Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents

Article abstract of DOI:10.1021/jm0204136

Several novel analogues of (+)-discodermolide were synthesized via a convergent strategy that used Wittig reactions to append left and right side chains to a central scaffold and then tested for biological activity. Three of the analogues in the 4-epi-7-d

Full text of DOI:10.1021/jm0204136

2846
J . Med. Chem. 2003, 46, 2846-2864
Sim p lified Discod er m olid e An a logu es: Syn th esis a n d Biologica l Eva lu a tion of
4-epi-7-Deh yd r oxy-14,16-d id em eth yl-(+)-d iscod er m olid es a s
Micr otu bu le-Sta bilizin g Agen ts
Nakyen Choy,† Youseung Shin,† Phu Qui Nguyen,† Dennis P. Curran,*,† Raghavan Balachandran,‡
Charitha Madiraju,‡ and Billy W. Day*,†,‡
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, and Department of
Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
Received September 20, 2002
Several novel analogues of (+)-discodermolide were synthesized via a convergent strategy that
used Wittig reactions to append left and right side chains to a central scaffold and then tested
for biological activity. Three of the analogues in the 4-epi-7-dehydroxy-14,16-didemethyl series,
6a -c, had interesting actions. The C3-methoxymethyl ether analogue 6b was more active in
antiproliferative cell-based assays as well as in hypernucleation and paclitaxel site competition
assays with isolated tubulin than the other analogues, including 6a , which contained a free
hydroxyl group at the C3 position. The biological results validated the initial hypothesis that
the C7 hydroxy group and the C14 and C16 methyl groups of (+)-discodermolide could be deleted
without undermining activity. Although less potent than (+)-discodermolide and paclitaxel,
compounds 6b and 6c both showed properties unique to (+)-discodermolide. These properties,
particularly the capacity to cause hypernucleation of isolated tubulin at lower temperature
than paclitaxel, as well as stabilizing preformed microtubules to cold disassembly, are considered
mechanistically superior to those of paclitaxel. Other variations in the right and left sides of
the discodermolide scaffold revealed additional structure/activity information.
In tr od u ction
with discodermolide analogues 3a -e prepared by acety-
lation of the hydroxyl groups at C3, C7, C11, and/or C17
of 1. Interestingly, C3- and/or C7-acetylated versions
3a -c of 1 retain cytotoxicities equivalent to that of 1
against carcinoma cells, while acetylation at the C11
and C17 hydroxyl groups (3d ,e) decreases biological
potency.12 Smith and co-workers constructed C14-cis/
trans-demethyl analogues 4a ,b and C3-dehydro and C3-
dehydro/C7-deoxy analogues 4c,d . Interestingly, the
C14-cis-demethyl analogue 4a is just 2-fold less cytotoxic
than 1. A large decrease in activity is associated with
the trans geometry at C14 4b. In addition, the C3-
dehydro and C3-dehydro/C7-deoxy analogues, 4c and
4d , are approximately 2-fold more and 3-fold less
cytotoxic, respectively, than 1. The Smith group re-
ported studies that suggest that one of the hydroxyl
groups at either C3 or C7 must be present in order for
an analogue to have activity similar to that of 1.3 The
Paterson group recently reported the synthesis of
several epimers of discodermolide,6 but did not give
results of biological analyses.
The microtubule-stabilizing agent (+)-discodermolide
(1, Figure 1)1 has potential as a cancer chemotherapeu-
tic agent. Compound 1 has significantly higher affinity
for the paclitaxel binding site on tubulin than does
paclitaxel itself2,3 and is a promising candidate for
clinical development in cancer chemotherapy either
alone4 or in combination with paclitaxel.5 The scarcity
of this marine sponge-derived product has spurred the
development of both total4-9 and partial syntheses.10
F igu r e 1. (+)-Discodermolide (1).
Four groups have reported the synthesis of analogues
for structure-activity relationship (SAR) studies.3,4,6,11
Key features of this work are summarized in Table 1.
Schreiber’s group reported that C16-demethyldiscoder-
molide (2) is no less antiproliferative than natural 1,
suggesting that no significant loss of microtubule bind-
ing is associated with the absence of the C16-methyl
group.4 Longley and co-workers reported SAR studies
Even with all of this information, the SAR analysis
of discodermolide is far from well understood. We sought
to develop a synthetic route that could easily access
simplified and more diverse analogues, an important
step for the further understanding of the SAR sur-
rounding 1. Herein we report the synthesis and com-
parison of biological activities of several new simplified
discodermolide analogues. The results present impor-
tant new structural information for the further develop-
ment of analogues of this potent microtubule-stabilizing
agent.
* To whom correspondence should be addressed. D.P.C.: 1101
Chevron Sciences Center, Pittsburgh, PA 15260, phone: 1-412-624-
8240, fax: 1-412-624-9861, e-mail: curran@pitt.edu. B.W.D.: 726 Salk
Hall, 3501 Terrace St., Pittsburgh, PA 15261, phone: 1-412-648-9706,
fax: 1-412-624-1850, e-mail: bday@pitt.edu.
† Department of Chemistry.
‡ Department of Pharmaceutical Sciences.
10.1021/jm0204136 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/29/2003

4-epi-7-Dehydroxy-14,16-didemethyldiscodermolides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2847
Ta ble 1. Antiproliferative Potencies (IC50, nM) Against A549
or MG63a Cells of Paclitaxel, Discodermolide (1), and
Literature Compounds 2-4d
F igu r e 2. Design of simplified analogues.
2). Protection of the C3 hydroxy group with methoxy-
methyl (MOM, CH2OCH3) was chosen to satisfy both
the synthetic approach and to provide an extended
H-bond acceptor compared to the free hydroxy group
found on the natural product.
Retr osyn th etic An a lysis. The retrosynthetic analy-
sis shown in Figure 3 includes two Wittig reactions to
generate the (Z)-alkenes between C8-C9 and C13-C14.
In addition, the aldehyde 10 was envisioned as a
penultimate form of the left-side lactone display18 and
three phosphonium salts 8, 9, 11 were selected for
Wittig reactions in the center and right displays. The
preparation of these fragments 8-11 of the molecule
begins with commercially available methacrolein (13),
1,4-butanediol (14), and (S)-3-hydroxy-2-methylpropi-
onic acid methyl ester (15) and features aldol condensa-
tions along with protecting group manipulations.
Syn th esis of Left Disp la y w ith Na tu r a l Con fig-
u r a tion . The synthesis of the left display 10a bearing
the configuration of (+)-discodermolide started with
commercially available methacrolein (13) (Scheme 1).
Reaction of 13 with the boron enolate of Evans oxazo-
lidinone 1619 gave the corresponding alcohol, which was
silylated to give compound 17 in 90% yield. Lactoniza-
tion followed by the introduction of an allyl group was
performed by our previously reported method to give
19 in good yield.7,10 Conversion to the methyl acetal was
easily accomplished by diisobutylaluminum hydride
(DIBAL) reduction to the corresponding lactol followed
by treatment with camphorsulfonic acid (CSA) in metha-
nol to give a desilylated intermediate, which was
protected with MOM chloride to give a mixture of
anomers 20 (â:R ) 1:1). These were separable by silica
gel flash chromatography. The final left display 10a was
obtained by hydroboration of the R-anomer r-20 with
BH3-DMS (borane-dimethyl sulfide) followed by oxi-
dation with SO3-pyridine.
a
IC50 values against MG63 cells are shown in parentheses.
b
Not determined.
Resu lts a n d Discu ssion
Str u ctu r e Design . The structure of 1 as determined
by X-ray crystallographic analysis1 shows that the
molecule adopts a curved conformation. The U-turn
shape at the center of 1 arises from avoidance of syn-
pentane interactions by the methyl groups in the main
chain and avoidance of A-1,3 strain by the vinyl groups
projecting from the methyl-bearing stereocenters.13 In
addition, avoidance of A-1,2 strain by the C14 methyl
group may also play a role. We have recently explored
SARs of the discodermolide backbone by using a fixed
center piece, or scaffold, including two cis-double bonds,
as shown in compound 5, while removing the lactone,
the hydroxy groups at C7 and the methyl groups at C14
and C16.14 Because of the additive negative effect of
removing those groups, however, we considered another
possibility: that hydrogen bonding between the C3
hydroxy group of the lactone and the C19 carbamate
might help to stabilize the U-turn shaped conformation.
NMR solution structures of 1 recently reported by
Smith15 and Snyder16 suggest possible hydrogen bond-
ing between those groups. Accordingly, as part of our
continuing efforts toward analogue syntheses using both
classical (5a )14 and fluorous mixture (5b)17 methods, we
decided to introduce lactone moieties 6 so as to compare
the original configuration of the left side of the natural
product with its C4-epi-lactone along with various
degrees of truncation of the right side from C19 (Figure
Syn th esis of Left Disp la y w ith C4-ep i Con figu -
r a tion . The synthesis of the C4-epi-lactone left display
10b started from 1,4-butanediol (14) (Scheme 2). Mono-
protection with p-methoxybenzyl (PMB) bromide was
performed with NaH in DMF.21 After oxidation, reaction
of the crude aldehyde 21 with the boron enolate of Evans
oxazolidinone 16 gave the corresponding syn-alcohol,
which was silylated to give compound 22 in 90% yield.
Lithium borohydride reduction followed by oxidation
gave the aldehyde 23. A second syn-aldol addition was

2848 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Choy et al.
F igu r e 3. Retrosynthetic analysis of discodermolide analogues.
Sch em e 1
by silica gel flash chromatography. The final left display
10b was obtained by hydrogenolysis of the PMB pro-
tecting group followed by Dess-Martin oxidation.
Sca ffold . Compound 28 was prepared from (S)-3-
hydroxy-2-methylpropionic acid methyl ester (15) by the
known procedure for the preparation of ent-28.21 Reduc-
tion of 28 with lithium borohydride gave the diol, which
was protected by anisaldehyde dimethyl acetal 29 to
give the acetal 30 (Scheme 3). Deprotection of the
primary TBS group with tetrabutylammonium fluoride
(TBAF), iodination, and treatment with triphenylphos-
phine afforded the phosphonium salt 1122 in 72% yield.
We had originally prepared the phosphonium salts 31
and 3214 for Wittig olefination, but reactions were
unsuccessful due to the hygroscopic properties of these
reagents. On the other hand, reactions with compound
11 were reliable even though no special care was taken
with its storage (for example, salt 11 was useful for
reactions even after it was stored at room temperature
for several months).
Ba ck bon e Assem bly a n d Testin g of C19-Tr u n -
ca ted An a logu es. Our attention turned to both sim-
plification at the C19 position and comparison of the
configuration at C4 along with a C3 MOM-protected
and/or free hydroxyl group (Scheme 4). The aldehydes
10a and 10b were separately reacted under Wittig
conditions with phosphonium salt 11 to give alkenes 33
and 34 in 60% and 67% yields, respectively. Selective
acetal opening was performed with DIBAL to give the
corresponding primary alcohols, which were oxidized
with the Dess-Martin periodinane to give aldehydes 35
and 36. Mono-TBS-protected 1,4-butanediol 14 was
oxidized to its aldehyde, which was used without
purification in an Evans syn-aldol condensation with 37
to give known compound 38.23 Reduction of 38 with
lithium borohydride gave a diol, which was treated with
performed with same Evans oxazolidinone 16 to give
the corresponding alcohol, which was protected with
MOM chloride to give compound 24. Desilylation of 24
with HF gave the cyclized product 25 in high yield.
Conversion to the methyl acetal was easily accomplished
by DIBAL reduction to the corresponding lactol followed
by treatment with pyridinium p-toluenesulfonate (PPTS)
in methanol to give 26 as a 2.5:1 (R:â) mixture of
anomers from which the major R-anomer was separable

4-epi-7-Dehydroxy-14,16-didemethyldiscodermolides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2849
Sch em e 2
Sch em e 3
DIBAL opening of acetals 40 and 41 were oxidized with
Dess-Martin periodinane to give aldehydes 42 and 43.
Treatment with isopropylmagnesium chloride24 and
carbamoylation afforded carbamates 44 and 45a in good
yields. For a truncated analogue where R1 ) H, the
primary alcohol derived from 41 was elaborated to the
carbamate to yield the PMB-protected methyl lactol
45b. The lactone was built from the methyl acetal in
44 and 45a ,b by using aqueous 60% acetic acid in THF
followed by Dess-Martin oxidation. The final target
compounds, 46 and 48a ,b, were prepared from their
respective intermediates by 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) oxidation. An additional analogue
47 containing a free C3 hydroxyl on the lactone ring
was obtained by the removal of MOM group with 4 N
HCl followed by removal of the PMB protecting group
by DDQ oxidation.
The biological activities of analogues 46, 47, and
48a ,b were measured in comparison to paclitaxel and
1 in several assays. Compound-induced hypernucleation
of isolated bovine brain tubulin was determined in a
standard assay (tubulin held at 2.5 °C, test agent or
DMSO added, temperature held at 2.5 °C for 1 min,
temperature raised to 30 °C in 0.5 min and held there
for 20 min, temperature lowered back to 2.5 °C within
2.5 min). Paclitaxel and 1, in the absence of GTP, cause
temperature-dependent assembly of the tubulin into
microtubules and ordered sheets of the protein. The
extent of this assembly is monitored by spectrophoto-
metric measurement of increases in absorbance (turbid-
ity). As shown in Table 2, compounds 46, 47, and 48a ,b
were inactive in this assay. Furthermore, these four
analogues showed neither appreciable antiproliferative
activity against human carcinoma cell lines, nor the
ability to compete with [3H]paclitaxel for binding to
preformed (with a nonhydrolyzable GTP analogue,
dideoxyGTP) microtubules.
p-anisaldehyde dimethyl acetal 29 to give p-methoxy-
phenyl (PMP) acetal 39. The second of the Wittig
reactions was performed with phosphonium salt 8,
which was prepared from compound 39, to give olefins
40 and 41 in good yield.
Alter a tion of th e Righ t Disp la y. On the basis of
the lack of biological activity exhibited by this first set
of analogues, our attention turned to analogues contain-
ing the original diene moiety in the right display along
To introduce an isopropyl group at C19 for truncated
analogues where R1 ) i-Pr, the primary alcohols from

2850 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Choy et al.
Sch em e 4
Ta ble 2. Microtubule-Stabilizing, Antiproliferative, and Paclitaxel Site-Competitive Properties of Compounds 46, 47, and 48a ,b in
Comparison to (+)-Discodermolide (1) and Paclitaxel
GI (µM)b
50
MT-stabilizing
activity (%)a
competition with
compound
MDA-MB231 (breast)
PC3 (prostate)
2008 (ovarian)
>50
>50
>50
>50
[3H]paclitaxel (%)c
46
47
48a
48b
7
13
<5
<5
>100
100
>50
>50
46 ( 1
30 ( 8
>50
10 ( 1
10 ( 3
3 ( 10
13 ( 1
64 ( 2
37 ( 1
>50
>50
>50
1
0.016 ( 0.003
0.0024 ( 0.0016
0.067 ( 0.004
0.015 ( 0.002
0.072 ( 0.005
0.0092 ( 0.0016
paclitaxel
a
Percent assembly of bovine brain tubulin induced by test agent at 10 µM vs that caused by 10 µM paclitaxel; single determinations
b
at 30 °C. Concentration at which test agent caused 50% inhibition of cell growth; means (N ) 4 over 10 concentrations) ( SD after 72
h of continuous exposure to the agent. c Percent competition by 4 µM test agent with 2 µM [3H]paclitaxel incubated with microtubules
formed from 2 µM bovine brain tubulin and 20 µM dideoxyGTP.
with a C4-epi-lactone in the left display. As shown in
Scheme 5, the construction of the right display featured
anti-aldol reactions. Selective opening of the benzylidine
ring of 39 with DIBAL gave a primary alcohol, which
was oxidized to aldehyde 49.25 The subsequent anti-
aldol condensation using Heathcock’s aldol reaction26
with dimethylphenyl propionate furnished compound 51
as the major product in 73% yield. The relative config-
uration of intermediate 51 was confirmed by 13C and
1H NMR analyses27 of the corresponding acetonide 55.
Silylation of the newly formed hydroxyl group of 51,
reduction of the aryl ester with DIBAL and Dess-
Martin oxidation of the resultant primary alcohol af-
forded aldehyde 52. The (Z)-diene moiety was intro-
duced by a two-step procedure developed by Paterson
and co-workers using a Nozaki-Hiyama reaction.28
Addition of the aldehyde 52 and allyl bromide 529 to a
suspension of CrCl2 in THF produced an intermediate
â-hydroxy silane (not shown), which upon treatment
with NaH underwent syn elimination to generate the
required (Z)-diene 54.6 Selective deprotection of the
primary TBS group, iodination, and then treatment

4-epi-7-Dehydroxy-14,16-didemethyldiscodermolides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2851
Sch em e 5
superior to paclitaxel in that it causes equivalent
microtubule assembly at both lower concentrations and
temperatures (the increase in absorbance caused by 1
occurs at a time point earlier than that caused by
paclitaxel). Additionally, the polymer induced to form
by 1 is more resistant to cold-induced disassembly than
is the paclitaxel-induced polymer. Both analogues 6b
(Figure 4C) and 6c (Figure 4D) showed these more rapid
polymer-inducing and cold-resistant properties, albeit
at lower potencies (for example, higher concentrations
of the analogues were necessary for these effects to be
detected) than 1. MOM ether lactone 6b was the most
potent among the new analogues.
Table 3 shows microtubule-stabilizing, antiprolifera-
tive, and paclitaxel site-competing properties of 6a -c.
Again, the lactone MOM ether 6b was more potent than
the lactol 6c or free hydroxy 6a relatives. The cellular
activity of 6b was encouraging, showing a submicromo-
lar 50% growth inhibitory (GI50) concentration. This
compound also showed considerable affinity for the
paclitaxel binding site on tubulin. Compound 6b com-
peted with [3H]paclitaxel for microtubules better than
paclitaxel and at almost the same potency as 1. Com-
pound 5a contains the pivaloyl group instead of a
lactone system in the left side region, and it is the most
potent of our previously reported discodermolide ana-
logues.14 Although 2- to 3-fold less potent than 6b as
an antiproliferative agent, it competed well for the
paclitaxel site on microtubules. But and in contrast to
6b, compound 5a catalyzed assembly of tubulin into
polymer only weakly and did not induce assembly at
low temperature (data not shown).
Wh olesa le Rep la cem en t of th e Dien e. Finally,
with highly active analogues in hand, we briefly inves-
tigated the wholesale replacement of the right-hand
diene fragment. Analogues 57 and 58 were targeted and
their preparations are summarized in Scheme 7. Both
analogues have the diene saturated and the C19 ste-
reocenter is erased. In compound 57, this was ac-
complished by deleting a methyl group and in compound
58 by adding one. Addition of hexylmagnesium bromide
to aldehyde 43 followed by carbamate formation and
deprotection gave 57. The requisite tertiary anion
needed for analogue 58 was prepared by reductive
metalation of 2-phenylthio-2-methylheptane with LDBB
(lithium di-tert-butylbiphenyl). Addition, carbamate
formation and deprotection as above provided analogue
58. The data in Table 3 show that both analogues 57
and 58 were considerably less active than the bench-
mark compound 6c, with antiproliferative potencies in
the 20-50 µM range and only modest ability to stabilize
microtubules or compete for the paclitaxel site on
microtubules.
with triphenylphosphine gave the phosphonium salt 914
in good yield.
Ba ck bon e Assem bly a n d Testin g of Dien e-Con -
ta in in g An a logu es w ith th e C4-epi-La cton e. The
second Wittig olefination was accomplished with phos-
phonium salt 9 (Scheme 6). Silyl ether deprotection with
TBAF followed by carbamoylation using Koc¸ovsky’s
method9,30 afforded the C19 carbamate-containing com-
pound 56. The lactone was built from the methyl acetal
in the left display using aqueous 60% acetic acid in THF
followed by Dess-Martin oxidation. The final target
compound 6a containing a free C3 hydroxy group on the
lactone was obtained by the removal of MOM group with
4N HCl followed by removal of the PMB protecting
group via DDQ oxidation. Two additional compounds,
6b and 6c, were prepared from the intermediate 56 by
using similar conditions. The three compounds were
then examined in the biological assays described above.
Con clu sion s
This work shows analogues of discodermolide that are
simpler and considerably more synthetically accessible
and which retain many of the interesting features of
the natural product. The biological results validated our
initial hypothesis that the C7 hydroxy group and the
C14 and C16 methyl groups can be deleted without
completely undermining activity. Moreover, our hypoth-
esis that extension of the H-bond acceptor at the C3
position, in the case of compounds 6b and 6c a MOM
All three of these analogues exhibited significant
biological activity. Surprisingly, the C3-MOM-protected
analogues 6b and 6c showed better microtubule hyper-
nucleation activities than the analogue with a free C3-
hydroxy group 6a . As can be seen in Figure 4A, 1 is

2852 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Choy et al.
Sch em e 6
Mattson Genesis Series Fourier transform spectrometer. Low
resolution electron ionization (EI) mass spectra were obtained
on a Hewlett-Packard 5971A MSD equipped with a 5890 Series
II GC, and both low and high-resolution spectra were obtained
on a VG 70-G or Micromass Autospec double focusing instru-
ment using EI or electrospray ionization (ESI). Flash chro-
matography was performed with ICN silica gel 60, 230-400
mesh, with the designated solvents. Reactions were monitored
by thin-layer chromatography on Kieselgel 60 F254 silica gel
plates. Optical rotations were recorded on a Perkin-Elmer 241
digital polarimeter with a sodium lamp at ambient tempera-
ether in place of the hydroxyl moiety in the natural
product, to assist in keeping the lactone and carbamate
moieties in close spatial proximity seems to be sup-
ported, as compound 6a with the C-3 hydroxyl was less
active than its MOM-bearing counterparts. Although
less potent than discodermolide and paclitaxel, com-
pounds 6b and 6c both showed properties unique to
discodermolide. These properties, particularly the ca-
pacity to cause hypernucleation of isolated tubulin at
lower temperature than paclitaxel as well as to stabilize
preformed MTs to cold disassembly (Figure 4), are
considered mechanistically superior to those of pacli-
taxel.
ture and are reported as [R]°C (c ) g/100 mL). The purity of
λ
compounds tested in biological assays was >95% as deter-
mined by HPLC analysis in two solvent systems as well as
high-resolution mass spectrometric and 13C NMR spectroscopic
analyses.
In the broader picture, our studies and those of others
suggest that the right display of discodermolide is much
more sensitive to change than is the left display. The
entire left side of discodermolide can be simplified to
an alkanoyl ester, and the resulting molecule still
retains the ability to compete for the paclitaxel site on
microtubules. This simplification causes, however, a
decrease in antiproliferative activity and has a negative
effect on its ability to cause hypernucleation of tubulin
to form microtubules at low temperatures. The terminal
alkene of the right side diene, which at present seems
to be the optimum substituent for activity, can be
replaced with a number of lipophilic groups while
retaining activity;14 however, the contraction of this
substituent to an isopropyl group or the wholesale
replacement of the diene with concomitant erasure of
the C19 stereocenter causes a significant drop in activ-
ity.
(4R)-4-Ben zyl-3-[(2R,3R)-3-(ter t-b u t yld im et h ylsila n -
yloxy)-2,4-d im et h ylp en t -4-en oyl]oxa zolid in -2-on e (17).
tert-Butyldimethylsilyl triflate (TBSOTf, 3.44 mL, 15 mmol)
was added to a stirred solution of 2,6-lutidine (2.32 mL, 20
mmol) and the Evans methacrolein aldol product (3.03 g, 10
mmol) obtained from compound 16 in CH2Cl2 (20 mL) at -78
°C. The mixture was stirred for 2 h at ambient temperature.
The reaction was quenched by the addition of aqueous HCl
(0.5 N, 50 mL). The resulting mixture was extracted with CH2-
Cl2 and dried over MgSO4 followed by the evaporation of
solvent under reduced pressure. The product was purified by
short column chromatography (hexane/EtOAc 9:1) and used
without further purification.
(2S,3R,4S,5R)-2-Allyl-6-m et h oxy-4-m et h oxym et h oxy-
3,5-d im eth yltetr a h yd r op yr a n (20). DIBAL (1 M in THF,
3.3 mL, 3.3 mmol) was added dropwise to a stirred solution of
19 (894 mg, 3 mmol) in anhydrous CH2Cl2 (30 mL) under an
atmosphere of N2 at -78 °C, and the resulting mixture was
stirred for an additional 1 h at -78 °C. The reaction was
quenched by the careful addition of saturated aqueous potas-
sium sodium tartrate (50 mL) and stirred for 3 h at room
temperature. Once the organic and aqueous layers had sepa-
rated, the aqueous layer was extracted with CH2Cl2. The
combined organic layer was washed with brine and dried over
MgSO4 followed by the evaporation of the solvent under
reduced pressure. The crude lactol was used for the next
reaction without further purification.
Exp er im en ta l Section
Ch em istr y. Gen er a l. All reactions were run under a dry
argon atmosphere unless otherwise noted. THF and benzene
were used freshly distilled from sodium benzophenone. Other
reagents were used as received from Aldrich Chemical Co.
NMR spectra were obtained on Bruker DPX-300 or DPX-500
spectrometers at ambient temperature in the solvent specified.
Chemical shifts are reported in parts per million (δ) downfield
from tetramethylsilane and proton-proton coupling constants
(J ) in Hz. Infrared (IR) spectra were recorded on an ATI
A solution of the lactol and CSA (0.3 mmol) in MeOH was
stirred for 24 h at room temperature. The reaction mixture
was diluted with EtOAc (100 mL) and washed with saturated
NaHCO3 (50 mL). The aqueous layer was extracted with

4-epi-7-Dehydroxy-14,16-didemethyldiscodermolides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2853
F igu r e 4. Tubulin assembly inducing properties of 1 (A), 6a (B), 6b (C), and 6c (D) in comparison to 10 µM paclitaxel (PTX).
Reaction mixtures containing 10 µM purified bovine brain tubulin in 0.8 M monosodium glutamate without test agent were
cooled to 0 °C and added to cuvettes held at 0.25-0.5 °C in a temperature-controlled spectrophotometer. Test agent in DMSO
(final concentration 4% v/v) was then rapidly mixed in the reaction mixture to give the concentrations listed. Baselines were
established at 0.25-2.5 °C, and temperature was rapidly raised to 30 °C (in approximately 1 min) and held there for 20 min. The
temperature was then rapidly lowered back to 0.25-2.5 °C. Each run contained 10 µM paclitaxel (blue diamonds) and a DMSO
only negative control (black squares).
Ta ble 3. Microtubule-Stabilizing, Antiproliferative, and Paclitaxel Site-Competitive Properties of Compounds 5a , 6a -c, 57, and 58
in Comparison to (+)-Discodermolide (1) and Paclitaxel
GI50 (µM)b
MT-stabilizing
activity (%)a
competition with
[3H]paclitaxel (%)c
compound
MDA-MB231 (breast)
PC3 (prostate)
2008 (ovarian)
1
>100
100
14
11
27
11
6
0.016 ( 0.003
0.0024 ( 0.0016
2.6 ( 0.9
0.067 ( 0.004
0.015 ( 0.002
3.0 ( 0.8
0.072 ( 0.005
0.0092 ( 0.0016
1.5 ( 1.0
64 ( 2
37 ( 1
32 ( 6
21 ( 1
57 ( 2
19 ( 2
9 ( 0
paclitaxel
5a (R1 ) t-Bu)14
6a
6b
6c
57
58
2.1 ( 1.8
7.5 ( 2.0
5.2 ( 1.0
0.87 ( 0.21
3.4 ( 0.8
24 ( 1
23 ( 0
1.8 ( 0.9
0.65 ( 0.25
4.7 ( 0.6
29 ( 4
42 ( 5
15 ( 3
>50
9
38 ( 1
15 ( 5
a
Percent assembly of bovine brain tubulin induced by 10 µM test agent vs that caused by 10 µM paclitaxel; single determinations at
b
30 °C. Concentration at which test agent caused 50% inhibition of cell growth; means (N ) 4 over 10 concentrations) ( SD after 72 h
of continuous exposure to the agent. c Percent competition by 4 µM test agent with 2 µM [3H]paclitaxel incubated with microtubules
formed from 2 µM bovine brain tubulin and 20 µM dideoxyGTP.
EtOAc (50 mL). The combined organic layer was dried over
MgSO4. The solvent was removed under reduced pressure, and
the crude product was used for the next reaction.
N,N-Diisopropylethylamine (7.5 mL) and chloromethyl meth-
yl ether (1.13 mL, 15 mmol) were added to a solution of the
alcohol in CH2Cl2 (15 mL). The reaction mixture was heated
to reflux and stirred overnight. The reaction was quenched
with saturated aqueous NaHCO3 (50 mL) followed by washing
with brine. The aqueous layer was extracted with CH2Cl2 (2
× 50 mL). The combined organic layer was dried over MgSO4.
The solvent was removed under reduced pressure, and the
crude product was purified by column chromatography (hex-
ane/EtOAc 7:3) to provide the pure anomers of 20 (â, 33%; R,
32%). â-20: IR (CHCl3) 3053, 2985, 2305, 1422, 1264 cm-1
;
1H NMR (300 MHz, CDCl3) δ 6.04 (m, 1H), 5.20-5.10 (m, 2H),
4.81 (d, 1H, J ) 6.9 Hz), 4.73 (d, 1H, J ) 2.37 Hz), 4.67 (d,
1H, J ) 6.8 Hz), 3.62 (m, 2H), 3.55 (s, 3H), 2.47 (m, 1H), 2.30
(m, 1H), 2.16 (m, 1H), 1.85 (m, 1H), 1.03 (d, 3H, J ) 7.1 Hz),

2854 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Choy et al.
anhydrous CH2Cl2 (110 mL) at 0 °C, followed by dropwise
addition of Bu2BOTf (1 M in CH2Cl2, 11 mL, 11 mmol). The
solution was stirred for 0.5 h at 0 °C. Crude 21 in anhydrous
CH2Cl2 (30 mL) was added at -78 °C. The mixture was stirred
for 10 min at -78 °C followed by an additional 2 h at 0 °C.
The reaction was quenched by addition of phosphate buffer,
pH 7.0 (50 mL). A solution of hydrogen peroxide (30%, 10 mL)
in methanol (20 mL) was added, and the mixture was allowed
to stir for 1 h at 0 °C. After separation of organic and aqueous
layers, the aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried over anhydrous MgSO4,
evaporated, and chromatographed (hexane/EtOAc 4:1) to yield
the aldol adduct (3.83 g, 87%) as a colorless oil: IR (CHCl3)
3472, 2954, 2860, 2252, 1778, 1691, 1383 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.48-7.36 (m, 7H), 7.01 (d, 2H, J ) 8.7 Hz),
4.58 (m, 1H), 4.33 (s, 2H), 4.18 (br s, 1H), 3.94 (s, 3H), 3.91
(m, 1H), 3.63 (t, 2 H, J ) 6.0 Hz), 3.40 (dd, 1H, J ) 3.2, 13.3
Hz), 3,37 (br s, 1H), 2.90 (dd, 1H, J ) 3.8, 13.3 Hz), 1.97-1.59
(m, 5H), 1.40 (d, 3H, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3)
177.3, 159.2, 153.1, 135.3, 130.6, 129.5, 129.3, 129.0, 127.4,
113.8, 72.5, 71.5, 69.9, 66.2, 55.2, 42.7, 37.7, 31.3, 26.4, 14.3,
11.1; HRMS (EI) calcd for C25H31NO6 441.2151, found 441.2162.
(4R)-4-Ben zyl-3-[(2R,3S)-3-(ter t-bu tyld im eth ylsila n yl-
oxy)-6-(4-m eth oxyben zyloxy)-2-m eth ylh exa n oyl]oxa zoli-
d in -2-on e (22). TBSOTf (1.7 mL, 7.5 mmol) was added to a
stirred solution of the above alcohol (2.20 g, 5 mmol) and 2,6-
lutidine (1.2 mL, 10 mmol) in CH2Cl2 (50 mL) at -78 °C, and
the mixture was stirred for 2 h at ambient temperature. The
reaction was quenched by addition of aqueous HCl (0.5 N, 100
mL). The reaction mixture was extracted with CH2Cl2 and
dried over MgSO4 followed by the evaporation of the solvent
under reduced pressure. The product was purified by column
chromatography (hexane/EtOAc 9:1) to yield 22: IR (CHCl3)
3020, 2955, 2858, 1779, 1362, 1211 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.45-7.36 (m, 7H), 7.00 (d, 2H, J ) 8.7 Hz), 4.70 (m,
1H), 4.56 (s, 2H), 4.27-4.15 (m, 3H), 4.04 (dd, 1H, J ) 5.4,
6.8), 3.91 (s, 3H), 3.60 (m, 3 H), 3.40 (dd, 1H, J ) 3.0, 13.2
Hz), 2.90 (dd, 1H, J ) 9.5, 13.2 Hz), 1.80 (br m, 4H), 1.38 (d,
3H, J ) 6.8 Hz), 1.05 (s, 9H), 0.21 (s, 3H), 0.17 (s, 3H); 13C
NMR (75 MHz, CDCl3) 175.4, 159.2, 153.2, 135.5, 130.9, 129.6,
129.3, 129.0, 127.4, 113.8, 72.9, 72.5, 70.2, 66.1, 55.9, 55.3, 42.8,
37.7, 32.1, 26.0, 25.2, 18.2, 12.2, -3.92, -4.65; LRMS (ESI)
578.3 (M + Na)+.
Sch em e 7
0.97 (d, 3H, J ) 6.8 Hz); 13C NMR (75 MHz, CDCl3) 135.1,
116.4, 101.3, 95.9, 81.9, 75.8, 56.4, 55.7, 37.5, 37.3, 33.6, 13.2,
9.9; HRMS (EI) calcd for C13H24O4 244.1596, found 244.1592.
R-20: 1H NMR (300 MHz, CDCl3) δ 6.00 (m, 1H), 5.22-5.12
(m, 2H), 4.83 (d, 1H, J ) 6.9 Hz), 4.69 (d, 1H, J ) 7.2 Hz),
4.49 (d, 1H, J ) 1.8 Hz), 3.88 (dt, 1H, J ) 3.6, 8.8 Hz), 3.53 (t,
2H, J ) 3.6 Hz), 3.48 (s, 3H), 2.45 (m, 1H), 2.28-2.11 (m, 3H),
1.94 (m, 1H), 1.12 (d, 3H, J ) 7.3 Hz), 1.00 (d, 3H, J ) 6.9
Hz); 13C NMR (75 MHz, CDCl3) 135.2, 116.7, 103.4, 95.6, 78.7,
69.6, 55.7, 37.2, 35.8, 33.6, 15.9, 13.5.
(2S,3R,4S,5R,6R)-3-(6-Meth oxy-4-m eth oxym eth oxy-3,5-
d im et h ylt et r a h yd r op yr a n -2-yl)p r op ion a ld eh yd e (10a ).
BH3-Me2S (1 M in THF, 3 mL, 3 mmol) was added to a solution
of 20 (488 mg, 2 mmol) in THF (10 mL) at 0 °C with stirring.
The mixture was allowed to warm to room temperature and
stirred for 3 h. The reaction was quenched with 2 N aqueous
NaOH (10 mL) followed by H2O2 (30%, 3 mL). After 1 h, the
mixture was extracted with CH2Cl2 (3 × 20 mL). The combined
organic layers were dried over anhydrous MgSO4, evaporated,
and chromatographed (hexane/EtOAc 7:3) to yield 392 mg
(75%) of alcohol as a colorless oil: IR (CHCl3) 3103, 2982, 1375,
1240 cm-1; H NMR (300 MHz, CDCl3) δ 4.83 (d, 1H, J ) 6.9
1
(2S,3S)-3-(ter t-Bu tyld im eth ylsila n yloxy)-6-(4-m eth oxy-
ben zyloxy)-2-m eth ylh exa n -1-ol. Lithium borohydride (2 M
in THF, 5 mL, 10 mmol) was added dropwise to a stirred
solution of 22 (2.77 g, 5 mmol) and methanol (0.4 mL, 10 mmol)
in anhydrous THF (20 mL) under an atmosphere of N2 at 0
°C. The mixture was stirred for 20 min at 0 °C and then
warmed to ambient temperature. After 3 h at room temper-
ature, the reaction was quenched with aqueous NH4Cl (100
mL) and extracted with CH2Cl2 (3 × 20 mL). The combined
organic layers were dried over anhydrous MgSO4, evaporated,
and chromatographed (hexane/EtOAc 7:3) to yield the alcohol
(1.48 g, 78%) as a colorless oil: IR (CHCl3) 2948, 2856, 2302,
Hz), 4.76 (d, 1H, J ) 2.4 Hz), 4.69 (d, 1H, J ) 6.9 Hz), 3.75 (t,
2H, J ) 5.4 Hz), 3.61 (t, 1H, J ) 2.7 Hz), 3.57 (s, 3H), 2.58 (br
s, 1H), 2.17 (m, 1H), 1.90-1.80 (m, 4H), 1.04 (d, 3H, J ) 7.1
Hz), 0.97 (d, 3H, J ) 6.8 Hz); 13C NMR (75 MHz, CDCl3) 101.5,
96.0, 82.0, 75.9, 62.8, 56.6, 55.8, 37.6, 34.0, 29.4, 28.6, 13.4,
9.8; HRMS (EI) calcd for C13H26O5 262.1780, found 262.1792.
Pyridinium sulfur trioxide (477 mg, 3 mmol) was added to
a stirred solution of alcohol (262 mg, 1 mmol) and N,N-
diisopropylethylamine (0.52 mL, 3 mmol) in anhydrous CH2-
Cl2 (6 mL) and DMSO (12 mL) at 0 °C. The reaction mixture
was stirred at the ambient temperature for 1 h. The mixture
was diluted with ethyl ether (50 mL) and washed with aqueous
HCl (0.5 N, 50 mL) and brine (10 mL). The organic layer was
dried over MgSO4, filtered, and concentrated under vacuum.
Flash silica gel column chromatography filtration (hexane/
EtOAc 4:1) to remove SO3-pyridine residue provided the crude
aldehyde 10a as a colorless oil, which was used without further
purification.
(4R)-4-Ben zyl-3-[(2R,3S)-3-h yd r oxy-6-(4-m eth oxyben z-
yloxy)-2-m eth ylh exan oyl]oxazolidin -2-on e. Pyridinium sul-
fur trioxide (7.15 g, 45 mmol) was added to a stirred solution
of the mono-PMB-protected alcohol derived from 14 (3.15 g,
15 mmol) and N,N-diisopropylethylamine (8.0 mL, 45 mmol)
in anhydrous CH2Cl2 (15 mL) and DMSO (30 mL) at 0 °C. The
mixture was stirred at ambient temperature for 1 h, diluted
with ethyl ether (300 mL), and washed with aqueous HCl (0.5
N, 200 mL) and then with brine. The separated organic layer
was dried over MgSO4. Filtration and concentration provided
the crude aldehyde 2131 as a colorless oil, which was used for
the next reaction without further purification.
1
1612, 1265 cm-1; H NMR (300 MHz, CDCl3) δ 7.27 (d, 2H, J
) 8.5 Hz), 7.00 (d, 2H, J ) 8.5 Hz), 4.43 (s, 2H), 3.78 (s, 3H),
3.67 (dd, 1 H, J ) 8.6, 10.5 Hz), 3.51-3.41 (m, 3H), 2.78 (br s,
1H), 1.94 (m, 1H), 1.72-1.49 (m, 4H), 0.90 (s, 9H), 0.81 (d,
3H, J ) 7.0 Hz), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz,
CDCl3) 159.2, 130.6, 129.3, 113.8, 75.4, 72.6, 70.1, 65.8, 55.9,
55.3, 39.7, 29.1, 26.6, 25.9, 18.0, 12.1, -4.28, -4.38; LRMS
(ESI) 405.2 (M + Na)+.
(4R)-4-Ben zyl-3-[(2R,3S,4R,5S)-5-(ter t-bu tyld im eth ylsi-
la n yloxy)-3-h yd r oxy-8-(4-m et h oxyb en zyloxy)-2,4-d im e-
th ylocta n oyl]oxa zolid in -2-on e. Pyridinium sulfur trioxide
(2.38 g, 15 mmol) was added to a stirred solution of the above
TBS-protected alcohol (1.91 g, 5 mmol) and N,N-diisopropyl-
ethylamine (2.65 mL, 15 mmol) in anhydrous CH2Cl2 (5 mL)
and DMSO (10 mL) at 0 °C. The mixture was stirred at the
ambient temperature for 1 h, diluted with ethyl ether (100
mL), washed with aqueous HCl (0.5 N, 100 mL) and brine,
then dried over MgSO4. Filtration and concentration provided
the crude aldehyde as a colorless oil, which was used without
further purification.
N,N-Diisopropylethylamine (1.9 mL, 11 mmol) was added
to a solution of propionyloxazolidinone (2.33 g, 10 mmol) in

4-epi-7-Dehydroxy-14,16-didemethyldiscodermolides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2855
N,N-Diisopropylethylamine (0.97 mL, 5.5 mmol) was added
to a solution of propionyloxazolidinone (1.16 g, 5 mmol) in
anhydrous CH2Cl2 (11 mL) at 0 °C, followed by dropwise
addition of Bu2BOTf (1 M in CH2Cl2, 5.5 mL, 5.5 mmol). The
solution was stirred for 0.5 h at 0 °C. A solution of crude
aldehyde from above in anhydrous CH2Cl2 (10 mL) was added
at -78 °C. The reaction mixture was stirred for 10 min at -78
°C then for 2 h at 0 °C. The reaction mixture was quenched
with phosphate buffer, pH 7.0 (50 mL). A solution of hydrogen
peroxide (30%, 10 mL) in methanol (20 mL) was slowly added,
and the mixture was stirred for 1 h. After the separation of
organic and aqueous layers, the aqueous layer was extracted
with CH2Cl2. The combined organic layers were dried over
anhydrous MgSO4, evaporated, and chromatographed (hexane/
EtOAc 4:1) to yield desired compound (2.29 g, 75%) as a
colorless oil: IR (CHCl3) 2949, 2855, 2253, 1779, 1692, 1463
r a n (26). Diisobutylaluminum hydride (1 M in THF, 2.2 mL,
2.2 mmol) was added dropwise to a stirred solution of 25 (732
mg, 2 mmol) in anhydrous CH2Cl2 (20 mL) under an atmos-
phere of N2 at -78 °C, and the mixture was stirred for 1 h at
-78 °C. The reaction was quenched by the careful addition of
saturated aqueous potassium sodium tartrate (50 mL) and
stirring for 3 h at room temperature. Once the organic and
aqueous layers separated, the aqueous layer was extracted
with CH2Cl2. The combined organic layer was washed with
brine and dried over MgSO4 followed by the evaporation of
solvent under reduced pressure. The crude lactol obtained was
used without further purification.
A solution of the lactol and PPTS (0.2 mmol) in MeOH was
stirred for 15 h at room temperature. The reaction mixture
was diluted with EtOAc (100 mL) and washed with saturated
aqueous NaHCO3 (50 mL). The aqueous layer was extracted
with EtOAc (50 mL). The combined organic layer was dried
over MgSO4. The solvent was removed under reduced pressure,
and the crude product was purified by column chromatography
(hexane/EtOAc 7:3) to provide the pure product each anomer
26 (â, 64%; R, 26%). â-26: IR (CHCl3) 3020, 2858, 2299, 1514,
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.33-7.19 (m, 7H), 7.01
(d, 2H, J ) 8.1 Hz), 4.42 (m, 1H), 4.44 (s, 2H), 4.16 (d, 1H, J
) 5.1 Hz), 4.01 (m, 1H), 3.95 (t, 1H, J ) 6.3 Hz), 3.85 (m, 1H),
3.79 (s, 3 H), 3.43 (br s, 2H), 3,24 (br s, 1H), 3.20 (dd, 1H, J )
2.4, 13.5 Hz), 2.77 (dd, 1H, J ) 9.6, 13.2 Hz), 1.56-1.31 (m,
5H), 1.32 (d, 3H, J ) 6.9 Hz), 0.95 (d, 3H, J ) 6.9 Hz), 0.89 (s,
9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3) 177.2, 159.2,
152.7, 135.1, 130.6, 129.5, 129.3, 129.0, 127.5, 113.8, 76.8, 74.2,
72.6, 70.0, 66.1, 55.3, 55.0, 40.6, 38.1, 37.8, 31.3, 25.9, 18.1,
13.2, 7.4, -3.5, -4.6; HRMS (EI) calcd for C34H51NO7Si
613.3435, found 613.3427.
1
1216 cm-1; H NMR (300 MHz, CDCl3) δ 7.35 (d, 2H, J ) 8.7
Hz), 6.95 (d, 2H, J ) 8.7 Hz), 4.76 (d, 2H, J ) 3.0 Hz), 4.52 (s,
2H), 4.37 (d, 1H, J ) 4.6 Hz), 4.09 (m, 1H), 3.89 (s, 2H), 3.57
(m, 2H), 3.47 (s, 3H), 3.32 (t, 1H, J ) 5.7 Hz), 1.89-1.71 (m,
6H), 1.16 (d, 3H, J ) 7.2 Hz), 1.07 (d, 3H, J ) 7.9 Hz); 13C
NMR (75 MHz, CDCl3) 159.2, 130.7, 129.3, 113.8, 103.2, 96.3,
82.0, 72.6, 69.9, 69.3, 55.7, 55.3, 39.1, 38.0, 27.1, 26.5, 16.0,
13.1; HRMS (EI) calcd for C21H34O6 382.2353, found 382.2355.
R-26: 1H NMR (300 MHz, CDCl3) δ 7.34 (d, 2H, J ) 8.7 Hz),
6.95 (d, 2H, J ) 8.7 Hz), 4.72 (s, 2H), 4.70 (d, 1H, J ) 2.8 Hz),
4.52 (s, 2H), 4.09 (br m, 4H), 3.67 (br s, 1H), 3.56 (m, 5H),
3.44 (s, 3H), 2.08-1.54 (m, 6H), 1.11 (d, 3H, J ) 3.0 Hz), 1.08
(d, 3H, J ) 2.9 Hz)
(4R)-4-Ben zyl-3-[(2R,3S,4R,5S)-5-(ter t-bu tyld im eth ylsi-
la n yloxy)-8-(4-m et h oxyb en zyloxy)-3-m et h oxym et h oxy-
2,4-d im eth ylocta n oyl]oxa zolid in -2-on e (24). N,N-Diiso-
propylethylamine (7.5 mL) and chloromethyl methyl ether
(1.13 mL, 9 mmol) were added to a solution of the alcohol from
above (1.83 g, 3 mmol) in CH2Cl2 (15 mL). The mixture was
stirred at reflux overnight. The reaction was quenched with
saturated aqueous NaHCO3 (50 mL) and washed with brine.
The aqueous layer was extracted with CH2Cl2 (2 × 50 mL).
The combined organic layer was dried over MgSO4. The solvent
was removed under reduced pressure, and the crude product
was purified by column chromatography (hexane/EtOAc 4:1)
to provide the pure product in 92% yield: IR (CHCl3) 3020,
(2S,3S,4S,5R,6R)-3-(6-Meth oxy-4-m eth oxym eth oxy-3,5-
d im eth yltetr a h yd r op yr a n -2-yl)p r op ion a ld eh yd e (10b). A
mixture of PMB ether 26 (458 mg, 1.2 mmol) and palladium
(10% Pd/C, 5 mg) was stirred in EtOAc (12 mL) for 3 h at room
temperature under an H2 atmosphere (balloon), filtered, and
concentrated to yield the debenzylated alcohol, which was used
without further purification.
1
2862, 1781, 1215 cm-1; H NMR (300 MHz, CDCl3) δ 7.36-
7.27 (m, 7H), 6.94 (d, 2H, J ) 8.7 Hz), 4.75 (s, 2H), 4.69 (m,
1H), 4.53 (s, 2H), 4.19 (dd, 1H, J ) 10.2, 15.0 Hz), 3.97 (dd,
1H, J ) 3.0, 6.6 Hz), 3.84 (br s, 4H), 3.43 (br t, 2H), 3,45 (s,
3H), 3.30 (dd, 1H, J ) 3.0, 13.2 Hz), 2.77 (dd, 1H, J ) 9.3,
13.5 Hz), 1.81-1.75 (m, 5H), 1.36 (d, 3H, J ) 6.9 Hz), 1.02 (d,
3H, J ) 6.9 Hz), 0.98 (s, 9H), 0.16 (s, 3H), 0.15 (s, 3H); 13C
NMR (75 MHz, CDCl3) 175.5, 159.1, 153.0, 135.4, 131.0, 129.5,
129.2, 129.0, 127.4, 113.7, 98.3, 80.3, 76.9, 73.2, 72.3, 70.5, 66.0,
56.3, 55.6, 55.2, 41.7, 40.8, 37.6, 30.6, 26.1, 24.2, 18.3, 14.0,
10.5, -3.9, -4.3; HRMS (EI) calcd for C34H50NO7Si (M - CH2-
OCH3) 612.3356, found 612.3367 (M - CH2OCH3).
The crude alcohol in CH2Cl2 (12 mL) was treated with Dess-
Martin periodinane (636 mg, 1.5 mmol) at room temperature.
The reaction was quenched with saturated aqueous NaHCO3
(20 mL). The aqueous layer was extracted with CH2Cl2 (2 ×
10 mL), and the combined extracts were dried over anhydrous
MgSO4. Filtration and concentration followed by short flash
column chromatography (hexane/EtOAc 4:1) provided 274 mg
(88%) of the crude aldehyde as a colorless oil which was used
without further purification: 1H NMR (500 MHz, CDCl3) δ 9.80
(s, 1H), 4.67 (dd, 2H, J ) 7.0, 12.5 Hz), 4.27 (d, 1H, J ) 4.5
Hz), 3.99 (dd, 1H, J ) 3.5, 4.0 Hz), 3.36 (s, 6H), 3.24 (t, 1H, J
) 6.0 Hz), 2.61 (m, 1H), 2.52 (m, 1H), 1.83 (m, 3H), 1.68 (m,
1H), 1.05 (d, 3H, J ) 7.0 Hz), 1.01 (d, 3H, J ) 7.5 Hz).
(2S,3R,4S)-5-(ter t-Bu tyld im eth ylsila n yloxy)-2,4-d im e-
th ylp en ta n e-1,3-d iol. Methanol (0.51 mL) and LiBH4 (2 M
in THF, 6.2 mL, 12.4 mmol) were added dropwise to a stirred
solution of aldol product 2822 (5.38 g, 12.3 mmol) in THF (50
mL) at 0 °C. After the mixture was stirred for 1 h at 0 °C,
saturated aqueous sodium potassium tartrate (70 mL) was
added. The mixture was allowed to warm to room temperature
and extracted with CH2Cl2 (2 × 50 mL). The combined organic
layer was washed with brine (40 mL), dried over anhydrous
MgSO4, concentrated, and flash column chromatographed
(hexane/EtOAc 4:1) to yield 2.99 g (92%) of the desired product
as a colorless oil: IR (CHCl3) 3409, 2958, 2927, 2853, 2878,
6-[(3R,4S,5S,6S)-3-(4-Meth oxyben zyloxy)pr opyl]-4-m eth -
oxym eth oxy-3,5-dim eth yltetr ah ydr opyr an -2-on e (25). HF-
pyridine (6 mL) was added to a solution of 24 (1.31 g, 2 mmol)
in MeOH (20 mL) and pyridine (10 mL) at 0 °C. The mixture
was stirred at room temperature for 48 h, diluted with EtOAc
(100 mL), and washed with aqueous HCl (0.5 N, 2 × 50 mL)
and with brine. The aqueous layer was extracted with EtOAc
(50 mL). The combined organic layer was dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure, and
the crude product was purified by column chromatography
(hexane/EtOAc 4:1) to provide the pure product in 83% yield:
1
IR (CHCl3) 3020, 2952, 1730, 1513, 1216 cm-1; H NMR (300
MHz, CDCl3) δ 7.24 (d, 2H, J ) 8.7 Hz), 6.87 (d, 2H, J ) 8.7
Hz), 4.72 (d, 1H, J ) 7.2 Hz), 4.60 (d, 1H, J ) 7.2 Hz), 4.48
(m, 1H), 4.43 (s, 2H), 3.80 (s, 3H), 3.50-3.39 (m, 2H), 3.39 (s,
3H), 3.26 (dd, 1H, J ) 1.1, 7.0 Hz), 2.58 (t, 1H, J ) 6.9 Hz),
2.03 (d, 1H, J ) 7.5 Hz), 1.81-1.63 (m, 4H), 1.31 (d, 3H, J )
6.7 Hz), 0.91 (d, 3H, J ) 7.3 Hz); 13C NMR (75 MHz, CDCl3)
174.1, 159.2, 130.5, 129.3, 113.8, 95.5, 82.6, 76.7, 72.6, 69.4,
55.9, 55.3, 40.5, 38.4, 28.6, 26.0, 14.4, 11.9, -3.9; HRMS (EI)
calcd for C20H30O6 366.2042, found 366.2050.
1469, 1385, 1361, 1252, 1082, 838, 773 cm-1 1H NMR (300
;
MHz, CDCl3) δ 4.45 (br s, 1H), 3.54 (br s, 1H), 1.92 (m, 1H),
1.83 (m, 1H), 1.06 (d, 3H, J ) 6.98 Hz), 1.00 (s, 9H), 0.84 (d,
3H, J ) 6.88 Hz), 0.19 (s, 6H); 13C NMR (75 MHz, CDCl3) 79.3,
69.7, 67.5, 37.4, 36.6, 25.9, 18.1, 12.8, 8.9, -5.5, -5.6; LRMS
(EI) 263 (M + H); HRMS (EI) calcd for C13H30O3Si 263.2042,
found 263.2042; [R]20 +35.5 (c 0.85, CHCl3).
D
2-Met h oxy-6-[(3R,4S,5S,6S)-3-(4-m et h oxyb en zyloxy)-
p r op yl]-4-m et h oxym et h oxy-3,5-d im et h ylt et r a h yd r op y-
(2S )-t er t -Bu t yl-{(4R ,5S )-2-[2-(4-m e t h oxyp h e n yl)-5-
m eth yl[1,3]d ioxa n -4-yl]p r op oxy}d im eth ylsila n e (30). A

2856 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Choy et al.
solution of the above diol (2.8 g, 10.7 mmol), p-anisaldehyde
dimethylacetal (2.0 mL, 11.7 mmol), and PPTS (0.27 g, 1.1
mmol) in benzene was heated to reflux for 3 h. The solvent
was evaporated under reduced pressure, and the residue was
purified by column chromatography (hexane/EtOAc 9:1) to give
30 (2.6 g, 6.8 mmol) in 64% yield: IR (CHCl3) 2955, 2927, 2853,
1617, 1518, 1459, 1382, 1157, 1101, 1033, 826 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.49 (m, 2H), 6.98 (m, 2H), 5.50 (m, 2H),
3.89 (s, 3H), 3.82 (dd, 1H, J ) 10.9, 4.9 Hz), 3.76 (dd, 2H, J )
8.1, 2.8 Hz), 1.87 (m, 1H), 1.71 (m, 1H), 1.23 (d, 3H, J ) 7.6
Hz), 1.00 (d, 3H, J ) 6.5 Hz); 13C NMR (75 MHz, CDCl3) 160.1,
132.1, 127.6, 113.8, 113.7, 101.9, 80.1, 74.3, 65.2, 64.3, 55.5,
37.4, 30.0, 26.3, 26.2, 18.7, 12.4, 11.3, -5.0, -5.1; LRMS (EI)
323, 207, 187, 157, 145, 121, 75; HRMS (EI) calcd for C21H36O4-
tracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were dried over anhydrous MgSO4, evaporated, and chromato-
graphed (hexane/ether 9:1) to yield 329 mg (67%) of 33 as a
colorless oil: IR (CHCl3) 2922, 2866, 2628, 2350, 1740, 1516
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.45 (d, 2H, J ) 8.4 Hz),
6.88 (d, 2H, J ) 8.4 Hz), 5.46 (m, 2H), 5.30 (t, 1H, J ) 9.9
Hz), 4.77 (d, 1H, J ) 6.9 Hz), 4.70 (d, 1H, J ) 1.8 Hz), 4.63 (d,
1H, J ) 6.9 Hz), 4.06 (br d, 1H, J ) 2.1 Hz), 3.80 (s, 3H), 3.54
(m, 3H), 3.43 (s, 3H), 3.32 (s, 3H), 2.77 (m, 1H), 2.31 (dd, 2H,
J ) 7.5, 14.7 Hz), 1.79-1.55 (m, 4H), 1.22 (d, 3H, J ) 6.6 Hz),
1.02 (d, 3H, J ) 7.2 Hz), 0.96 (d, 3H, J ) 6.9 Hz), 0.86 (d, 3H,
J ) 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 159.7, 133.4, 131.8,
130.1, 127.3, 113.3, 101.5, 101.3, 95.9, 83.5, 82.0, 75.2, 73.9,
56.4, 55.7, 55.2, 37.6, 34.2, 33.6, 33.0, 30.0, 23.4, 16.1, 13.3,
11.2, 9.9; HRMS (EI) calcd for C27H40O6 460.2824, found
460.2846.
Si1 323.1678 (M - C4H9), found 323.1694 (M - C4H9); [R]20
D
-33.6 (c 1.24, CHCl3).
(2S )-2-[(4R ,5S )-2-(4-Me t h oxyp h e n yl)-5-m e t h yl[1,3]-
d ioxa n -4-yl]p r op a n -1-ol. TBAF (1 M in THF, 22 mL, 22
mmol) was added to a solution of 30 (2.8 g, 7.3 mmol) in THF
(70 mL) at room temperature, and the mixture was stirred
for 2 h. The mixture was diluted with ethyl ether (100 mL)
and brine. The organic layer was dried over MgSO4. Filtration
and concentration followed by flash column chromatography
(hexane/EtOAc 7:3) provided alcohol (1.95 g, 7.2 mmol) in 99%
yield as a yellow oil: IR (CHCl3) 3428, 2964, 2930, 2835, 1614,
1512, 1463, 1391, 1249, 1098, 1027 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.38 (m 2H), 6.87 (m, 2H), 5.48 (s, 1H), 4.11 (dd, 2H,
J ) 4.6, 4.5 Hz), 3.75 (s, 3H), 3.73 (m, 2H), 3.52 (apparent t,
1H, J ) 11.1 Hz), 2.08 (m, 1H), 2.00 (m, 1H), 1.04 (d, 3H, J )
7.1 Hz), 0.77 (d, 3H, J ) 6.7 Hz); 13C NMR (75 MHz, CDCl3)
160.0, 131.5, 127.4, 113.6, 101.6, 83.4, 73.9, 66.3, 55.2, 36.8,
30.4, 11.9, 9.9; LRMS (EI) 266, 207, 177, 153, 135, 77; HRMS
(4R ,5S )-4-{(1S ,2Z)-5-[(2S ,3S ,4S ,5R ,6R )-6-Me t h oxy-4-
m eth oxym eth oxy-3,5-d im eth yltetr a h yd r op yr a n -2-yl]-1-
m eth ylp en t-2-en yl}-2-(4-m eth oxyp h en yl)-5-m eth yl[1,3]-
d ioxa n e (34). NaHMDS (1 M in THF, 1.1 mL, 1.1 mmol) was
slowly added to a solution of the salt 9 (0.70 g, 1.1 mmol) in
dry THF (2 mL) at 0 °C. The resulting red solution was stirred
at room temperature for 20 min. The mixture was cooled to
-78 °C, and a solution of the aldehyde 10b (260 mg, 1 mmol)
in THF (1 mL) was added dropwise. The mixture was stirred
for 20 min at -78 °C and then warmed to room temperature.
After 4 h at room temperature, the reaction was quenched with
saturated aqueous NH4Cl (10 mL) and extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were dried over
anhydrous MgSO4, evaporated, and chromatographed (hexane/
ether 9:1) to yield 329 mg (67%) of 34 as a colorless oil: IR
(CHCl3) 2922, 2866, 2628, 2350, 1740, 1516 cm-1 1H NMR
;
(EI) calcd for C15H22O4 266.1518, found 266.1517; [R]20 -4.8
(300 MHz, CDCl3) δ 7.48 (d, 2H, J ) 9.0 Hz), 6.91 (d, 2H, J )
9.0 Hz), 5.46 (m, 2H), 5.32 (t, 1H, J ) 9.6 Hz), 4.73 (s, 2H),
4.31 (d, 1H, J ) 5.4 Hz), 4.07 (br s, 2H), 3.81 (s, 1H), 3.57 (dd,
1H, J ) 1.8, 9.6 Hz), 3.45 (s, 3H), 3.43 (s, 3H), 3.20 (t, 1H, J
) 6.6 Hz), 2.77 (m, 1H), 2.31-2.17 (m, 2H), 1.90-1.62 (m, 4H),
1.24-0.98 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 159.7, 133.7,
131.7, 129.4, 127.2, 113.4, 102.8, 101.5, 96.6, 83.5, 82.2, 73.9,
70.0, 55.7, 55.2, 39.8, 38.4, 33.6, 30.0, 29.9, 24.3, 15.9, 15.5,
13.2, 11.1; HRMS (EI) calcd for C27H40O6 (M-HOCH3) 460.2824,
found 460.2846.
(2R ,3S ,4S ,5Z)-3-(4-Me t h o x y b e n zy lo x y )-8-[(2S ,3R ,-
4S,5R,6R)-6-m eth oxy-4-m eth oxym eth oxy-3,5-dim eth yltet-
r a h yd r op yr a n -2-yl]-2,4-d im eth yloct-5-en a l (35). DIBAL (1
M in hexane, 2.1 mL, 2.1 mmol) was added dropwise to a
solution of the acetal 33 (329 mg, 0.67 mmol) in dry CH2Cl2
(6.7 mL) at 0 °C. After being stirred for 2 h, the reaction was
quenched with saturated aqueous sodium tartrate (20 mL)
then vigorously stirred for several hours. The aqueous phase
was extracted with CH2Cl2 (3 × 10 mL), and the combined
organic layers were washed with brine (10 mL). The residue
obtained after drying over MgSO4 and evaporation under
vacuum was dissolved in anhydrous CH2Cl2 (6 mL) and DMSO
(12 mL), treated with N,N-diisopropylethylamine (0.52 mL, 3
mmol), cooled to 0 °C, and treated with pyridinium sulfur
trioxide (477 mg, 3 mmol). The reaction mixture was stirred
at ambient temperature for 1 h, diluted with ethyl ether (50
mL), and washed with aqueous HCl (0.5 N, 50 mL) and brine
(10 mL). The separated organic layer was dried over MgSO4.
Filtration and concentration followed by short flash column
chromatography (hexane/EtOAc 4:1) provided the crude alde-
hyde 35 (270 mg, 0.55 mmol) as a colorless oil, which was used
without further purification.
D
(c 0.67, CHCl3).
(2S)-{2-[(4R,5S)-2-(4-Met h oxyp h en yl)-5-m et h yl[1,3]-
d ioxa n -4-yl]p r op yl}tr ip h en ylp h osp h a n e Iod id e (11). I2
(4.48 g, 17.6 mmol) was added at 0 °C to a solution of the
alcohol from above (2.35 g, 8.82 mmol) in CH2Cl2 (110 mL)
containing imidazole (1.32 g, 19.4 mmol) and triphenylphos-
phine (4.63 g, 17.6 mmol). The resulting slurry was stirred
for 1 h and quenched with saturated aqueous Na2S2O3(10 mL).
The organic layer was separated, washed with water (20 mL)
and brine, and dried over anhydrous MgSO4. The solvent was
evaporated under reduced pressure, and the residue was
purified by column chromatography (hexane/EtOAc 9:1) to give
the pure iodide.
The iodide was quickly dissolved in benzene (44 mL), PPh3
was added (11.5 g, 44.1 mmol), and the mixture was heated
to reflux for 36 h. The reaction mixture was cooled to room
temperature, and anhydrous ethyl ether (50 mL) was added,
whereupon a white solid precipitated. Filtration followed by
washing of the solid with ethyl ether (10 mL) provided the
phosphonium salt (4.5 g) as a white foam: IR (CHCl3) 3054,
1
2961, 2909, 1611, 1515, 1435, 1246, 1107, 993, 752 cm-1; H
NMR (300 MHz, CDCl3) δ 7.55 (m, 9H), 7.37 (m, 6H), 7.21 (m,
2H), 6.65 (m, 1H), 5.41 (s, 1H), 3.95 (d, 1H, J ) 10.2 Hz), 3.68
(d, 2H, J ) 12.3 Hz), 3.54 (s, 3H), 3.26 (m, 1H), 1.85 (m, 1H),
1.46 (apparent d, 1H, J ) 6.5 Hz), 0.78 (d, 3H, J ) 6.8 Hz),
0.44 (d, 3H, J ) 6.6 Hz); 13C NMR (75 MHz, CDCl3) 160.0,
135.2, 135.1, 133.7, 133.5, 131.1, 130.5, 130.4, 127.9, 119.0,
117.9, 113.5, 101.9, 82.3, 82.1, 73.2, 55.5, 30.7, 29.2, 25.3, 15.7,
10.4 HRMS (EI) calcd for C33H36O3P 511.2402, found 511.2428;
[R]20 +31.9 (c 0.78, CHCl3).
D
(4R,5S)-4-{(1S,2Z)-5-[(2S,3R,4S,5R,6R)-6-Me t h oxy-4-
m eth oxym eth oxy-3,5-d im eth yltetr a h yd r op yr a n -2-yl]-1-
m eth ylp en t-2-en yl}-2-(4-m eth oxyp h en yl)-5-m eth yl[1,3]-
d ioxa n e (33). NaHMDS (1 M in THF, 1.1 mL, 1.1 mmol) was
slowly added to a solution of the salt 11 (701 mg, 1.1 mmol) in
dry THF (2.2 mL) at 0 °C. The resulting red solution was
stirred at room temperature for 20 min. The mixture was
cooled to -78 °C, and a solution of the aldehyde 10a (260 mg,
1 mmol) in THF (2 × 1 mL) was added dropwise. The mixture
was stirred for 20 min at -78 °C and then warmed to room
temperature. After 4 h at room temperature, the mixture was
quenched with saturated aqueous NH4Cl (10 mL) and ex-
(2R ,3S ,4S ,5Z)-3-(4-Me t h o x y b e n zy lo x y )-8-[(2S ,3S ,-
4S,5R,6R)-6-m eth oxy-4-m eth oxym eth oxy-3,5-dim eth yltet-
r a h yd r op yr a n -2-yl]-2,4-d im eth yloct-5-en a l (36). DIBAL (1
M in hexane, 2.1 mL, 2.1 mmol) was added dropwise to a
solution of the acetal 34 (329 mg, 0.67 mmol) in dry CH2Cl2
(6.7 mL) at 0 °C. After the mixture was stirred for 2 h, the
reaction was quenched with saturated aqueous sodium tartrate
(20 mL) followed by vigorous stirring for several hours. The
aqueous phase was extracted with CH2Cl2 (3 × 10 mL), and
the combined organic layers were washed with brine (10 mL).
After being dried over MgSO4 and evaporation under vacuum,

4-epi-7-Dehydroxy-14,16-didemethyldiscodermolides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2857
the residue was used for the next reaction without further
purification. The crude alcohol in CH2Cl2 (13 mL) was treated
with Dess-Martin periodinane (341 mg, 0.80 mmol). After the
reaction was complete, the mixture was quenched with satu-
rated NaHCO3 (20 mL). The aqueous layer was extracted with
CH2Cl2 (2 × 10 mL), and the combined extracts were dried
over anhydrous MgSO4. Filtration and concentration followed
by short flash column chromatography filtration (hexane/
EtOAc 9:1) provided crude aldehyde 36 (267 mg, 81%) as a
colorless oil, which was used without further purification.
(4R,5R)-ter t-Bu tyl-{3-[2-(4-m eth oxyp h en yl)-5-m eth yl-
[1,3]d ioxa n -4-yl]p r op oxy}d im eth ylsila n e (39). Lithium
borohydride (2 M in THF, 25 mL, 50 mmol) was added
dropwise to a stirred solution of 38 (8.70 g, 20 mmol) and
MeOH (1.61 mL, 40 mmol) in anhydrous THF (100 mL) under
an atmosphere of N2 at 0 °C. The mixture was stirred for 20
min at 0 °C and then warmed to ambient temperature. After
2 h at room temperature, the reaction was quenched with
aqueous NH4Cl (100 mL) and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried over anhydrous
MgSO4, evaporated, and chromatographed (hexane/EtOAc 7:3)
to yield 4.97 g (95%) of the diol as a colorless oil.
A solution of the diol (2.62 g, 10 mmol), anisaldehyde
dimethyl acetal (2.00 g, 11.0 mmol), and PPTS (0.1 equiv) in
benzene was stirred for 15 h at reflux. The reaction mixture
was quenched with saturated aqueous NaHCO3 (50 mL)
followed by washing with water. The aqueous layer was
extracted with ethyl ether (2 × 50 mL). The combined organic
layer was dried over MgSO4. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatography (hexane/EtOAc 7:3) to provide the pure 38
in 72% yield: IR (CHCl3) 2992, 1742, 1373, 1240 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.43 (d, 2H, J ) 8.4 Hz), 6.88 (d, 2H, J )
8.4 Hz), 5.45 (s, 1H), 4.08 (dd, 2H, J ) 10.5, 29.9 Hz), 3.90 (br
s, 1H), 3.80 (s, 3H), 3.67 (m, 2H), 1.67-1.50 (m, 5H), 1.17 (d,
3H, J ) 7.0 Hz), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz,
CDCl3) 159.9, 131.6, 127.4, 113.6, 101.7, 79.7, 73.9, 63.1, 55.3,
31.8, 29.3, 28.7, 26.0, 18.4, 11.1, -5.1; LRMS (ESI) 402.68 (M
+ Na).
(4S,5R)-4-{(3Z,5S,6S,7S,8Z)-6-(4-Met h oxyb en zyloxy)-
11-[(2S,3R,4S,5R,6R)-6-m eth oxy-4-m eth oxym eth oxy-3,5-
d im eth yltetr a h yd r op yr a n -2-yl]-5,7-d im eth ylu n d eca -3,8-
d ien yl}-2-(4-m eth oxyp h en yl)-5-m eth yl[1,3]d ioxa n e (40).
NaHMDS (1 M in THF, 1.1 mL, 1.1 mmol) was slowly added
to a solution of the salt 8 (350 mg, 0.55 mmol) in dry THF (1.1
mL) at 0 °C. The resulting red solution was stirred at room
temperature for 20 min. The mixture was cooled to -78 °C,
and a solution of the aldehyde 35 (246 mg, 0.5 mmol) in THF
(2 × 0.5 mL) was added dropwise. The mixture was stirred
for 20 min at -78 °C and then warmed to room temperature.
After 4 h at room temperature, the reaction was quenched with
saturated aqueous NH4Cl (10 mL) and extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were dried over
anhydrous MgSO4, evaporated, and flash column chromato-
graphed (hexane/diethyl ether 9:1) to yield 329 mg (67%) of
40 as a colorless oil: IR (CHCl3) 3020, 2752, 2332, 1516, 1216
cm-1 1H NMR (300 MHz, CDCl3) 7.50 (d, 2H, J ) 8.7 Hz),
;
7.37 (d, 2H, J ) 8.4 Hz), 6.95 (m, 4H), 5.58-5.32 (m, 5H), 4.81
(d, 1H, J ) 6.9 Hz), 4.74 (d, 1H, J ) 2.1 Hz), 4.64 (m, 3H),
4.10 (dd, 2H, J ) 9.6, 18.3 Hz), 3.95 (t, 1H, J ) 6.0 Hz), 3.85
(s, 6H), 3.59 (m, 2H), 3.56 (s, 3H), 3.46 (s, 3H), 3.14 (dd, 1H,
J ) 3.3, 7.5 Hz), 2.89 (m, 1H), 2.76 (m, 1H), 2.33-2.11 (m,
5H), 1.82-1.51 (m, 6H), 1.24 (d, 3H, J ) 6.9 Hz), 1.12 (m, 6H),
1.02 (d, 3H, J ) 7.0 Hz), 0.94 (d, 3H, J ) 6.9 Hz); 13C NMR
(75 MHz, CDCl3) 159.9, 159.1, 134.0, 132.5, 131.6, 131.3, 129.5,
129.2, 128.4, 127.4, 113.7, 113.6, 101.7, 101.3, 96.0, 88.0, 82.0,
79.2, 75.2, 74.9, 73.8, 56.4, 55.8, 55.3, 37.6, 35.9, 35.3, 34.2,
33.2, 32.9, 31.7, 23.4, 19.0, 17.6, 13.5, 11.2, 9.9; LRMS (ESI)
747.4 (M + Na)+.
(4S,5R)-4-{(3Z,5S,6S,7S,8Z)-6-(4-Met h oxyb en zyloxy)-
11-[(2S,3S,4S,5R,6R)-6-m eth oxy-4-m eth oxym eth oxy-3,5-
d im eth yltetr a h yd r op yr a n -2-yl]-5,7-d im eth ylu n d eca -3,8-
d ien yl}-2-(4-m eth oxyp h en yl)-5-m eth yl[1,3]d ioxa n e (41).
This was prepared by the same procedure as compound 40.
1
IR (CHCl3) 3020, 2752, 2332, 1516, 1216 cm-1; H NMR (300
MHz, CDCl3) 7.42 (d, 2H, J ) 7.8 Hz), 7.27 (d, 2H, J ) 7.8
Hz), 6.87 (m, 4H), 5.53-5.30 (m, 5H), 4.67 (br t, 2H, J ) 7.5
Hz), 4.54 (dd, 1H, J ) 10.5, 21.3 Hz), 4.26 (d, 1H, J ) 4 86
Hz), 4.07-3.98 (m, 3H), 3.87 (t, 1H, J ) 6.0 Hz), 3.79 (s, 6H),
3.39 (s, 6H), 3.19 (t, 1H, J ) 6.3 Hz), 3.07 (dd, 1H, J ) 3.9, 6.9
Hz), 2.75-2.62 (m, 2H), 2.16 (m, 5H), 1.87 (m, 3H), 1.63 (m,
3H), 1.16 (d, 3H, J ) 6.6 Hz), 1.08-0.96 (m, 12H); 13C NMR
(75 MHz, CDCl3) 159.9, 159.1, 134.1, 132.7, 131.6, 131.3, 129.2,
128.9, 128.3, 127.4, 113.7, 103.0, 101.7, 96.5, 88.0, 82.1, 79.3,
75.0, 73.8, 69.7, 55.8, 55.7, 55.3, 39.4, 38.3, 35.8, 35.4, 32.8,
31.6, 30.3, 29.8, 24.2, 23.3, 18.9, 17.4, 15.7, 13.2, 11.2; LRMS
(ESI) 747.4 (M + Na)+.
(4S,5R)-{3-[2-(4-Meth oxyp h en yl)-5-m eth yl[1,3]d ioxa n -
4-yl]p r op yl}tr ip h en yl-l5-p h osp h a n e Iod id e (8). TBAF (1
M in THF, 20 mL, 20 mmol) was added at room temperature
to a solution of 39 (3.80 g, 10 mmol) in THF (30 mL). After 2
h, the mixture was diluted with ethyl ether (100 mL) and brine
followed by drying over MgSO4. The solvent was evaporated
under reduced pressure and the residue was purified by
column chromatography (hexane/EtOAc 9:1) to give the pure
alcohol in 97% yield: IR (CHCl3) 2949, 2854, 2253, 1616, 1465,
1
1248 cm-1; H NMR (300 MHz, CDCl3) δ 7.50 (d, 2H, J ) 8.6
(2S,3R,6Z,8S,9S,10S,11Z)-3,9-Bis(4-m eth oxyben zyloxy)-
14-[(2S,3R,4S,5R,6R)-6-m eth oxy-4-m eth oxym eth oxy-3,5-
dim eth yltetr ah ydr opyr an -2-yl)-2,8,10-tr im eth yltetr adeca-
6,11-d ien a l (42). DIBAL (1 M in hexane, 0.3 mL, 0.3 mmol)
was added dropwise to a solution of 40 (72.4 mg, 0.1 mmol) in
dry CH2Cl2 (10 mL) at 0 °C. After the mixture was stirred for
2 h, the reaction was quenched with saturated aqueous sodium
tartrate (10 mL) followed by vigorous stirring for several hours.
The aqueous phase was extracted with CH2Cl2 (3 × 10 mL),
and the combined organic layers were washed with brine (10
mL). After drying over MgSO4 and evaporation under vacuum,
the residue was used for the next reaction without further
purification. The crude alcohol in CH2Cl2 (10 mL) was treated
with Dess-Martin periodinane (63.6 mg, 0.15 mmol). After
the reaction was complete, it was quenched with saturated
aqueous NaHCO3 (20 mL). The aqueous layer was extracted
with CH2Cl2 (2 × 10 mL), and the combined extracts were
dried over anhydrous MgSO4. Filtration and concentration
followed by short flash column chromatography filtration
(hexane/EtOAc 9:1) provided 60 mg (83%) of the crude alde-
hyde 42 as a colorless oil which was used without further
purification.
Hz), 6.96 (d, 2H, J ) 8.7 Hz), 5.55 (s, 1H), 4.21-4.00 (m, 4H),
3.87 (s, 3H), 3.54 (s, 3H), 3.72 (t, 2H, J ) 5.7 Hz), 1.99 (br s,
1H), 1.78-162 (m, 5H), 1.27 (d, 3H, J ) 6.9 Hz); 13C NMR (75
MHz, CDCl3) 160.0, 131.3, 127.4, 113.7, 101.8, 80.1, 73.9, 62.8,
55.0, 32.2, 29.8, 29.3, 11.2; HRMS (EI) calcd for C15H22O4
266.1518, found 266.1513.
I2 (4.48 g, 17.6 mmol) was added to a solution of the alcohol
from above (2.35 g, 8.82 mmol) containing imidazole (1.32 g,
19.4 mmol) and triphenylphosphine (4.63 g, 7.6 mmol) in CH2-
Cl2 (88 mL) at 0 °C. The resulting slurry was stirred for 1 h
and quenched with saturated aqueous Na2S2O3 (10 mL). The
organic layer was separated and washed with water (20 mL)
and brine and dried over anhydrous MgSO4. The solvent was
evaporated under reduced pressure, and the residue was used
for the next reaction without further purification.
The iodide was quickly dissolved in benzene (88 mL), PPh3
was added (11.5 g, 44.1 mmol), and the mixture was heated
to reflux for 36 h. The reaction mixture was cooled to room
temperature and anhydrous ethyl ether (50 mL) was added,
whereupon a white solid precipitated. Filtration and washing
with diethyl ether (10 mL) provided the phosphonium salt (4.5
g) as a white foam: 1H NMR (300 MHz, CDCl3) δ 8.27-7.40
(m, 17H), 6.96 (d, 2H, J ) 7.8 Hz), 5.71 (s, 1H), 4.42 (d, 1H, J
) 9.5 Hz), 4.32 (d, 1H, J ) 10.7 Hz), 4.20 (m, 1H), 4.06 (d, 1H,
J ) 11.3 Hz), 3.95 (s, 3H), 3.65 (m, 1H), 2.07-1.74 (m, 5H),
0.98 (d, 3H, J ) 6.8 Hz).
(2S,3R,6Z,8S,9S,10S,11Z)-3,9-Bis(4-m eth oxyben zyloxy)-
14-[(2S,3S,4S,5R,6R)-6-m eth oxy-4-m eth oxym eth oxy-3,5-
dim eth yltetr ah ydr opyr an -2-yl]-2,8,10-tr im eth yltetr adeca-
6,11-d ien a l (43). DIBAL (1 M in hexane, 0.3 mL, 0.3 mmol)
was added dropwise to a solution of 41 (72.4 mg, 0.1 mmol) in

2858 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Choy et al.
dry CH2Cl2 (10 mL) at 0 °C. After stirring for 2 h, the reaction
was quenched with saturated aqueous sodium tartrate (10 mL)
followed by vigorous stirring for several hours. The aqueous
phase was extracted with CH2Cl2 (3 × 10 mL), and the
combined organic layers were washed with brine (10 mL). After
drying over MgSO4 and evaporation under vacuum, the residue
was purified by column chromatography (hexane/EtOAc 7:3)
to give the alcohol: IR (CHCl3) 3019, 2897, 2286, 1778, 1515,
1216 cm-1; 1H NMR (300 MHz, CDCl3) 7.43 (m, 2H), 6.99 (m,
4H), 5.64 (t, 1H, J ) 10.8 Hz), 5.54-5.37 (m, 3H), 4.81 (dd,
2H, J ) 6.9, 9.6 Hz), 4.72-4.57 (m, 4H), 4.39 (d, 1H, J ) 5.1
Hz), 4.12 (m, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.81 (m, 1H), 3.63
(m, 2H), 3.52 (s, 6H), 3.33 (t, 1H, J ) 6.3 Hz), 3.19 (dd, 1H, J
) 3.9, 7.5 Hz), 2.91 (m, 1H), 2.75 (m, 1H), 2.31-1.38 (m, 11H),
1.21-0.99 (m, 15H); 13C NMR (75 MHz, CDCl3) 159.3, 159.1,
134.0, 132.8, 131.3, 130.5, 129.6, 129.2, 128.9, 128.4, 113.9,
113.7, 103.9, 96.6, 88.0, 82.2, 81.6, 75.0, 71.5, 69.8, 66.1, 55.8,
55.7, 55.3, 39.5, 38.3, 37.0, 35.9, 35.4, 30.3, 29.8, 24.5, 24.3,
19.0, 17.5, 15.7, 13.2, 11.8; LRMS (ESI) 749.5; HRMS (ESI)
calcd for C43H66O9Na 749.4605, found 749.4601 (M + Na)+.
The alcohol in CH2Cl2 (10 mL) was treated with Dess-
Martin periodinane (63.6 mg, 0.15 mmol). After the reaction
was complete, it was quenched with saturated aqueous
NaHCO3 (20 mL). The aqueous layer was extracted with CH2-
Cl2 (2 × 10 mL), and the combined organic layers were dried
over anhydrous MgSO4. Filtration and concentration followed
by short flash column chromatography filtration (hexane/
EtOAc 9:1) to remove the residue from Dess-Martin reagent
provided 60 mg (83%) of the crude aldehyde 43 as a colorless
oil, which was used without further purification.
55.3, 37.6, 37.2, 35.8, 35.3, 34.2, 33.1, 30.8, 30.0, 23.6, 23.3,
19.6, 18.9, 17.5, 14.2, 13.4, 10.1, 9.9; LRMS (ESI) 834.7 (M +
Na)+.
(1S,2S,3R,6Z,8S,9S,10S,11Z)-5,11-Bis(4-m et h oxyb en z-
yloxy)-16-[(2R,3S,4S,5R,6R)-6-m eth oxy-4-m eth oxym eth -
oxy-3,5-d im et h ylt et r a h yd r op yr a n -2-yl]-2,4,10,12-t et r a -
m eth ylh exa d eca -8,13-d ien -3-ol. This was prepared by the
procedure described for compound 44. IR (CHCl3) 3019, 2897,
2286, 1778, 1515 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.39 (m,
4H), 6.99 (m, 4H), 5.64 (t, 1H, J ) 10.8 Hz), 5.55-5.43 (m,
3H), 4.81 (dd, 1H, J ) 6.9, 9.6 Hz), 4.73-4.62 (m, 3H), 4.48
(d, 1H, J ) 10.8 Hz), 4.39 (d, 1H, J ) 5.1 Hz), 4.19 (m, 1H),
3.93 (s, 3H), 3.92 (s, 3H), 3.67 (m, 1H), 3.53 (s, 6H), 3.42 (m,
2H), 3.33 (t, 1H, J ) 6.9 Hz), 3.20 (dd, 1H, J ) 3.9, 7.5 Hz),
2.90 (m, 1H), 2.75 (dd, 1H, J ) 7.8, 15.0 Hz), 2.27-1.67 (m,
6H), 1.22-1.10 (m, 15H), 1.05 (d, 3H, J ) 7.2 Hz), 0.95 (d,
3H, J ) 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 159.3, 159.1,
134.2, 132.7, 131.3, 130.2, 129.4, 129.2, 129.0, 128.2, 114.0,
113.8, 103.1, 96.6, 88.0, 84.1, 82.2, 81.4, 76.7, 75.0, 70.8, 69.8,
55.8, 55.7, 55.3, 39.5, 38.4, 36.2, 35.4, 31.4, 30.5, 30.4, 24.3,
23.9, 19.6, 19.2, 18.9, 17.5, 15.7, 13.2, 5.9; LRMS (ESI) 791.5
(M + Na)+.
Ca r ba m ic Acid , (1S,2S,3R,6Z,8S,9S,10S,11Z)-1-Isop r o-
p yl-3,9-bis(4-m eth oxyben zyloxy)-14-[(2R,3S,4S,5R,6R)-6-
m eth oxy-4-m eth oxym eth oxy-3,5-d im eth yltetr a h yd r op y-
r an -2-yl]-2,8,10-tr im eth yltetr adeca-6,11-dien yl Ester (45a).
This was prepared by the procedure described for compound
44. IR (CHCl3) 3103, 3020, 2866, 2399, 1730, 1248, 1216 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.34 (m, 4H), 6.95 (m, 4H), 5.57
(t, 1H, J ) 10.5 Hz), 5.41 (m, 3H), 4.78-4.72 (m, 5H), 4.66-
4.52 (m, 2H), 4.43 (d, 1H, J ) 11.1 Hz), 4.33 (d, 1H, J ) 5.1
Hz), 4.06 (m, 1H), 3.86 (s, 6H), 3.32 (d, 1H, J ) 5.4 Hz), 3.27
(t, 1H, J ) 6.6 Hz), 3.15 9dd, 1H, J ) 3.9, 7.2 Hz), 2.84-2.71
(m, 2H), 2.25-1.57 (m, 11H), 1.38 (m, 1H), 1.04-0.93 (m, 21
H); 13C NMR (75 MHz, CDCl3) δ 159.1, 159.0, 157.3, 133.8,
132.8, 131.4, 131.0, 129.3, 129.2, 128.8, 128.6, 113.7, 102.9,
96.5, 88.0, 82.1, 80.1, 79.8, 75.0, 71.2, 69.8, 55.7, 55.3, 52.3,
39.5, 38.2, 37.3, 35.8, 35.4, 30.8, 30.2, 30.0, 24.2, 23.6, 18.9,
17.6, 15.7, 13.2, 11.4; LRMS (ESI) 834.7 (M + Na)+.
Ca r ba m ic Acid , (1S,2S,3R,6Z,8S,9S,10S,11Z)-1-Isop r o-
p yl-3,9-bis(4-m eth oxyben zyloxy)-14-[(2R,3R,4S,5R,6R)-6-
m eth oxy-4-m eth oxym eth oxy-3,5-d im eth yltetr a h yd r op y-
r an -2-yl]-2,8,10-tr im eth yltetr adeca-6,11-dien yl Ester (44).
Isopropylmagnesium chloride (1 M in THF, 0.8 mL, 0.8 mmol)
was added to a solution of 42 (60 mg, 0.083 mmol) in dry THF
at 0 °C. The mixture was allowed to warm to room temperature
and stirred overnight. The reaction was quenched with satu-
rated aqueous NH4Cl (10 mL) and extracted with CH2Cl2 (3
× 10 mL). The combined organic layers were dried over
anhydrous MgSO4, evaporated, and chromatographed (hexane/
ether 9:1) to yield the alcohol (41.4 mg, 65%) as a colorless oil:
Ca r b a m ic Acid , (2S,3R,6Z,8S,9S,10S,11Z)-3,9-Bis(4-
m et h oxyb en zyloxy)-14-[(2R,3S,4S,5R,6R)-6-m et h oxy-4-
m eth oxym eth oxy-3,5-dim eth yltetr ah ydr opyr an -2-yl]-2,8,-
10-tr im eth yl-1-(1-m eth ylp en ta -2,4-d ien yl)tetr a d eca -6,11-
d ien yl Ester (45b). DIBAL (1 M in hexane, 0.3 mL, 0.3 mmol)
was added dropwise to a solution of 41 (72.4 mg, 0.1 mmol) in
dry CH2Cl2 (10 mL) at 0 °C. After the mixture was stirred for
2 h, the reaction was quenched with saturated aqueous sodium
tartrate (10 mL) followed by vigorous stirring for several hours.
The aqueous phase was extracted with CH2Cl2 (3 × 10 mL),
and the combined organic layers were washed with brine (10
mL). After the organic fraction was dried over MgSO4 and
evaporated under vacuum, the residue was purified by column
chromatography (hexane/EtOAc 7:3) to give the alcohol. IR
1
IR (CHCl3) 3019, 2897, 2286, 1778, 1515 cm-1; H NMR (300
MHz, CDCl3) 7.35 (m, 4H), 6.95 (m, 4H), 5.57 (t, 1H, J ) 10.5
Hz), 5.44-5.35 (m, 3H), 4.81 (d, 1H, J ) 7.2 Hz), 4.72 (d, 1H,
J ) 2.4 Hz), 4.67 (m, 4H), 4.43 (d, 1H, J ) 10.8 Hz), 3.58 (t,
1H, J ) 2.4 Hz), 3.55 (s, 3H), 3.46 (s, 3H), 3.36 (m, 1H), 3.14
(dd, 1H, J ) 3.6, 7.5 Hz), 2.86 (m, 1H), 2.69 (m, 1H), 2.36-
1.53 (m, 6H), 1.24-0.98 (m, 21H); 13C NMR (75 MHz, CDCl3)
159.7, 159.1, 134.1, 132.4, 131.3, 129.5, 129.4, 129.2, 128.1,
113.9, 113.7, 101.3, 95.9, 88.0, 84.1, 82.0, 81.5, 75.1, 74.9, 70.7,
56.4, 55.8, 55.3, 37.6, 36.0, 35.3, 34.2, 33.1, 31.7, 31.4, 30.4,
23.9, 23.3, 19.6, 19.2, 17.7, 14.2, 13.4, 9.9, 5.8; LRMS (ESI)
791.5 (M + Na)+.
(CHCl3) 3019, 2897, 2286, 1778, 1515, 1216 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 7.43 (m, 2H), 6.99 (m, 4H), 5.64 (t, 1H, J
) 10.8 Hz), 5.54-5.37 (m, 3H), 4.81 (dd, 2H, J ) 6.9, 9.6 Hz),
4.72-4.57 (m, 4H), 4.39 (d, 1H, J ) 5.1 Hz), 4.12 (m, 1H), 3.93
(s, 3H), 3.91 (s, 3H), 3.81 (m, 1H), 3.63 (m, 2H), 3.52 (s, 6H),
3.33 (t, 1H, J ) 6.3 Hz), 3.19 (dd, 1H, J ) 3.9, 7.5 Hz), 2.91
(m, 1H), 2.75 (m, 1H), 2.31-1.38 (m, 11H), 1.21-0.99 (m, 15H);
13C NMR (75 MHz, CDCl3) δ 159.3, 159.1, 134.0, 132.8, 131.3,
130.5, 129.6, 129.2, 128.9, 128.4, 113.9, 113.7, 103.9, 96.6, 88.0,
82.2, 81.6, 75.0, 71.5, 69.8, 66.1, 55.8, 55.7, 55.3, 39.5, 38.3,
37.0, 35.9, 35.4, 30.3, 29.8, 24.5, 24.3, 19.0, 17.5, 15.7, 13.2,
11.8; LRMS (ESI) 749.5; HRMS (ESI) calcd for C43H66O9Na
749.4605, found 749.4601 (M + Na)+.
A solution of the alcohol in CH2Cl2 (8 mL) at 0 °C was
treated with trichloroacetyl isocyanate (0.05 mL, 0.42 mmol)
and stirred at room temperature. After 30 min, the solution
was concentrated under reduced pressure, and the residue was
taken up in MeOH (4 mL). Solid K2CO3 (50 mg) was added to
this solution, and the mixture was stirred at room temperature
for 3 h. The mixture was diluted with EtOAc (30 mL), and
the organic layer was washed with brine. The aqueous layer
was extracted with EtOAc, and the combined extracts were
A solution of the alcohol in CH2Cl2 (8 mL) at 0 °C was
treated with trichloroacetyl isocyanate (0.025 mL, 0.21 mmol)
and stirred at room temperature. After 30 min, the solution
was concentrated under reduced pressure, and the residue was
taken up in MeOH (4 mL). Solid K2CO3 (50 mg) was added to
this solution, and the mixture was stirred at room temperature
for 3 h. The mixture was diluted with EtOAc (30 mL), and
the organic layer was washed with brine. The aqueous layer
was extracted with EtOAc, and the combined extracts were
dried over anhydrous Na2SO4. Filtration and concentration
followed by flash column chromatography (hexane/EtOAc 3:2)
provided carbamate 44 (84.9 mg, 72%) as a yellow oil: IR
(CHCl3) 3103, 3020, 2866, 2399, 1730, 1248, 1216 cm-1
;
1H
NMR (300 MHz, CDCl3) 7.33 (m, 4H), 6.91 (m, 4H), 5.54 (t,
1H, J ) 10.5 Hz), 5.35 (m, 3H), 5.14 (br s, 1H), 4.93 (s, 1H),
4.81-4.29 (m, 7H), 3.86 (s, 3H), 3.84 (s, 3H), 3.72 (s, 2H), 3.60-
3.34 (m, 8H), 3.32 (m, 1H), 3.13 (dd, 1H, J ) 3.0, 7.5 Hz), 2.85
(m, 1H), 2.71 (q, 1H, J ) 7.5 Hz), 2.35 (m 12H), 1.10-0.92 (m,
21 H); 13C NMR (75 MHz, CDCl3) 159.1, 159.0, 157.5, 133.7,
132.6, 131.4, 131.0, 129.4, 129.3, 129.2, 128.6, 113.7, 101.2,
95.9, 88.0, 82.0, 80.1, 79.7, 75.2, 74.8, 71.2, 60.4, 56.4, 55.8,

4-epi-7-Dehydroxy-14,16-didemethyldiscodermolides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2859
dried over anhydrous Na2SO4. Filtration and concentration
followed by flash column chromatography (hexane/EtOAc 3:2)
provided carbamate 45b (63.0 mg, 82%) as a yellow oil: IR
lactone (40.0 mg, 0.05 mmol) in THF (5 mL). The flask was
fitted with a glass stopper, and the resulting solution was
stirred at room temperature for 72 h. Saturated aqueous K2-
CO3 was added dropwise followed by EtOAc. The organic layer
was extracted with EtOAc, and the combined extracts were
dried over MgSO4. Filtration and concentration followed by
flash column chromatography (EtOAc/hexane 3:2) provided the
crude MOM-deprotected compound. The PMB was removed
by treatment with NaHCO3 and DDQ. Flash chromatography
(EtOAc/hexane 3:2) of the crude product provided 47 (2.9 mg,
49%, three steps) as a colorless oil: IR (CHCl3) 3114, 2745,
(CHCl3) 3103, 3020, 2866, 2399, 1730, 1514 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 7.41 (m, 4H), 7.00 (m, 4H), 5.64 (t, 1H, J
) 10.8 Hz), 5.55-5.40 (m, 3H), 4.91 (br s, 2H), 4.79 (dd, 2H, J
) 7.2, 13.2 Hz), 4.69 (d, 1H, J ) 10.5 Hz), 4.57 (d, 1H, J ) 10
5 Hz), 4.51 (d, 1H, J ) 5.1 Hz), 4.24-4.06 (m, 3 H), 3.93 (s,
3H), 3.91 (s, 3H), 3.52 (s, 6H), 3.33 (t, 1H, J ) 6.6 Hz), 3.20
(dd, 1H, J ) 3.6, 7.5 Hz), 2.88 (m, 1H), 2.76 (m, 1H), 2.30-
1.64 (m, 11H), 1.21-1.05 (m, 15H); 13C NMR (75 MHz, CDCl3)
δ 159.19, 159.12, 157.1, 133.9, 132.7, 131.3, 130.9, 129.3, 129.2,
128.9, 128.4, 113.8, 113.7, 103.0, 96.5, 88.0, 82.1, 78.8, 75.0,
71.7, 69.4, 67.4, 55.8, 55.7, 55.3, 39.4, 38.3, 35.9, 35.8, 35.4,
31.2, 30.3, 29.8, 24.2, 18.9, 17.6, 15.7, 13.2, 11.4; LRMS (ESI)
792.5 (M + Na)+.
Ca r ba m ic Acid , (1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-Dih y-
dr oxy-14-[(2S,3R,4S,5R)-4-m eth oxym eth oxy-3,5-dim eth yl-
6-oxot et r a h yd r op yr a n -2-yl]-2,8,10-t r im et h yl-1-(1-m et h -
ylp en ta -2,4-d ien yl)tetr a d eca -6,11-d ien yl Ester (46). A
solution of 44 (40.5 mg, 0.05 mmol) in THF (0.5 mL) and 60%
aqueous acetic acid (2.5 mL) was stirred at 70 °C for 4 h. After
the reaction was complete by TLC, the reaction mixture was
neutralized slowly with saturated aqueous K2CO3 and diluted
with EtOAc (20 mL). The aqueous phase was extracted with
EtOAc (2 × 10 mL). The combined organic layers were dried
over MgSO4 and evaporated under reduced pressure. The
crude lactol was used without further purification.
2323, 1706, 1487, 1215 cm-1 1H NMR (300 MHz, CDCl3) δ
;
5.58-5.43 (m, 4H), 4.85 (br s, 2H), 4.67 (dd, 1H, J ) 3.6, 7.3
Hz), 4.41 (dt, 3.1, J ) 3.1, 9.0 Hz), 3.81 (br t, 1H), 3.69 (dd,
1H, J ) 2.1, 6.0 Hz), 3.32 (t, 1H, J ) 5.7 Hz), 3.68 (m, 2H),
2.74 (m, 3H), 2.36-1.72 (m, 10H), 1.61 (t, 1H, J ) 7.5 Hz),
1.40 (d, 3H, J ) 7.2 Hz), 1.14 (d, 3H, J ) 7.2 Hz), 1.08-0.94
(m, 15H); 13C NMR (125 MHz, CDCl3) δ 174.2, 157.8, 133.5,
132.6, 130.0, 128.9, 81.6, 79.5, 79.3, 73.4, 43.3, 39.8, 35.5, 35.3,
35.1, 34.7, 33.1, 30.8, 29.8, 24.3, 23.0, 19.3, 18.3, 18.1, 15.9,
15.8, 12.7, 7.9; LRMS (ESI) 534.8 (M + Na)+; HRMS (ESI)
calcd for C28H49NO7Na 534.3407, found 534.3383 (M + Na)+;
[R]20 +6.9 (c 0.35, CHCl3).
D
Ca r ba m ic Acid , (1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-Dih y-
dr oxy-14-[(2S,3R,4R,5R)-4-m eth oxym eth oxy-3,5-dim eth yl-
6-oxot et r a h yd r op yr a n -2-yl]-2,8,10-t r im et h yl-1-(1-m et h -
ylp en t a -2,4-d ien yl)t et r a d eca -6,11-d ien yl E st er (48a ).
Prepared by the procedure described for compound 47. IR
(CHCl3) 3020, 2400, 1730, 1216 cm-1 1H NMR (300 MHz,
;
Dess-Martin periodinane reagent (31.8 mg, 0.075 mmol)
was added to a solution of the lactol in CH2Cl2 (5 mL). The
resulting solution was stirred for 1 h and quenched by the
simultaneous addition of saturated aqueous Na2S2O3 (5 mL)
and saturated aqueous NaHCO3. The aqueous layer was
extracted with CH2Cl2 (2 × 10 mL), and the combined extracts
were dried over anhydrous MgSO4. Filtration and concentra-
tion followed by flash column chromatography (hexane/EtOAc
4:1) provided 27.0 mg (68%) of the lactone PMB ether as a
color oil: IR (CHCl3) 2992, 2361, 2332, 1742, 1374, 1242, 1047
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.37 (m, 4H), 6.94 (m, 4H),
5.60 (t, 1H, J ) 7.8 Hz), 5.37 (m, 3H), 5.44-5.32 (m, 10H),
3.87 (s, 3H), 3.85 (s, 3H), 3.64 (t, 1H, J ) 3.0 Hz), 3.45 (s, 3H),
3.49 (dd, 1H, J ) 5.4, 11.1 Hz), 3.15 (dd, 1H, J ) 3.9, 7.4 Hz),
2.88 (m, 2H), 2.72 (m, 1H), 2.25 (m, 4H), 2.00 (m, 4H), 1.68
(m, 6H), 1.34 (m, 6H), 1.10-0.95 (m, 15H); 13C NMR (75 MHz,
CDCl3) δ 173.9, 159.1, 159.0, 157.3, 133.7, 133.5, 131.4, 131.0,
129.3, 129.2, 128.6, 128.1, 113.79, 113.71, 96.0, 88.0, 80.4, 80.2,
79.7, 79.2, 74.9, 71.3, 55.9, 55.3, 40.7, 37.3, 35.9, 35.3, 33.5,
33.1, 30.8, 30.0, 29.8, 23.6, 22.7, 19.6, 18.9, 17.5, 17.4, 16.4,
13.4, 10.9; LRMS (ESI) 818.7 (M + Na)+.
CDCl3) 5.46 (m, 4H), 4.81 (d, 1H, J ) 7.2 Hz), 4.74 (br s, 2H),
4.70 (d, 1H, J ) 7.2 Hz), 4.58 (d, 1H, J ) 7.5 Hz), 3.87 (m,
2H), 3.71 (m, 1H), 3.49 (s, 3H), 3.36 (d, 1H, J ) 7.2 Hz), 3.25
(t, 1H, J ) 5.7 Hz), 2.71 (m, 2H), 2.71 (m, 2H), 2.37-1.57 (m,
11H), 1.40 (d, 3H, J ) 7.5 Hz), 1.07-0.84 (m, 18H); 13C NMR
(100 MHz, CDCl3) 173.3, 157.6, 133.3, 132.8, 129.6, 113.7 95.4,
82.6, 81.5, 79.1, 73.3, 55.8, 40.4, 39.7, 35.3, 34.8, 34.6, 33.6,
31.9, 29.6, 24.2, 22.6, 19.2, 18.1, 17.9, 15.6, 14.3, 11.9, 7.9;
LRMS (ESI) 578.3 (M + Na)+; HRMS (ESI) calcd for C30H54
-
NO8 556.3849, found 556.3800 (M + H)+; [R]20 +8.6 (c 0.15,
D
CHCl3).
Car bam ic Acid, (2S,3R,6Z,8S,9S,10S,11Z)-3,9-Dih ydr oxy-
14-[(2S,3R,4R,5R)-4-m eth oxym eth oxy-3,5-dim eth yl-6-oxo-
tetrahydropyran-2-yl]-2,8,10-trimethyltetradeca-6,11-dienyl
Ester (48b). A solution of 26b (38.4 mg, 0.05 mmol) in THF
(0.5 mL) and 60% aqueous acetic acid (2.5 mL) was stirred at
70 °C for 4 h. After the reaction was complete by TLC, it was
neutralized slowly with saturated aqueous K2CO3 and diluted
with EtOAc (20 mL). The aqueous phase was extracted with
EtOAc (2 × 10 mL). The combined organic layers were dried
over MgSO4 and evaporated under reduced pressure. The
crude lactol was used without further purification.
Dess-Martin periodinane reagent (31.8 mg, 0.075 mmol)
was added to a solution of the lactol in CH2Cl2 (5 mL). The
resulting solution was stirred for 1 h and quenched by the
simultaneous addition of saturated aqueous Na2S2O3 (5 mL)
and saturated aqueous NaHCO3. The aqueous layer was
extracted with CH2Cl2 (2 × 10 mL), and the combined extracts
were dried over anhydrous MgSO4. Filtration and concentra-
tion followed by flash column chromatography (hexane/EtOAc
4:1) provided 18.8 mg (50%) of the lactone PMB ether as a
colorless oil: IR (CHCl3) 3024, 2954, 2873, 1730, 1374, 1241
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 4H), 6.99 (m, 4H),
5.68 (t, 1H, J ) 9.9 Hz), 5.45-5.35 (m, 3H), 4.87-4.51 (m, 7H),
4.13 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.53 (s, 6H), 3.40 (d,
1H, J ) 7.2 Hz), 3.20 (dd, 1H, J ) 3.6, 7.8 Hz), 2.76 (m, 1H),
2.71 (m, 2H), 2.31-1.68 (m, 14H), 1.45 (d, 3H, J ) 6.6 Hz),
1.17-1.02 (m, 15H); 13C NMR (75 MHz, CDCl3) δ 174.2, 159.2,
157.1, 133.6, 131.2, 131.0, 129.4, 129.3, 128.6, 127.9, 113.8,
95.5, 88.0, 82.7, 78.8, 75.1, 71.7, 67.4, 55.9, 55.4, 40.6, 38.7,
36.1, 35.8, 35.4, 31.8, 31.2, 29.8, 24.2, 23.7, 19.1, 17.7, 14.5,
12.1, 11.5; LRMS (ESI) 776.4 (M + Na)+.
A solution of the PMB ether (16 mg, 0.02 mmol) from above
in CH2Cl2 (2 mL) at 0 °C was treated with NaHCO3 (4.2 mg,
0.5 mmol) and DDQ (0.2 M in CH2Cl2, 0.75 mL, 0.15 mmol).
After 1 h, the mixture was diluted with CH2Cl2 and washed
with water. The aqueous layer was extracted with CH2Cl2, and
the combined extracts were dried over anhydrous MgSO4.
Filtration and concentration followed by flash column chro-
matography (EtOAc/hexane 3:2) provided carbamate 46 (8.6
mg, 78%) as a colorless oil: IR (CHCl3) 3402, 2363, 1751, 1373,
1
1240, 1052 cm-1; H NMR (300 MHz, CDCl3) 5.53-5.44 (m,
4H), 4.80 (d, 1H, J ) 7.2 Hz), 4.74 (br s, 2H), 4.69 (d, 1H, J )
7.2 Hz), 4.40 (dt, 1H, J ) 2.4, 9.0 Hz), 3.68 (m, 2H), 3.47 (s,
3H), 3.32 (t, 1H, J ) 5.7 Hz), 2.91 (ddd, 1H, J ) 3.6, 7.5, 18.3
Hz), 2.74 (m, 2H), 2.37-1.57 (m, 11H), 1.38 (d, 3H, J ) 7.5
Hz), 1.27-0.92 (m, 18H); 13C NMR (125 MHz, CDCl3) 173.9,
157.7, 133.5, 132.7, 130.0, 95.9, 81.5, 80.4, 79.2, 79.1, 73.3, 55.9,
40.7, 39.7, 35.4, 34.7, 34.6, 33.6, 33.2, 30.7, 24.2, 22.8, 19.3,
18.1, 18.0, 16.4, 15.5, 13.4, 7.9; LRMS (ESI) 578.6 (M + Na)+;
HRMS (ESI) calcd for C30H53NO8Na 578.3669, found 578.3680
(M + Na)+; [R]20 +32.0 (c 0.25, CHCl3).
D
Ca r ba m ic Acid , (1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-Dih y-
dr oxy-14-[(2S,3R,4S,5R)-4-h ydr oxy-3,5-dim eth yl-6-oxotet-
r ah ydr opyr an -2-yl]-1-isopr opyl-2,8,10-tr im eth yltetr adeca-
6,11-d ien yl Ester (47). Compound 44 (8.49 mg, 0.01 mmol)
was subjected to the lactonization procedure described above.
Aqueous 4 N HCl (2.5 mL) was added to a solution of the
A solution of the PMB ether (15.0 mg, 0.02 mmol) from
above in CH2Cl2 (2 mL) at 0 °C was treated with NaHCO3 (4.2
mg, 0.5 mmol) and DDQ (0.2 M in CH2Cl2, 0.5 mL, 0.10 mmol).
After 1 h, the mixture was diluted with CH2Cl2 and washed

2860 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Choy et al.
with water. The aqueous layer was extracted with CH2Cl2, and
the combined extracts were dried over anhydrous MgSO4.
Filtration and concentration followed by flash column chro-
matography (hexane/EtOAc 2:3) provided carbamate 48b (3.8
mg, 38%) as a colorless oil: IR (CHCl3) 3020, 2400, 1730, 1216
DIBAL (1 M in THF, 6 mL, 6 mmol) was added dropwise to
a stirred solution of the TBS-protected aryl ester (1.90 g, 2
mmol) from above in anhydrous CH2Cl2 (20 mL) under an
atmosphere of N2 at 0 °C, and the mixture was stirred for
additional 1 h at 0 °C. The reaction was quenched by the
careful addition of saturated aqueous potassium sodium
tartrate (50 mL). The mixture was stirred for 3 h at room
temperature. Once the aqueous and organic layers had sepa-
rated, the aqueous layer was extracted with CH2Cl2 (20 mL).
The combined organic layer was washed with brine and dried
over MgSO4 followed by the evaporation of the solvent under
reduced pressure. The residue was purified by column chro-
matography (EtOAc/hexane 7:3) to give the title compound in
pure form (997 mg, 1.8 mmol): IR (CHCl3) 3125, 1544, 1289,
1
cm-1; H NMR (300 MHz, CDCl3) δ 5.46-5.35 (m, 4H), 4.79
(br s, 2H), 4.75 (d, 1H, J ) 7.2 Hz), 4.62 (d, 1H, J ) 7.2 Hz),
4.48 (br d, 1H, J ) 8.1 Hz), 4.20 (dd, 1H, J ) 9.3, 10.7 Hz),
3.86 (dd, 1H, J ) 5.4, 11.1 Hz), 3.64 (br s, 1H), 3.40 (s, 3H),
3.27 (m, 2H), 2.62 (m, 3H), 2.46 (br s, 1H), 2.26-2.01 (m, 5H),
1.89-1.57 (m, 5H), 1.33 (d, 3H, J ) 6.6 Hz), 1.04-0.86 (m,
12H); 13C NMR (100 MHz, CDCl3) δ 174.2, 157.6, 133.6, 132.9,
129.7, 128.9, 95.5, 82.7, 79.3, 69.8, 67.3, 55.9, 40.6, 38.7, 38.3,
35.5, 35.0, 34.1, 31.7, 24.4, 23.9, 18.3, 15.9, 14.5, 12.1, 9.8;
LRMS (ESI) 536.3 (M + Na)+; HRMS (ESI) calcd for C27H47
-
1065 cm-1, H NMR (300 MHz, CDCl3) δ 7.28 (d, 2H, J ) 8.7
1
NO8Na 536.3199, found 536.3197 (M + Na)+; [R]20 +27.4 (c
Hz), 6.89 (d, 2H, J ) 8.7 Hz), 4.51 (d, 1H, J ) 11.1), 4. 41 (d,
1H, J ) 10.8 Hz), 3.83 (d, 3H), 3.79 (m, 1H), 3.64 (m, 4H),
3.36 (m, 1H), 2.45 (br s, 1H), 1.93 (m, 2H), 1.63 (m, 4H), 1.00
(d, 2H, J ) 7.0 Hz), 0.92 (s, 24H), 0.14 (s, 6H), 0.13 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 159.1, 130.6, 129.4, 113.6, 80.3,
76.0, 71.2, 65.2, 63.0, 55.1, 39.1, 39.0, 29.0, 27.1, 26.1, 25.9,
18.2, 14.5, 11.6, -3.6, -3.9, -5.3; LRMS (ESI) 576.8 (M +
Na)+.
D
0.58, CHCl3).
(2S,3R)-6-(ter t-Bu tyld im eth ylsila n yloxy)-3-(4-m eth oxy-
ben zyloxy)-2-m eth ylh exa n a l (49). DIBAL (1 M in THF, 15
mL, 15 mmol) was added dropwise to a stirred solution of 39
(1.90 g, 5 mmol) in anhydrous CH2Cl2 (50 mL) under an
atmosphere of N2 at 0 °C, and the mixture was stirred for 1 h
at 0 °C. The reaction was quenched by the careful addition of
saturated aqueous potassium sodium tartrate (100 mL) and
stirring for 3 h at room temperature. The aqueous layer was
extracted with CH2Cl2. The combined organic layer was
washed with brine and dried over MgSO4 followed by the
evaporation of the solvent under reduced pressure. The crude
alcohol (1.56 g, 4.1 mmol) was used without further purifica-
tion.
Pyridinium sulfur trioxide (2.38 g, 15 mmol) was added to
a stirred solution of the crude alcohol from above and diiso-
propylethylamine (2.6 mL, 15 mmol) in anhydrous CH2Cl2 (10
mL) and DMSO (20 mL) at 0 °C. The mixture was stirred at
ambient temperature for 1 h. After the reaction was complete,
the mixture was diluted with diethyl ether (100 mL) and
washed with 0.5 N HCl (100 mL) and brine (100 mL). The
organic layer was dried over MgSO4. Filtration and concentra-
tion followed by short flash column chromatography filtration
(hexane/EtOAc 4:1) to remove SO3-pyridine provided the
crude aldehyde 49 as a colorless oil, which was used without
further purification.
(2R,3S,4R,5R)-3,8-Bis(ter t-bu tyld im eth ylsila n yloxy)-5-
(4-m eth oxyben zyloxy)-2,4-d im eth ylocta n a l (52). Pyridin-
ium sulfur trioxide (858 mg, 5.4 mmol) was added to a stirred
solution of the alcohol (997 mg, 1.8 mmol) from above,
diisopropylethylamine (0.94 mL, 5.4 mmol) in anhydrous CH2-
Cl2 (3.6 mL), and DMSO (7.2 mL) at 0 °C. The mixture was
stirred at ambient temperature for 1 h. After the reaction was
complete, the mixture was diluted with ethyl ether (50 mL)
and washed with aqueous HCl (0.5N, 50 mL) and brine (10
mL). The organic layer was dried over MgSO4. Filtration and
concentration followed by short flash column chromatography
filtration (hexane/EtOAc 4:1) to remove SO3-pyridine provided
the crude aldehyde 52 as a colorless oil which was used without
further purification: 1H NMR (300 MHz, CDCl3) δ 9.69 (s, 1H),
7.22 (d, 2H, J ) 8.6 Hz), 6.85 (d, 2H, J ) 8.6 Hz), 4.45 (d, 1H,
J ) 11.1 Hz), 4.28 (d, 1H, J ) 11.1 Hz), 3.94 (dd, 1H, J ) 5.5,
4.0 Hz), 3.79 (s, 3H), 3.60 (t, 2H, J ) 6.0 Hz), 3.40-3.34 (m,
1H), 2.66-2.58 (m, 1H), 1.92-1.84 (m, 1H), 1.67-1.59 (m, 2H),
1.55-1.45 (m, 2H), 1.02 (d, 3H, J ) 7.0 Hz), 0.98 (d, 3H, J )
7.0 Hz), 0.89 (s, 9H), 0.86 (s, 9H), 0.05 (s, 3H), 0.04 (s, 9H).
(1R,2R,3S,4S,5Z)-1-{3-(ter t-Bu tyld im eth ylsila n yloxy)-
1-[3-(ter t-bu tyld im eth ylsila n yloxy)p r op yl]-2,4-d im eth yl-
octa -5,7-d ien yloxym eth yl}-4-m eth oxyben zen e (54). CrCl2
(1.09 g, 9.0 mmol) was added to a stirred solution of the crude
aldehyde (1.8 mmol) from above and 1-bromoallyltrimethyl-
silane 53 (578 mg, 5.4 mmol) in anhydrous THF (18 mL) under
an atmosphere of N2 at room temperature. The mixture was
stirred for 14 h at ambient temperature, then diluted with
ethyl ether followed by filtration through Celite. After the
evaporation of the solvent under reduced pressure, the residue
was purified by short column silica gel column chromatography
(CH2Cl2).
(2R,3R,4R,5R)-8-(ter t-Bu t yld im et h ylsila n yloxy)-3-h y-
dr oxy-5-(4-m eth oxyben zyloxy)-2,4-dim eth yloctan oic acid,
2,6-d im eth ylp h en yl Ester (51). LDA (2 M in THF, 3.1 mL,
6.2 mmol) was added to a solution of 2,6-dimethylphenyl
propionate (1.10 g, 6.2 mmol) in anhydrous THF (12.4 mL) at
-78 °C, followed by stirring for 1 h at -78 °C. The crude
aldehyde (4.1 mmol) from above was dissolved in anhydrous
THF (10 mL) and added slowly at -78 °C. After 2 h at room
temperature, the mixture was quenched with saturated aque-
ous NH4Cl (10 mL) and extracted with CH2Cl2 (3 × 10 mL).
The combined organic layer was dried over anhydrous MgSO4,
evaporated, and chromatographed (hexane/EtOAc 4:1) to yield
51 (1.67 g, 2.99 mmol) as a colorless oil: IR (CHCl3) 3120, 2857,
1744, 1514, 1216, 1099 cm-1 1H NMR (300 MHz, CDCl3) δ
;
The above product in THF (50 mL) was cooled to 0 °C, and
NaH (95% w/ w in mineral oil, 207 mg, 9.0 mmol) was added
in one portion. The ice bath was removed after 15 min, and
the mixture was stirred for 2 h at ambient temperature. The
reaction mixture was cooled to 0 °C, quenched with H2O (10
mL), and extracted with diethyl ether (2 × 50 mL). The
combined organic layer was washed with brine and dried over
MgSO4 followed by the evaporation of the solvent under
reduced pressure. The residue was purified by column chro-
matography (hexane/EtOAc 4:1) to give pure 54 (622 mg, 1.2
mmol): IR (CHCl3) 2954, 2931, 2857, 1608, 1513, 1463, 1251,
7.26 (d, 2H, J ) 8.4 Hz), 6.87 (d, 2H, J ) 8.4 Hz), 4.62 (d, 1H,
J ) 11.1 Hz), 4.40 (d, 1H, J ) 11.1 Hz), 4.06 (d, 1H, J ) 6.8
Hz), 3.79 (s, 3H), 3.66-3.61 (m, 3H), 2.89 (m, 1H), 2.19 (s, 6H),
1.86 (m, 2H), 1.55 (m, 3H), 1.27 (d, 3H, J ) 6.8 Hz), 1.01 (d,
3H, J ) 6.9 Hz), 0.93 (s, 9 H), 0.07 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 173.5, 159.2, 148.0, 130.0, 129.9, 129.4, 128.4, 125.6,
113.8, 83.5, 70.7, 62.9, 55.1, 44.0, 35.6, 28.7, 26.6, 25.8, 18.2,
16.3, 14.2, 5.7, -5.3; HRMS (EI) calcd for C32H50O6Si 558.3377,
found 558.3392.
(2S,3S,4R,5R)-3,8-Bis(ter t-bu tyld im eth ylsila n yloxy)-5-
(4-m et h oxyb en zyloxy)-2,4-d im et h yloct a n -1-ol. TBSOTf
(0.68 mL, 3 mmol) was added to a stirred solution of 51 (1.11
g, 2 mmol) and 2,6-lutidine (0.69 mL, 6 mmol) in CH2Cl2 (20
mL) at -78 °C. The mixture was stirred for 2 h at ambient
temperature. The reaction was quenched by the addition of
0.5 N HCl (50 mL). The reaction mixture was extracted with
CH2Cl2 and dried over MgSO4, and the solvent was removed
under reduced pressure. Short column chromatography (hex-
ane/EtOAc 4:1) provided the crude product.
1
1098, 1047 cm-1; H NMR (300 MHz, CDCl3) δ 7.35 (d, 2H, J
) 8.6 Hz), 6.96 (d, 2H, J ) 8.6 Hz), 6.41 (ddd, 1H, J ) 16.7,
11.0, 10.1 Hz), 6.04 (dd, 1H, J ) 11.1, 11.0 Hz), 5.57 (dd, 1H,
J ) 10.1, 16,8 Hz), 5.20 (d, 1H, J ) 16.7 Hz), 5.06 (d, 1H, J )
10.1 Hz), 4.51 (d, 1H, J ) 11.3 Hz), 4.35 (d, 1H, J ) 11.3 Hz),
3.81 (s, 3H), 3.63-3.57 (m, 3H), 3.28 (dt, 1H, J ) 5.5, 5.5 Hz),
2.70 (ddq, 1H, J ) 10.3, 6.9, 3.2 Hz), 1.73-1.58 (m, 3H), 1.50-
1.44 (m, 2H), 0.94 (d, 3H, J ) 6.9 Hz), 0.93-0.91 (m, 21H),
0.06 (s, 6H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3) 159.1,

4-epi-7-Dehydroxy-14,16-didemethyldiscodermolides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2861
134.8, 132.5, 131.0, 129.5, 128.9, 117.1, 113.7, 78.9, 76.6, 70.7,
63.2, 55.2, 40.0, 36.4, 31.6, 28.7, 26.2, 26.0, 18.9, 18.5, 18.3,
10.9, -3.3, -3.4, -5.3; LRMS (EI) 576, 519, 467, 387, 357, 293,
225, 121; HRMS (EI) calcd for C29H51O4Si2 519.3326, found
this solution and the mixture was stirred at room temperature
for 3 h at room temperature. The mixture was diluted with
EtOAc (30 mL). The organic layer was washed with brine. The
aqueous layer was extracted with EtOAc, and the combined
extracts were dried over anhydrous Na2SO4. Filtration and
concentration followed by flash column chromatography (hex-
ane/EtOAc 3:2) provided carbamate 56 (84.9 mg, 72%) as a
519.3332; [R]20 -18.8° (c 0.75, CHCl3).
D
(2R)-2-{(4R,5S,6R)-6-[3-(ter t-Bu tyld im eth ylsila n yloxy)-
p r op yl]-2,2,5-tr im eth yl[1,3]d ioxa n -4-yl}p r op a n oic Acid ,
2,6-Dim eth ylp h en yl Ester (55). A mixture of PMB ether 51
(55.8 mg, 0.1 mmol) and palladium (10% Pd/C, 5 mg) in EtOAc
(10 mL) was stirred at room temperature under an H2
atmosphere (balloon) for 3 h. The mixture was filtered and
concentrated to yield the diol, which was used without further
purification. A solution of the crude diol, 2,2-dimethoxypropane
(12.4 mg, 0.12 mmol) and PPTS (0.1 equiv) in benzene was
stirred for 5 h at 65 °C. The reaction was quenched with
saturated aqueous NaHCO3 (50 mL) followed by washing with
water. The aqueous layer was extracted with ethyl ether (2 ×
50 mL). The combined organic layer was dried over MgSO4.
The solvent was removed under reduced pressure, and the
crude product was purified by column chromatography (hex-
ane/EtOAc 9:1) to provide the pure 55 in 52% yield: IR (CHCl3)
yellow oil: IR (CHCl3) 3100, 3019, 2430, 2286, 1720, 1524 cm-1
;
1H NMR (300 MHz, CDCl3) 7.41 (m, 4H), 7.01 (m, 4H), 6.46
(ddd, 1H, J ) 16.8, 11.0, 10.1 Hz), 6.11 (t, 1H, J ) 10.8 Hz),
5.62 (t, 1H, J ) 10.5 Hz), 5.53-5.18 (m, 6H), 4.94 (t, 1H, J )
6.0 Hz), 4.84 (br s, 2H), 4.81 (d, 2H, J ) 2.1 Hz), 4.71-4.45
(m, 4H), 4.39 (d, 1H, J ) 5.1 Hz), 4.12 (m, 1H), 3.37 (m, 2H),
3.19 (dd, 1H, J ) 4.5, 6.9 Hz), 2.90 (m, 3H), 2.27 (m, 2H), 1.91
(m, 2H), 1.74-1.61 (m, 4H), 1.11-0.99 (m, 18H); 13C NMR (75
MHz, CDCl3) 159.2, 159.0, 157.1, 133.7, 133.3, 132.8, 132.2,
131.4, 130.9, 129.8, 129.6, 129.1, 128.5, 117.8, 113.8, 113.7,
102.9, 96.5, 88.0, 82.1, 78.4, 78.1, 74.9, 70.5, 69.8, 55.8, 55.7,
55.3, 39.5, 38.2, 37.7, 35.8, 35.4, 34.3, 30.6, 30.3, 24.2, 23.6,
18.9, 17.8, 17.4, 15.7, 13.2, 9.8; LRMS (ESI) 888.4 (M + K)+.
Ca r ba m ic Acid , (1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-Bis(4-
m eth oxyben zyloxy)-14-[(2S,3S,4S,5R)-4-m eth oxym eth oxy-
3,5-dim eth yl-6-oxotetr ah ydr opyr an -2-yl]-2,8,10-tr im eth yl-
1-[(1S ,2Z)-1-m e t h y lp e n t a -2,4-d ie n y l]t e t r a d e c a -6,11-
d ien yl Ester . A solution of 56 (42.4 mg, 0.05 mmol) in THF
(0.5 mL) and 60% aqueous acetic acid (2.5 mL) was stirred at
70 °C for 4 h. After the reaction was complete by TLC, the
mixture was neutralized slowly with saturated aqueous K2-
CO3 and diluted with EtOAc (20 mL). The aqueous phase was
extracted with EtOAc (2 × 10 mL). The combined organic
layers were dried over MgSO4 and evaporated under reduced
pressure. The crude lactol was used for the next reaction
without further purification.
2855, 1742, 1510, 1091 cm-1 1H NMR (500 MHz, CDCl3) δ
;
7.03 (br s, 3H), 4.20 (dd, 1H, J ) 1.7, 10.2 Hz), 3.91 (m, 1H),
3.64 (m, 2H), 2.91 (dq, 1H, J ) 10.2, 6.9 Hz), 2.16 (s, 6H), 1.59-
1.32 (m, 6H), 1.41 (s, 3H), 1.39 (s, 3H), 1.24 (d, 3H, J ) 4.2
Hz), 0.92 (br s, 12H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3)
173.7, 148.2, 130.3, 128.5, 125.8, 99.1, 75.2, 73.0, 63.1, 42.3,
31.8, 29.9, 29.3, 28.8, 26.0, 19.5, 18.4, 16.4, 12.9, 4.54, -5.19;
HRMS (EI) calcd for C27H46O5Si 478.3115, found 463.2889 (M
- CH3)+.
(1S,2S,3R,6Z,8S,9S,10S,11Z)-[3,9-Bis(4-m et h oxyb en z-
yloxy)-14-[(2S,3S,4S,5R,6R)-6-m eth oxy-4-m eth oxym eth -
oxy-3,5-dim eth yltetr ah ydr opyr an -2-yl]-2,8,10-tr im eth yl-1-
[(1S,2Z)-1-m eth ylp en ta -2,4-d ien yl)tetr a d eca -6,11-d ien yl-
oxy]-ter t-bu tyld im eth ylsila n e. NaHMDS (1 M in THF, 0.54
mL, 0.54 mmol) was added slowly to a solution of the salt 9
(475.9 mg, 0.54 mmol) in dry THF (1.08 mL) at 0 °C. The
mixture was cooled to -78 °C, and a solution of the aldehyde
36 (267 mg, 0.54 mmol) in THF (1.08 mL) was added dropwise.
The mixture was stirred for 20 min at -78 °C and then
warmed to room temperature. After 4 h at room temperature,
the mixture was quenched with saturated aqueous NH4Cl (10
mL) and extracted with CH2Cl2 (3 × 10 mL). The combined
organic layer was dried over anhydrous MgSO4, evaporated,
and chromatographed (hexane/EtOAc 9:1) to yield the desired
compound (257 mg, 0.28 mmol) as a colorless oil: IR (CHCl3)
2920, 2861, 2620, 1740, 1520 cm-1, 1H NMR (300 MHz, CDCl3)
7.38 (m, 4H), 6.96 (m, 4H), 6.47 (ddd, 1H, J ) 16.8, 11.0, 10.1
Hz), 6.04 (t, 1H, J ) 11.1 Hz), 5.57 (t, 1H, J ) 10.5 Hz), 5.49-
5.12 (m, 6H), 4.75 (d, 2H, J ) 2.1 Hz), 4.67-4.33 (m, 5H), 4.07
(m, 1H), 3.65 (dd, 1H, J ) 3.3, 6.0 Hz), 3.47 (br s, 7H), 3.35
(dd, 1H, J ) 4.5, 4.7 Hz), 3.27 (t, 1H, J ) 6.6 Hz), 3.15 (dd,
1H, J ) 4.5, 6.9 Hz), 2.77 (m, 3H), 2.18 (m, 2H), 1.91 (m, 2H),
1.74-1.62 (m, 4H), 1.11-0.99 (m, 18H), 0.12 (s, 6H); 13C NMR
(75 MHz, CDCl3) 159.2, 159.0, 134.7, 133.7, 132.9, 132.5, 131.4,
131.0, 129.6, 129.1, 128.9, 128.6, 117.3, 113.8, 113.7, 103.0,
96.5, 88.0, 82.1, 78.8, 74.9, 70.8, 69.7, 55.8, 55.3, 40.0, 39.5,
38.3, 35.6, 35.4, 31.3, 30.3, 26.4, 24.2, 23.7, 19.0, 18.8, 18.6,
17.3, 15.7, 13.2, 11.0, -3.1, -3.2; LRMS (ESI) 942.5 (M + Na)+.
Ca r ba m ic Acid , (1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-Bis(4-
m et h oxyb en zyloxy)-14-[(2S,3S,4S,5R,6R)-6-m et h oxy-4-
m et h oxym et h oxy-3,5-d im et h ylt et r a h yd r op yr a n -2-yl]-
2,8,10-tr im eth yl-1-[(1S,2Z)-1-m eth ylp en ta -2,4-d ien yl]tet-
r a d eca -6,11-d ien yl Ester (56). The above compound (128.5
mg, 0.14 mmol) in THF (4 mL) was treated with TBAF (1 M
in THF, 0.40 mL, 0.40 mmol), and the mixture was stirred at
room temperature for 48 h. The mixture was diluted with ethyl
ether (30 mL) and washed with water (10 mL). After drying
over MgSO4 and evaporation under vacuum, the resulting
alcohol was used without further purification.
Dess-Martin periodinane reagent (31.8 mg, 0.075 mmol)
was added to a solution of the lactol in CH2Cl2 (5 mL). The
resultant solution was stirred for 1 h and quenched by the
simultaneous addition of saturated aqueous Na2S2O3 (5 mL)
and saturated aqueous NaHCO3. The aqueous layer was
extracted with CH2Cl2 (2 × 10 mL), and the combined extracts
were dried over anhydrous MgSO4. Filtration and concentra-
tion followed by flash column chromatography (hexane/EtOAc
8:2) provided 28.3 mg (68%) of the lactone as a colorless oil:
IR (CHCl3) 2992, 2361, 2332, 1742, 1374, 1242, 1047 cm-1; 1H
NMR (300 MHz, CDCl3) 7.40 (m, 4H), 7.03 (m, 4H), 6.51 (ddd,
1H, J ) 16.8, 11.1, 10.0 Hz), 6.11 (t, 1H, J ) 11.1 Hz), 5.67 (t,
1H, J ) 10.8 Hz), 5.52-5.18 (m, 7H), 4.94 (t, 1H, J ) 6.0 Hz),
4.87-4.47 (m, 9H), 3.94 (br s, 4H), 3.93 (s, 3H), 3.54 (s, 3H),
3.40 (m, 2H), 3.19 (dd, 1H, J ) 4.5, 6.9 Hz), 2.87 (m, 2H), 2.72
(m, 2H), 2.32-1.89 (m, 7H), 1.45 (d, 3H, J ) 6.6 Hz), 1.15-
01.02 (m, 15H); 13C NMR (75 MHz, CDCl3) 174.2, 159.2, 159.0,
156.9, 133.6, 133.5, 133.4, 132.2, 131.3, 130.9, 129.8, 129.6,
129.5, 129.2, 128.7, 127.8, 113.8, 113.7, 95.4, 88.0, 82.7, 79.9,
78.4, 76.5, 75.0, 55.9, 55.7, 55.3, 40.5, 38.6, 37.7, 36.0, 35.4,
34.3, 31.3, 30.6, 23.9, 23.6, 23.5, 19.0, 17.8, 14.4, 12.1, 9.8;
LRMS (ESI) 872.4 (M + K)+.
Ca r ba m ic Acid , (1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-Dih y-
d r oxy-14-[(2S,3S,4S,5R)-4-h yd r oxy-3,5-d im eth yl-6-oxotet-
r a h yd r op yr a n -2-yl]-2,8,10-t r im et h yl-1-[(1S,2Z)-1-m et h -
ylp en ta -2,4-d ien yl]tetr a d eca -6,11-d ien yl Ester (6a ). A
solution of the above lactone (2.83 mg, 0.005 mmol) in THF (2
mL) was treated with 4 N HCl (1 mL). The flask was fitted
with a glass stopper, and the resulting solution was stirred at
room temperature for 48 h. Saturated aqueous K2CO3 was
added dropwise followed by EtOAc. The aqueous layer was
extracted with EtOAc, and the combined extracts were dried
over MgSO4. Filtration and concentration followed by simple
short flash column chromatography (EtOAc/hexane/diethyl
ether 3:2:1) provided the crude MOM-deprotected compound.
A solution of PMB ether in CH2Cl2 (2 mL) at 0 °C was treated
with NaHCO3 (4.2 mg, 0.5 mmol). After 1 h, the mixture was
diluted with CH2Cl2 and washed with water. The aqueous
layer was extracted with CH2Cl2, and the combined extracts
were dried over anhydrous MgSO4. Filtration and concentra-
tion followed by flash column chromatography (EtOAc/hexane
3:2) provided carbamate 6a (1.1 mg, 0.002 mmol) as a colorless
A solution of the alcohol in CH2Cl2 (8 mL) at 0 °C was
treated with trichloroacetyl isocyanate (0.05 mL, 0.42 mmol)
and stirred at room temperature. After 30 min, the solution
was concentrated under reduced pressure, and the residue was
taken up in MeOH (4 mL). Solid K2CO3 (50 mg) was added to

2862 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Choy et al.
oil: IR (CHCl3) 2995, 2937, 2323, 1755, 1449, 1374, 1242, 1049
cm-1; 1H NMR (500 MHz, CDCl3) 6.63 (ddd, 1H, J ) 16.8, 11.0,
10.1 Hz), 6.06 (t, 1H, J ) 11.0 Hz), 5.46-5.32 (m, 5H), 5.25
(d, 1H, J ) 17 Hz), 5.14 (d, 1H, J ) 10.0 Hz), 4.94 (t, 1H, J )
6.0 Hz), 4.74 (m, 1H), 4.60 (br s, 1H), 4.54 (m, 1H), 3.65 (m,
1H), 3.38 (d, 1H, J ) 5.0 Hz), 3.27 (t, 1H, J ) 6.0 Hz), 3.00
(m, 1H), 2.78 (m, 1H), 2.63 (m, 2H), 2.18 (m, 1H), 2.01 (m,
1H), 1.83 (m, 1H), 1.77 (m, 1H), 1. 35 (d, 3H, J ) 7.0), 1.01-
0.93 (m, 15H); 13C NMR (125 MHz, CDCl3) 174.2, 157.3, 133.6,
132.9, 129.6, 128.9, 125.0, 121.4, 118.0, 95.5, 82.6, 79.7, 79.2,
72.8, 55.9, 40.5, 39.9, 38.6, 35.4, 34.7, 31.6, 23.8, 19.2, 18.2,
17.7, 15.7, 14.8, 12.0; LRMS (ESI) 572.4 (M + Na)+; HRMS
(ESI) calcd for C31H51NO7K 588.3303, found 588.3336 (M +
night. The reaction was quenched with saturated aqueous NH4-
Cl (5 mL), and the mixture was extracted with CH2Cl2 (3 × 5
mL). The combined organic layers were dried over MgSO4, and
the crude product was purified by column chromatography
(pentane/diethyl ether 2:1) to provide the pure product (25 mg,
0.031 mmol, 78%) as a colorless oil: IR (CHCl3) 3462, 2923,
1
1612, 1513, 1249 cm-1; H NMR (300 MHz, CDCl3) δ 7.42 (d,
J ) 8.5 Hz, 2H), 7.37 (d, J ) 8.5 Hz, 2H), 7.00 (d, J ) 7.1 Hz,
2H), 7.00 (d, J ) 7.1 Hz, 2H), 5.65 (dd, J ) 10.3, 10.3 Hz, 1H),
5.53 (m, 3H), 4.83 (d, J ) 7.1 Hz, 1H), 4.80 (d, J ) 7.1 Hz,
1H), 4.67 (m, 3H), 4.48 (d, J ) 10.9 Hz, 1H), 4.41 (d, J ) 5.0
Hz, 1H), 4.13 (m, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.86 (m, 1H),
3.68 (m, 1H), 3.53 (s, 6H), 3.35 (dd, J ) 11.5, 5.0 Hz, 1H), 3.21
(dd, J ) 7.1, 3.5 Hz, 1H), 2.89 (m, 1H), 2.76 (m, 1H) 2.24 (m,
2H), 2.11 (m, 2H), 1.95 (m, 3H), 1.76 (m, 6H), 1.42 (m, 10H),
1.13 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 159.3, 159.1, 134.2,
132.7, 132.3, 130.3, 129.4, 129.1, 128.9, 128.1, 114.0, 113.7,
103.1, 96.5 88.0, 83.9, 82.3, 75.6, 74.9, 70.8, 69.8, 55.7, 55.6,
55.3, 39.4, 39.0, 38.4, 35.9, 35.4, 35.3, 31.9, 30.4, 30.3, 29.4,
26.2, 24.2, 23.9, 22.6, 18.8, 17.4, 15.7, 14.1, 13.2, 5.8.
K)+; [R]20 +34.0 (c 0.05, CHCl3).
D
Ca r ba m ic Acid , (1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-Dih y-
dr oxy-14-[(2S,3S,4S,5R)-4-m eth oxym eth oxy-3,5-dim eth yl-
6-oxotetr a h yd r op yr a n -2-yl]-2,8,10-tr im eth yl-1-[(1S,2Z)-1-
m eth ylp en ta -2,4-d ien yl]tetr a d eca -6,11-d ien yl Ester (6b).
Carbamate 56 (8.49 mg, 0.01 mmol) was subjected to the
lactonization procedure described above. Removal of the PMB
protecting group was accomplished by treating with NaHCO3
and DDQ. Flash chromatography (EtOAc/hexane 3:2) provided
6b (2.9 mg, 49%, 3 steps) as a colorless oil: IR (CHCl3) 3404,
2362, 1749, 1373, 1241, 1049 cm-1; 1H NMR (500 MHz, CDCl3)
6.62 (ddd, 1H, J ) 16.8, 11.0, 10.1 Hz), 6.04 (t, 1H, J ) 11.0
Hz), 5.48-5.33 (m, 5H), 5.24 (d, 1H, J ) 17 Hz), 5.13 (d, 1H,
J ) 10.0 Hz), 4.77-4.60 (br m, 5H), 4.48 (m, 1H), 3.65 (m,
1H), 3.41 (s, 3H), 3.28 (d, 1H, J ) 7.0 Hz), 3.23 (t, 1H, J ) 5.5
Hz), 3.02 (m, 1H), 2.62 (m, 2H), 2.25-2.18 (m, 3H), 2.04 (m,
2H), 1.90 (m, 1H), 1.88 (m, 1H), 1.83 (m, 1H), 1.77-1.67 (m,
2H), 1.51 (m, 2H), 1.34 (d, 3H, J ) 7.0), 1.02-0.92 (m, 15H);
13C NMR (125 MHz, CDCl3) 174.1, 157.3, 133.6, 132.9, 132.2,
129.6, 128.9, 125.0, 121.4, 118.0, 95.5, 82.6, 79.7, 79.2, 72.8,
55.9, 40.5, 39.8, 38.6, 35.4, 34.9, 34.7, 31.6, 23.8, 19.2, 18.2,
17.2, 15.7, 14.8, 12.0; LRMS (ESI) 616.3 (M + Na)+; HRMS
(ESI) calcd for C33H55NO8Na 616.3825, found 616.3829 (M +
The above alcohol (23 mg, 0.028 mmol) in CH2Cl2 (2.5 mL)
was treated at 0 °C with trichloroacetyl isocyanate (0.014 mL,
0.118 mmol). After 40 min., the solvent was removed under
reduced pressure, and the residue was taken up in MeOH (1
mL). Solid K2CO3 (15 mg) was added. The mixture was stirred
for 3 h at room temperature, diluted with EtOAc (8 mL), and
washed with brine, and the aqueous layer was extracted with
EtOAc. The combined organic layers were dried over MgSO4,
and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography (pen-
tane/EtOAc 3:1) to provide the pure carbamate (18 mg, 0.021
mmol, 75%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
7.44 (d, J ) 8.3 Hz, 2H), 7.39 (d, J ) 8.3 Hz, 2H), 7.01 (d, J )
2.6 Hz, 2H), 6.99 (d, J ) 2.6 Hz, 2H), 5.52 (m, 4H), 4.97 (m,
1H), 4.83 (d, J ) 7.0 Hz, 1H), 4.80 (d, J ) 7.0 Hz, 1H), 4.72
(br s, 2H), 4.58 (m, 4H), 4.40 (d, J ) 5.1 Hz, 1H), 4.13 (m, 1H),
3.94 (s, 3H), 3.92 (s, 3H), 3.53 (s, 6H), 3.44 (m, 1H), 3.33 (m,
1H), 3.21 (dd, J ) 7.2, 3.8 Hz, 1H), 2.85 (m, 2H), 2.24 (m, 3H),
2.09 (m, 1H), 1.96 (m, 3H), 1.74 (m, 3H), 1.65 (m, 3H), 1.39
(m, 10H), 1.15 (m, 18H), 1.03 (t, J ) 6.0 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 159.0, 158.9, 156.8, 133.7, 132.7, 131.2, 130.9,
129.2, 128.8, 128.5, 113.6, 113.6, 102.9, 96.4, 87.9, 82.1, 79.6,
78.5, 76.2, 74.9, 70.9, 69.7, 55.7, 55.6, 55.2, 39.4, 39.2, 38.2,
35.8, 32.4, 31.7, 30.9, 30.2, 29.7, 29.3, 25.5, 24.1, 23.7, 22.6,
18.8, 17.4, 15.6, 14.1, 13.1 10.0; LRMS (ESI) 876.6 (M + Na)+.
The carbamate obtained above (15 mg, 0.018 mmol) in CH2-
Cl2 (2 mL) was treated with NaHCO3 (4.3 mg, 0.5 mmol) and
DDQ (34 mg, 0.15 mmol). After being stirred for 1 h at room
temperature, the mixture was diluted with CH2Cl2 (5 mL) and
washed with H2O (10 mL), and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried over MgSO4, and the solvent was removed
under reduced pressure. The crude product was purified by
column chromatography (pentane/EtOAc 1:1) to provide pure
57 (4.0 mg, 0.0031 mmol, 35%) as a colorless oil: IR (CHCl3):
3684, 3620, 3020, 2976, 2400, 1521, 1423, 1208 cm-1; 1H NMR
(500 MHz, CDCl3): δ 5.52 (m, 1H), 5.38 (m, 3H), 4.85 (m, 1H),
4.71 (d, J ) 7.0 Hz, 1H), 4.68 (d, J ) 7.0 Hz, 1H), 4.65 (br s,
2H), 4.30 (d, J ) 5.2 Hz, 1H), 4.02 (m, 1H), 3.68 (m, 1H), 3.43
(s, 3H), 3.40 (s, 3H), 3.23 (m, 2H), 2.66 (m, 2H), 2.16 (m, 4H),
1.84 (m, 2H), 1.64 (m, 3H), 1.51 (m, 3H), 1.28 (m, 10H), 1.09
(d, J ) 7.1 Hz, 3H), 1.00 (m, 9H), 0.93 (d, J ) 7.0 Hz, 3H),
0.89 (t, J ) 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 157.2,
133.7, 132.1, 131.0, 128.8, 103.1, 96.6, 82.2, 79.1, 72.94, 69.8,
55.8, 41.9, 39.5, 38.4, 35.5, 34.9, 34.7, 33.0, 31.8, 30.2, 29.8,
19.3, 25.7, 24.3, 24.2, 22.6, 18.1, 15.7, 15.4, 14.1, 13.2, 8.0;
HRMS (ESI) calcd for C34H63NO8Na 636.4451, found 636.4460
Na)+; [R]20 +59.0 (c 0.1, CHCl3).
D
Ca r ba m ic Acid , (1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-Dih y-
dr oxy-14-[(2S,3S,4S,5R,6R)-6-m eth oxy-4-m eth oxym eth oxy-
3,5-d im et h ylt et r a h yd r op yr a n -2-yl]-2,8,10-t r im et h yl-1-
[(1S ,2Z )-1-m e t h y lp e n t a -2,4-d i e n y l]t e t r a d e c a -6,11-
d ien yl Ester (6c). Carbamate 56 (4.25 mg, 0.005 mmol) was
subjected to the deprotection procedure of PMB described in
the preparation of 6a . Flash chromatography (EtOAc/hexane
3:2) of the crude product provided 6c (2.8 mg, 92%) as a
colorless oil: IR (CHCl3) 3115, 2749, 2328, 1676, 1508, 1215
cm-1; 1H NMR (300 MHz, CDCl3) 6.76 (ddd, 1H, J ) 16.8, 11.0,
10.1 Hz), 6.18 (t, 1H, J ) 10.8 Hz), 5.70-5.46 (m, 5H), 5.35
(d, 1H, J ) 16.8 Hz), 4.49 (dd, J ) 4.5, 6.6 Hz), 4.82 (d, 2H, J
) 2.4 Hz), 4. 73 (br s, 2H), 4. 43 (d, 1H, J ) 5.1 Hz), 4.15, (m,
1H), 3.78 (m, 1H), 3.56 (s, 3H), 3.54 (s, 3H), 3.36 (t, 2H, J )
6.9 Hz), 3.14 (m, 1H), 2.76 (m, 2H), 2.35-2.18 (m, 6H), 2.00-
1.60 (m, 7H), 1.22 (d, 3H, J ) 7.2 Hz), 1.16-1.12 (m, 12H),
1.07 (d, 3H, J ) 7.2 Hz); 13C NMR (125 MHz, CDCl3) 157.3,
133.7, 133.5, 132.2, 132.0, 130.0, 128.7, 118.0, 109.6, 103.0,
96.5, 82.1, 79.7, 79.1, 72.7, 55.8, 39.9, 39.5, 38.3, 35.5, 35.0,
34.8, 34.6, 30.2, 29.8, 24.3, 18.1, 17.7, 15.7, 15.4, 14.2, 13.2,
8.1; LRMS (ESI) 632.4 (M + Na)+; HRMS (ESI) calcd for
C
33H55NO8Na 632.4138, found 632.4139 (M + Na)+; [R]20
D
+21.6 (c 0.25, CHCl3).
Ca r ba m ic Acid 1-Hexyl-3,9-d ih yd r oxy-14-(6-m eth oxy-
4-m eth oxym eth oxy-3,5-d im eth yltetr a h yd r op yr a n -2-yl)-
2,8,10-tr im eth yltetr a d eca -6,11-d ien yl Ester (57). Dess-
Martin periodinane (26.1 mg, 0.062 mmol) was added to a
solution of 41 (30 mg, 0.041 mmol) in CH2Cl2. After 2 h at
room temperature, saturated aqueous NaHCO3 (10 mL) and
saturated aqueous Na2S2O3 (10 mL) were added. After being
stirred for 30 min at room temperature, the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried over MgSO4 to provide the crude aldehyde
43 as a colorless oil, which was used without further purifica-
tion.
(M + Na)+; [R]25 -3.8 (c 0.26, CHCl3).
D
Ca r ba m ic Acid 1-(1,1-Dim eth ylh exyl)-3,9-d ih yd r oxy-
14-(6-m eth oxy-4-m eth oxym eth oxy-3,5-d im eth yltetr a h y-
d r op yr a n -2-yl)-2,8,10-tr im eth yltetr a d eca -6,11-d ien yl Es-
ter (58). A solution of LDBB (2 mmol, prepared from 532 mg
DBB and 14 mg of Li in 5 mL THF at 0 °C) was cooled to -78
°C and treated with 2-phenylthio-2-methylhexane (222 mg, 1
mmol). The dark blue solution turned to red. After 15 min,
Hexylmagnesium bromide (2 M in THF, 0.2 mL, 0.04 mmol)
was added to a solution of 43 in THF (0.2 mL) at 0 °C. The
mixture was warmed to room temperature and stirred over-

4-epi-7-Dehydroxy-14,16-didemethyldiscodermolides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2863
half of the solution was transferred via cannula to a solution
of the crude aldehyde obtained above. The mixture was stirred
4 h at -78 °C and 4 h at room temperature, quenched with
saturated aqueous NaHCO3, and extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were washed with brine
and dried over MgSO4, and the solvent was removed under
reduced pressure. The crude product was purified by column
chromatography (pentane/diethyl ether 2:1) to provide the pure
product (20.9 mg, 0.025 mmol) as a colorless oil: IR (CHCl3)
3684, 3020, 2400, 1522, 1424, 1221 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.42 (d, J ) 9.3 Hz, 2H), 7.38 (d, J ) 8.6 Hz, 2H),
7.01 (d, J ) 8.6 Hz, 2H), 7.00 (d, J ) 8.6 Hz, 2H), 5.64 (m,
1H), 5.47 (m, 3H), 4.83 (d, J ) 7.0 Hz, 1H), 4.80 (d, 7.0 J )
Hz, 1H), 4.72 (d, J ) 10.5 Hz, 1H), 4.65 (d, J ) 10.9 Hz, 1H),
4.64 (d, J ) 10.5 Hz, 1H), 4.52 (d, J ) 10.9 Hz, 1H), 4.41 (d,
J ) 5.1 Hz, 1H), 4.13 (m, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.53
(s, 6H), 3.34 (m, 1H), 3.22 (dd, J ) 7.3, 3.9 Hz, 1H), 2.89 (m,
1H), 2.77 (m, 1H), 2.31-2.02 (m, 5H), 1.95 (m, 3H), 1.83-1.64
(m, 5H), 1.50-1.29 (m, 8 H), 1.22-0.99 (m, 24H); 13C NMR
(75 MHz, CDCl3) δ 159.2, 159.1, 139.9, 132.6, 131.2, 130.3,
129.4, 129.1, 128.9, 128.2, 113.8, 113.6, 103.0, 96.4, 87.9, 85.4,
82.0, 80.3, 74.9, 70.9, 69.6, 55.7, 55.6, 55.2, 39.9, 39.4, 38.2,
37.9, 35.8,35.3, 34.4, 33.0, 30.3, 29.7, 24.2, 23.7, 23.5, 22.7, 18.8,
17.4, 15.7, 14.2, 13.1, 8.2; LRMS (ESI) 861.5 (M + Na)+.
The above alcohol (19 mg, 0.023 mmol) in CH2Cl2 (2 mL)
was treated at 0 °C with trichloroacetyl isocyanate (0.014 mL,
0.118 mmol). After 40 min, the solvent was removed under
reduced pressure, the residue was taken up in MeOH (1 mL),
and solid K2CO3 (15 mg) was added. The mixture was stirred
for 3 h at room temperature, diluted with EtOAc (8 mL), and
washed with brine, the aqueous layer was extracted with
EtOAc, the combined organic layers were dried over MgSO4,
and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography (pen-
tane/EtOAc 3:1) to provide the pure carbamate (15.7 mg, 0.018
mmol, 78%) as a colorless oil: IR (CHCl3) 3155, 2979, 2874,
2254, 1794, 1711 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.25 (m,
4H), 6.82 (m, 4H), 5.34, (m, 4H), 4.70 (m, 1H), 4.66 (d, J ) 7.0
Hz, 1H), 4.63 (d, J ) 7.0 Hz, 1H), 4.54 (br s, 2H), 4.45 (m,
3H), 4.34 (d, J ) 10.9 Hz, 1H), 4.23 (d, J ) 5.2 Hz, 1H), 3.95
(m, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.36 (s, 6H), 3.16 (m, 2H),
3.03 (dd, J ) 7.2, 4.2 Hz, 1H), 2.72 (m, 1H), 2.61 (m, 1H), 2.11
(m, 3H), 1.80 (m, 3H), 1.56 (m, 5H), 1.24 (m, 8H), 1.04 (d, J )
7.1 Hz, 3H), 0.99 (d, J ) 6.8 Hz, 3H), 0.94 (d, J ) 3.9 Hz, 3H),
0.92 (d, 3.6, 3H), 0.84 (m, 12H); 13C NMR (75 MHz, CDCl3) δ
159.0, 156.7, 133.7, 133.0, 131.4, 131.1, 129.3, 129.1, 128.7,
113.6, 103.0, 96.5, 88.0, 82.9, 82.2, 79.5, 74.8, 71.5, 69.8, 55.7,
55.6, 55.2, 39.5, 39.0, 38.9, 38.3, 35.6, 35.5, 35.4, 32.9, 30.9,
30.2, 29.7, 24.3, 24.1, 23.7, 23.5, 22.6, 18.7, 17.1, 15.6, 15.3
14.1, 13.1, 11.5; LRMS (ESI) 904.5 (M + Na)+.
tion. Ca2+- and Mg2+-free RPMI-1640 culture medium were
from GIBCO/BRL-Life Technologies. Fetal bovine serum (FBS)
was from Hyclone. Cell lines were obtained from American
Type Culture Collection (Manassas, VA).
Tu bu lin Assem bly.33 Tubulin assembly was followed in a
Beckman-Coulter 7400 spectrophotometer, equipped with an
electronic Peltier temperature controller, reading absorbance
(turbidity) at 350 nm. Reaction mixtures (0.25 mL final
volume) contained tubulin (final concentration 10 µM; 1 mg/
mL), monosodium glutamate (0.8 M from a stock solution
adjusted to pH 6.6 with HCl), DMSO (final concentration 4%
v/ v), and differing concentrations of test agent where indi-
cated. Reaction mixtures without test agent were cooled to 0
°C and added to cuvettes held at 0.25-0.5 °C in the spectro-
photometer. Test agent in DMSO was then rapidly mixed in
the reaction mixture. Each run contained one positive control
(paclitaxel, 10 µM final concentration) and one negative control
(DMSO only). Baselines were established at 0.25-2.5 °C and
temperature was rapidly raised to 30 °C (in approximately 1
min) and held there for 20 min. The temperature was then
rapidly lowered back to 0.25-2.5 °C.
Cell Gr ow th In h ibition .34 Cells were plated (500-2000
cells/well depending on the cell line) in 96-well microplates,
allowed to attach and grow for 48 h, then treated with vehicle
(4% DMSO, a concentration that allowed doubling times of 24
h or less) or test agent (50, 10, 2, 0.4, and 0.08 µM for the new
agents; 0.100, 0.020, 0.004, 0.0008, and 0.00016 µM for
paclitaxel and discodermolide) for the given times. One plate
consisted of cells from each line used for a time zero cell
number determination. The other plates in a given determi-
nation contained eight wells of control cells, eight wells of
medium and each agent concentration tested in quadruplicate.
Cell numbers were obtained spectrophotometrically (absor-
bance at 490 nm minus that at 630 nm) in a Dynamax plate
reader after treatment with 3-(4,5-dimethylthiazol-2-yl)-5-(3-
carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS)
using phenazine methanesulfonate as the electron acceptor.
After initial screening with the above 5-fold dilutions, 50%
growth inhibitory concentration (GI50) values were determined
for each agent by repeating the screen using 2-fold dilutions
(five concentrations) centered on the initial estimated GI50
concentration, again in quadruplicate.
P a clita xel Bin d in g Site Com p etition Assa y.35 A stock
solution of [3H]paclitaxel (26.8 µM, 16.2 Ci/mmol), obtained
from the NCI, was prepared in 37% (v/v) DMSO. The test
agents were prepared in 25% (v/v) DMSO-0.75 M monosodium
glutamate (prepared from a 2 M stock solution adjusted to pH
6.6 with HCl). The radiolabeled paclitaxel and test agents, as
indicated in terms of final concentrations, were mixed in equal
volumes and warmed to 37 °C. A reaction mixture (50 µL)
containing 0.75 M monosodium glutamate, 4.0 µM tubulin, and
40 µM ddGTP (a nonhydrolyzable analogue of GTP) was
prepared and incubated at 37 °C for 30 min to preform
microtubules. An equivalent volume of drug mixture with [3H]-
paclitaxel was added to preformed polymer and incubated for
30 min at 37 °C. Bound [3H]paclitaxel was separated from free
drug by centrifugation of the reaction mixtures at 14000 rpm
for 20 min at room temperature. Radioactive counts from the
supernatant (50 µL) were determined by scintillation spec-
trometry. Bound [3H]paclitaxel was calculated from the fol-
lowing: total paclitaxel added to each reaction mixture minus
the paclitaxel present in the supernatant (free drug). The %
bound values were normalized to the control values with no
inhibitor added.
The carbamate obtained above (3.5 mg, 3.97 µmol) in CH2-
Cl2 (1 mL) was treated with NaHCO3 (1.2 mg, 14.3 µmol) and
DDQ (3.9 mg, 17.3 µmol). After being stirred for 1 h at room
temperature, the solvent was removed with a stream of Ar.
The crude product was purified by column chromatography
(pentane/EtOAc 1:1) to provide pure 58 (2.1 mg, 3.28 µmol,
83%) as a colorless oil: IR (CHCl3) 3154, 2253, 1816, 1794,
1
1470, 1382 cm-1; H NMR (500 MHz, CDCl3) δ 5.53 (m, 1H),
5.36 (m, 3H), 5.13 (m, 1H), 4.71 (d, J ) 7.0 Hz, 1H), 4.68 (d, J
) 7.0 Hz, 1H), 4.70 (br s, 2H), 4.30 (d, J ) 5.1 Hz, 1H), 4.02
(m, 1H), 3.62 (m, 1H), 3.43 (s, 3H), 3.40 (s, 3H), 3.23 (m, 2H),
2.67 (m, 2H), 2.17 (m, 4H), 1.83 (m, 2H), 1.58 (m, 5H), 1.31
(m, 8H), 1.09 (d, J ) 7.1, 3H), 0.99 (m, 9H), 0.89 (m, 9H), 0.83
(d, J ) 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.4, 135.3,
133.7, 132.3, 131.1, 103.1, 96.2, 83.7, 82.1, 79.1, 75.4, 55.8, 39.5,
38.8, 38.4, 38.3, 35.6, 34.4, 34.2, 32.9, 32.3, 30.2, 29.8, 29.4,
26.5, 24.6, 24.3, 23.5, 23.4, 23.1, 22.7, 17.9, 15.8, 14.9, 14.2,
13.2, 7.7; LRMS (ESI) 664.5 (M + Na)+; HRMS (ESI) calcd for
Ack n ow led gm en t. This work was supported by a
grant from the National Institutes of Health (CA78039).
The authors wish to thank Dr. Kenneth Bair at Novartis
for the generous gift of (+)-discodermolide.
C
36H67NO8Na 664.4764, found 664.4757 (M + Na)+; [R]D25 -6.9
(c 0.11, CHCl3).
Biology. Gen er a l. Tubulin without microtubule-associated
proteins was prepared from fresh bovine brains.32 Paclitaxel
was provided by the Drug Synthesis and Chemistry Branch,
National Cancer Institute. (+)-Discodermolide was received
from Dr. Kenneth Bair at Novartis Pharmaceutical Corpora-
Su ppor tin g In for m ation Available: Representative HPLC
chromatograms for key analogues subjected to biological
testing. This material is available free of charge via the
Internet at http://pubs.acs.org.

2864 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
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manuscript reposted J une 16, 2003.
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J M0204136