.) The methyl group
on C14 of discodermolide 2 is not essential for biological
activity; 14-normethyldiscodermolide 3 is a highly potent
compound, as are a number of other 14-normethyl analogs.12
If the C16 methyl group of dictyostatin is dispensable, then
the synthesis of such molecules would be simpler than the parent
series because of the effort needed to install this isolated
stereocenter. To provide a detailed understanding of SAR in
* To whom correspondence should be addressed. Billy W. Day, 10017
BST3, 3501 Fifth Avenue, University of Pittsburgh, Pittsburgh, Pennsylvania
15261. Phone: 1-412-648-9706. Fax: 1-412-383-5298. E-mail: bday@
pitt.edu; Dennis P. Curran, 1101 Chevron Science Center, 219 Parkman
Avenue, University of Pittsburgh, Pittsburgh, Pennsylvania 15260. Phone:
1-412-624-8240. Fax: 412-624-9861. E-mail: curran@pitt.edu.
† Department of Chemistry.
‡ Department of Pharmaceutical Sciences.
§ Department of Pharmacology.
10.1021/jm061385k CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/02/2007

2952 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Scheme 1. Synthesis of Middle Fragment 8
Jung et al.
this key region, we undertook the syntheses and biological
characterization of 16-normethyldictyostatin 4, 16-epi-dictyo-
statin 5, and 16-normethyl-15,16-dehydrodictyostatin 6 and
report herein the full details of this work. Along the way, we
continued to refine and improve the synthesis of the dictyo-
statins. We also discovered a ring contraction following the
macrolactonization that provides new constitutional isomers
called iso-dictyostatins. The synthesis and some preliminary
biological data on the highly active 16-normethyldictyostatin 4
have been previously communicated.13 The present results show
that Z-alkene 6 is also highly active, but that the 16-R-epimer
5 has significantly reduced activity. Taken together with prior
results, these data provide an expanded understanding of the
SAR of dictyostatin.
Figure 2. Strategy for the synthesis of 16-normethyldictyostatin 4.
of alcohol 11 to the aldehyde and Corey-Fuchs dibromo-
olefination followed by BuLi-promoted conversion of the
resulting dibromoolefin into the corresponding alkyne14 supplied
the middle fragment 8 in 55% yield for the three steps.
The fragment couplings and completion of the synthesis of
4 are shown in Scheme 2. The bottom and middle fragments
were united first. To this end, the lithium acetylide of 8 was
combined with Weinreb amide 9 to give the coupled fragment
in 86% yield. Stereoselective carbonyl reduction with the (S,S)-
Noyori catalyst15 followed by Lindlar hydrogenation16 supplied
12 in 86% yield for the two steps. In preparation for the second
coupling step, the newly formed hydroxyl group was protected
as the TBS-ether and the primary TBS group was selectively
removed by using HF‚pyridine. The resulting hydroxy group
was oxidized with Dess-Martin periodinane, and the top
fragment 7 was connected by using Horner-Wadsworth-
Emmons (HWE) conditions, employing Ba(OH)2 as the base.
This fragment coupling proceeded efficiently, furnishing 13 in
85% yield over two steps.
Results and Discussion
Synthesis of 16-Normethyldictyostatin 4. The strategy for
the synthesis of 16-normethyldictyostatin 4 was patterned after
the synthesis of dictyostatin4b,9 and is summarized in Figure 2.
We made the same three primary (in red) and two secondary
(in black) disconnections to arrive at top 7, middle 8, and bottom
9 fragments. The top 7 and bottom 9 fragments are the same as
those used for dictyostatin and their syntheses are detailed
elsewhere.9
The synthesis of the middle fragment 8 is shown in Scheme
1 and departs from the prior work at the readily available
unsaturated ester 10. Conjugate reduction to the saturated ester
and then DIBALH reduction led to a primary alcohol (75%),
which was protected as the TBS-ether. Cleavage of the PMB-
ether revealed the primary hydroxy group at the other terminus
of the molecule, providing 11 in 90% yield for the two steps.
Completion of the fragment was effected by the formation of a
terminal alkyne by using established conditions. Thus, oxidation
Completion of the synthesis followed the established route.9
Conjugate reduction of 13 using a sodium borohydride/nickel-
(II) chloride reagent was followed by carbonyl reduction using
Li(t-BuO)3AlH and TBS-protection of the resulting alcohol to
give 14. A considerably greater stereoselectivity (19:1 in favor
of the desired â-alcohol) was observed compared to the
analogous step in the synthesis of (-)-dictyostatin (2.4:1). As
usual, the C19 epimers were readily separable by flash chro-
matography. The terminal diene was constructed by first opening
Scheme 2. Fragment Coupling and Completion of the Synthesis of 16-Normethyldictyostatin

Dictyostatin C-16 Analogs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2953
Scheme 3. Synthesis of Middle Fragment 18
the PMP-acetal with DIBALH to reveal the primary hydroxyl
group, which was oxidized to the corresponding aldehyde by
Dess-Martin reagent. Using Paterson’s protocol17 for Nozaki-
Hiyama-Kishi reaction, followed by Peterson elimination, the
aldehyde was reacted with 1-bromo-1-trimethylsilyl-2-propene
to provide a mixture of â-hydroxysilanes, which upon treatment
with NaH provided the Z-diene 15 in 82% yield for the three-
step sequence.
Turning to the bottom part of the molecule and the formation
of the dienoate, ZnBr2-promoted cleavage of the trityl ether of
15 was followed by oxidation of the resulting alcohol to an
aldehyde. Still-Gennari olefination18 furnished the dienoate 16
with the desired (2Z,4E)-geometry in 88% yield over two steps.
DDQ-deprotection of 16 followed by ester hydrolysis provided
the seco-acid for the Yamaguchi macrolactonization.19 Treatment
of this seco-acid with trichlorobenzoyl chloride followed by
dilute DMAP in toluene resulted in the clean formation of the
macrolactone in 76% yield. Finally, global deprotection using
3 M methanolic HCl provided the target 16-normethyldictyo-
statin 4 in 24% yield after flash chromatographic purification.20
Synthesis of 16-epi-Dictyostatin 5. The preparation of 16-
epi-dictyostatin was based on our improved synthesis of
dictyostatin as summarized in Figure 3. Here, the C23-C26
diene was already present in the top fragment 17, and this
significantly increased the convergency of the synthesis. Also
required were the usual bottom fragment 9 and the new middle
fragment 18.
Figure 3. Strategy for 16-epi-dictyostatin 5.
reagent 19 with LDA and alkylation with the iodide 20 provided
the adduct 21 in 71% yield (over two steps based on the alcohol
precursor of iodide 20). Reductive cleavage of 21 provided
1
alcohol 22. Comparison of the H NMR spectrum of 22 with
spectra of the epimer at C-169 revealed that 22 was isomerically
pure. A 7-step sequence analogous to that used in the total
synthesis of dictyostatin9 was then employed to elaborate
compound 22 into the middle fragment 18. To simplify the
selective desilylation of the C-17 alcohol in preparation for the
HWE reaction, we protected this fragment with a TES group
rather than a TBS group.
The fragment couplings and completion of the synthesis of
5 are summarized in Scheme 4. First the bottom and middle
fragments were combined by addition of the lithium acetylide
of 18 to the Weinreb amide 9. Stereoselective reduction of the
carbonyl group with the (S,S)-Noyori catalyst15 followed by
Lindlar hydrogenation16 and protection furnished 23 in 82%
yield. To prepare for the second coupling reaction, the TES
group was removed and the resulting alcohol was oxidized to
the corresponding aldehyde. HWE conditions were then em-
ployed to join the top fragment 17, thus providing the fully
coupled enone 24.
Conjugate reduction of 24 was first required to remove the
double bond resulting from the HWE reaction, but the previously
used conditions (nickel boride) were incompatible with the
diene. However, we were able to effect this transformation in
The middle fragment 18 is a diastereomer of that used to
make dictyostatin and was prepared analogously by Myers
alkylation21 as shown in Scheme 3. Deprotonation of the Myers
Scheme 4. Fragment Coupling and Completion of the Synthesis of 16-epi-Dictyostatin 5

2954 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Jung et al.
Scheme 5. Synthesis of Bottom Fragment 30
Figure 4. Key chemical shifts and three-bond HMBC correlations
(double-headed arrows) in 5 and 27.
Scheme 6. Synthesis of the Middle Fragment 29
molecules were assigned, with the exception of a few overlap-
ping resonances in the unsubstituted C17-C19 aliphatic region.
The COSY experiments were used to assign the protons from
C18 through to the diene terminus for each compound. An
HMBC experiment on 5 showed a cross-peak between H21 and
C1, thereby confirming the 22-membered lactone structure
(Figure 4).
The structure of 16-epi-isodictyostatin 27 was determined to
be that of a two-atom ring-contracted version of 16-epi-
dictyostatin, wherein the lactone was formed at C19 rather than
at the expected C21 position. The assignment was initially made
by a comparison of chemical shift data of H19 and H21 for
compounds 5 and 27; in 5, H21 is downfield of H19, but in 27,
H19 is downfield of H21. This tentative assignment was later
confirmed by observing the three-bond coupling between H19
and C1 in the HMBC spectrum of 27.
Figure 5. Strategy for the synthesis of 16-normethyl-15,16-dehyd-
rodictyostatin 6.
high yield by using 0.6 equiv of Stryker’s reagent4a,22 (3.6 equiv
of hydride) provided that slow stirring was applied and that the
quality of the reagent was high. Stereoselective carbonyl
reduction with Li(t-BuO)3AlH provided the alcohol as a 5/1
mixture of epimers in 82% yield for the two steps. Separation
of the major â-alcohol from its R-isomer by flash chromatog-
raphy, followed by protection of the hydroxyl group and removal
of the trityl group with ZnBr2 supplied compound 25 in 66%
overall yield. Slow addition of the ZnBr2 as a solution was
crucial to maintaining the integrity of the other protecting
groups. Dess-Martin oxidation of 25 followed by a Still-
Gennari modification of the HWE olefination efficiently estab-
lished the (2Z,4E)-diene methyl ester. Oxidative cleavage of
the PMB-ether and hydrolysis of the methyl ester furnished the
seco-acid. In parallel, a small sample from the PMB deprotection
but prior to the hydrolysis was desilylated as usual to provide
an open-chain pentahydroxy methyl ester called seco-5a in Table
1 below (structure not shown, see Supporting Information).
Treatment of the seco-acid precursor under Yamaguchi’s
macrolactonization conditions provided macrolactone 26 in 45%
yield for the two steps. Finally, global deprotection yielded an
approximately equimolar mixture of two compounds, 16-epi-
dictyostatin 5 (31%) and a ring-contracted isomer 27 (28%),
which were easily separable by column chromatography.
Resubmission of each of these two compounds to the depro-
tection conditions resulted in a similar mixture of the two
compounds, so we believe that this may be an equilibrium
mixture.
With a sample of pure ring-contracted lactone 27 in hand
1
and well characterized, we revisited H NMR spectra of prior
crude products from the macrolactonization/deprotection se-
quence. In the case of dictyostatin and several of its isomers,9
we were indeed able to identify small peaks in the crude spectra
that we can attribute to the analogous ring-contracted isomer;20
however, in no case was this present in the amount as high as
in the 16-epi series. Apparently, the configuration at C16 is
especially important in determining either the rate or the position
of the translactonization equilibrium. Related trans-lactoniza-
tions have been observed with other macrolactones, including
apoptolidin23 and dolabelide.24
Synthesis of 16-Normethyl-15,16-dehydrodictyostatin, 6.
Z-Alkene 6 was broken down retrosynthetically by three key
disconnections, as shown in Figure 5. As with dictyostatin, the
first two were at the lactone and the C9-C10 bonds. The final
disconnection, however, now occurred at C15-C16 by a Wittig
olefination transformation.
High-field (600 MHz) two-dimensional NMR experiments
were employed to discern the identities of the two compounds.
Through a series of 1H-COSY, HMBC, HMQC, DEPT-135, and
13C experiments, all protons and carbons in each of the two
This strategy is highly convergent because there are no
secondary disconnections at either diene, and accordingly, no

Dictyostatin C-16 Analogs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2955
Scheme 7. Synthesis of Top Fragment 28
The synthesis of middle fragment 29 is summarized in
Scheme 6. Because of the increased convergence of the plan,
the fragment couplings took place back-to-back, the middle
fragment 29 containing both coupling functionalities, the
Z-alkenyliodide and the aldehyde, in unprotected form. Oxida-
tion of known alcohol 36,26 (readily available from commercial
(S)-Roche ester) was followed by a Roush anti-crotylation
reaction27 and protection of the resulting secondary alcohol
provided TBS-ether 37 in 55% yield. Single-step osmylation
and diol-cleavage was followed by a Corey-Fuchs reaction to
generate a dibromoalkene, which was converted into a terminal
alkyne 38 with BuLi. The acetylene 38 was deprotonated, and
the resulting lithium acetylide was iodinated. cis-Reduction of
the resulting iodoacetylene using NBSH and triethylamine28
provided Z-alkenyl iodide 39 in 94% yield for the two steps.
Finally, oxidative cleavage of the PMB-ether (98%) followed
by Dess-Martin oxidation (100%) of the resulting alcohol
furnished the middle fragment 29.
The preparation of the top fragment 28 began with Evans
aldol adduct 40,26 which was converted into Weinreb amide 41
in 96% yield (Scheme 7). Addition of the alkyllithium reagent
derived from iodide 42 followed by syn-reduction of the
carbonyl group furnished diol 43 in 71% yield for the two steps.
Oxidation of the PMB-ether to the corresponding PMP-acetal
(60%) followed by protection of the remaining hydroxyl-group
with TBSOTf (99%) provided PMP-acetal 44. DIBALH reduc-
tion of the PMP-acetal furnished primary alcohol 45 in 71%
yield. Oxidation of the alcohol followed by conversion of the
resulting aldehyde to the terminal Z-diene via a two-step protocol
involving a Nozaki-Hiyama-Kishi reaction followed by a
Petersen olefination provided diene 46 in 85% yield.29 Depro-
tection of the primary hydroxyl group, iodination, and then
reaction with triphenylphosphine were employed sequentially
to provide phosphonium salt 28.
Scheme 8. Fragment Coupling En Route to 6
The fragment coupling stage of the synthesis required only
two steps, as summarized in Scheme 8. Deprotonation of salt
28 with NaHDMS followed by addition of aldehyde 29 provided
15-(Z)-alkene 47 in 82% yield. Lithium-iodine exchange with
47 followed by addition of aldehyde 30 then provided a 1.6/l
mixture of alcohols 48â/R. These C9-epimers were separated
by flash chromatography.
C-C bonds need to be formed after the fragment couplings
begin. This is the first example of such a “maximally conver-
gent” approach to dictyostatin, where the coupling of the three
main fragments is followed only by refunctionalization, mac-
rolactonization, and deprotection.
Assignment of the configuration of the newly formed
1
stereocenter (C9) was based on experimental and H NMR
similarities between this series of compounds and analogous
intermediates in the dictyostatin synthesis.30 As a representative
example, the signal for H-9 in R-TBS-ether of seco-acid 50R
(Scheme 9) is a dd at δ 4.5, with J-values of 12.4 and 7.6 Hz.
For all analogs of dictyostatin modified at the C-15 and C-16
positions, dd’s with similar chemical shifts and J-values were
observed for H-9. However, the â-alcohol of 50â (not shown)
gave rise to a signal more closely resembling a triplet at δ 4.4,
with a J-value of 8.1 Hz.
The three disconnections led to the top 28, middle 29, and
bottom 30 fragments. We incorporated the entire (23Z)-diene
into the top fragment 28. However, due to the possibility of
isomerization of the (2Z,4E)-dienoate ester in the bottom
fragment to the more stable (2E,4E)-dienoate ester, we focused
our attention on a protected precursor 30 with C1 in an alcohol
oxidation state. The synthesis of this compound is shown in
Scheme 5. The two stereocenters in 30 were established by a
Brown anti-crotylation reaction with aldehyde 31. Protection
of the resulting alcohol with TBSCl provided 32. This alkene
was subjected to Grubbs-II cross-metathesis with crotonalde-
hyde25 to cleanly furnish unsaturated aldehyde 33 in 91% yield.
Addition of the Z-alkene was carried out by the Still-Gennari
protocol to yield methyl dienoate 34 as a single isomer. Selective
cleavage of the primary TBS-ether, oxidation, and conversion
of the resulting carboxylic acid to the corresponding Weinreb
amide furnished compound 35 in 58% yield. Single-step
reduction of both the ester and the Weinreb amide functionalities
of 35 followed by TBS protection of the resulting allylic alcohol
provided the bottom fragment 30 in 96% yield.
The completion of the synthesis of analog 6 is summarized
in Scheme 9. Protection of the secondary alcohol of 48R with
TBSOTf followed by selective desilylation of the primary TBS-
ether provided alcohol 49R in 85% yield. Two-step oxidation
of 49R to the acid followed by removal of the PMB-group with
DDQ provided the requisite seco-acid 50R for the macrolac-
tonization. Treatment of 50R with trichlorobenzoyl chloride
followed by addition of dilute (0.01 M) DMAP in toluene
(Yamaguchi conditions) supplied the crude macrolactone 51R
in 71% yield. Global deprotection under acidic conditions
furnished a 14:1 mixture of dictyostatin analog 6 and its 2-E-
isomer 53 in 45% yield. These were separated by flash

2956 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Jung et al.
Scheme 9. Completion of the Syntheses of 6 and Isomers 53-55
Table 1. Biological Activities of Dictyostatin (1) and Analogs as Compared to Discodermolide 2, 14-Normethyldiscodermolide (3), and Paclitaxel
cellular
in vitro
% tubulin polymerized
MDECa for
tubulin polymer
increase, nM
( SD (N)
% inhibition of binding
of [3H]paclitaxel to
tubulin polymerd
(N g 3)
GI50,b nM (fold-resistance)
by 10 µM test agent
relative to 10 µM
paclitaxelc
(N ) 4)
test
agent
1A9
1A9/Ptx10
1A9/Ptx22
1
2
3
4
5
5.4 ( 1.9 (4)
65 ( 0 (2)
29 ( 21 (2)
25 ( 9 (3)
1278 ( 181 (3)
nd
11 ( 2 (3)
>5000 (3)
647 ( 106 (4)
>5000 (1)
>5000 (1)
5.2 ( 0.4 (4)
0.69 ( 0.80
1.7 ( 1.2
3.2 ( 2.4 (5)
1.3 ( 1.0 (2)
7.0 ( 8.4 (4)
30 ( 0 (8)
5.6 ( 4.7 (14)
543 ( 140 (9)
2600 ( 980
62 ( 5 (7)
157
148
nd
91
9
7
107
3
75 ( 5 (6)
76 ( 6 (6)
75 ( 3 (3)
48 ( 3 (3)
11 ( 3 (3)
7 ( 5 (3)
38 ( 9 (3)
4 ( 0 (3)
5 ( 2 (3)
11 ( 1 (3)
7 ( 2
6.2 ( 3.6 (4)
3.7 ( 1.5
33 ( 18 (9)
0.41 ( 0.52
61 ( 6
9140 ( 3290
8.3 ( 0.8
470 ( 70 (1146)
862 ( 1680 (14)
25920 ( 4250
942 ( 250 (113)
44190 ( 890 (6)
23680 ( 1090 (113)
19300 ( 530 (5)
32700 ( 510
seco-5e
6
27
53
54
55
paclitaxel
7800 ( 1410
210 ( 110
4260 ( 400
>50000
53760 ( 3880 (7)
847 ( 140 (4)
4600 ( 500
>50000
10
1
6
0.71 ( 0.11
64 ( 8 (90)
51 ( 9 (72)
100
a Minimum detectable effective concentration of the test agent in HeLa cells after 21 h of continuous exposure. b Fifty percent growth inhibitory concentration
after 72 h of continuous exposure to the test agent. c Bovine brain tubulin (10 µM) in 0.2 M monosodium glutamate was treated at 0 °C with the test agent
(predissolved in DMSO). The mixture was transferred to a cuvette in a 6-channel, temperature-controlled spectrophotometer, and the temperature was
rapidly raised to 30 °C. Tubulin assembly was monitored by turbidity development at 350 nm, and the percent assembly reported is relative to that caused
by 10 µM paclitaxel, analyzed in the same experiment in one of the six cuvettes, after 20 min at 30 °C. d Percent competition at 37 °C by 4 µM test agent
with 2 µM [3H]paclitaxel for binding to microtubules formed from 2 µM bovine brain tubulin and 20 µM dideoxyGTP. e The open chain methyl ester analog
of 5.
chromatography. Carrying out the same seven-step sequence
beginning with 48â provided the C-9 epimer of this analog 54
along with its ring-contracted congener 55. The structures of
these two compounds were assigned analogously to those of 5
and 27, as described above.
In total, the synthesis of the 15,16-dehydro-16-normethyl
analog of dictyostatin was carried out in nine steps, starting
from the three fragments and in 1.7% overall yield. The
synthesis also provided two new stereoisomers and a constitu-
tional isomer for SAR studies.
molide 2 and paclitaxel. Methods used are described in detail
elsewhere.9 The minimum detectable effective concentrations
(MDECs) for increases in cellular tubulin polymer mass in HeLa
cells caused by 21 h continuous exposure to the agents are given
in Table 1. Both 16-normethyl-15,16-dehydrodictyostatin 6 and
16-normethyldictyostatin 4 were effective in the low nanomolar
range, comparable to dictyostatin 1, 14-normethyldiscodermolide
3, and paclitaxel. Discodermolide 2 was slightly less active. The
fifty percent antiproliferative (growth inhibitory) concentrations
(GI50s) of the agents against human ovarian carcinoma 1A9 cells
(Table 1) were for the most part well-correlated with the MDECs
in HeLa cells: in most instances, the GI50 values were about 2-
to 7-fold lower than the MDECs. The exceptions were disco-
dermolide 2, as previously noted (30-fold lower GI50), and 16-
Biological Evaluation. Compounds 4, 5, 6, 27, and 53-55,
along with 14-normethyldiscodermolide 312a (a kind gift from
Prof. Amos B. Smith, III) were screened for cellular and
biochemical activity in comparison to dictyostatin 1, discoder-

Dictyostatin C-16 Analogs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2957
dependent ability of 16-normethyldictyostatin 4 to cause as-
sembly of bovine brain tubulin in comparison to that of 10 µM
dictyostatin 1 is shown in Figure 6. Compounds 5 and 53 were
less potent than expected based on their cell-based activities.
Finally, in good accord with the other biological and
biochemical assays, the agents effectively competed with [3H]-
paclitaxel for binding to preformed microtubules. Dictyostatin
1, discodermolide 2, and 14-normethyldiscodermolide 3 were
the most, and essentially equally, potent in this regard.
Compounds 4 and 6 had, respectively, 65 and 50% of the
potency of compounds 1-3.
Structure-Activity Relationships. The present data along
with earlier data7,9,10d,11a,11b,13 comprise extensive information
on over 20 dictyostatin analogs with a wide range of potencies,
and inspection of the data begins to reveal SAR as summarized
in Figure 7. The C16 methyl substituent, if present, must be in
the S-configuration (compare compounds 1 and 5). This
substituent is disposable (compound 4), however, and a C15:
16-(Z)-alkene without the C16 methyl group is well-tolerated
(compound 6). Also readily apparent from the present data is
the importance for C2:3-(Z)-geometry and the 22-membered
lactone (C1-C21 ester linkage). A 20-membered lactone (C1-
C19 ester linkage) ablates the desired biological actions. A
macrolactone is not an absolute necessity, though, as an open-
chain methyl ester analog with appropriate, dictyostatin-like
substituent configurations and geometries retains good potency.
Previously obtained data also clearly show that the C9 hydroxy
group must be in the S-configuration and that all but a C6,C7,-
C9 anti-syn arrangement of substituents provides extremely
good potencies. However, one of our early analogs with a
saturated C2-C9 region did retain weak biological activity.
Another finding is that the R-configuration at C19 (hydroxy
group) confers better biological activity. This appears to also
be true for the C14 methyl substituent.
Figure 6. Concentration-dependent tubulin polymerization-inducing
actions of 16-normethyldictyostatin 4 in comparison to dictyostatin 1
(see Table 1, footnote c for experimental conditions).
epi-dictyostatin 5 (20-fold lower GI50). The GI50 values
determined in the mutant â-tubulin-expressing, paclitaxel-
resistant clones of the 1A9 cells, 1A9/Ptx10 (âPhe270->Val),
and 1A9/Ptx22 (âAla364->Thr) are also given in Table 1. Most
of the compounds did not experience appreciable cross-
resistance (as compared to the parental, wild type â-tubulin-
expressing parental 1A9 cells). However, the very large cross-
resistance of the 1A9/Ptx cell lines toward compounds 4, 6,
and 53 revealed some potentially telling clues about the
orientation of the dictyostatin macrocyclic core within the taxoid
binding site. Specifically, the C-16 region of these molecules
likely interacts with or is situated near the Phe270 region of
the binding pocket of â-tubulin. In surprising contrast, 14-
normethyldiscodermolide, a direct analog of 4, experienced no
cross-resistance in this cell line, further suggesting the possibility
that the dictyostatins and discodermolides may not adopt the
same orientations within the taxoid binding site.
With isolated bovine brain tubulin at 30 °C, the test agents
were potent inducers of polymer assembly (Table 1). Their
potencies in this assay were in general accord with their MDECs
for tubulin polymer increase in cells. Dictyostatin 1 and
discodermolide 2 were the most potent and nearly equally so,
followed by analogs 6 and 4, both essentially equipotent with
paclitaxel. A representative trace showing the concentration-
Conclusions
In summary, total synthesis of multimilligram quantities of
the C16 analogs of (-)-dictyostatin was achieved via a versatile
synthetic strategy. Geometric isomerization at C2:3 alkene and
C16-epimerization were detrimental to activity, as was formation
of a 20-membered macrolactone (iso-dictyostatins). 16-Norm-
ethyldictyostatin and the C16-normethyl-C15:16-(Z)-analog had
biological activities near those of the parent compound, and their
preparation was achieved in several fewer steps than that
required for the natural product. Qualitative structure-activity
Figure 7. Qualitative structure-activity relationships in dictyostatins.

2958 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Jung et al.
1412, 1196, 1176, 837 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.33
(dd, J ) 11.3, 15.4 Hz, 1H), 6.53 (t, J ) 11.3 Hz, 1H), 5.97 (dd,
J ) 7.8, 15.4 Hz, 1H), 5.59 (d, J ) 11.3 Hz, 1H), 3.83 (dt, J )
4.5, 7.0 Hz, 1H), 3.73-3.65 (m, 5H), 2.53 (m, 1H), 2.16 (s, 1H),
1.73-1.57 (m, 2H), 1.06 (d, J ) 6.8 Hz, 3H), 0.87 (s, 9H), 0.07
(s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 147.2,
145.5, 126.8, 115.5, 73.2, 59.4, 51.0, 42.7, 36.0, 25.8, 18.0, 15.0,
relationships developed from this data and that from previously
generated dictyostatin analogs provide insight into the next
generation of targets to prepare. In agreement with recently
published modeling studies done taking into account results with
a photoaffinity analog of discodermolide,31 the sum of the
biological data place the C16 position of dictyostatin in close
proximity to Phe270 of the taxoid binding site on â-tubulin.
The fact that 14-normethyldiscodermolide, a direct analog of
16-normethyldictyostatin, does not experience the same cross-
resistance in a cell line where this residue is mutated suggests
that the dictyostatins and discodermolides may not adopt exactly
the same orientations within the taxoid binding site.
-4.4, -4.5; [R]20 -14.3 (c 0.21, CHCl3).
D
(2Z,4E,6R,7S)-Methyl 7-(tert-Butyldimethylsilyloxy)-9-(meth-
oxy(methyl)amino)-6-methyl-9-oxonona-2,4-dienoate (35). A so-
lution of the alcohol prepared above (0.52 g, 1.58 mmol) and
triethylamine (0.66 mL, 4.74 mmol) in CH2Cl2 (4 mL) and DMSO
(2 mL) at 0 °C was treated dropwise with a solution of SO3‚pyr
(0.63 g, 3.96 mmol) in DMSO (5 mL) over 2 min, and the reaction
mixture was stirred for 1 h. After quenching by addition of water
(50 mL), the mixture was extracted with EtOAc (3 × 30 mL). The
combined organic layers were washed with satd aq CuSO4 (2 ×
30 mL) and brine, dried (MgSO4), and concentrated. Purification
by column chromatography (9:1 hexanes/EtOAc) provided the
desired aldehyde (0.47 g, 91%) as a pale yellow oil, which was
used immediately in the next step: 1H NMR (300 MHz, CDCl3) δ
9.78 (dd, J ) 1.7, 2.5 Hz, 1H), 7.39 (ddd, J ) 1.1, 11.2, 15.4 Hz,
1H), 6.56 (dt, J ) 0.7, 11.3 Hz, 1H), 6.02 (dd, J ) 7.6, 15.6 Hz,
1H), 5.65 (d, J ) 11.3 Hz, 1H), 4.22 (ddd, J ) 4.0, 4.9, 6.8 Hz,
1H), 3.75 (s, 3H), 2.63-2.42 (m, 3H), 1.11 (d, J ) 6.8 Hz, 3H),
0.88 (s, 9H), 0.09 (s, 3H), 0.05 (s, 3H).
Experimental Section
The Experimental Section contains details of the synthesis of
the 16-normethyl-15,16-dehydrodictyostatin 6 and related analogs;
details for syntheses of 4, 5, and their cogeners are found in the
Supporting Information.
(2Z,4E,6R,7S)-Methyl 7,9-Bis(tert-butyldimethylsilyloxy)-6-
methylnona-2,4-dienoate (34). A mixture of the shown alkene 32
(0.046 mL, 0.112 mmol) and crotonaldehyde (0.018 mL, 0.224
mmol) in degassed CH2Cl2 (1.1 mL, argon sparged) was refluxed
for 15 min and then cooled to ambient temperature. Grubbs second
generation catalyst (0.007 g, 0.008 mmol) was added and the
mixture was refluxed at 50 °C. After 15 h, the mixture was
concentrated under vacuum. Purification by column chromatography
(4:1 hexanes/diethyl ether) provided the aldehyde 33 (0.039 g, 91%)
as a colorless oil, which was used immediately in the next step:
1H NMR (300 MHz, CDCl3) δ 9.58 (d, J ) 7.9 Hz, 1H), 6.93 (dd,
J ) 7.6, 15.8 Hz, 1H), 6.18 (dd, J ) 7.9, 15.8 Hz, 1H), 3.96 (m,
1H), 3.72 (t, J ) 5.9 Hz, 1H), 2.72 (m, 1H), 1.82-1.55 (m, 2H),
1.21 (d, J ) 6.8 Hz, 3H), 0.98 (s, 9H), 0.96 (s, 9H), 0.15 (s, 3H),
0.14 (s, 3H), 0.11 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 194.0,
160.5, 133.2, 72.4, 59.6, 42.6, 37.7, 26.1, 18.4, 18.3, 15.5, -4.2,
-4.3, -5.4.
A mixture of the aldehyde (0.43 g, 1.32 mmol) and NaH2PO4‚
H2O (1.09 g, 7.92 mmol) in t-BuOH (97 mL) and H2O (32 mL) at
0 °C was treated with a 2.0 M solution of 2-methyl-2-butene in
THF (33.0 mL, 66.00 mmol) and then NaClO4 (0.35 g, 3.96 mmol)
was added. The reaction mixture was stirred at 0 °C for 15 min
and at ambient temperature for 2 h. After quenching by addition
of a mixture of satd aq NH4Cl (20 mL) and brine (20 mL), the
mixture was extracted with diethyl ether (4 × 80 mL). The
combined organic layers were washed with brine, dried (MgSO4),
and concentrated. The carboxylic acid as a pale yellow oil was
used immediately in the next step without further purification.
A solution of the carboxylic acid (0.43 g, 1.32 mmol) in CH2-
Cl2 (8.4 mL) at 0 °C was treated with triethylamine (0.35 mL, 2.50
mmol), N,O-dimethylhydroxylamine hydrochloride (0.16 g, 1.67
mmol), and DCC (0.34 g, 1.67 mmol). The reaction mixture was
warmed to ambient temperature and stirred for 12 h. After
concentration under vacuum, purification by column chromatog-
raphy (2:1 hexanes/EtOAc) provided the target Weinreb amide 35
(0.36 g, 70% for two steps) as a colorless oil: IR (NaCl) 2955,
A mixture of bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)-
phosphonate (0.97 mL, 4.56 mmol) and 18-crown-6 (5.02 g, 19.00
mol) in THF (19 mL) at -78 °C was treated with a 0.5 M solution
of potassium bis(trimethylsilyl)amide in toluene (11.40 mL, 5.70
mmol) dropwise over 12 min. The mixture was stirred at -45 °C
for 1 h, cooled to -78 °C. A solution of the aldehyde 33 (1.47 g,
3.80 mmol) in THF (4 mL) was added. The mixture was stirred to
-78 °C for 5.5 h and warmed to ambient temperature over 30 min.
After quenching by addition of satd aq NH4Cl (50 mL), the mixture
was extracted with EtOAc (3 × 50 mL) and the combined organic
layers were washed with brine, dried (MgSO4), and concentrated.
Purification by column chromatography (19:1 hexanes/EtOAc)
provided the dienoate 34 (1.68 g, 100%) as a colorless oil: IR
1
2895, 2856, 1721, 1666, 1439, 1196, 836 cm-1; H NMR (300
MHz, CDCl3) δ 7.38 (dd, J ) 11.2, 15.4 Hz, 1H), 6.57 (t, J )
11.3 Hz, 1H), 6.09 (dd, J ) 8.0, 15.4 Hz, 1H), 5.60 (d, J ) 11.3
Hz, 1H), 4.29 (ddd, J ) 3.2, 5.1, 7.4 Hz, 1H), 3.72 (s, 3H), 3.65
(s, 3H), 3.17 (s, 3H), 2.68-2.48 (m, 2H), 2.33 (dd, J ) 5.2, 15.4
Hz, 1H), 1.13 (d, J ) 6.8 Hz, 3H), 0.88 (s, 9H), 0.09 (s, 3H), 0.03
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.6, 167.1, 146.7, 145.6,
127.6, 115.9, 72.6, 61.5, 51.3, 43.4, 37.1, 26.1, 18.3, 15.8, -4.2,
-4.6; LRMS (ESI) 408 [M + Na]+; HRMS (ESI) calcd for C19H35-
1
(NaCl) 2954, 2857, 1721, 1175, 1097, 835, 775 cm-1; H NMR
(300 MHz, CDCl3) δ 7.23 (ddd, J ) 0.9, 11.3, 15.4 Hz, 1H), 6.44
(t, J ) 11.2 Hz, 1H), 5.93 (dd, J ) 7.9, 15.3 Hz, 1H), 5.46 (d, J
) 11.3 Hz, 1H), 3.69 (m, 1H), 3.60 (s, 1H), 3.52 (dt, J ) 2.0, 6.5
Hz, 1H), 2.37 (m, 1H), 1.56-1.39 (m, 3H), 0.96 (d, J ) 6.8 Hz,
3H), 0.80-0.74 (m, 18H), -0.06 (s, 6H), -0.08 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 167.1, 147.6, 145.8, 127.1, 115.6, 72.6, 60.0,
51.2, 42.9, 37.4, 26.1, 18.5, 18.3, 15.7, -4.1, -5.0; [R]20D -6.6 (c
0.36, CHCl3).
(2Z,4E,6R,7S)-Methyl 7-(tert-Butyldimethylsilyloxy)-9-hydroxy-
6-methylnona-2,4-dienoate. A solution of the TBS ether 34 (0.80
g, 1.75 mmol) in THF (9 mL) at 0 °C was treated with a solution
of HF‚pyr in pyr/THF (39 mL, prepared by slow dropwise addition
of HF‚pyr (3 mL) to a solution of pyridine (12 mL) and THF (24
mL)). The reaction mixture was warmed to ambient temperature
and stirred for 8 h. After quenching by addition of satd aq NaHCO3,
the mixture was extracted with EtOAc (4 × 40 mL). The combined
organic layers were washed with satd aq CuSO4 (3 × 30 mL) and
brine, dried (MgSO4), and concentrated. Purification by column
chromatography (2:1 hexanes/EtOAc) provided the target alcohol
(0.54 g, 92%) as a colorless oil: IR (NaCl) 3428, 2953, 2857, 1719,
NO5SiNa [M + Na]+, 408.2182; found, 408.2177; [R]20 -53.6
D
(c 0.33, CHCl3).
(2S,3S,4S)-1-(4-Methoxybenzyloxy)-2,4-dimethylhex-5-en-3-
ol. A solution of the alcohol 36 (4.20 g, 20.0 mmol) and
diisopropylethylamine (9.90 mL, 60.0 mmol) in CH2Cl2 (200 mL)
and DMSO (40 mL) at 0 °C was treated dropwise with a solution
of SO3‚pyr (9.74 g, 60.0 mmol) in DMSO (60 mL) over 20 min.
The reaction mixture was stirred for 1 h. After quenching by
addition of H2O (200 mL), the mixture was extracted with EtOAc
(3 × 100 mL). The combined organic layers were washed with
satd aq CuSO4 (2 × 50 mL) and brine and dried (MgSO4). The
concentration under vacuum provided the aldehyde as a colorless
oil, which was used immediately in the next step without further
purification.
A 1.0 M solution of (R,R)-diisopropyl tartrate (E)-crotylboronate
in toluene (28.16 mL, 28.16 mmol) was added to a slurry of
powdered 4 Å molecular sieves (0.8 g) in toluene (17 mL) at

Dictyostatin C-16 Analogs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2959
ambient temperature. After 20 min, the mixture was cooled to -78
°C, then a solution of the aldehyde (4.20 g, 20.0 mmol) in toluene
(17 mL) was added via cannula over 50 min. After 8 h, the reaction
mixture was quenched by 1 M NaOH (60 mL), stirred vigorously
for 30 min, and extracted with diethyl ether (3 × 50 mL). The
combined organic layers were washed with brine, dried (MgSO4),
and concentrated. Purification by column chromatography (4:1
hexanes/EtOAc) provided the alcohol (3.54 g, 67% for two steps)
as a colorless oil: IR (NaCl) 3479, 2966, 2932, 1613, 1513, 1248,
SiBr2Na [M + Na]+, 557.0698; found, 557.0715; [R]20 +3.7 (c
D
0.27, CHCl3).
((2S,3S,4S)-1-(4-Methoxybenzyloxy)-2,4-dimethylhex-5-yn-3-
yloxy)(tert-butyl)dimethylsilane (38). A solution of the dibro-
moolefin prepared above (6.43 g, 12.00 mmol) in THF (60 mL) at
-78 °C was treated dropwise with a 1.6 M solution of BuLi in
hexane (18.75 mL, 30.00 mmol) over 10 min. After 30 min, an
additional solution of BuLi (9.3 mL, 14.88 mmol) was added and
the mixture was stirred for 2.5 h. After quenching by the addition
of satd aq NH4Cl (50 mL) at -78 °C, the mixture was extracted
with EtOAc (3 × 50 mL) and the combined organic layers were
washed with brine, dried (MgSO4), and concentrated. Purification
by column chromatography (19:1 hexanes/EtOAc) provided the
terminal alkyne 38 (4.36 g, 96%) as a colorless oil: IR (NaCl)
1
1036 cm-1; H NMR (300 MHz, CDCl3) δ 7.25 (d, J ) 8.5 Hz,
2H), 6.87 (d, J ) 8.5 Hz, 2H), 5.80 (ddd, J ) 8.4, 10.2, 17.1 Hz,
1H), 5.17-5.06 (m, 2H), 4.45 (s, 2H), 3.80 (s, 3H), 3.58-3.43
(m, 3H), 2.28 (m, 1H), 1.97 (m, 1H), 0.98 (d, J ) 6.8 Hz, 3H),
0.94 (d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.5,
142.1, 130.7, 129.4, 115.8, 114.1, 75.9, 74.7, 73.2, 55.5, 42.1, 35.4,
1
3309, 2955, 2930, 2856, 1513, 1249, 1055, 836 cm-1; H NMR
16.9, 10.2; [R]20 -2.4 (c 1.08, CHCl3).
D
(300 MHz, CDCl3) δ 7.28 (d, J ) 8.7 Hz, 2H), 6.89 (d, J ) 8.7
Hz, 2H), 4.42 (s, 2H), 3.81 (s, 3H), 3.79 (dd, J ) 3.3, 5.1 Hz, 1H),
3.45 (dd, J ) 6.8, 9.2 Hz, 1H), 3.29 (dd, J ) 6.6, 9.2 Hz, 1H),
2.62 (m, 1H), 2.21 (m, 1H), 2.04 (d, J ) 2.5 Hz, 1H), 1.20 (d, J )
7.1 Hz, 3H), 0.98-0.89 (m, 12H), 0.09 (s, 3H), 0.05 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 159.2, 130.9, 129.3, 113.8, 87.4, 74.5,
73.2, 72.5, 70.1, 55.3, 37.0, 31.7, 26.2, 18.5, 17.5, 12.2, -3.7, -4.0;
LRMS (ESI) 399 [M + Na]+; HRMS (ESI) calcd for C22H36O3-
SiNa [M + Na]+, 399.2331; found, 399.2336; [R]20D +2.2 (c 0.23,
CHCl3).
((2S,3S,4S)-1-(4-Methoxybenzyloxy)-2,4-dimethylhex-5-en-3-
yloxy)(tert-butyl)dimethylsilane (37). A solution of the alcohol
prepared above (3.50 g, 13.2 mmol) and 2,6-lutidine (4.0 mL, 17.2
mmol) in CH2Cl2 (130 mL) at -78 °C was treated with TBSOTf
(4.6 mL, 39.6 mmol). The reaction mixture was stirred for 1 h and
warmed to 0 °C over 30 min. After quenching by addition of satd
aq NaHCO3 (75 mL), the mixture was extracted with CH2Cl2 (3 ×
75 mL) and the combined organic layers were washed with brine,
dried (MgSO4), and concentrated. Purification by column chroma-
tography (19:1 hexanes/EtOAc) provided the TBS-ether 37 (4.07
g, 82%) as a colorless oil: IR (NaCl) 2957, 2929, 2856, 1513,
((2S,3S,4S)-1-(4-Methoxybenzyloxy)-6-iodo-2,4-dimethylhex-
5-yn-3-yloxy)(tert-butyl)dimethylsilane. A solution of the alkyne
38 (3.50 g, 9.29 mmol) in THF (46 mL) at -50 °C was treated
dropwise with a 1.6 M solution of BuLi in hexane (7.00 mL, 11.15
mmol) over 7 min. After 1 h, a solution of I2 (4.00 g, 15.79 mmol)
in THF (4 mL) was added. The mixture was stirred for 20 min and
warmed to ambient temperature over 30 min. After quenching by
the addition of a mixture of satd aq Na2S2O3 (25 mL) and brine
(25 mL), the mixture was extracted with EtOAc (3 × 50 mL) and
the combined organic layers were washed with brine, dried
(MgSO4), and concentrated. Purification by column chromatography
(19:1 hexanes/EtOAc) provided the iodoalkyne (4.60 g, 99%) as a
colorless oil: IR (NaCl) 2930, 2881, 2855, 1612, 1513, 1462, 1248,
1
1249, 1039, 836 cm-1; H NMR (300 MHz, CDCl3) δ 7.27 (d, J
) 7.6 Hz, 2H), 6.89 (d, J ) 8.5 Hz, 2H), 5.86 (ddd, J ) 7.7, 10.2,
17.8 Hz, 1H), 5.01-4.94 (m, 2H), 4.43 (d, J ) 11.5 Hz, 1H), 4.38
(d, J ) 11.5 Hz, 1H), 3.81 (s, 3H), 3.65 (dd, J ) 3.4, 4.6 Hz, 1H),
3.37 (dd, J ) 6.6, 9.0 Hz, 1H), 3.22 (dd, J ) 6.8, 8.8 Hz, 1H),
2.35 (m, 1H), 1.94 (m, 1H), 1.01 (d, J ) 6.9 Hz, 3H), 0.91-0.89
(m, 12H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 159.1, 142.0, 130.9, 129.2, 114.1, 113.8, 76.0, 73.4, 72.5, 55.3,
42.9, 37.2, 26.2, 18.5, 17.4, 12.4, -3.5, -3.9; LRMS (ESI) 401
[M + Na]+; HRMS (ESI) calcd for C22H38O3SiNa, 401.2488 [M
+ Na]+; found, 401.2481; [R]20 -5.0 (c 0.20, CHCl3).
D
((2S,3S,4S)-1-(4-Methoxybenzyloxy)-6,6-dibromo-2,4-dimeth-
ylhex-5-en-3-yloxy)(tert-butyl)dimethylsilane. A solution of the
alkene 37 (4.00 g, 10.56 mmol) in dioxane (75 mL) and H2O (25
mL) at ambient temperature was treated with 2,6-lutidine (2.5 mL,
21.12 mmol), OsO4 (2.5% in 2-methyl-2-propanol, 2.2 mL, 0.02
mmol), and NaIO4 (9.00 g, 42.24 mmol). After 5 h, additional OsO4
(2.5% in 2-methyl-2-propanol, 1.1 mL, 0.01 mmol) was added and
the mixture was stirred for 1 h. After quenching by the addition of
satd aq Na2S2O3 (50 mL), the mixture was extracted with CH2Cl2
(3 × 50 mL) and the combined organic layers were washed with
brine, dried (MgSO4), and concentrated. The aldehyde as a pale
yellow oil was used immediately in the next step without further
purification.
1
1062, 837 cm-1; H NMR (300 MHz, CDCl3) δ 7.28 (d, J ) 8.4
Hz, 2H), 6.90 (d, J ) 8.5 Hz, 2H), 4.42 (s, 2H), 3.81 (s, 3H), 3.75
(dd, J ) 3.0, 5.5 Hz, 1H), 3.43 (dd, J ) 7.0, 9.0 Hz, 1H), 3.26 (dd,
J ) 6.6, 9.0 Hz, 1H), 2.76 (m, 1H), 2.04 (m, 1H), 1.18 (d, J ) 7.1
Hz, 3H), 0.93-0.85 (m, 12H), 0.09 (s, 3H), 0.04 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 159.2, 130.8, 129.3, 113.8, 97.8, 74.8, 73.0,
72.5, 55.3, 36.9, 34.0, 26.2, 18.5, 17.7, 11.7, -3.7, -4.0, -4.4;
LRMS (EI) 445 (M - tert-Bu)+; HRMS (EI) calcd for C18H26O3-
SiI (M - tert-Bu)+, 445.0696; found, 445.0672; [R]20 -3.3
D
(c 0.42, CHCl3).
((2S,3S,4S,Z)-1-(4-Methoxy)benzyloxy)-6-iodo-2,4-dimethyl-
hex-5-en-3-yloxy)(tert-butyl)dimethylsilane (39). A solution of the
iodoalkyne prepared above (3.50 g, 9.29 mmol) in THF (20 mL)
and i-PrOH (20 mL) at ambient temperature was treated with
triethylamine (1.70 mL, 12.21 mmol) and o-nitrobenzenesulfonyl
hydrazide (2.30 g, 10.58 mmol). After 12 h, additional triethylamine
(0.79 mL, 5.69 mmol) and o-nitrobenzenesulfonylhydrazide (1.06
g, 4.88 mmol) were added and the mixture was stirred for 12 h.
After quenching by the addition of H2O (50 mL), the mixture was
extracted with EtOAc (3 × 50 mL) and the combined organic layers
were washed with brine, dried (MgSO4), and concentrated. Purifica-
tion by column chromatography (19:1 hexanes/EtOAc) provided
the Z-iodoalkene 39 (3.90 g, 95%) as a colorless oil: IR (NaCl)
2955, 2929, 2855, 1513, 1249, 1039, 837, 773 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.27 (d, J ) 8.4 Hz, 2H), 6.87 (d, J ) 8.6 Hz,
2H), 6.24 (dd, J ) 7.3, 8.8 Hz, 1H), 6.13 (d, J ) 7.3 Hz, 1H), 4.61
(s, 2H), 3.81 (s, 3H), 3.74 (t, J ) 3.8 Hz, 1H), 3.40 (dd, J ) 5.8,
9.0 Hz, 1H), 3.21 (dd, J ) 7.1, 9.0 Hz, 1H), 2.69 (m, 1H), 1.90
(m, 1H), 1.00 (d, J ) 7.0 Hz, 3H), 0.94 (d, J ) 6.9 Hz, 3H), 0.90
(s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
159.2, 144.0, 130.9, 129.3, 113.8, 81.8, 76.0, 72.7, 55.3, 43.8, 38.9,
26.3, 18.5, 17.7, 13.4, -3.5, -3.7; LRMS (EI) 447 (M - tert-
A solution of PPh3 (11.08 g, 42.24 mmol) in CH2Cl2 (35 mL) at
0 °C was treated with CBr4 (7.00 g, 21.12 mmol) portionwise over
7 min. After 10 min, 2,6-lutidine (6.1 mL, 52.80 mmol) was added
and the mixture was stirred for 10 min. A solution of the aldehyde
in CH2Cl2 (20 mL) was added and the mixture was stirred for 1 h.
After quenching by the addition of satd aq NH4Cl (50 mL), the
mixture was extracted with CH2Cl2 (2 × 50 mL) and the combined
organic layers were washed with brine, dried (MgSO4), and
concentrated. Purification by column chromatography (19:1
hexanes/EtOAc) provided the dibromoolefin (4.20 g, 74% for two
steps) as a colorless oil: IR (NaCl) 2955, 2930, 2856, 1513, 1249,
1
1038, 838 cm-1; H NMR (300 MHz, CDCl3) δ 7.27 (d, J ) 8.5
Hz, 2H), 6.90 (d, J ) 8.6 Hz, 2H), 6.4 (d, J ) 9.5 Hz, 1H), 4.44
(d, J ) 11.6 Hz, 1H), 4.39 (d, J ) 11.6 Hz, 1H), 3.81 (s, 3H), 3.69
(t, J ) 3.9 Hz, 1H), 3.38 (dd, J ) 6.1, 8.9 Hz, 1H), 3.21 (dd, J )
7.0, 8.9 Hz, 1H), 2.62 (m, 1H), 1.89 (m, 1H), 1.00 (d, J ) 7.0 Hz,
3H), 0.93-0.90 (m, 12H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 159.2, 141.7, 130.7, 129.4, 113.8, 88.0, 75.8,
72.7, 72.4, 55.4, 42.6, 38.5, 26.2, 26.1, 18.4, 17.2, 12.5, -3.7, -3.8;
LRMS (ESI) 559 [M + Na]+; HRMS (ESI) calcd for C22H36O3-

2960 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Jung et al.
Bu)+; HRMS (EI) calcd, 447.0853 (M - tert-Bu)+; found,
(m, 3H), 3.57 (dd, J ) 4.6, 9.1 Hz, 1H), 3.48 (t, J ) 8.6 Hz, 1H),
1.99 (m, 1H), 1.65-1.53 (m, 5H), 0.91 (d, J ) 7.0 Hz, 3H), 0.89
(s, 9H), 0.77 (d, J ) 6.9 Hz, 3H), 0.05 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 159.6, 130.1, 129.5, 114.1, 81.9, 76.8, 76.0, 73.4, 63.6,
55.4, 38.5, 36.3, 32.1, 29.9, 26.2, 18.5, 13.5, 4.6, -5.0; LRMS
(ESI) 463 [M + Na]+; HRMS (ESI) calcd for C24H44O5SiNa [M
+ Na]+, 463.2856; found, 463.2851; [R]20D +17.7 (c 0.18, CHCl3).
(2S,3R)-6-(tert-Butyldimethylsilyloxy)-2-((2S,4S,5S)-2-(4-meth-
oxyphenyl)-5-methyl-1,3-dioxan-4-yl)hexan-3-ol. A solution of
the diol 43 (3.48 g, 7.93 mmol) in CH2Cl2 (136 mL) was treated
with 4 Å molecular sieves (3.00 g). After 20 min, the mixture was
cooled to 0 °C and DDQ (3.09 g, 13.62 mmol) was added in three
portions over 3 min. The reaction mixture was stirred for 1.5 h,
warmed to ambient temperature over 30 min, and then filtered
through Celite. Satd aq NaHCO3 (100 mL) was added, the mixture
was extracted with CH2Cl2 (2 × 100 mL), and the combined organic
layers were washed with satd aq NaHCO3 (2 × 100 mL), dried
(MgSO4), and concentrated. Purification by column chromatography
(5:1 hexanes/EtOAc) provided the PMB acetal (3.47 g, 60%) as a
colorless oil: IR (NaCl) 3535, 2954, 2929, 2855, 1518, 1251, 1100,
447.0851; [R]20 +32.4 (c 0.61, CHCl3).
D
(2S,3S,4S,Z)-3-(tert-Butyldimethylsilyloxy)-6-iodo-2,4-dimeth-
ylhex-5-en-1-ol. A mixture of the PMB ether 39 (1.5 g, 2.97 mmol)
in CH2Cl2 (60 mL) and H2O (4 mL) at 0 °C was treated with DDQ
(0.81 g, 3.56 mmol). After 25 min, additional DDQ (0.24 g, 1.48
mmol) was added and the mixture was stirred for 15 min. After
quenching by the addition of satd aq NaHCO3 (50 mL), the mixture
was extracted with EtOAc (3 × 50 mL) and the combined organic
layers were washed with satd aq NaHCO3 and brine, dried (MgSO4),
and concentrated. The residue was diluted with CH2Cl2 (15 mL)
and MeOH (1.5 mL). The mixture was cooled to 0 °C and NaBH4
(0.11 g, 2.97 mmol) was added. After 30 min, satd aq NH4Cl (50
mL) was added, the mixture was extracted with EtOAc (3 × 50
mL), and the combined organic layers were washed with brine,
dried (MgSO4), and concentrated. Purification by column chroma-
tography (4:1 hexanes/EtOAc) provided the alcohol (1.13 g, 98%)
as a colorless oil: IR (NaCl) 3353, 2956, 2929, 2856, 1471, 1461,
1
1256, 1024, 837, 773 cm-1; H NMR (300 MHz, CDCl3) δ 6.37
(dd, J ) 7.4, 9.0 Hz, 1H), 6.18 (d, J ) 7.3 Hz, 1H), 3.76 (t, J )
3.4 Hz, 1H), 3.68 (m, 1H), 3.46 (m, 1H), 2.75 (m, 1H), 2.05-1.88
(m, 2H), 1.05 (d, J ) 7.0 Hz, 3H), 0.96-0.87 (m, 12H), 0.12 (s,
3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 143.5, 81.9, 77.5,
65.4, 42.6, 40.9, 26.1, 18.3, 18.2, 13.1, -3.8, -3.9; LRMS (EI)
327 (M - tert-Bu)+; HRMS (EI) calcd for C10H20IO2Si (M - tert-
1
834 cm-1; H NMR (300 MHz, CDCl3) δ 7.37 (d, J ) 8.7 Hz,
2H), 6.98 (d, J ) 8.7 Hz, 2H), 5.50 (s, 1H), 4.12 (dd, J ) 4.7, 11.2
Hz, 1H), 3.87 (m, 1H), 3.79 (s, 3H), 3.69 (dd, J ) 2.1, 9.9, 2H),
3.65 (m, 1H), 3.52 (t, J ) 11.1 Hz, 1H), 3.24 (s, 1H), 2.12 (m,
1H), 1.80 (tq, J ) 1.8, 7.1 Hz, 1H), 1.67-1.49 (m, 4H), 1.04 (d,
J ) 7.1 Hz, 3H), 0.90 (s, 9H), 0.77 (d, J ) 6.7 Hz, 3H), 0.06 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 160.0, 131.1, 127.5, 113.9,
101.4, 88.7, 76.2, 73.4, 63.5, 55.5, 37.8, 31.6, 30.7, 29.7, 26.2, 18.6,
12.2, 6.3, -4.9; LRMS (ESI) 461 [M + Na]+; HRMS (ESI) calcd
Bu)+, 327.0277; found, 327.0286; [R]20 +2.3 (c 0.57, CHCl3).
D
(5R,6S,7S)-8-(4-Methoxybenzyloxy)-1-(tert-butyldimethylsily-
loxy)-6-hydroxy-5,7-dimethyloctan-4-one. A solution of tert-butyl-
(3-iodopropoxy)dimethylsilane 42 (8.53 g, 28.38 mmol) in diethyl
ether (240 mL) at -78 °C was treated dropwise with a 1.7 M
solution of tert-BuLi in pentane (35.6 mL, 60.54 mmol) over 30
min. After 15 min, a solution of the Weinreb amide 41 (3.08 g,
9.46 mmol) in diethyl ether (20 mL) was added dropwise over 15
min. The mixture was stirred at -78 °C for 1 h and at -40 °C for
2.5 h. After quenching at -78 °C by the addition of a satd aq NH4-
Cl (50 mL), the mixture was extracted with diethyl ether (3 × 50
mL) and the combined organic layers were washed with brine, dried
(MgSO4), and concentrated. Purification by column chromatography
(2:1 hexanes/diethyl ether) provided the ketone (3.48 g, 84%) as a
colorless oil: IR (NaCl) 3480, 2955, 2930, 2856, 1705, 1613, 1249,
for C24H42O5SiNa [M + Na]+, 461.2699; found, 461.2673; [R]20
+38.6 (c 0.15, CHCl3).
D
(2S,4S,5S)-4-((2R,3R)-3,6-Bis(tert-butyldimethylsilyloxy)hexan-
2-yl)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxane (44). A solution
of the PMB acetal (3.47 g, 7.91 mmol) and 2,6-lutidine (2.80 mL,
23.73 mmol) in CH2Cl2 (79 mL) at -78 °C was treated with
TBSOTf (2.40 mL, 10.28 mmol). The reaction mixture was stirred
for 1 h and warmed to 0 °C over 30 min. After quenching by the
addition of satd aq NaHCO3 (50 mL), the mixture was extracted
with CH2Cl2 (3 × 50 mL) and the combined organic layers were
washed with brine, dried (MgSO4), and concentrated. Purification
by column chromatography (9:1 hexanes/EtOAc) provided the target
TBS ether 44 (4.32 g, 99%) as a colorless oil: IR (NaCl) 2954,
2929, 2856, 1518, 1462, 1251, 1038, 835, 774 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.40 (d, J ) 8.7 Hz, 2H), 6.90 (d, J ) 8.7 Hz,
2H), 5.43 (s, 1H), 4.11 (dd, J ) 4.6, 11.1 Hz, 1H), 3.81 (s, 3H),
3.74 (m, 1H), 3.69 (dd, J ) 1.4, 10.1, 2H), 3.60 (m, 1H), 3.51 (t,
J ) 11.1 Hz, 1H), 3.24 (s, 1H), 2.05 (m, 1H), 1.80 (dqn, J ) 1.2,
7.0 Hz, 1H), 1.60 (m, 4H), 1.03 (d, J ) 7.0 Hz, 3H), 0.92 (s, 9H),
0.90 (s, 9H), 0.76 (d, J ) 6.7 Hz, 3H), 0.06 (d, J ) 2.7 Hz, 6H),
0.04 (d, J ) 1.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 159.8,
131.7, 127.3, 113.5, 100.7, 81.9, 74.4, 73.4, 63.6, 55.3, 38.8, 30.8,
29.8, 28.3, 26.1, 18.4, 18.2, 12.4, 10.7, -4.1 -4.2, -5.1 -5.2;
LRMS (ESI) 575 [M + Na]+; HRMS (ESI) calcd for C30H56O5-
1
1094, 835 cm-1; H NMR (300 MHz, CDCl3) δ 7.26 (d, J ) 8.5
Hz, 2H), 6.88 (d, J ) 8.5 Hz, 2H), 4.43 (s, 2H), 3.89 (dd, J ) 8.4,
3.3 Hz, 1H), 3.79 (s, 3H), 3.60 (t, J ) 6.1 Hz, 3H), 3.55 (m, 2H),
2.64 (m, 1H), 2.60 (t, J ) 7.2 Hz, 2H), 1.91 (m, 1H), 1.82 (qn, J
) 6.8 Hz, 2H), 1.13 (d, J ) 7.0 Hz, 3H), 0.90 (d, J ) 4.5 Hz, 3H),
0.88 (s, 9H), 0.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 214.6,
159.5, 130.3, 129.6, 114.1, 75.3, 74.5, 73.4, 62.4, 55.5, 49.0, 37.5,
36.2, 27.0 26.2, 18.5, 14.2, 9.4, -5.0; LRMS (ESI) 461 [M + Na]+;
HRMS (ESI) calcd for C24H42O5SiNa [M + Na]+, 461.2699; found,
461.2671; [R]20 +22.5 (c 0.08, CHCl3).
D
(2S,3S,4S,5R)-1-(4-Methoxybenzyloxy)-8-(tert-butyldimethyl-
silyloxy)-2,4-dimethyloctane-3,5-diol (43). A solution of the ketone
prepared above (3.48 g, 7.93 mmol) in THF (79 mL) and MeOH
(20 mL) at -78 °C was treated dropwise with a 1.0 M solution of
Et2BOMe in THF (12.7 mL, 12.69 mmol) over 10 min. After 30
min, NaBH4 (0.36 g, 9.52 mmol) was added in three portions over
10 min. The mixture was stirred at -78 °C for 7 h and quenched
by the dropwise addition of acetic acid (7 mL). Water (80 mL)
was added, the mixture was extracted with CH2Cl2 (3 × 50 mL),
and the combined organic layers were washed with NaOH (1.0 M,
100 mL), dried (MgSO4), and concentrated. The residue was taken
up in a 1.0 M solution of NaOAc in MeOH (360 mL) and H2O (40
mL) and then 30% H2O2 (30 mL) was added. After stirring at
ambient temperature for 1 h, the mixture was concentrated, then
diluted with H2O (50 mL), extracted with CH2Cl2 (4 × 50 mL),
dried (MgSO4), and concentrated. Purification by column chroma-
tography (1:1 hexanes/diethyl ether) provided the target diol 43
(2.95 g, 85%) as a colorless oil: IR (NaCl) 3440, 2953, 2930, 2856,
1513, 1463, 1249, 1096, 835 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.25 (d, J ) 8.5 Hz, 2H), 6.89 (d, J ) 8.6 Hz, 2H), 4.46 (s, 2H),
4.41 (s, 1H), 4.06 (s, 1H), 3.84 (m, 1H), 3.80 (s, 3H), 3.71-3.64
Si2Na [M + Na]+, 575.3564; found, 575.3616; [R]20 +26.2 (c
D
0.16, CHCl3).
(2S,3S,4R,5R)-3-(4-Methoxybenzyloxy)-5,8-bis(tert-butyldim-
ethylsilyloxy)-2,4-dimethyloctan-1-ol (45). A solution of the PMB
acetal 44 (3.70 g, 6.69 mmol) in CH2Cl2 (33 mL) at -78 °C was
treated dropwise with a 1.0 M solution of diisobutylaluminum
hydride in hexane (66.9 mL, 66.9 mmol) over 30 min, and the
reaction mixture was stirred at -45 °C for 12 h. After quenching
by the addition of satd aq potassium sodium tartrate (130 mL), the
mixture was stirred at ambient temperature for 1 h and extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were
washed with brine, dried (MgSO4), and concentrated. Purification
by column chromatography (4:1 hexanes/EtOAc) provided the
alcohol 45 (1.49 g, 41%) as a colorless oil and the corresponding
more polar bis-primary diol (1.57 g, 55%) as a colorless oil: IR
(NaCl) 3434, 2954, 2929, 2856, 1514, 1250, 1036, 835, 773 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.28 (d, J ) 8.7 Hz, 2H), 6.89 (d,
J ) 8.7 Hz, 2H), 4.52 (s, 2H), 3.82 (dd, J ) 3.4, 11.0 Hz, 1H),

Dictyostatin C-16 Analogs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2961
3.80 (s, 3H), 3.68 (m, 1H), 3.61-3.56 (m, 3H), 3.47 (dd, J ) 4.7,
6.3 Hz, 1H), 2.65 (s, 1H), 1.95 (m,1H), 1.88 (m, 1H), 1.59 (m,
2H), 1.48 (m, 2H), 1.11 (d, J ) 7.0 Hz, 3H), 1.02 (d, J ) 6.9 Hz,
3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H), 0.05 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 159.5, 130.8, 129.5, 114.1,
86.0, 75.4, 73.6, 65.6, 63.4, 55.5, 40.9, 37.4, 31.1, 28.9, 26.2, 18.5,
18.4, 15.9, 10.4, -3.5, -4.1, -5.0; LRMS (ESI) 577 [M + Na]+;
HRMS (ESI) calcd for C30H58O5Si2Na [M + Na]+, 557.3721; found,
was extracted with EtOAc (4 × 80 mL). The combined organic
layers were washed with satd aq CuSO4 (3 × 50 mL) and brine,
dried (MgSO4), and concentrated. Purification by column chroma-
tography (4:1 hexanes/EtOAc) provided the target primary alcohol
(1.20 g, 75%) as a colorless oil: IR (NaCl) 3366, 2954, 2929, 1514,
1
1249, 1038, 835 cm-1; H NMR (300 MHz, CDCl3) δ 7.27 (d, J
) 8.5 Hz, 2H), 6.86 (d, J ) 8.6 Hz, 2H), 6.60 (dt, J ) 10.3, 16.8
Hz, 1H), 6.01 (t, J ) 11.0 Hz, 1H), 5.56 (t, J ) 10.5 Hz, 1H), 5.21
(d, J ) 16.8 Hz, 1H), 5.11 (d, J ) 10.1 Hz, 1H), 4.57 (d, J ) 10.6
Hz, 1H), 4.46 (d, J ) 10.6 Hz, 1H), 3.78 (s, 3H), 3.66 (m, 1H),
3.55 (t, J ) 6.4 Hz, 2H), 3.33 (dd, J ) 3.9, 7.0 Hz, 1H), 2.99 (m,
1H), 1.71 (m, 1H), 1.50 (m, 2H), 1.41 (m, 2H), 1.09 (d, J ) 6.8
Hz, 3H), 0.96 (d, J ) 6.8 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.06
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.3, 135.1, 132.7, 131.6,
129.4, 129.2, 117.6, 113.9, 84.2, 75.1, 72.7, 63.2, 55.5, 40.7, 35.6,
31.4, 28.8, 26.2, 19.0, 18.4, 9.8, -3.4, -4.1; LRMS (ESI) 485 [M
+ Na]+; HRMS (ESI) calcd for C27H46O4SiNa [M + Na]+,
557.3687; [R]20 +3.5 (c 0.17, CHCl3).
D
Conversion of Diol to 45. A solution of the diol resulting from
the reduction of the PMB acetal above (1.57 g, 3.68 mmol) and
imidazole (0.38, 5.52 mmol) in CH2Cl2 (37 mL) was treated with
a solution of TBSCl (0.57 g, 0.57 mmol) in CH2Cl2 (18 mL) at
-78 °C. The reaction mixture was warmed to 0 °C over 3 h and
then additional imidazole (0.38, 5.52 mmol) and TBSCl (0.57 g,
0.57 mmol) were added. The mixture was stirred at -25 °C for 2
h and at ambient temperature for 1.5 h. After concentration in
vacuum, purification by column chromatography (4:1 hexanes/
EtOAc) provided 45 (1.09 g, 55%), which was identified by TLC
485.3063; found, 485.3071; [R]20 +38.6 (c 0.07, CHCl3).
D
((4R,5R,6S,7S,Z)-6-(4-Methoxybenzyloxy)-1-iodo-5,7-dimethy-
lundeca-8,10-dien-4-yloxy)(tert-butyl)dimethylsilane. A solution
of the alcohol prepared above (1.10 g, 2.38 mmol) in benzene (15
mL) and diethyl ether (30 mL) at ambient temperature was treated
with triphenylphosphine (0.93 g, 3.56 mmol) and imidazole (0.24
g, 3.56 mmol). Then iodine (0.90 g, 3.56 mmol) was added to the
vigorously stirred mixture portionwise over 10 min. After 30 min,
the mixture was diluted with EtOAc (50 mL), quenched with satd
aq Na2S2O3 (50 mL), and extracted with EtOAc (3 × 50 mL). The
combined organic layers were washed with satd aq Na2S2O3 and
brine, dried (MgSO4), and concentrated. Purification by column
chromatography (19:1 hexanes/EtOAc) provided the desired primary
iodide (1.26 g, 93%) as a colorless oil: IR (NaCl) 2955, 2928,
1
and H NMR comparison to the above sample.
1-(((5S,6S,7R,8R,Z)-8,11-Bis(tert-butyldimethylsilyloxy)-5,7-
dimethylundeca-1,3-dien-6-yloxy)methyl)-4-methoxybenzene (46).
A solution of the alcohol 45 (2.10 g, 3.78 mmol) and triethylamine
(1.60 mL, 11.34 mmol) in CH2Cl2 (8 mL) and DMSO (6 mL) at 0
°C was treated dropwise with a solution of SO3‚pyr (1.50 g, 9.45
mmol) in DMSO (9.5 mL) over 10 min. The reaction mixture was
stirred for 1 h. After quenching by the addition of H2O (80 mL),
the mixture was extracted with EtOAc (3 × 50 mL). The combined
organic layers were washed with brine, dried (MgSO4), and
concentrated. The aldehyde as a colorless oil was used immediately
in the next step without further purification.
A suspension of CrCl2 (5.11 g, 41.58 mmol) in THF (42 mL) at
ambient temperature was treated with a solution of the aldehyde
and 1-bromoallyltrimethylsilane (4.38 g, 22.68 mmol) in THF (19
mL) via cannula, and the mixture was stirred for 17 h. After
quenching by the addition of pH 7 phosphate buffer (250 mL), the
mixture was extracted with diethyl ether (3 × 150 mL). The
combined organic layers were washed with brine, dried (MgSO4),
and concentrated. The alcohol as a pale blue oil was used
immediately in the next step without further purification.
1
1514, 1249, 835 cm-1; H NMR (300 MHz, CDCl3) δ 7.30 (d, J
) 8.4 Hz, 2H), 6.89 (d, J ) 8.5 Hz, 2H), 6.60 (dt, J ) 10.4, 16.9
Hz, 1H), 6.04 (t, J ) 11.0 Hz, 1H), 5.58 (t, J ) 10.5 Hz, 1H), 5.25
(d, J ) 16.8 Hz, 1H), 5.16 (d, J ) 10.0 Hz, 1H), 4.60 (d, J ) 10.5
Hz, 1H), 4.51 (d, J ) 10.5 Hz, 1H), 3.81 (s, 3H), 3.67 (m, 1H),
3.36 (dd, J ) 3.6, 7.2 Hz, 1H), 3.11 (t, J ) 6.3 Hz, 2H), 2.99 (m,
1H), 1.66 (m, 3H), 1.58 (m, 2H), 1.12 (d, J ) 6.8 Hz, 3H), 0.99
(d, J ) 6.8 Hz, 3H), 0.94 (s, 9H), 0.01 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 159.3, 134.9, 132.5, 131.5, 129.4, 129.3, 117.9, 114.0,
84.1, 75.1, 71.9, 55.5, 40.9, 35.8, 35.6, 29.6, 26.2, 19.0, 18.4, 9.8,
7.4, -3.4, -4.1; LRMS (EI) 515 (M - tert-Bu)+; HRMS (EI) calcd
A solution of the alcohol in THF (95 mL) at 0 °C was treated
with NaH (95 wt %, 1.91 g, 75.60 mmol) in three portions over 3
min. The mixture was stirred at 0 °C for 15 min and at ambient
temperature for 1 h. After quenching by the addition of water (100
mL), the mixture was extracted with diethyl ether (3 × 100 mL).
The combined organic layers were washed with brine, dried
(MgSO4), and concentrated. Purification by column chromatography
(19:1 hexanes/EtOAc) provided the terminal diene 46 (1.85 g, 85%
for three steps) as a colorless oil: IR (NaCl) 2955, 2929, 2856,
1514, 1249, 1085, 835, 773 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.29 (d, J ) 8.8 Hz, 2H), 6.88 (d, J ) 8.6 Hz, 2H), 6.61 (dt, J )
10.6, 16.6 Hz, 1H), 6.01 (t, J ) 11.0 Hz, 1H), 5.58 (t, J ) 10.7
Hz, 1H), 5.21 (d, J ) 16.9 Hz, 1H), 5.12 (d, J ) 10.1 Hz, 1H),
4.57 (d, J ) 10.5 Hz, 1H), 4.50(d, J ) 10.5 Hz, 1H), 3.80 (s, 3H),
3.65 (m, 1H), 3.53 (dt, J ) 1.7, 6.2 Hz, 2H), 3.34 (dd, J ) 3.4, 7.6
Hz, 1H), 2.98 (m, 1H), 1.67 (m, 1H), 1.52 (m, 2H), 1.36 (m, 2H),
1.11 (d, J ) 6.8 Hz, 3H), 0.97 (d, J ) 6.8 Hz, 3H), 0.92 (s, 9H),
0.88 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H), 0.05 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 159.3, 134.9, 132.6, 131.7, 129.4, 129.2, 117.5,
113.9, 84.5, 75.2, 72.8, 63.4, 55.5, 40.8, 35.6, 31.5, 28.9, 26.3, 26.2,
19.0, 18.5, 18.4, 9.5, -3.4, -4.2, -4.9; LRMS (ESI) 599 [M +
Na]+; HRMS (ESI) calcd for C33H60O4Si2Na [M + Na]+, 599.3928;
for C23H36IO3Si (M - tert-Bu)+, 515.1479; found, 515.1481; [R]20
+24.6 (c 0.15, CHCl3).
D
((4R,5R,6S,7S,Z)-6-(4-Methoxybenzyloxy)-4-(tert-butyldimeth-
ylsilyloxy)-5,7-dimethylundeca-8,10-dienyl)triphenylphospho-
nium Iodide (28). A solution of the iodide prepared above (1.26
g, 2.20 mmol) in benzene (8 mL) at ambient temperature was treated
with triphenylphosphine (2.97 g, 11.0 mmol). The mixture was
heated at 80 °C for 16 h in the dark. After concentration under
vacuum, purification by column chromatography (19:1 CH2Cl2/
MeOH) provided the phosphonium salt 28 (1.42 g, 78%) as a white
solid: IR (NaCl) 2955, 2928, 2855, 1513, 1438, 1248, 1112 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.86-7.73 (m, 15H), 7.29 (d, J )
8.4 Hz, 2H), 6.87 (d, J ) 8.3 Hz, 2H), 6.59 (dt, J ) 10.6, 16.8 Hz,
1H), 5.91 (t, J ) 10.9 Hz, 1H), 5.60 (t, J ) 10.4 Hz, 1H), 5.06 (d,
J ) 15.8 Hz, 1H), 5.01 (d, J ) 9.4 Hz, 1H), 4.64 (d, J ) 11.0 Hz,
1H), 4.47 (d, J ) 11.0 Hz, 1H), 3.78 (s, 3H), 3.68 (dd, J ) 7.2,
12.2 Hz, 1H), 3.59 (q, J ) 5.0 Hz, 1H), 3.47 (t, J ) 5.0 Hz, 1H),
3.39 (dd, J ) 7.2, 12.5 Hz, 1H), 2.95 (m, 1H), 1.96 (m, 1H), 1.77
(m, 1H), 1.58 (m, 3H), 1.03 (d, J ) 6.7 Hz, 3H), 0.93 (d, J ) 6.6
Hz, 3H), 0.83 (s, 9H), 0.04 (s, 3H), -0.04 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.1, 135.8, 135.5, 135.4, 133.9, 133.8, 132.6,
131.8, 130.9, 130.7, 129.4, 128.9, 128.5, 118.8, 117.7, 117.5, 113.9,
83.4, 74.6, 72.6, 55.6, 40.5, 36.0, 35.6, 35.4, 26.2, 23.9, 23.3, 18.7,
18.5, 18.3, 10.2, -3.5, -4.1; LRMS (ESI) 707 M+; HRMS (ESI)
found, 599.3958; [R]20 +2.2 (c 0.10, CHCl3).
D
(4R,5R,6S,7S,Z)-6-(4-Methoxybenzyloxy)-4-(tert-butyldimeth-
ylsilyloxy)-5,7-dimethylundeca-8,10-dien-1-ol. A solution of the
TBS ether 46 (3.70 g, 6.69 mmol) in THF (34 mL) at 0 °C was
treated dropwise with a solution of HF‚pyr in pyr/THF (78 mL,
prepared by slow addition of HF‚pyr (6 mL) to a solution of
pyridine (24 mL) and THF (48 mL)), and the reaction mixture was
stirred at 0 °C for 1 h and at ambient temperature for 5 h. After
quenching by the addition of satd aq NaHCO3 (150 mL), the mixture
calcd for C45H60O3PSi M+, 707.4049; found, 707.4058; [R]20
+23.3 (c 2.7, CHCl3).
D
1-(((3Z,5S,6S,7R,8R,11Z,13S,14R,15S,16Z)-8,14-Bis(tert-bu-
tyldimethylsilyloxy)-17-iodo-5,7,13,15-tetramethylheptadeca-
1,3,11,16-tetraen-6-yloxy)methyl)-4-methoxybenzene (47). A so-

2962 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Jung et al.
lution of the alcohol prepared above (0.38 g, 1.00 mmol) in CH2Cl2
(10 mL) at 0 °C was treated with Dess-Martin periodinane (0.57
g, 1.30 mmol). The mixture was warmed to ambient temperature
and stirred for 1 h. After quenching by the addition of a mixture of
satd aq Na2S2O3 (10 mL) and satd aq NaHCO3 (10 mL), the mixture
was extracted with EtOAc (3 × 20 mL) and the combined organic
layers were washed with satd aq NaHCO3 (2 × 20 mL) and brine
and dried (MgSO4). The concentration under vacuum provided the
aldehyde 29 as a coloress oil, which used immediately in the next
step without further purification.
A solution of the vinyl iodide 47 (0.76 g, 0.94 mmol) in diethyl
ether (47 mL) at -78 °C was treated dropwise with a 1.7 M solution
of tert-BuLi in pentane (1.26 mL, 2.13 mmol) over 5 min. After
15 min, a solution of the aldehyde 30 (0.37 g, 0.88 mmol) in diethyl
ether (12 mL) was added via cannula over 10 min. The mixture
was warmed to -10 °C over 1 h. After quenching at -10 °C by
the addition of a satd aq NH4Cl (30 mL), the mixture was extracted
with diethyl ether (3 × 30 mL) and the combined organic layers
were washed with brine, dried (MgSO4), and concentrated. The
residue was diluted with CH2Cl2 (10 mL) and MeOH (1 mL). The
mixture was cooled to 0 °C and NaBH4 (0.10 g, 2.64 mmol) was
added. After 30 min, satd aq NH4Cl (30 mL) was added, the mixture
was extracted with diethyl ether (3 × 30 mL), and the combined
organic layers were washed with brine, dried (MgSO4), and
concentrated. Purification by column chromatography (15:1 hex-
anes/ EtOAc) provided the desired R-alcohol 48R (0.26 g, 27%)
as a colorless oil and the less polar C9 â-epimer 48â (0.42 g, 43%)
as a colorless oil: IR (NaCl) 3493, 2956, 2929, 2856, 1514, 1471,
A solution of the phosphonium salt 28 (0.64 g, 0.77 mmol, dried
azeotropically with benzene and at 40 °C for 1 h under vacuum) in
THF (2 mL) at 0 °C was treated dropwise with a 1.0 M solution of
sodium bis(trimethylsilyl)amide in THF (0.71 mL, 0.71 mmol) over
5 min. The mixture was warmed to ambient temperature and stirred
for 45 min. The mixture was cooled to -78 °C, and a solution of
the aldehyde 29 (0.38 g, 1.00 mmol) in THF (2 mL) was added
via cannula over 5 min. The mixture was warmed to ambient
temperature and stirred for 4 h. After quenching by the addition of
satd aq NH4Cl (30 mL), the mixture was extracted with EtOAc (3
× 30 mL) and the combined organic layers were washed with brine,
dried (MgSO4), and concentrated. Purification by column chroma-
tography (19:1 hexanes/EtOAc) provided the coupled Z-alkene 47
(0.47 g, 82%) as a colorless oil: IR (NaCl) 2956, 2929, 2856, 1514,
1461, 1250, 1078, 1038, 836, 773 cm-1; 1H NMR (500 MHz, C6D6)
δ 7.31 (d, J ) 8.5 Hz, 2H), 6.82 (d, J ) 8.6 Hz, 2H), 6.75 (dt, J
) 10.4, 16.7 Hz, 1H), 6.30 (t, J ) 7.7 Hz, 1H), 6.08 (t, J ) 11.0
Hz, 1H), 6.00 (d, J ) 7.3 Hz, 1H), 5.76 (t, J ) 10.7 Hz, 1H), 5.41
(dt, J ) 7.0, 10.7 Hz, 1H), 5.20 (t, J ) 10.3 Hz, 1H), 5.18 (d, J )
18.0 Hz, 1H), 5.11 (d, J ) 10.1 Hz, 1H), 4.57 (q, J ) 10.6 Hz,
2H), 3.84 (m, 1H), 3.49 (dd, J ) 3.6, 7.0 Hz, 1H), 3.38 (dd, J )
2.5, 7.8 Hz, 1H), 3.30 (s, 3H), 3.15 (m, 1H), 2.84 (m, 1H), 2.62
(m, 1H), 2.13 (m, 1H), 2.06 (m, 1H), 1.93 (m, 1H), 1.81 (m, 1H),
1.66 (m, 1H), 1.24-1.17 (m, 7 H), 1.07 (d, J ) 6.9 Hz, 3H), 1.05
(s, 9H), 1.03 (d, J ) 7.1 Hz, 3H), 0.99 (s, 9H), 0.15 (s, 3H) 0.14
(s, 3H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 159.3, 143.6,
134.9, 133.3, 132.7, 131.6, 129.5, 129.3, 129.1, 117.6, 114.0, 84.4,
82.2, 79.9, 75.3, 73.0, 55.5, 44.5, 41.0, 37.4, 35.7, 35.6, 26.6, 26.3,
24.1, 19.1, 18.7, 18.6, 18.5, 17.2, 9.8, -3.0, -3.1, -3.3, -3.9;
LRMS (ESI) 833 [M + Na]+; HRMS (ESI) calcd for C41H71IO4-
1
1462, 1251, 903, 807, 774 cm-1; H NMR (300 MHz, CDCl3) δ
7.28 (m, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 6.60 (dt, J ) 11.1, 16.7
Hz, 1H), 6.27 (dd, J ) 11.0, 15.0 Hz, 1H), 6.02 (t, J ) 11.2 Hz,
1H), 5.98 (t, J ) 11.1 Hz, 1H), 5.64-5.48 (m, 3H), 5.44 (dt, J )
6.4, 10.9 Hz, 1H), 5.34 (dd, J ) 8.4, 11.0 Hz, 1H), 5.24-5.15 (m,
3H), 5.10 (d, J ) 10.2 Hz, 1H), 4.59 (m, 1H), 4.55 (d, J ) 10.5
Hz, 1H), 4.48 (d, J ) 10.5 Hz, 1H), 4.34 (d, J ) 6.3 Hz, 1H),
3.89-3.75 (m, 4H), 3.65 (m, 1H), 3.37-3.26 (m, 2H), 2.99 (m,
1H), 2.68 (m, 1H), 2.58-2.40 (m, 3H), 1.95-1.62 (m, 4H), 1.53
(m, 1H), 1.45 (m, 1H), 1.11 (d, J ) 6.8 Hz, 3H), 1.00 (d, J ) 6.9
Hz, 3H), 0.98 (d, J ) 8.0 Hz, 3H), 0.95 (d, J ) 7.0 Hz, 3H), 0.94-
0.85 (m, 39H), 0.13-0.03 (m, 24H); 13C NMR (75 MHz, CDCl3)
δ 159.3, 138.6, 134.8, 134.5, 134.1, 132.6, 132.5, 131.6, 129.6,
129.4, 129.3, 128.5, 125.6, 117.6, 113.9, 84.4, 80.5, 75.3, 73.6,
72.8, 65.0, 60.0, 55.5, 42.8, 40.8, 39.8, 37.0, 36.3, 35.6, 35.5, 26.5,
26.3, 26.2, 23.8, 19.8, 19.0, 18.7, 18.4, 18.3, 17.2, 15.1, 9.6, -2.9,
-3.2, -3.4, -4.1, -4.2, -4.8; LRMS (ESI) 1119 [M + Na]+;
HRMS (ESI) calcd for C63H116O7Si4Na [M + Na]+, 1119.7696;
found, 1119.7727; [R]20 +42.0 (c 0.94, CHCl3).
D
48â: IR (NaCl) 3385, 2956, 2929, 2856, 1514, 1462, 1251, 1082,
836, 774 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.27 (m, 2H), 6.87
(d, J ) 8.5 Hz, 2H), 6.58 (dt, J ) 10.5, 16.8 Hz, 1H), 6.27 (dd, J
) 11.2, 14.9 Hz, 1H), 6.01 (t, J ) 11.3 Hz, 1H), 5.97 (t, J ) 11.1
Hz, 1H), 5.64 (dd, J ) 7.8, 15.1 Hz, 1H), 5.57 (t, J ) 10.5 Hz,
1H), 5.50-5.32 (m, 3H), 5.28-5.16 (m, 3H), 5.11 (d, J ) 10.0
Hz, 1H), 4.55 (d, J ) 10.5 Hz, 1H), 4.47 (d, J ) 10.5 Hz, 1H),
4.43-4.25 (m, 3H), 3.87-3.72 (m, 4H), 3.66 (m, 1H), 3.37-3.25
(m, 2H), 2.99 (m, 1H), 2.62 (m, 1H), 2.56-2.38 (m, 2H), 2.01 (m,
1H), 1.98-1.73 (m, 2H), 1.72-1.60 (m, 2H), 1.48-1.37 (m, 2H),
1.10 (d, J ) 6.7 Hz, 3H), 1.04 (d, J ) 6.7 Hz, 3H), 0.96 (d, J )
6.8 Hz, 3H), 0.96-0.83 (m, 42H), 0.11-0.00 (m, 24H); 13C NMR
(75 MHz, CDCl3) δ 159.3, 137.9, 134.9, 134.2, 134.1, 133.3, 132.6,
131.6, 129.6, 129.5, 129.4, 129.3, 128.7, 125.8, 117.6, 114.0, 84.4,
80.5, 75.2, 74.5, 72.9, 66.1, 60.0, 55.5, 42.3, 41.3, 40.8, 37.4, 36.6,
35.7, 35.5, 35.0, 34.1, 26.6, 26.3, 26.2, 25.9, 23.9, 19.1, 19.0, 18.7,
18.5, 18.3, 17.8, 15.8, 9.7, -2.7, -3.3, -3.4, -4.0, -4.1, -4.7;
LRMS (ESI) 1119 [M + Na]+; HRMS (ESI) calcd for C63H116O7-
Si4Na [M + Na]+, 1119.7696; found, 1119.7708; [R]20D +38.4 (c
0.19, CHCl3).
(2Z,4E,6R,7S,9S,10Z,12S,13R,14S,15Z,19R,20R,21S,22S,23Z)-
21-(4-Methoxybenzyloxy)-7,9,13,19-tetrakis(tert-butyldimethyl-
silyloxy)-6,12,14,20,22-pentamethylhexacosa-2,4,10,15,23,25-
hexaen-1-ol (49R). A solution of the alcohol 48R (0.26 g, 0.24
mmol) and 2,6-lutidine (0.083 mL, 0.71 mmol) in CH2Cl2 (4.7 mL)
at -78 °C was treated with TBSOTf (0.082 mL, 0.36 mmol). The
reaction mixture was stirred for 1 h and warmed to 0 °C over 30
min. After quenching by the addition of satd aq NaHCO3 (5 mL),
the mixture was extracted with CH2Cl2 (3 × 5 mL) and the
combined organic layers were washed with brine, dried (MgSO4),
and concentrated to provide the desired TBS ether (0.29 g, 100%)
as a colorless oil, which was used in the next step without further
purification: IR (NaCl) 2956, 2929, 2857, 1471, 1462, 1252, 1171,
836, 774 cm-1; 1H NMR (300 MHz, C6D6) δ 7.32 (d, J ) 8.4 Hz,
Si2Na [M + Na]+, 833.3833; found, 833.3850; [R]20 +117.8 (c
D
0.09, CHCl3).
(2Z,4E,6R,7S,9S,10Z,12S,13R,14S,15Z,19R,20R,21S,22S,23Z)-
21-(4-Methoxybenzyloxy)-1,7,13,19-tetrakis(tert-butyldimethyl-
silyloxy)-6,12,14,20,22-pentamethylhexacosa-2,4,10,15,23,25-
hexaen-9-ol (48R). A solution of the Weinreb amide 35 (0.37 g,
0.96 mmol) in THF (5 mL) at -78 °C was treated dropwise with
a 1.0 M solution of diisobutylaluminum hydride in hexane (3.16
mL, 3.16 mmol) over 3 min, and the reaction mixture was warmed
to ambient temperature over 1 h. After quenching by the addition
of satd aq potassium sodium tartrate (7 mL), the mixture was stirred
for 1 h at ambient temperature and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were washed with brine, dried
(MgSO4), and concentrated. The alcohol as a pale yellow oil was
used immediately in the next step without further purification.
A solution of the alcohol and 2,6-lutidine (0.34 mL, 2.88 mmol)
in CH2Cl2 (10 mL) at -78 °C was treated with TBSOTf (0.28 mL,
1.25 mmol). The reaction mixture was stirred for 1 h. After
quenching by the addition of satd aq NaHCO3 (10 mL) at -78 °C,
the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with brine, dried (MgSO4), and
concentrated. Purification by column chromatography (4:1 hexanes/
EtOAc) provided the aldehyde 30 (0.38 g, 95%) as a colorless
oil, which was used immediately in the next step: 1H NMR (300
MHz, CDCl3) δ 9.77 (dd, J ) 1.8, 2.6 Hz, 1H), 6.28 (dd, J )
11.0, 15.1 Hz, 1H), 5.97 (t, J ) 11.0 Hz, 1H), 5.59 (dd, J ) 7.9,
15.2 Hz, 1H), 5.54 (dt, J ) 6.3, 10.9 Hz, 1H), 4.32 (dd, J ) 1.5,
6.4 Hz, 1H), 4.17 (ddd, J ) 4.3, 5.0, 6.7 Hz, 1H), 2.58-2.38 (m,
3H), 1.05 (d, J ) 6.9 Hz, 3H), 0.91-0.86 (m, 18H), 0.09-0.04
(m, 12H).

Dictyostatin C-16 Analogs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2963
2H), 6.96-6.70 (m, 3H), 6.50 (dd, J ) 11.0, 15.4 Hz, 1H), 6.12 (t,
J ) 11.0 Hz, 1H), 6.05 (t, J ) 11.2 Hz, 1H), 5.83-5.69 (m, 2H),
5.67-5.42 (m, 6H), 5.23 (d, J ) 16.9 Hz, 1H), 5.13 (d, J ) 10.4
Hz, 1H), 4.77 (t, J ) 7.6 Hz, 1H), 4.59 (d, J ) 10.6 Hz, 1H), 4.54
(d, J ) 10.6 Hz, 1H), 4.40 (d, J ) 6.3 Hz, 1H), 4.16 (m, 1H), 3.87
(m, 1H), 3.54-3.42 (m, 2H), 3.32 (s, 3H), 3.15 (m, 1H), 2.92-
2.74 (m, 2H), 2.60 (m, 1H), 2.29-1.87 (m, 3H), 1.86-1.53 (m
4H), 1.27-1.14 (m, 12H), 1.12-0.97 (m, 48H), 0.29-0.06 (m,
30H); 13C NMR (75 MHz, CDCl3) δ 159.3, 138.5, 134.8, 134.2,
133.9, 132.6, 132.1, 131.6, 129.6, 129.5, 129.3, 129.1, 128.5, 125.4,
117.6, 113.9, 84.5, 80.7, 75.3, 72.7, 72.6, 66.9, 60.0, 55.5, 43.4,
42.2, 40.8, 36.7, 36.1, 35.6, 35.5, 26.6, 26.3, 26.2, 26.0, 23.8, 19.1,
18.9, 18.7, 18.6, 18.5, 18.4, 17.1, 14.4, 9.6, -2.6, -2.7, -2.8, -3.3,
-3.4, -3.7, -3.9, -4.0, -4.1, -4.7, -4.9; LRMS (ESI) 1233 [M
+ Na]+; HRMS (ESI) calcd for C69H130O7Si5Na [M + Na]+,
mmol) and then NaClO4 (68 mg, 0.60 mmol) was added. The
reaction mixture was stirred at 0 °C for 15 min and at ambient
temperature for 2 h. After quenching by the addition of a mixture
of satd aq NH4Cl (5 mL) and brine (5 mL), the mixture was
extracted with diethyl ether (4 × 20 mL). The combined organic
layers were washed with brine, dried (MgSO4), and concentrated.
The carboxylic acid as a pale yellow oil was used immediately in
the next step without further purification: IR (NaCl) 2956, 2856,
1693, 1471, 1462, 1250, 1039, 835, 773 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.32 (dd, J ) 11.5, 15.2 Hz, 1H), 7.28 (d, J ) 8.5 Hz,
2H), 6.85 (d, J ) 8.5 Hz, 2H), 6.62 (t, J ) 11.4 Hz, 1H), 6.58 (dt,
J ) 10.6, 16.9 Hz, 1H), 6.03 (dd, J ) 7.2, 15.9 Hz, 1H), 5.99 (t,
J ) 11.0 Hz, 1H), 6.02 (t, J ) 11.2 Hz, 1H), 5.58 (d, J ) 11.1 Hz,
1H), 5.55 (t, J ) 10.6 Hz, 1H), 5.43-5.31 (m, 2H), 5.29-5.15
(m, 3H), 5.10 (d, J ) 10.3 Hz, 1H), 4.56 (d, J ) 10.6 Hz, 1H),
4.52-4.43 (m, 2H), 3.91(m, 1H), 3.79 (s, 3H), 3.65 (m, 1H), 3.35
(dd, J ) 3.2, 7.9 Hz, 1H), 3.28 (t, J ) 4.6 Hz, 1H), 2.98 (m, 1H),
2.61-2.42 (m, 3H), 1.85 (m, 1H), 1.79-1.63 (m, 2H), 1.60-1.36
(m 4H), 1.08 (d, J ) 6.8 Hz, 3H), 1.02 (t, J ) 6.7 Hz, 6H), 0.99-
0.77 (m, 42H), 0.12-0.00 (m, 24H); 13C NMR (125 MHz, CDCl3)
δ 170.9, 159.0, 148.1, 147.1, 134.2, 133.7, 133.4, 132.1, 131.5,
130.9, 129.3, 128.9, 128.1, 126.9, 117.3, 115.1, 113.6, 84.2, 80.3,
74.9, 72.2, 71.9, 66.4, 55.1, 43.3, 42.2, 40.2, 36.3, 35.8, 35.1, 29.6,
26.1, 25.8, 23.4, 18.6, 18.3, 18.0, 17.0, 13.4, 9.1, -3.2, -3.7, -4.2,
-4.5, -4.6; LRMS (ESI) 1133 [M + Na]+; HRMS (ESI) calcd
for C63H114O8Si4Na [M + Na]+, 1133.7489; found, 1133.7568;
1233.8561; found, 1233.8673; [R]20 +17.0 (c 0.20, CHCl3).
D
A solution of the TBS ether (0.29 g, 0.24 mmol) in THF (1 mL)
at 0 °C was treated dropwise with a solution of HF‚pyr in pyr/
THF (8 mL, prepared by slow addition of HF‚pyr (0.6 mL) to a
solution of pyridine (2.4 mL) and THF (4.8 mL)). The reaction
mixture was warmed to ambient temperature and stirred for 8 h.
After quenching by addition of satd aq NaHCO3, the mixture was
extracted with EtOAc (4 × 10 mL). The combined organic layers
were washed with satd aq CuSO4 (3 × 6 mL) and brine, dried
(MgSO4), and concentrated. Purification by column chromatography
(19:1 hexanes/EtOAc) provided the target allylic alcohol 49R (0.22
g, 85%) as a colorless oil: IR (NaCl) 3422, 2955, 1613, 1514,
1462, 1250, 1039, 835, 773, 735 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.29 (d, J ) 8.5 Hz, 2H), 6.88 (d, J ) 8.6 Hz, 2H), 6.60 (dt, J
) 10.6, 16.8 Hz, 1H), 6.30 (dd, J ) 11.1, 14.9 Hz, 1H), 6.06 (t, J
) 11.3 Hz, 1H), 6.02 (t, J ) 11.2 Hz, 1H), 5.67 (dd, J ) 7.0, 15.1
Hz, 1H), 5.58 (t, J ) 10.9 Hz, 1H), 5.50 (dt, J ) 7.0, 10.7 Hz,
1H), 5.39 (t, J ) 11.0 Hz, 1H), 5.34-5.16 (m, 4H), 5.12 (d, J )
10.1 Hz, 1H), 4.58-4.44 (m, 3H), 4.28 (dd, J ) 2.4, 6.7 Hz, 2H),
3.91(m, 1H), 3.81 (s, 3H), 3.67 (m, 1H), 3.42-3.26 (m, 2H), 3.01
(m, 1H), 2.68-2.36 (m, 3H), 1.95-1.64 (m, 3H), 1.60-1.31 (m
4H), 1.12 (d, J ) 6.7 Hz, 3H), 1.04-0.82 (m, 48H), 0.15-0.02
(m, 24H); 13C NMR (75 MHz, CDCl3) δ 158.9, 139.1, 134.3, 133.7,
133.5, 132.1, 131.4, 131.2, 131.1, 129.1, 128.9, 128.1, 127.4, 124.5,
117.3, 113.6, 84.1, 80.3, 75.0, 72.2, 72.1, 66.4, 58.7, 55.1, 42.9,
41.8, 40.3, 36.1, 35.8, 35.1, 26.1, 25.8, 23.4, 18.6, 18.4, 18.0, 17.0,
13.4, 9.1, -3.0, -3.2, -3.7, -4.1, -4.3, -4.4, -4.5; LRMS (ESI)
1119 [M + Na]+; HRMS (ESI) calcd for C63H116O7Si4Na [M +
[R]20 +15.9 (c 0.27, CHCl3).
D
(2Z,4E,6R,7S,9S,10Z,12S,13R,14S,15Z,19R,20R,21S,22S,23Z)-
7,9,13,19-Tetrakis(tert-butyldimethylsilyloxy)-21-hydroxy-6,12,-
14,20,22-pentamethylhexacosa-2,4,10,15,23,25-hexaenoic Acid
(50R). A mixture of the PMB-ether prepared above in CH2Cl2 (20
mL) and H2O (2 mL) at 0 °C was treated with DDQ (0.81 g, 3.56
mmol). After 25 min, additional DDQ (0.136 g, 0.60 mmol) was
added and the mixture was stirred for 15 min. After quenching by
the addition of satd aq NaHCO3 (20 mL), the mixture was extracted
with EtOAc (3 × 20 mL) and the combined organic layers were
washed with satd aq NaHCO3 and brine, dried (MgSO4), and
concentrated. Purification by column chromatography (two col-
umns: 95:1 MeOH/ CH2Cl2, then 4:1 hexanes/EtOAc) provided
the seco-acid 50R (0.062 g, 31% for three steps) as a colorless oil,
which was used immediately in the next step: 1H NMR (300 MHz,
CDCl3) δ 7.35 (dd, J ) 11.3, 15.2 Hz, 1H), 6.72-6.53 (m, 2H),
6.10 (t, J ) 11.0 Hz, 1H), 6.03 (dd, J ) 6.9, 15.5 Hz, 1H), 5.60 (d,
J ) 11.4 Hz, 1H), 5.47-5.36 (m, 2H), 5.34-5.17 (m, 4H), 5.13
(d, J ) 10.1 Hz, 1H), 4.56 (d, J ) 10.6 Hz, 1H), 4.48 (m, 1H),
3.93 (m, 1H), 3.77 (m, 1H), 3.49 (dd, J ) 3.5, 7.0 Hz, 1H), 3.32
(dd, J ) 4.1, 5.5 Hz, 1H), 2.83 (m, 1H), 2.65-2.45 (m, 3H), 2.08-
1.80 (m, 2H), 1.78-1.35 (m, 5H), 1.08-0.82 (m, 51H), 0.12-
0.02 (m, 24H).
(3Z,5E,7R,8S,10S,11Z,13S,14R,15S,16Z,20R,21S,22S)-8,10,14,-
20-Tetrakis(tert-butyldimethylsilyloxy)-7,13,15,21-tetramethyl-
22-((1S,2Z)-1-methyl-penta-2,4-dienyl)-oxa-cyclodocosa-3,5,11,-
16-tetraen-2-one (51R). A solution of the crude seco-acid 50R
(0.062 g, 0.063 mmol) in THF (6.3 mL) at 0 °C was treated with
triethylamine (0.061 mL, 0.434 mmol) and 2,4,6-trichlorobenzoyl
chloride (0.049 mL, 0.313 mmol). The reaction mixture was stirred
at 0 °C for 30 min and at ambient temperature for 1 h. A solution
of DMAP (0.076 g, 0.625 mmol) in toluene (63 mL) was added at
ambient temperature. The reaction mixture was stirred for 17 h.
After quenching by the addition of satd aq NaHCO3 (30 mL), the
mixture was extracted with diethyl ether (3 × 30 mL) and the
combined organic layers were washed with a 0.2 M solution of
HCl (3 × 50 mL) and a satd aq NaHCO3 (50 mL), brine, then
dried (MgSO4), and concentrated. Purification by column chroma-
tography (98:2 hexanes/EtOAc) provided the macrolactone 51R
(0.043 g, 71%) as a colorless oil: IR (NaCl) 3359, 2956, 2926,
2855, 1713, 1463, 1256, 1086, 835, 773 cm-1; 1H NMR (600 MHz,
CDCl3) δ 7.10 (dd, J ) 11.5, 14.7 Hz, 1H), 6.61 (dt, J ) 10.7,
16.7 Hz, 1H), 6.55 (t, J ) 11.2 Hz, 1H), 6.07 (dd, J ) 7.6, 15.4
Hz, 1H), 6.00 (t, J ) 11.0 Hz, 1H), 5.63 (t, J ) 8.2 Hz, 1H), 5.57
Na]+, 1119.7696; found, 1119.7795; [R]20 +16.9 (c 0.61, CHCl3).
D
(2Z,4E,6R,7S,9S,10Z,12S,13R,14S,15Z,19R,20R,21S,22S,23Z)-
21-(4-Methoxybenzyloxy)-7,9,13,19-tetrakis(tert-butyldimethyl-
silyloxy)-6,12,14,20,22-pentamethylhexacosa-2,4,10,15,23,25-
hexaenoic Acid. A solution of the alcohol 49R (0.22 g, 0.20 mmol)
in CH2Cl2 (20 mL) at 0 °C was treated with Dess-Martin
periodinane (0.17 g, 0.40 mmol). The mixture was warmed to
ambient temperature and stirred for 2 h. After quenching by the
addition of a mixtue of satd aq Na2S2O3 (10 mL) and satd aq
NaHCO3 (10 mL), the mixture was extracted with EtOAc (3 × 20
mL). The combined organic layers were washed with satd aq
NaHCO3 (20 mL) and brine and dried (MgSO4). The concentration
under vacuum provided the aldehyde as a colorless oil, which was
used in the next step without further purification: 1H NMR (300
MHz, CDCl3) δ 10.18 (d, J ) 8.1 Hz, 1H), 7.29 (d, J ) 8.4 Hz,
2H), 7.02 (dd, J ) 11.9, 14.3 Hz, 1H), 6.91 (t, J ) 10.5 Hz, 1H),
6.86 (d, J ) 8.6 Hz, 2H), 6.58 (dt, J ) 10.6, 16.8 Hz, 1H), 6.10
(dd, J ) 7.2, 14.3 Hz, 1H), 6.01 (t, J ) 11.0 Hz, 1H), 5.80 (dd, J
) 8.2, 10.3 Hz, 1H), 5.57 (t, J ) 10.7 Hz, 1H), 5.37 (t, J ) 11.1
Hz, 1H), 5.32-5.14 (m, 4H), 5.10 (d, J ) 10.2 Hz, 1H), 4.59-
4.43 (m, 3H), 3.93 (m, 1H), 3.80 (s, 3H), 3.66 (m, 1H), 3.38-3.27
(m, 2H), 3.00 (m, 1H), 2.64-2.46 (m, 3H), 1.91-1.62 (m, 3H),
1.54 (m, 1H), 1.49-1.36 (m 3H), 1.11 (d, J ) 6.8 Hz, 3H), 1.05
(d, J ) 6.7 Hz, 3H), 1.02-0.81 (m, 45H), 0.16-0.01 (m, 24H).
A mixture of the aldehyde and NaH2PO4‚H2O (0.165 g, 1.20
mmol) in t-BuOH (15 mL) and H2O (5 mL) at 0 °C was treated
with a 2.0 M solution of 2-methyl-2-butene in THF (5.00 mL, 10.00

2964 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Jung et al.
(d, J ) 11.5 Hz, 1H), 5.40 (t, J ) 10.3 Hz, 1H), 5.32 (dd, J ) 8.1,
11.1 Hz, 1H), 5.20 (d, J ) 16.8 Hz, 1H), 5.17-5.10 (m, 4H), 4.46
(q, J ) 7.1 Hz, 1H), 3.88 (m, 1H), 3.54 (m, 1H), 3.37 (d, J ) 4.0
Hz, 1H), 3.04 (m, 1H), 2.55-2.29 (m, 3H), 1.96 (m, 1H), 1.85 (m,
1H), 1.77 (m, 1H), 1.65-1.51 (m, 2H), 1.48-1.28 (m, 2H), 1.04
(dd, J ) 7.1, 9.7 Hz, 6H), 1.00 (t, J ) 6.6 Hz, 6H), 0.97-0.84 (m,
39H), 0.12-0.01 (m, 24H); 13C NMR (125 MHz, CDCl3) δ 166.3,
144.7, 142.8, 134.0, 133.6, 133.4, 132.1, 131.2, 129.7, 128.1, 127.7,
117.7, 117.5, 79.9, 77.3, 73.4, 71.6, 66.8, 66.1, 43.5, 39.5, 37.6,
37.3, 34.5, 34.4, 29.7, 26.1, 25.9, 25.8, 25.4, 19.6, 18.5, 18.0, 17.9,
17.5, 15.4, 10.5, -2.8, -3.1, -3.6, -4.0, -4.3; LRMS (ESI) 995
[M + Na]+; HRMS (ESI) calcd for C55H104O6Si4Na [M + Na]+,
(2Z,4E,6R,7S,9R,10Z,12S,13R,14S,15Z,19R,20R,21S,22S,23Z)-
21-(4-Methoxybenzyloxy)-7,9,13,19-tetrakis(tert-butyldimethyl-
silyloxy)-6,12,14,20,22-pentamethylhexacosa-2,4,10,15,23,25-
hexaen-1-ol (49â). Following the procedure for 48R, the alcohol
48â (0.20 g, 0.20 mmol) in CH2Cl2 (4.0 mL) was reacted with
2,6-lutidine (0.069 mL, 0.59 mmol) and TBSOTf (0.068 mL, 0.30
mmol) to provide the TBS ether as a colorless oil, which was used
in the next step without further purification.
The TBS ether at 0 °C was treated with a solution of HF‚pyr in
pyr/THF (6.7 mL) for 14 h. Purification by column chromatography
(9:1 hexanes/EtOAc) provided the alcohol 49â (0.12 g, 60%) as a
colorless oil: IR (NaCl) 3400, 2956, 2928, 2856, 1250, 1084, 1037,
995.6808; found, 995.6902; [R]20 +5.6 (c 0.20, CHCl3).
1
835, 773 cm-1; H NMR (300 MHz, CDCl3) δ 7.30 (d, J ) 8.5
D
Hz, 2H), 6.88 (d, J ) 8.5 Hz, 2H), 6.61 (dt, J ) 10.5, 16.8 Hz,
1H), 6.30 (dd, J ) 11.1, 15.2 Hz, 1H), 6.15-5.95 (m, 2H), 5.85
(dd, J ) 8.6, 15.2 Hz, 1H), 5.59 (t, J ) 10.5 Hz, 1H), 5.50-5.05
(m, 7H), 4.58 (d, J ) 10.5 Hz, 1H), 4.51 (d, J ) 10.5 Hz, 1H),
4.40 (m, 1H), 4.30 (dd, J ) 7.4, 12.8 Hz, 1H), 4.23 (dd, J ) 6.9,
12.8 Hz, 1H), 3.87(m, 1H), 3.80 (s, 3H), 3.68 (m, 1H), 3.40 (t, J
) 4.2 Hz, 1H), 3.35 (dd, J ) 3.2, 7.7 Hz, 1H), 3.00 (m, 1H), 2.67-
2.49 (m, 2H), 2.43 (m, 1H), 1.92-1.80 (m, 2H), 1.69 (m, 1H),
1.62-1.40 (m, 4H), 1.12 (d, J ) 6.8 Hz, 3H), 1.08 (d, J ) 6.9 Hz,
3H), 1.00-0.84 (m, 45H), 0.12-0.02 (m, 24H); 13C NMR (75 MHz,
CDCl3) δ 159.3, 152.4, 138.8, 134.8, 134.5, 133.6, 132.6, 131.6,
129.4, 129.3, 128.2, 127.5, 125.5, 118.8, 117.5, 114.0, 84.5, 79.8,
75.3, 72.7, 66.7, 59.1, 55.5, 44.8, 41.0, 40.7, 37.7, 35.9, 35.6, 35.4,
29.9, 26.5, 26.2, 26.1, 23.7, 19.0, 18.9, 18.7, 18.4, 18.3, 17.0, 9.68,
-3.2, -3.3, -3.7, -4.1, -4.3, -4.4; LRMS (ESI) 1119 [M +
Na]+; HRMS (ESI) calcd for C63H116O7Si4Na [M + Na]+,
(3Z,5E,7R,8S,10S,11Z,13S,14R,15S,16Z,20R,21S,22S)-8,10,14,-
20-Tetrahydroxy-7,13,15,21-tetramethyl-22-((1S,2Z)-1-methyl-
penta-2,4-dienyl)-oxacyclodocosa-3,5,11,16-tetraen-2-one (6). A
solution of macrolactone 51R (0.043 g, 0.044 mmol) in THF (2.4
mL) at 0 °C was treated with a 6 M solution of HCl in H2O/MeOH
(2.4 mL, prepared by slow addition of conc. HCl (1.2 mL) to MeOH
(1.2 mL)). The reaction mixture was warmed to ambient temperature
and stirred. Three portions of a 6 M solution of HCl (2.4 mL) and
THF (2.4 mL) were added every 45 min. After 4 h, the solid
NaHCO3 was added to the reaction mixture until no gas evolved.
The mixture was extracted with diethyl ether (3 × 30 mL) and the
combined organic layers were washed with brine, dried (MgSO4),
and concentrated. Purification by column chromatography (3:17
hexanes/EtOAc) provided 16-normethyl-15,16-dehydrodictyostatin
6 (0.0096 mg, 42%) as a colorless powder and the more polar C2-
C3 E-isomer 53 (0.0007 g, 3%) as a colorless powder.
1119.7696; found, 1119.7700; [R]20 +50.0 (c 0.18, CHCl3).
16-Normethyl-15,16-dehydrodictyostatin 6: IR (NaCl) 3390,
D
1
2965, 2927, 1704, 1639, 1455, 1275, 1179, 1002, 959 cm-1; H
(2Z,4E,6R,7S,9R,10Z,12S,13R,14S,15Z,19R,20R,21S,22S,23Z)-
7,9,13,19-Tetrakis(tert-butyldimethylsilyloxy)-21-hydroxy-6,12,-
14,20,22-pentamethylhexacosa-2,4,10,15,23,25-hexenoic Acid (50â).
A solution of the alcohol 49â (0.11 g, 0.10 mmol) in CH2Cl2 (10
mL) at 0 °C was treated with Dess-Martin periodinane (0.085 g,
0.20 mmol). The mixture was warmed to ambient temperature and
stirred for 1 h. After quenching by the addition of a mixture of
satd aq Na2S2O3 (5 mL) and satd aq NaHCO3 (5 mL), the mixture
was extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with satd aq NaHCO3 (10 mL) and brine and
dried (MgSO4). The concentration under vacuum provided the
aldehyde as a pale yellow oil, which was used in the next step
without further purification.
The aldehyde in t-BuOH (6 mL) and H2O (2 mL) was reacted
with NaH2PO4‚H2O (0.083 g, 0.60 mmol), a 2.0 M solution of
2-methyl-2-butene in THF (2.50 mL, 5.00 mmol), and NaClO4
(0.034 g, 0.30 mmol) to provide the carboxylic acid as a pale yellow
oil, which was used in the next step without further purification.
The carboxylic acid in CH2Cl2 (10 mL) and H2O (1 mL) was
reacted with DDQ (0.068 g, 0.30 mmol). Purification by chroma-
tography (15:1 hexanes/EtOAc) provided the seco acid 50â (0.047
g, 47% for three steps) as a colorless oil, which was used
immediately in the next step: 1H NMR (300 MHz, CDCl3) δ 7.38
(dd, J ) 11.4, 17.3 Hz, 1H), 6.75-6.52 (m, 2H), 6.24 (dd, J )
8.7, 15.3 Hz, 1H), 6.11 (t, J ) 10.9 Hz, 1H), 5.58 (d, J ) 11.3 Hz,
1H), 5.52-5.33 (m, 3H), 5.32-5.17 (m, 3H), 5.13 (d, J ) 10.2
Hz, 1H), 4.41 (t, J ) 8.0 Hz, 1H), 3.92 (d, J ) 9.4 Hz, 1H), 3.80
(m, 1H), 3.52 (dd, J ) 2.6, 7.5 Hz, 1H), 3.41 (t, J ) 3.8 Hz, 1H),
2.81 (m, 1H), 2.64-2.44 (m, 2H), 2.10-1.82 (m, 2H), 1.78 (m,
1H), 1.72-1.31 (m, 5H), 1.11 (d, J ) 6.7 Hz, 1H), 1.02-0.80 (m,
48H), 0.18-0.02 (m, 24H).
NMR (600 MHz, CDCl3) δ 7.20 (dd, J ) 11.2, 15.5 Hz, 1H), 6.60
(dt, J ) 11.0, 16.8 Hz, 1H), 6.53 (t, J ) 11.3 Hz, 1H), 6.01 (dd,
J ) 8.5, 15.5 Hz, 1H), 6.00 (t, J ) 10.8 Hz, 1H), 5.62 (t, J ) 10.8
Hz, 1H), 5.54 (d, J ) 11.5 Hz, 1H), 5.52 (dd, J ) 8.9, 10.7 Hz,
1H), 5.32 (t, J ) 10.5 Hz, 1H), 5.22 (dt, J ) 6.9, 10.9 Hz, 1H),
5.19 (t, J ) 11.0 Hz, 1H), 5.18 (d, J ) 16.7 Hz, 1H), 5.10 (dd, J
) 2.9, 8.6 Hz, 1H), 5.08 (d, J ) 11.0 Hz, 1H), 4.66 (dt, J ) 3.8,
8.4 Hz, 1H), 4.01 (dt, J ) 2.6, 10.7 Hz, 1H), 3.38 (ddd, J ) 2.8,
6.8, 12.7 Hz, 1H), 3.29 (dd, J ) 3.6, 8.0 Hz, 1H), 3.05 (m, 1H),
2.66 (m, 1H), 2.51 (m, 1H), 2.38 (m, 1H), 2.14 (m, 1H), 1.97 (m,
1H), 1.90 (dt, J ) 3.0, 6.9 Hz, 1H), 1.66 (m, 1H), 1.59 (ddd, J )
3.9, 10.5, 14.3 Hz, 1H), 1.44 (ddd, J ) 2.4, 8.3, 14.2 Hz, 1H),
1.22 (dt, J ) 4.1, 9.6 Hz, 1H), 1.17 (d, J ) 6.8 Hz, 3H), 1.10 (d,
J ) 6.9 Hz, 3H), 1.08 (d, J ) 6.9 Hz, 3H), 1.02 (d, J ) 6.8 Hz,
3H), 1.00 (d, J ) 6.7 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ
166.6, 134.0, 132.5, 132.3, 132.0, 131.8, 129.9, 129.5, 127.9, 79.0,
76.4, 73.0, 71.1, 65.4, 43.3, 40.2, 40.1, 36.9, 35.4, 34.4, 33.9, 24.8,
19.3, 18.0, 17.4, 15.8, 10.1; LRMS (ESI) 539 [M + Na]+; HRMS
(ESI) calcd for C31H48O6Na [M + Na]+, 539.3349; found, 539.3352;
[R]20 -74.0 (c 0.17, CHCl3).
D
The C2-C3 E-Isomer 53: IR (NaCl) 3408, 2962, 2926, 1698,
1640, 1455, 1300, 1261, 1003 cm-1; 1H NMR (600 MHz, CDCl3)
δ 7.15 (dd, J ) 10.9, 15.3 Hz, 1H), 6.59 (dt, J ) 10.3, 17.3 Hz,
1H), 6.16 (dt, J ) 10.8, 15.2 Hz, 1H), 6.04 (dd, J ) 7.9, 15.3 Hz,
1H), 5.97 (t, J ) 10.9 Hz, 1H), 5.73 (d, J ) 15.3 Hz, 1H), 5.50
(dd, J ) 8.8, 11.0 Hz, 1H), 5.42 (t, J ) 10.1 Hz, 1H), 5.38-5.32
(m, 2H), 5.20 (t, J ) 10.8 Hz, 1H), 5.17 (d, J ) 17.7 Hz, 1H),
5.09 (d, J ) 10.1 Hz, 1H), 4.96 (dd, J ) 1.7, 8.7 Hz, 1H), 4.79 (dt,
J ) 2.7, 7.3 Hz, 1H), 4.03 (d, J ) 10.5 Hz, 1H), 3.48-3.35 (m,
2H), 3.01 (m, 1H), 2.73 (m, 1H), 2.61 (m, 1H), 2.42 (m, 1H), 2.20
(m, 1H), 2.10 (m, 1H), 1.83 (m, 1H), 1.69 (ddd, J ) 2.5, 10.6,
13.9 Hz, 1H), 1.58 (m, 1H), 1.54 (m, 1H), 1.34-1.28 (m, 2H),
1.16 (d, J ) 6.8 Hz, 3H), 1.10 (d, J ) 6.9 Hz, 3H), 1.02 (d, J )
6.8 Hz, 3H), 1.00 (d, J ) 6.7 Hz, 3H), 0.93 (d, J ) 6.9 Hz, 3H);
13C NMR (151 MHz, CDCl3) δ 166.7, 145.5, 145.1, 134.3, 133.2,
131.9, 131.5, 131.3, 130.7, 129.7, 129.0, 119.7, 117.8, 78.3, 76.1,
71.7, 71.2, 65.8, 42.4, 40.5, 40.2, 35.9, 34.2, 34.1, 31.8, 23.7, 19.3,
17.3, 15.7, 14.6, 9.8; LRMS (ESI) 539 [M + Na]+; HRMS (ESI)
calcd for C31H48O6Na [M + Na]+, 539.3349; found, 539.3362;
(3Z,5E,7R,8S,10R,11Z,13S,14R,15S,16Z,20R,21S,22S)-8,10,14,-
20-Tetrahydroxy-7,13,15,21-tetramethyl-22-((1S,2Z)-1-methyl-
penta-2,4-dienyl)-oxacyclodocosa-3,5,11,16-tetraen-2-one (54). A
solution of the seco-acid 50â (0.037 g, 0.037 mmol) in THF (3.7
mL) at 0 °C was treated with triethylamine (0.036 mL, 0.259 mmol)
and 2,4,6-trichlorobenzoyl chloride (0.029 mL, 0.186 mmol). The
reaction mixture was stirred at 0 °C for 30 min and at ambient
temperature for 1 h. A solution of DMAP (0.045 g, 0.370 mmol)
in toluene (37 mL) was added at ambient temperature. The reaction
mixture was stirred for 15 h. After quenching by addition of satd
[R]20 +21.9 (c 0.16, CHCl3).
D

Dictyostatin C-16 Analogs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2965
aq NaHCO3 (15 mL), the mixture was extracted with diethyl ether
(3 × 15 mL) and the combined organic layers were washed with
a 0.2 M solution of HCl (3 × 25 mL), satd aq NaHCO3 (25 mL),
and brine, then dried (MgSO4), and concentrated. Purification by
column chromatography (98:2 hexanes/EtOAc) provided the mix-
ture 51â (0.035 g) of (3Z) and (3E) as a pale yellow oil. The same
reaction with 0.034 g of the seco-acid gave the mixture of
macrolactone (0.027 g).
pages). This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Boyd, M. R.; Schmidt, J. M.
Isolation and structure of the cancer cell growth inhibitor dictyostatin
1. J. Chem. Soc., Chem. Commun. 1994, 1111-1112.
(2) Isbrucker, R. A.; Cummins, J.; Pomponi, S. A.; Longley, R. E.;
Wright, A. E. Tubulin polymerizing activity of dictyostatin-1, a
polyketide of marine sponge origin. Biochem. Pharm. 2003, 66, 75-
82.
(3) Paterson, I.; Britton, R.; Delgado, O.; Wright, A. E. Stereochemical
determination of dictyostatin, a novel microtubule-stabilizing mac-
rolide from the marine sponge Corallistidae sp. Chem. Commun.
2004, 632-633.
(4) (a) Paterson, I.; Britton, R.; Delgado, O.; Meyer, A.; Poullennec, K.
G. Total synthesis and configurational assignment of (-)-dictyostatin,
a microtubule-stabilizing macrolide of marine sponge origin. Angew.
Chem., Int. Ed. 2004, 43, 4629-4633. (b) Shin, Y.; Fournier, J. H.;
Fukui, Y.; Bru¨ckner, A. M.; Curran, D. P. Total synthesis of (-)-
dictyostatin: Confirmation of relative and absolute configurations.
Angew. Chem., Int. Ed. 2004, 43, 4634-4637. See reference 9 for
the full paper. (c) Reviewed in Yeung, K. S.; Paterson, I. Advances
in the total synthesis of biologically important marine macrolides.
Chem. ReV. 2005, 105, 4237-4313.
A solution of macrolactone 51â (0.062 g, 0.064 mmol) in THF
(3.2 mL) at 0 °C was treated with a 6 M solution of HCl in H2O/
MeOH (3.2 mL, prepared by the slow addition of concd HCl (1.6
mL) to MeOH (1.6 mL)). The reaction mixture was warmed to
ambient temperature and stirred. Three portions of a 6 M solution
of HCl (1.6 mL) and THF (1.6 mL) were added every 45 min.
After 8 h, the solid NaHCO3 was added to the reaction mixture
until no gas evolved. The mixture was extracted with diethyl ether
(3 × 50 mL) and the combined organic layers were washed with
brine, dried (MgSO4), and concentrated. Purification by column
chromatography (3:17 hexanes/EtOAc) provided the title compound
54 (0.004 g, 14%, two steps) as a colorless powder and the more
polar C19-lactone 55 (0.005 g, 16%, two steps) as a colorless
powder: IR (NaCl) 3384, 2964, 1698, 1635, 1456, 1271, 1001
cm-1; 1H NMR (600 MHz, CDCl3) δ 7.28 (dd, J ) 10.9, 15.8 Hz,
1H), 6.61 (dt, J ) 10.7, 16.8 Hz, 1H), 6.55 (t, J ) 11.4 Hz, 1H),
6.05 (t, J ) 11.0 Hz, 1H), 6.02 (dd, J ) 5.9, 16.0 Hz, 1H), 5.59
(dd, J ) 8.4, 10.9 Hz, 1H), 5.58 (d, J ) 11.2 Hz, 1H), 5.38-5.32
(m, 2H), 5.28 (dt, J ) 4.9, 10.2 Hz, 1H), 5.22 (d, J ) 16.8 Hz,
1H), 5.12 (d, J ) 10.0 Hz, 1H), 4.87 (dd, J ) 3.3, 6.7 Hz, 1H),
4.67 (dt, J ) 3.6, 9.0 Hz, 1H), 4.14 (m, 1H), 3.58 (dt, J ) 4.4, 6.4
Hz, 1H), 3.15 (t, J ) 7.3 Hz, 1H), 3.00 (m, 1H), 2.74 (m, 2H),
2.61 (m, 1H), 2.40 (m, 1H), 2.05 (m, 1H), 1.80 (m, 1H), 1.66 (m,
1H), 1.55 (m, 1H), 1.31 (m, 1H), 1.10 (d, J ) 6.6 Hz, 3H), 1.08
(d, J ) 7.1 Hz, 3H), 1.06 (d, J ) 6.8 Hz, 3H), 1.00 (d, J ) 6.7 Hz,
3H), 0.97 (d, J ) 7.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ
167.3, 146.3, 144.6, 134.5, 133.9, 133.8, 133.2, 130.0, 128.6, 126.5,
118.0, 116.7, 79.2, 78.7, 73.2, 72.3, 67.8, 41.0, 38.9, 38.3, 38.2,
35.6, 34.1, 29.7, 23.6, 19.1, 18.9, 17.5, 14.7, 8.3; LRMS (ESI) 539
[M + Na]+; HRMS (ESI) calcd for C31H48O6Na [M + Na]+,
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539.3349; found, 539.3339; [R]20 -58.0 (c 0.20, CHCl3).
D
(3Z,5E,7R,8S,10S,11Z,13S,14R,15S,16Z,20R)-8,10,14-Trihy-
droxy-20-((1′R,2′S,3′S,4′Z)-2′-hydroxy-1′,3′-dimethylhepta-4′,6′-
dienyl)-7,13,15-trimethyloxacycloeicosa-3,5,11,16-tetraen-2-
one (55). IR (NaCl) 3390, 2963, 2929, 1698, 1635, 1456, 1267,
1
1180, 1003 736 cm-1; H NMR (600 MHz, CDCl3) δ 7.27 (m,
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1H), 6.66 (dt, J ) 10.2, 16.8 Hz, 1H), 6.58 (t, J ) 11.2 Hz, 1H),
6.17 (t, J ) 10.9 Hz, 1H), 6.14 (dd, J ) 6.4, 15.7 Hz, 1H), 5.63 (d,
J ) 11.3 Hz, 1H), 5.50 (dd, J ) 8.8, 11.0 Hz, 1H), 5.41-5.29 (m,
3H), 5.27 (d, J ) 16.7 Hz, 1H), 5.18 (d, J ) 10.1 Hz, 1H), 5.07
(dd, J ) 5.0, 6.4 Hz, 1H), 4.57 (m, 1H), 3.40 (dd, J ) 3.2, 7.9 Hz,
1H), 3.17 (dd, J ) 6.0, 7.7 Hz, 1H), 2.86 (m, 1H), 2.67 (m, 1H),
2.58 (m, 1H), 2.48 (q, J ) 7.5 Hz, 1H), 2.13 (m, 1H), 2.00 (dt, J
) 3.3, 6.7 Hz, 1H), 1.81 (m, 2H), 1.70 (ddd, J ) 7.3, 10.1, 14.1
Hz, 1H), 1.60 (ddd, J ) 3.5, 5.2, 14.1 Hz, 1H), 1.14 (d, J ) 7.0
Hz, 3H), 1.05 (d, J ) 6.7 Hz, 3H), 1.02 (d, J ) 6.9 Hz, 3H), 1.01
(d, J ) 6.7 Hz, 3H), 0.98 (d, J ) 6.7 Hz, 3H); 13C NMR (151
MHz, CDCl3) δ 166.3, 146.1, 143.8, 134.1, 134.0, 133.8, 133.7,
132.0, 131.4, 128.1, 126.7, 118.7, 117.3, 78.8, 76.2, 75.0, 72.7,
67.3, 41.3, 39.8, 38.4, 38.1, 37.6, 36.1, 31.4, 22.9, 19.5, 18.0, 17.1,
14.1, 8.8; LRMS (ESI) 539 [M + Na]+; HRMS (ESI) calcd for
C31H48O6Na [M + Na]+, 539.3349; found, 539.3356; [R]20D -10.5
(c 0.19, CHCl3).
Acknowledgment. We thank the National Institutes of
Health for support through Grant CA078390. We thank Drs.
Kenneth Bair and Fred Kinder for the gift of discodermolide
and Prof. Amos B. Smith, III for the gift of 14-normethyldis-
codermolide.
Supporting Information Available: Detailed descriptions of
the synthesis and characterization of the dictyostatin analogs 5 and
6 along with copies of NMR spectra of all compounds tested (64

2966 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Jung et al.
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JM061385K