Synthesis of the macrolactone of migrastatin and analogues with potent cell-migration inhibitory activity

Article abstract of DOI:10.1002/ejoc.201001097

The synthesis of the macrolactone core of migrastatin 2, its potent anti-metastasis analogue 34, and ester derivatives 35 and 38 are reported. The approach involves the use of a dihydroxylation reaction to establish the desired C-8 stereocenter followed by a metathesis cyclization reaction. The effects of the compounds on the migration and invasion of human breast cancer cells were evaluated by using the wound-healing and the Boyden-chamber cell-migration and cell-invasion assays. The results revealed a high potency of the macrolactones 2 and 34 and the ester analogues 35 and 38, which suggests they have potential as antimetastatic agents. The synthesis of macrolactones 2 and 34 as well as esters 35 and 38 proceeds in good overall yields. Macrolactone 34 and ester 38 are amongst the most active compoundsof the migrastatin family prepared so far and show good promise as anticancer compounds. Copyright

Full text of DOI:10.1002/ejoc.201001097

FULL PAPER
DOI: 10.1002/ejoc.201001097
Synthesis of the Macrolactone of Migrastatin and Analogues with Potent Cell-
Migration Inhibitory Activity
Luiz C. Dias,*[a] Fernanda G. Finelli,[a] Leila S. Conegero,[a] Renata Krogh,[b] and
Adriano D. Andricopulo[b]
Keywords: Total synthesis / Natural products / Lactones / Antitumor agents / Inhibition
The synthesis of the macrolactone core of migrastatin 2, its
potent anti-metastasis analogue 34, and ester derivatives 35
and 38 are reported. The approach involves the use of a dihy-
droxylation reaction to establish the desired C-8 stereocenter
followed by a metathesis cyclization reaction. The effects of
the compounds on the migration and invasion of human
breast cancer cells were evaluated by using the wound-heal-
ing and the Boyden-chamber cell-migration and cell-in-
vasion assays. The results revealed a high potency of the
macrolactones 2 and 34 and the ester analogues 35 and 38,
which suggests they have potential as antimetastatic agents.
metastasis, thus becoming an interesting target for synthe-
sis.[3–7] These important features of migrastatin have re-
Introduction
Migrastatin (1) is a natural product isolated from the cul- sulted in the partial and total synthesis of this compound
tured broth of Streptomyces sp. MK 929-43F1 by Imoto as well as the synthesis of closely related analogues by Dan-
and co-workers in 2000 (Figure 1).[1] In 2002, researchers at ishefsky, Cossy, and Das and their co-workers.[8] Among the
Kosan Bioscience also isolated this 14-membered macrolac- various compounds of this family, the macrolactone core 2
tone with a glutarimide-containing side-chain from cultures of migrastatin and its analogue 3 (lacking the double bond
of Streptomyces platensis (NRRL 18993).[2] Migrastatin in- between C2 and C3) have exhibited the most potent antitu-
duces an inhibitory effect on the migration of human tumor mor activity in 4T1 tumor cells (IC50 = 22 and 24 nm,
cells (IC50 = 29 μm in 4T1 cells) and has been considered respectively) of all the analogues synthesized to date (Fig-
an attractive lead compound for the treatment of tumor ure 1).
Figure 1. Structures of migrastatin (1) and macrolactones 2 and 3, which exhibit potent antitumor activity in 4T1 mouse breast tumor
cells.
In 2005, Danishefsky and co-workers published the results
[a] Institute of Chemistry, University of Campinas, UNICAMP,
of initial studies of the mechanism of action of migra-
P. O. Box 6154, 13084-971 Campinas, SP, Brazil
statin analogues.[9a] They reported that these compounds
block Rac activation, lamellipodia formation, and cell mi-
gration, and that they are associated with the invasion step
of the metastatic process.[9,10]
Recently, Chen et al.[11] showed that migrastatin ana-
logues target the actin-binding sites on fascin, a small pro-
tein involved in cancer invasion and the metastasis of mul-
Fax: +55-19-3521-3023
E-mail: ldias@iqm.unicamp.br
[b] Laboratório de Química Medicinal e Computacional, Centro
de Biotecnologia Molecular Estrutural, Instituto de Física de
São Carlos, Universidade de São Paulo,
Av. Trabalhador São-Carlense 400, 13560-970 São Carlos, SP,
Brazil
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001097.
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Synthesis of the Macrolactone of Migrastatin and Analogues
tiple epithelial cancer types.[12] Following this disclosure, on treatment with 4-methylmorpholine N-oxide (NMO)
Danishefsky and co-workers[13] published a correction to and catalytic amounts of OsO4 in acetone/H2O at 0 °C
the report of Chen et al., establishing that the molecule in (Scheme 1).[17,18]
the complex with fascin is a stereoisomer of the cited ana-
logues.
At room temperature this process led to the formation of
a mixture of lactones 9 and 10 in 77% yield with 74:26
diastereoselectivity. These lactones were readily separated
by flash column chromatography, and the oxazolidinone
chiral auxiliary was recovered by crystallization from the
reaction mixture.[18] We were able to prepare significant
amounts of 9 and 10 to proceed with the synthesis. As
shown in Scheme 2, treatment of lactone 10 with 4-meth-
oxybenzyl 2,2,2-trichloroacetimidate in the presence of
catalytic 10-camphorsulfonic acid (CSA) provided lactone
11 in 67% yield, which, after reduction with LiAlH4, pro-
vided primary alcohol 12 in 75% yield. Selective protection
of the primary alcohol 12 as its TBS ether (95% yield) fol-
Based on the importance of migrastatin-related com-
pounds as an attractive strategy for the development of
novel anticancer therapies and as part of our ongoing re-
search program aimed at discovering new potent cell-
migration inhibitors, we report herein the synthesis, spectro-
scopic and physical characterization, and biological evalu-
ation of the macrolactone of migrastatin and its new ana-
logues.[10–12]
Results and Discussion
Our approach started with an asymmetric aldol addition lowed by methylation with a proton sponge and Me3OBF4
of the titanium enolate derived from N-propionyloxazolid- gave bis(silyl ether) 14 in 75% yield.[19] Removal of the
inone (R)-4 to acrolein to give aldol adduct 5 (87% yield, PMB group with DDQ/H2O and exposure of the resulting
dr Ͼ 95:5; Scheme 1).[14–16] Protection of the secondary primary alcohol to the oxidation protocol of Ley et al.[20]
alcohol as its TBS ether cleanly provided aldol 6 in 93% provided an intermediate aldehyde, which was treated under
yield, which was smoothly converted into lactones 9 and 10 the olefination conditions of Petasis and Bzowej[21] to give
in 70% yield and with more than 95:5 diastereoselectivity olefin 15 in 44% yield in three steps.
Scheme 1. Preparation of lactones 9 and 10.
Scheme 2. Preparation of primary olefin 15.
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Efficient selective removal of the primary TBS group in alcohol 30 was prepared in 13% overall yield in 11 steps
15 was achieved after treatment with HF–Pyr–THF in THF starting from lactone 9 in a sequence similar to that em-
to give the primary alcohol in 80% yield. Alcohol 16 was ployed for the preparation of 19 (Schemes 2 and 3).
treated with TPAP in the presence of NMO followed by
To prepare the C-8 epimer of macrolactone 3, allylic
phosphonate ester 17 under Ando’s conditions[22] to give alcohol 30 was coupled with commercially available hept-6-
(Z)-α,β-unsaturated ester 18 (Z/E = 85:15) in 58% yield enoic acid (31) to give ester 32 in 92% yield (Scheme 6).
over the two-step sequence (Scheme 3). Ester 18 was easily Treatment of ester 32 with Grubbs II catalyst[24] in toluene
converted into allylic alcohol 19, a key synthetic intermedi- under reflux occurred readily to give the desired macrolac-
ate, after treatment with DIBAL-H in CH2Cl2. The relative tone 33 in 80% yield. The last step involved removal of the
stereochemistry of alcohol 19 was confirmed by correlation TBS protecting group to give the new macrolactone 34 in
with the spectroscopic data described in the literature.[8,18]
55% yield. The 17-step sequence starting from (R)-4 pro-
With fragments 19 and 20 in hand we proceeded to as- ceeded in 3% overall yield and is amenable to a gram scale-
semble the two compounds (Scheme 4). This was ac- up. At this point we decided to remove the TBS protecting
complished by a peptide-type coupling reaction in the pres- group at C-9 in ester 32 to evaluate the potential in vitro
ence of DCC and DMAP to provide ester 21 in 74% activity of the corresponding derivative to inhibit tumor cell
yield.[23] Treatment of ester 21 with Grubbs II catalyst in migration. For this purpose, ester 35 was prepared in 73%
toluene at reflux provided macrolactone 22 in 43% yield.[24] yield after treatment of 32 with HF in CH3CN/CH2Cl2.
The conclusion of the synthesis required removal of the
To synthesize the C-8 epimer of macrolactone 2, allylic
TBS protecting group positioned at C-9 to provide the de- alcohol 30 was coupled with carboxylic acid 20 to give ester
sired macrolactone of migrastatin 2 in 44% yield. The spec- 36 in 98% yield (Scheme 7). Unfortunately, all our attempts
troscopic and physical data (1H and 13C NMR, IR, [α]D, to prepare the corresponding macrolactone 37 by a meta-
Rf) for 2 were identical in all respects to the published thesis reaction failed. As before, we decided to remove the
data.[8] The 17-step sequence (longest linear sequence) start- TBS protecting group at C-9 in ester 36 to evaluate the po-
ing from (R)-4 proceeded in 0.1% overall yield.
tential of ester 38 to inhibit tumor cell migration. After
At this stage we decided to prepare the C-8 epimers of treatment of 36 with HF in CH3CN/CH2Cl2, ester 38 was
macrolactones 2 and 3. As illustrated in Scheme 5; allylic prepared in 70% yield.
Scheme 3. Preparation of allylic alcohol 19.
Scheme 4. Synthesis of macrolactone 2.
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Synthesis of the Macrolactone of Migrastatin and Analogues
Scheme 5. Preparation of allylic alcohol 30.
Scheme 6. Synthesis of macrolactone 34 and ester 35.
Scheme 7. Attempts to prepare macrolactone 37 and ester 38.
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Biological Studies
ferent concentrations of the compounds for 6 h, the number
of cells that migrate from the upper chamber through the
insert membrane to the lower compartment are counted.[9]
The macrolactones 2 and 34 as well as esters 35 and 38
were evaluated for their in vitro ability to inhibit cell mi-
gration by using MDA-MB-231 human breast tumor cells.
First, we investigated the effects of these compounds on
the migration of tumor cells using the wound-healing assay.
Figure 2 shows the high potential of the two macrolactones
2 and 34 to inhibit cell migration in concentrations up to
1 μm.
Table 1. Chamber cell-migration and cell-invasion assays with
MDA-MB 213 human breast tumor cells.
Compound
IC50 [nm][a,b]
IC50 [nm][a,c]
2
34Ϯ6
14Ϯ2
53Ϯ8
22Ϯ2
280Ϯ20
7Ϯ2
5Ϯ1
33Ϯ3
9Ϯ2
34
35
38
Evodiamine[d]
590Ϯ104
[a] Average of three independent experiments consisting of 6–8 data
points (corresponding to 6–8 different concentrations of the com-
pounds). [b] Cell-migration assay. [c] Cell-invasion assay. [d] Used
as a standard in all assays.
Figure 3. Effect of macrolactone 34 on the cell-migration assay (A)
and on Matrigel invasion (B) by using MDA-MB-231 human
breast cancer cells. The dark spots refer to the cells that migrated
to the lower side of the membrane and were fixed with 100% meth-
anol and then stained with Toluidine Blue. For more details see the
Supporting Information (chamber cell-invasion assay).
Figure 2. Wound-healing assay results for MDA-MB-231 human
breast tumor cells. The figure shows a comparison between the
effects of compounds 2 and 34 on the inhibition of tumor-cell mi-
gration and those of evodiamine (used as a standard in this study)
and a control (no inhibitor). The black dots near the center of the
figures refer to the shadow of the microscope light beam (as also in
Figure 4). See the Supporting Information for experimental details,
including results for esters 35 and 38.
The results presented in Table 1 and Figure 3 demon-
strate the remarkable inhibition of tumor cell migration
(MDA-MB-231 cells) exhibited by 2, 34, 35, and 38 with
These results encouraged us to perform the Boyden- IC50 values ranging from 14 to 53 nm. The macrolactone
chamber cell-migration assay to quantitatively analyze the 34 (IC50 = 14 nm) was over two-fold more potent than the
different effects of the compounds on cell migration and macrolactone of migrastatin, five-fold more potent than its
cell invasion (Table 1 and Figure 3). The Boyden-chamber epimer 3, and 20-fold more potent than evodiamine, a natu-
cell-migration assay is based on a chamber of two medium- ral product with potent anti-angiogenic properties[6–11] used
filled compartments separated by a microporous membrane as a standard for comparison purposes. Note that the ester
in which the cells are seeded in the upper compartment and analogues 35 and 38 also exhibited high potency with IC50
are allowed to migrate through the transwell insert mem- values of 53 and 22 nm, respectively.
brane into the lower compartment in which the test com-
Interestingly, the macrolactone of migrastatin 2 and its
pound is present. A medium containing serum is added to analogue 3[8c] (Figure 1) had previously shown excellent in-
the lower chamber. After incubation in the presence of dif- hibition of mouse breast tumor 4T1 cell migration (IC50
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Synthesis of the Macrolactone of Migrastatin and Analogues
values of 22 and 24 nm, respectively). However, the ana- pound 2 under the same experimental conditions, see the
logue 3 exhibited only moderate inhibition of migration of Supporting Information for details).
the human breast cancer cell MDA-MB-435 (IC50 = 68 nm)
in comparison with the inhibitory effect on the 4T1 mouse
breast cancer cell line.[8c] The migratory ability of tumor
cells is a requirement for achieving tumor-cell invasion.
We then investigated the effects of compounds 2 and 34
on the invasiveness of the MDA-MB-231 breast cancer cells
using an in vitro Matrigel invasion assay, which mimics the
in vivo process. This is a modified Boyden-chamber assay
that uses a basement membrane matrix preparation (Matri-
gel) as the matrix barrier (see the Supporting Information
for experimental details).
As shown in Table 1, compounds 2, 34, 35, and 38 signif-
icantly suppressed the invasion of MDA-MD-231 cells into
Matrigel with IC50 values of 7, 5, 33, and 9 nm, respectively.
The effect of the most potent compound 34 on cell invasion
is also depicted in Figure 3. This compound is more than
100-fold more potent than evodiamine. The results obtained
with this assay show a strong correlation between the ability
of tumor cells to invade in vitro and their invasive behavior
in vivo.
The effects of compounds 2, 34, 35, and 38 were further
evaluated by using the DU-145 human prostate cancer cells.
The tumor cells were treated with increasing concentrations
of the compounds up to 1 μm. Even at high concentrations,
the compounds were considered inactive, which reveals
valuable new information about the selectivity of these
compounds for cancer-cell cytotoxicity. These findings con-
firm previous studies that showed that selectivity for cancer-
cell cytotoxicity can be achieved by different synthetic mig-
rastatin analogues such as macroketones, macrolactones,
and macrolactams.[8–11]
Conclusions
We have synthesized the macrolactone 2 of migrastatin
and its analogues 34, 35, and 38. Notable features of this
approach include convergence, a dihydroxylation reaction
to establish the desired C-8 stereocenter and a metathesis
cyclization reaction in the case of 2 and 34. This approach
compares favorably with previously published routes and,
in principle, it is readily applicable to the preparation of
additional novel structural analogues. Further optimization
of the synthesis as well as application of this strategy to the
synthesis of new migrastatin analogues are underway, and
the results will be reported in due course. In addition, the
macrolactones 2 and 34 as well as esters 35 and 38 exhibit
significant in vitro potency against human breast cancer cell
migration and invasion, being inactive against human pros-
tate cancer cells. In a very recent report, Chen et al.[11]
showed that a macroketone targets and inhibits fascin, pro-
viding a novel molecular basis by which migrastatin ana-
logues inhibit tumor-cell migration and invasion. The struc-
ture of this molecule was corrected by Danishefsky and co-
workers.[13] Owing to our interest in understanding the
mechanism of action of our compounds in the inhibition of
tumor metastasis, we are also investigating the interaction
between our analogue and fascin (see the Supporting Infor-
mation for details of molecular modeling). Further studies
will be required to extend these findings and to determine
the ultimate role of the highly active migrastatin-based
macrolactones in the inhibition of tumor-cell migration, in-
vasion, and metastasis.
Figure 4 shows that the macrolactone 34 exhibits no in-
hibitory effects (similar behavior was observed for com-
Experimental Section
General: All reactions were carried out under argon or nitrogen in
flame-dried glassware. Dichloromethane, toluene, triethylamine,
2,6-lutidine, diisopropylethylamine, N,N-dimethylformamide, and
titanium tetrachloride were distilled from CaH2. Dimethyl sulfox-
ide was distilled under reduced pressure from calcium hydride and
stored over molecular sieves. THF and diethyl ether were distilled
from sodium/benzophenone ketyl. Purification of reaction products
was carried out by flash chromatography using silica gel (230–
400 mesh). Analytical thin layer chromatography was performed on
silica gel 60 and GF (5–40 μm thickness) plates. Visualization was
accomplished with UV light and phosphomolybdic acid followed
by heating. H and H-decoupled 13C NMR spectra were taken in
C6D6 or CDCl3 at 250, 300 or 500 MHz (1H) and 62.5, 75 or 125
MHz (13C). The chemical shifts (δ) are reported in ppm by using
the solvent as an internal standard (C6D6 at δ = 7.16 ppm and
CDCl3 at δ = 7.26 ppm) or with addition of TMS. Data are re-
ported as: s = singlet, d = doublet, t = triplet, q = quartet, quint
= quintuplet, sext = sextuplet, dd = doublet of doublets, dt = doub-
let of triplets, ddd = doublet of doublet of doublets, m = multiplet,
qd = quartet of doublets, dsept = doublet of septet, br. d = broad
doublet, br. s = broad singlet, dq = doublet of quartet; coupling
constant(s) in Hz; integration. IR spectra were recorded with a Per-
kin-Elmer Paragon 1000 spectrometer and are reported in terms of
1
1
Figure 4. Effect of macrolactone 34 on DU-145 human prostate
cancer cells. Wound-healing assay results show that 34 does not
inhibit the migration of human prostate tumor cells induced by
serum. See the Supporting Information for experimental details.
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frequency of absorption (cm–1). Mass spectra were obtained from
LCMS-IT-TOF (225-07100-34) SHIMADZU by electrospray ion-
ization (ESI) techniques and high-resolution hybrid quadrupole
(Q) and orthogonal time-of-flight (TOF) instruments. Optical rota-
at room temperature for 10 h, and the reaction was quenched by
the addition of a 45% aqueous solution of Na2S2O5 (118 mL; m/
v) and then stirred for 40 min and filtered. The solvent was evapo-
rated, and the aqueous layer was extracted with ethyl acetate
tions were measured with a Carl Zeiss Jena Polamat polarimeter (3ϫ120 mL). The combined organic layers were washed with brine
with [α]D values reported in 10–1 degcm2 g–1; concentration (c) is in
g/100 mL.
(15 mL), dried with MgSO4, filtered, and concentrated. Purifica-
tion by silica gel flash column chromatography (50% EtOAc/hex-
ane) afforded lactone 9 (8.74 g, 57% yield) and lactone 10 (3.07 g,
20% yield) as a white solid. M.p. 74–76 °C. Rf = 0.40 (30% EtOAc/
hexane). [α]2D0 = –31 (c = 1.2, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 0.11 (s, 3 H), 0.12 (s, 3 H), 0.90 (s, 9 H), 1.27 (d, J =
7.5 Hz, 3 H), 2.16–2.14 (m, 1 H), 2.67 (quint, J = 6.2 Hz, 1 H),
3.97–3.85 (m, 2 H), 4.28 (t, J = 6.2 Hz, 1 H), 4.50–4.47 (m, 1 H)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = –4.96, –4.71, 13.44, 17.87,
(S)-4-Benzyl-3-[(2S,3R)-3-hydroxy-2-methylpent-4-enoyl]oxazolidin-
2-one (5): Freshly distilled titanium(IV) chloride (0.29 mL,
2.61 mmol) was added dropwise to a solution of (S)-4-benzyl-3-
propionyloxazolidin-2-one [(R)-4; 580 mg, 2.48 mmol] in CH2Cl2
(25 mL) under argon, and the resulting yellow solution was
warmed to 0 °C. After stirring for 5 min, diisopropyl(ethyl)amine
(1.08 mL, 6.20 mmol) was added dropwise, and the resulting brown
solution was stirred at 0 °C for 1 h. The mixture was cooled to
–78 °C, and freshly distilled acrolein (0.25 mL, 3.72 mmol) was
added dropwise. After 1 h, the solution was warmed to 0 °C and
stirred at that temperature for 12 h. The reaction was quenched
by the addition of saturated aqueous NH4Cl (5 mL). The reaction
mixture was filtered (Celite), and the organic layer was separated.
The aqueous phase was extracted with CH2Cl2 (3ϫ10 mL), and
the combined organic phases were washed with saturated aqueous
NaHCO3 and brine. The organic solution was dried with anhy-
drous MgSO4 and purified by silica gel flash column chromatog-
25.57, 43.36, 61.65, 75.89, 80.65, 177.22 ppm. IR (KBr pellet): ν =
˜
3460, 3019, 2931, 2860, 1774, 1463, 1386, 1216, 1132, 1051, 931,
838, 779, 669 cm–1. HRMS: calcd. for C12H25O4Si [M]+ 261.1522;
found 261.1699.
(3S,4S,5S)-4-[(tert-Butyldimethylsilyl)oxy]-5-[(4-methoxybenzyl-
oxy)methyl]-3-methyldihydrofuran-2(3H)-one (11): p-Methoxy-
benzyl 2,2,2-trichloroacetimidate (155 mg, 0.55 mmol) and CSA
(3.0 mg, 0.013 mmol) were added to a stirred solution of lactone
10 (120 mg, 0.46 mmol) in CH2Cl2 (2 mL). The reaction mixture
was stirred at room temperature for 12 h. Next, it was diluted with
Et2O (10 mL) and washed with a saturated aqueous solution of
raphy (20% EtOAc/hexanes) to give 624.2 mg of the syn-aldol ad-
1
duct 5 (87%) as a white solid. Rf = 0.27 (40% EtOAc/hexane). H NaHCO3 (5 mL), brine (5 mL), and H2O (5 mL), dried with
NMR (500 MHz, CDCl3): δ = 1.25 (d, J = 7.0 Hz, 3 H), 2.89–2.77
(m, 1 H), 2.90 (s, 1 H), 3.26 (d, J = 13.4 Hz, 1 H), 3.88–3.86 (m, 1
H), 4.52–4.19 (m, 1 H), 4.51 (br. s, 1 H), 4.73–4.79 (m, 1 H), 5.23
(d, J = 10.7 Hz, 1 H), 5.36 (d, J = 17.0 Hz, 1 H), 5.88–5.82 (m, 1
MgSO4, and concentrated under reduced pressure. The crude mate-
rial was washed with cold hexane to separate the precipitate. Ad-
ditional purification by silica gel flash column chromatography
(15% EtOAc/hexanes) gave lactone 11 (117.3 mg, 67% yield). Rf =
1
H), 7.35–7.20 (m, 5 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 0.35 (15% EtOAc/hexane). [α]2D0 = –25 (c = 1.4, CHCl3). H NMR
10.91, 37.76, 42.42, 55.12, 66.20, 72.52, 116.33, 127.44, 128.96,
(250 MHz, CDCl3): δ = 0.05 (s, 3 H), 0.08 (s, 3 H), 0.88 (s, 9 H),
129.41, 134.97, 137.20, 153.09, 176.63 ppm. IR (film): ν = 3531, 1.23 (d, J = 7.5 Hz, 3 H), 2.72–2.61 (m, 1 H), 3.73–3.70 (m, 2 H),
˜
3156, 3032, 2985, 2918, 1780, 1691, 1385, 1211, 1109, 1016, 912,
3.80 (s, 3 H), 4.17 (t, J = 5.6 Hz 1 H), 4.56–4.48 (m, 3 H), 6.87 (d,
J = 8.7 Hz, 2 H), 7.24 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = –5.04, –4.79, 13.17, 17.89, 25.55, 43.49,
55.21, 67.45, 73.23, 75.36, 80.13, 113.74 (2 C), 129.33 (2 C), 129.7,
904 cm–1.
(S)-4-Benzyl-3-{(2S,3R)-3-[(tert-butyldimethylsilyl)oxy]-2-methyl-
pent-4-enoyl}oxazolidin-2-one (6): TBSOTf (0.09 mL, 0.37 mmol)
was added dropwise to a solution of syn-aldol adduct 5 (100 mg,
0.34 mmol) and 2,6-lutidine (0.05 mL, 0.40 mmol) in CH2Cl2
(3 mL) at 0 °C. After 20 min, the reaction was quenched by the
addition of water (8 mL), and the organic layer was extracted with
Et2O (3ϫ5 mL). The combined organic layers were washed in se-
quence with a cold 1% aqueous solution of HCl (3 mL), a satu-
rated aqueous solution of NaHCO3 (3 mL), and brine (3 mL),
dried with MgSO4, filtered, and concentrated. Purification by silica
gel flash column chromatography (10% EtOAc/hexane) gave the
desired product 6 in 93% yield as a colorless oil. Rf = 0.64 (30%
150.20, 177.73 ppm. IR (film): ν = 3020, 2956, 2860, 1774, 1645,
˜
1514, 1215, 1134, 1035 cm–1. HRMS: calcd. for C20H33O5Si [M]+
381.2097; found 381.2208.
(2R,3S,4S)-3-[(tert-Butyldimethylsilyl)oxy]-5-(4-methoxybenzyl-
oxy)-2-methylpentane-1,4-diol (12): LiAlH4 was added (47.0 mg,
1.25 mmol) to a solution of lactone 11 (190 mg, 0.50 mmol) in THF
(10 mL) at –78 °C. After 30 min, the reaction was quenched by the
addition of an aqueous solution of 0.1 m NaOH (10 mL), and the
reaction mixture was stirred for 1 h. The mixture was extracted
with Et2O (3ϫ5 mL). The combined organic layers were washed
with brine, dried with MgSO4, concentrated under reduced pres-
sure, and purified by silica gel flash column chromatography (40%
1
EtOAc/hexane). H NMR (300 MHz, CDCl3): δ = –0.08 (s, 3 H),
–0.06 (s, 3 H), 0.80 (s, 9 H), 1.12 (d, J = 6.9 Hz, 3 H), 2.68 (dd, J
= 13.2, 9.9 Hz, 1 H), 3.18 (dd, J = 13.2, 2.93 Hz, 1 H), 3.89 (quint, EtOAc/hexanes) to give alcohol 12 in 75% yield. Rf = 0.30 (30%
J = 6.6 Hz, 1 H), 4.10–3.99 (m, 2 H), 4.25 (t, J = 6.2 Hz, 1 H),
4.51 (ddd, J = 9.5, 6.2, 2.9 Hz, 1 H), 5.02 (d, J = 10.2 Hz, 1 H),
5.10 (d, J = 17.2 Hz, 1 H), 5.77 (ddd, J = 17.2, 10.2, 6.2 Hz, 1 H),
EtOAc/hexane). [α]2D0 = +11 (c = 1.6, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 0.04 (s, 3 H), 0.07 (s, 3 H), 0.89 (s, 9 H), 0.96 (d, J =
7.3 Hz, 3 H), 1.84–1.73 (m, 1 H), 3.00–2.97 (m, 1 H), 3.48–3.33 (m,
7.27–7.11 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = –5.15, 4 H), 3.76 (dd, J = 4.75, 1.5 Hz, 1 H), 3.89–3.85 (m, 2 H), 4.46 (s,
–4.44, 12.41, 18.08, 25.73, 37.75, 44.04, 55.60, 65.92, 75.15, 115.68,
127.29, 128.89, 129.43, 135.34, 139.17, 153.16, 174.62 ppm.
2 H), 6.87 (d, J = 8.5 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 2 H) ppm. 13C
NMR (62.5 MHz, CDCl3): δ = –4.89, –4.37, 12.89, 18.04, 25.80,
39.79, 55.19, 62.11, 68.24, 70.99, 72.88, 73.11, 113.74, 129.36,
(3S,4S,5S)-4-[(tert-Butyldimethylsilyl)oxy]-5-(hydroxymethyl)-3-
methyldihydrofuran-2(3H)-one (10): A solution of 0.2 m OsO4
(23.6 mL, 4.72 mmol) was added to a solution of NMO (13.81 g,
118 mmol) in acetone/H2O (8:1, 200 mL) at 0 °C. After 5 min, a
solution of olefin 6 (23.84 g, 59 mmol) in acetone (60 mL) was
added slowly (through cannula). The resulting solution was stirred
129.91, 159.20 ppm. IR (film): ν = 3450, 3020, 2956, 2858, 1645,
˜
1514, 1463, 1249, 1218, 1035 cm–1. HRMS: calcd. for C20H37O5Si
[M + H]+ 385.2410; found 385.2464.
(2S,3S,4R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-1-(4-methoxy-
benzyloxy)-4-methylpentan-2-ol (13): Imidazole (71 mg, 1.04 mmol)
6754
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6748–6759

Synthesis of the Macrolactone of Migrastatin and Analogues
and TBSCl (128 mg, 0.84 mmol) were added sequentially to a solu-
tion of diol 12 (250 mg, 0.65 mmol) in CH2Cl2 (7 mL) at 0 °C. The
resulting mixture was stirred for 1 h. The solution was diluted with
brine (10 mL), and the aqueous phase was extracted with CH2Cl2
(3ϫ5 mL). The combined organic phases were dried with MgSO4,
the solvent was removed under reduced pressure, and the resulting
mixture was purified by silica gel flash column chromatography
(20% EtOAc/hexanes) to give alcohol 13 in 95% yield as a colorless
oil. Rf = 0.50 (30% EtOAc/hexane). [α]2D0 = +1 (c = 1.4, CH2Cl2).
1H NMR (250 MHz, CDCl3): δ = 0.04 (s, 6 H), 0.06 (s, 3 H), 0.07
(s, 3 H), 0.90–0.87 (m, 21 H), 1.83–1.74 (m, 1 H), 3.10–3.02 (m, 1
H), 3.41 (d, J = 6.3 Hz, 2 H), 3.57 (dd, J = 5.8, 1.3 Hz, 2 H), 3.76–
3.74 (m, 1 H), 3.80 (s, 3 H), 3.84–3.80 (m, 1 H), 4.47 (s, 2 H), 6.87
(d, J = 8.8 Hz, 2 H), 7.25 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR
lar sieves (4 Å) were added to a stirred solution of the previously
prepared primary alcohol (1.09 g, 2.78 mmol) in CH2Cl2 (56 mL).
The mixture was stirred for 15 min before 4-methylmorpholine N-
oxide (488 mg, 4.17 mmol) was added followed by TPAP (49 mg,
0.14 mmol) after 15 min. The resulting mixture was stirred for
30 min, filtered (Celite), and the filtrate was concentrated to give
an intermediate aldehyde. Without purification, Cp2TiMe2 (0.5 m,
12 mL) was added to a solution of this aldehyde in toluene
(13.7 mL) under argon. The resulting mixture was protected from
light and stirred vigorously at 70 °C for 4 h. The mixture was con-
centrated, and the residue was purified by silica gel flash column
chromatography (2% EtOAc/hexane) to afford olefin 15 (538 mg,
50% for two steps). Rf = 0.60 (2% EtOAc/hexane). [α]2D0 = –7 (c =
1.5, CH2Cl2). 1H NMR (250 MHz, CDCl3): δ = 0.02 (s, 6 H), 0.06
(125 MHz, CDCl3): δ = –5.41, –5.40, –4.48, –4.37, 12.24, 18.24, (s, 3 H), 0.07 (s, 3 H), 0.76 (d, J = 6.7 Hz, 3 H), 0.88 (s, 9 H), 0.89
18.31, 25.89, 26.00, 40.09, 55.25, 64.40, 70.34, 71.38, 72.68, 72.92, (s, 9 H), 1.74–1.62 (m, 1 H), 3.21 (s, 3 H), 3.42–3.33 (m, 2 H), 3.51
113.73, 129.33, 130.34, 159.16 ppm. HRMS: calcd. for C26H51O5Si2 (dd, J = 9.8, 8.3 Hz, 1 H), 3.80 (dd, J = 8.0, 1.7 Hz, 1 H), 5.21 (dd,
[M + H]+ 499.3275; found 499.3211.
J = 10.3, 2.0 Hz, 1 H), 5.26 (d, J = 2.3, 1 H), 5.63–5.48 (m, 1 H)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.31, –5.08, –3.78, 9.26,
18.22, 18.60, 25.91, 26.18, 38.01, 55.94, 65.69, 73.43, 86.86, 118.49,
135.16 ppm.
(5S,6R)-5-[(S)-1-Methoxy-2-(4-methoxybenzyloxy)ethyl]-2,2,3,3,
6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecane (14): A proton
sponge [1,8-bis(dimethylamino)naphthalene, 1.3 g, 6.06 mmol] and
Me3OBF4 (0.8 g, 5.4 mmol) were added to a solution of alcohol 13
(1.49 g, 2.98 mmol) in CH2Cl2 (55 mL) at room temperature under
argon, and the heterogeneous reaction mixture was stirred with
protection from light for 12 h. The reaction was quenched by the
addition of a cold 1% aqueous solution of HCl (165 mL), and the
mixture was extracted with Et2O (3ϫ165 mL). The combined or-
ganic layers were filtered through silica, dried with anhydrous
MgSO4, and concentrated in vacuo. The resulting mixture was
purified by silica gel flash column chromatography (5% EtOAc/
hexanes) to give the methylated product 14 in 75% yield. Rf = 0.40
(6% EtOAc/hexane). [α]2D0 = –1 (c = 1.6, CH2Cl2). 1H NMR
(250 MHz, CDCl3): δ = 0.04 (s, 6 H), 0.06 (s, 3 H), 0.08 (s, 3 H),
0.78 (d, J = 6.8 Hz, 3 H), 0.88 (s, 9 H), 0.89 (s, 9 H), 1.85–1.71 (m,
1 H), 3.54–3.27 (m, 4 H), 3.41 (s, 3 H), 3.62 (dd, J = 10.2, 2.5 Hz,
1 H), 3.80 (s, 3 H), 3.97 (dd, J = 6.8, 2.5 Hz, 1 H), 4.44 (d, J =
11.8 Hz, 1 H), 4.50 (d, J = 11.8 Hz, 1 H), 6.90–6.84 (m, 2 H), 7.28–
7.24 (m, 2 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.35,
–4.88, –4.02, 10.85, 18.21, 18.34, 25.90, 26.06, 37.42, 55.21, 58.04,
65.69, 69.15, 70.85, 73.05, 83.69, 113.67, 129.23, 130.39,
159.08 ppm. HRMS: calcd. for C26H50O5Si [M]+ 499.3275; found
499.3211.
(2R,3S,4S)-3-[(tert-Butyldimethylsilyl)oxy]-4-methoxy-2-methylhex-
5-en-1-ol (16): A solution of HF/pyridine/THF (1:4:5, 14 mL) was
added to a stirred solution of TBS ether 15 (538 mg, 1.39 mmol) in
THF (18 mL) at 0 °C. The reaction mixture was stirred at ambient
temperature for 12 h and then diluted with Et2O (180 mL); pow-
dered NaHCO3 was added until pH = 7. After 10 min, the reaction
mixture was filtered and concentrated. Purification by silica gel
flash column chromatography (20 % EtOAc/hexane) provided
alcohol 16 (305 mg, 80% yield). Rf = 0.60 (20% EtOAc/hexane).
[α]2D0 = –9 (c = 0.4, CH2Cl2). 1H NMR (300 MHz, C6D6): δ = 0.19
(s, 3 H), 0.22 (s, 3 H), 0.83 (d, J = 6.8 Hz, 3 H), 1.04 (s, 9 H), 1.74–
1.63 (m, 1 H), 3.04 (s, 3 H), 3.52–3.31 (m, 3 H), 3.90 (dd, J = 7.5,
2.5 Hz, 1 H), 5.08–5.01 (s, 2 H), 5.56–5.42 (m, 1 H) ppm. 13C NMR
(62.5 MHz, C6D6): δ = –4.72, –3.51, 10.34, 18.85, 26.47, 38.37
55.87, 65.46, 74.61, 86.65, 118.45, 135.53 ppm. HRMS: calcd. for
C14H31O3Si [M + H]+ 275.2042; found 275.2105.
Ethyl (4R,5S,6S,Z)-5-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-2,4-
dimethylocta-2,7-dienoate (18): At ambient temperature molecular
sieves (4 Å) were added to a stirred solution of alcohol 16 (123 mg,
0.44 mmol) in CH2Cl2 (8.9 mL). The mixture was stirred for 15 min
before adding 4-methylmorpholine N-oxide (78.8 mg, 0.67 mmol)
followed by TPAP (a few crystals) after15 min. The resulting mix-
ture was stirred for 30 min, filtered (plug of silica gel), and the
filtrate was concentrated. Ester phosphonate 17 (405 mg,
1.12 mmol) in THF (8 mL) was added to a stirred suspension of
60% NaH (44.6 mg, 1.12 mmol, previously washed with hexane) in
THF (4.5 mL) under argon at 0 °C. After stirring at 0 °C for
15 min, a solution of the previously prepared unpurified aldehyde
in THF (5.0 mL) was added. The resulting mixture was warmed to
ambient temperature and stirred for 12 h. The reaction mixture was
diluted with H2O (15 mL), extracted with EtOAc (2ϫ10 mL), and
the combined organic layers were dried with MgSO4, filtered, and
concentrated. Purification by silica gel flash column chromatog-
raphy (5% EtOAc/hexane) gave (Z)-unsaturated ester 18 (122.8 mg,
58% yield, two steps). Rf = 0.60 (5% EtOAc/hexane). [α]2D0 = –5 (c
(2S,3S,4R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-2-methoxy-4-
methylpentan-1-ol: Compound 14 (1.87 g, 3.65 mmol) was diluted
with CH2Cl2 (38 mL) and H2O (2.0 mL), and then DDQ (995 mg,
4.38 mmol) was added at ambient temperature. After 2 h, the reac-
tion mixture was washed with a saturated aqueous NaHCO3 solu-
tion (90 mL) and a saturated aqueous NaCl solution (90 mL) and
then extracted with CH2Cl2 (3ϫ180 mL). The combined organic
layers were dried with anhydrous MgSO4 and concentrated in
vacuo. Purification by silica gel flash column chromatography by
using 20% EtOAc/hexane afforded 1.27 g of the corresponding pri-
mary alcohol in 88% yield. Rf = 0.60 (20% EtOAc/hexane). [α]2D0
1
= –3 (c = 0.8, CH2Cl2). H NMR (250 MHz, CDCl3): δ = 0.03 (s,
6 H), 0.06 (s, 3 H), 0.09 (s, 3 H), 0.81 (d, J = 7.0 Hz, 3 H), 0.88 (s,
9 H), 0.89 (s, 9 H), 1.84–1.74 (m, 1 H), 1.90 (br. s, 1 H), 3.26–3.20
(m, 1 H), 3.42 (s, 3 H), 3.56 (dd, J = 11.7, 5.7 Hz, 1 H), 3.51–3.51
(m, 2 H), 3.80 (dd, J = 11.7, 3.5 Hz, 1 H), 4.02 (dd, J = 6.7, 2.2 Hz,
1 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.35, –4.86, –4.09,
10.74, 18.21, 18.29, 25.88, 26.02, 37.20, 58.20, 61.16, 65.63, 70.15,
84.47 ppm.
1
= 1.06, CHCl3). H NMR (250 MHz, CDCl3): δ = 0.029 (s, 3 H),
0.05 (s, 3 H), 0.90 (s, 9 H), 0.92 (d, J = 6.5 Hz, 3 H), 1.28 (t, J =
7.3 Hz, 3 H), 1.87 (d, J = 1.5 Hz, 3 H), 3.19 (s, 3 H), 3.28–3.18 (m,
1 H), 3.40–3.33 (m, 1 H), 3.61 (dd, J = 7.5, 2.5 Hz, 1 H), 4.17 (q,
J = 7.3 Hz, 2 H), 5.31–5.19 (m, 2 H), 5.73–5.56 (m, 1 H), 5.96 (dd,
(5S,6R)-5-[(S)-1-Methoxyallyl]-2,2,3,3,6,9,9,10,10-nonamethyl- J = 9.8, 1.5 Hz, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
4,8-dioxa-3,9-disilaundecane (15): At ambient temperature molecu-
–5.03, –3.82, 12.94, 14.28, 18.52, 20.74, 26.12, 35.32, 55.95, 60.00,
Eur. J. Org. Chem. 2010, 6748–6759
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6755

L. C. Dias et al.
FULL PAPER
77.5, 86.64, 118.67, 125.27, 134.87, 146.96, 167.87 ppm. IR (film):
5.50 (m, 2 H), 5.73 (d, J = 15.5 Hz, 1 H), 6.85–6.79 (m, 1 H) ppm.
ν = 3020, 2929, 2856, 2401, 1701, 1471, 1379, 1215, 1118, 1033, 13C NMR (125 MHz, CDCl3): δ = –5.02, –3.56, 12.90, 18.71, 22.17,
˜
931, 759, 669 cm–1. HRMS: calcd. for C19H37O4Si [M + H]+ 26.27, 30.02, 32.46, 33.11, 55.83, 65.57, 77.47, 85.83, 121.82,
357.2461; found 357.2415.
126.59, 130.49, 130.50, 132.00, 149.95, 165.39 ppm.
(4R,5S,6S,Z)-5-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-2,4-di-
methylocta-2,7-dien-1-ol (19): A solution of DIBAL-H in toluene
(1.5 m, 0.34 mL, 0.51 mmol) was added dropwise to a solution of
(3E,7E,9S,10S,11R,12Z)-10-Hydroxy-9-methoxy-11,13-dimethyl-
1-oxacyclotetradeca-3,7,12-trien-2-one (2): 48% HF (1 drop) was
added to a solution of macrolactone 22 (9.5 mg, 0.024 mmol) in
unsaturated ester 18 (98 mg, 0.204 mmol) in CH2Cl2 (1 mL) at CH3CN/CH2Cl2 (2:1; 2.0 mL) at room temperature. After stirring
–15 °C. After stirring for 1 h, the reaction mixture was warmed to for 24 h, the reaction mixture was diluted with Et2O and carefully
0 °C, and EtOAc (15 mL) was added. After 30 min, the reaction treated with NaHCO3 (pH = 7), filtered, and concentrated under
mixture was warmed to ambient temperature, and a cold solution
of aqueous potassium sodium tartrate (10 mL) was added. The re-
sulting mixture was vigorously stirred at ambient temperature until
phase separation occurred (about 1 h). The aqueous phase was ex-
reduced pressure. Purification by silica gel flash column chromatog-
raphy (EtOAc/hexane 5%) afforded macrolactone 2 (3.1 mg, 44%).
[α]2D0 = +87.5 (c = 0.30, CHCl3). 1H NMR (500 MHz, CDCl3): δ =
0.88 (d, J = 6.5 Hz, 3 H), 1.68 (s, 3 H), 2.31–2.19 (m, 2 H), 2.47–
tracted with CH2Cl2 (3ϫ15 mL), the combined organic layers were 2.38 (m, 2 H), 3.04–2.98 (m, 1 H), 3.28 (s, 3 H), 3.41–3.39 (m, 2
dried with MgSO4, filtered, and concentrated. The residue was
purified by silica gel flash column chromatography (20% EtOAc/
hexane) to provide allylic alcohol 19 (63 mg, 0.2 mmol, 98% yield)
H), 4.63 (d, J = 15.5 Hz, 1 H), 4.72 (d, J = 15.5 Hz, 1 H), 5.14 (dd,
J = 15.0, 6.5 Hz, 1 H), 5.63–5.55 (m, 2 H), 5.73 (d, J = 16.0 Hz, 1
H), 6.78 (ddd, J = 16.0, 8.0, 6.5 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 12.67, 22.28, 29.99, 31.37, 32.22, 56.25,
as an oil. Rf = 0.60 (20% EtOAc/hexane). [α]2D0 = –2 (c = 1.80,
1
CHCl3). H NMR (250 MHz, CDCl3): δ = 0.04 (s, 3 H), 0.06 (s, 3 65.41, 76.11, 84.63, 122.16, 127.50, 129.53, 129.82, 133.83, 149.50,
H), 0.92–0.88 (m, 12 H), 1.78 (d, J = 1.4 Hz, 3 H), 2.69–2.61 (m, 165.35 ppm. HRMS: calcd. for C16H24O4Na [M + Na]+] 303.1567;
1 H), 3.22 (s, 3 H), 3.48–3.43 (m, 2 H), 4.00 (dd, J = 6.5, 11.7 Hz,
1 H), 4.12 (dd, J = 4.9, 11.7 Hz, 1 H), 5.30–5.24 (m, 3 H), 5.73–
5.66 (m, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –4.71,
–3.89, 15.28, 18.48, 21.50, 26.09, 34.20, 56.10, 61.71, 78.28, 85.89,
found 303.1563.
(3S,4S,5R)-4-[(tert-Butyldimethylsilyl)oxy]-5-(hydroxymethyl)-3-
methyldihydrofuran-2(3H)-one (9): A solution of 0.2 m OsO4 in
tBuOH (2 mL, 0.4 mmol) was added to a solution of NMO (1.17 g,
10.0 mmol) in acetone/H2O (8:1) at 0 °C. After 5 min, a solution
of olefin 5 (2.02 g, 5.00 mmol) in acetone (5 mL) was added slowly.
118.52, 133.01, 133.03, 135.12 ppm. IR (film): ν = 3442, 2931, 2858,
˜
1471, 1254, 1216, 1126, 1004, 933, 835, 730, 669 cm–1.
(E)-[(4R,5S,6S,Z)-5-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-2,4-di- The resulting solution was stirred at room temperature for 10 h and
methylocta-2,7-dienyl] Hepta-2,6-dienoate (21): DCC (96.4 mg, quenched by adding a solution of 45 % Na2S2O5 (10 mL; m/v),
0.467 mmol) and DMAP (14.3 mg, 0.11 mmol) were added to a
solution of carboxylic acid 20 (59 mg, 0.0.47 mmol) in CH2Cl2
(2 mL) under argon at ambient temperature. A solution of allylic
alcohol 19 (73.5 mg, 0.23 mmol) in CH2Cl2 (2 mL) was added to
the reaction mixture through cannula. After stirring at that tem-
perature for 12 h, the crude reaction mixture was concentrated. Pu-
rification by silica gel flash column chromatography (20% EtOAc/
hexane) gave the desired ester 21 (72 mg, 74% yield). Rf = 0.80
(10% EtOAc/hexane). [α]2D0 = +4 (c = 1.00, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 0.02 (s, 3 H), 0.05 (s, 3 H), 0.88 (d, J =
7.3 Hz, 3 H), 0.90 (s, 9 H), 1.73 (d, J = 1.2 Hz, 3 H), 2.32–2.17 (m,
stirred for 40 min, and filtered. The solvent was removed, and the
aqueous layer was extracted with ethyl acetate (3ϫ10 mL). The
combined organic layers were washed with brine (15 mL), dried
with MgSO4, filtered, and concentrated. The crude product was
purified by silica gel flash column chromatography (50% EtOAc/
hexane) to afford lactone 9 (70% yield) as a colorless oil. Rf = 0.58
(30% EtOAc/hexane). [α]2D0 = +105 (c = 1.0, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 0.09 (s, 3 H), 0.10 (s, 3 H), 0.88 (s, 9 H),
1.27 (d, J = 7.3 Hz, 3 H), 2.50 (s, 1 H), 2.63–2.58 (m, 1 H), 3.66
(dd, J = 13.0, 2.9 Hz, 1 H), 3.97 (dd, J = 13.0, 1.6 Hz, 1 H), 4.16–
4.10 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.76, –4.35,
4 H), 2.63–2.57 (m, 1 H), 3.19 (s, 3 H), 3.51–3.35 (m, 2 H), 4.62– 12.60, 17.70, 25.52, 44.25, 59.99, 74.15, 84.33, 176.89 ppm. IR
4.55 (m, 2 H), 5.08–4.98 (m, 2 H), 5.30–5.25 (m, 2 H), 5.44 (d, J (film): ν = 3450, 3060, 2935, 2858, 1780, 1462, 1403, 1263, 1170,
˜
= 9.7 Hz, 1 H), 5.87–5.55 (m, 3 H), 6.96 (dt, J = 15.6, 6.4 Hz, 1
1120, 1040, 896, 836 cm–1. HRMS: calcd. for C12H25O4Si [M]+
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –4.86, –3.82, 13.95, 261.1522; found 261.1699.
18.52, 21.48, 26.13, 31.47, 32.00, 34.25, 56.04, 63.05, 78.36, 86.25,
115.52, 118.78, 121.51, 128.19, 135.08, 135.57, 137.03, 148.46,
(3S,4S,5R)-4-[(tert-Butyldimethylsilyl)oxy]-5-[(4-methoxybenzyl-
oxy)methyl]-3-methyldihydrofuran-2(3H)-one (23): p-Meth-
oxybenzyl 2,2,2-trichloroacetimidate (155 mg, 0.55 mmol) and
CSA (3.0 mg, 0.013 mmol) were added to a stirred solution of lac-
166.55 ppm. IR (film): ν = 3020, 2931, 2858, 2401, 2360, 1712,
˜
1471, 1215, 1126, 1027, 929, 758, 669 cm–1.
(3E,7E,9S,10S,11R,12Z)-10-[(tert-Butyldimethylsilyl)oxy]-9-meth- tone 9 (120 mg, 0.46 mmol) in CH2Cl2 (2 mL). The reaction mix-
oxy-11,13-dimethyl-1-oxacyclotetradeca-3,7,12-trien-2-one (22):
Grubbs II catalyst (12 mg, 0.013 mmol) was added to a solution of
ester 21 (28.9 mg, 0.068 mmol) in toluene (103 mL) at reflux. After
stirring for 15 min, the reaction mixture was cooled to room tem-
perature and filtered through a plug of silica gel (hexane/EtOAc,
4:1). Purification by silica gel flash column chromatography (5%
EtOAc/hexane) afforded the desired macrolactone 22 (11.7 mg,
43 %). Rf = 0.80 (10 % EtOAc/hexane). 1H NMR (500 MHz,
CDCl3): δ = 0.06 (s, 3 H), 0.07 (s, 3 H), 0.83 (d, J = 6.5 Hz, 3 H),
ture was stirred at room temperature for 12 h. Next, it was diluted
with Et2O (10 mL), washed with a saturated aqueous solution of
NaHCO3 (5 mL), brine (5 mL), and H2O (5 mL), dried with
MgSO4, and concentrated under reduced pressure. The crude mate-
rial was washed with cold hexane to separate the precipitate. Ad-
ditional purification by silica gel flash column chromatography
(20% EtOAc/hexanes), gave lactone 23 (83%) as a yellow oil. Rf =
0.50 (20% EtOAc/hexane). [α]2D0 = +27 (c = 2.5, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 0.01 (s, 3 H), 0.06 (s, 3 H), 0.86 (s, 9 H),
0.92 (s, 9 H), 1.64 (s, 3 H), 2.21–2.14 (m, 1 H), 2.31–2.21 (m, 1 H), 1.23 (d, J = 7.3 Hz, 3 H), 2.62–2.50 (m, 1 H), 3.56 (dd, J = 11.3,
2.47–2.37 (m, 2 H), 3.03–2.95 (m, 1 H), 3.17 (s, 3 H), 3.33–3.30 (m,
1 H), 3.44 (dd, J = 1.5, 8.5 Hz, 1 H), 4.62 (d, J = 15.5 Hz, 1 H),
4.68 (d, J = 15.5 Hz, 1 H), 5.12 (dd, J = 9.0, 15.5 Hz, 1 H), 5.56–
3.8 Hz, 1 H), 3.71 (dd, J = 11.3, 2.3 Hz, 1 H), 3.79 (s, 3 H), 4.12–
4.05 (m, 1 H), 4.19–4.14 (m, 1 H), 4.46 (d, J = 12 Hz, 1 H), 4.51
(d, J = 12 Hz, 1 H), 6.86 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 8.8 Hz,
6756
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6748–6759

Synthesis of the Macrolactone of Migrastatin and Analogues
2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = –4.77, –4.31, 12.86,
(100 mg, 0.44 mmol) was added at ambient temperature. After 2 h,
17.77, 25.58, 44.27, 55.26, 67.16, 73.21, 75.02, 83.44, 113.82, the reaction mixture was washed with a saturated aqueous
129.49, 129.56, 159.34, 176.68 ppm. IR (film): ν = 3001, 2933, 2852, NaHCO3 solution (10 mL) and a saturated aqueous NaCl solution
˜
1784, 1612, 1514, 1457, 1302, 1248, 1171, 1075, 1036 cm–1. HRMS:
calcd. for C20H33O5Si [M]+ 381.2097; found 381.2208.
and extracted with CH2Cl2 (3ϫ20 mL). The organic layers were
dried with anhydrous MgSO4 and concentrated in vacuo. Purifica-
tion by silica gel flash column chromatography by using 20 %
EtOAc/hexane afforded 100.5 mg of 26 in 64% yield for the two-
step sequence. Rf = 0.53 (20% EtOAc/hexane). [α]2D0 = +1 (c = 1.0,
(2R,3S,4R)-3-[(tert-Butyldimethylsilyl)oxy]-5-(4-methoxybenzyl-
oxy)-2-methylpentane-1,4-diol (24): LiAlH4 was added (47.0 mg,
1.25 mmol) to a solution of lactone 23 (190 mg, 0.50 mmol) in THF
(10 mL) at 0 °C (when using more than 5 mol of lactone 23, the
reaction has to be performed at –78 °C to avoid loss of the TBS
group). After 30 min, the reaction was quenched by the addition
of an aqueous solution of 0.1 m NaOH (10 mL), and the reaction
mixture was stirred for 1 h. The mixture was extracted with Et2O
(3ϫ5 mL). The combined organic layers were washed with brine
and dried with MgSO4, concentrated under reduced pressure, and
purified by silica gel flash column chromatography (40% EtOAc/
hexanes) to give alcohol 24 (75%) as a colorless oil. Rf = 0.30 (40%
EtOAc/hexane). [α]2D0 = +3 (c = 1.0, CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = –0.04 (s, 3 H), –0.01 (s, 3 H), 0.78 (s, 9 H), 0.83 (d, J
= 7.3 Hz, 1 H), 1.88 (sextd, J = 6.9, 2.4 Hz, 1 H), 2.16 (br. s, 1 H),
2.63 (br. d, J = 1.5 Hz, 1 H), 3.39 (dd, J = 9.3, 6.9 Hz, 1 H), 3.46–
3.44 (m, 2 H), 3.52 (dd, J = 9.3, 2.7 Hz, 1 H), 3.75–3.68 (m, 5 H),
1
CH2Cl2). H NMR (250 MHz, CDCl3): δ = 0.04 (s, 6 H), 0.06 (m,
3 H), 0.10 (s, 3 H), 0.89 (s, 18 H), 0.92 (d, J = 7.5 Hz, 3 H), 1.84–
1.74 (m, 1 H), 2.09 (s, 1 H), 3.30–3.24 (m, 1 H), 3.42 (s, 3 H), 3.52–
3.46 (m, 2 H), 3.70 (t, J = 5.8 Hz, 2 H), 3.96 (t, J = 4.0 Hz, 1 H)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.44, –5.38, –4.77, –4.17,
12.23, 18.19, 18.34, 25.86, 26.03, 38.81, 57.71, 61.30, 65.50, 72.02,
83.69 ppm. IR (film): ν = 3059, 2960, 2030, 2894, 2858, 1471, 1385,
˜
1265, 1107, 1045 cm–1.
(5S,6R)-5-[(R)-1-Methoxyallyl]-2,2,3,3,6,9,9,10,10-nonamethyl-
4,8-dioxa-3,9-disilaundecane (27): At ambient temperature molecu-
lar sieves (4 Å) were added to a stirred solution of alcohol 26
(50 mg, 0.13 mmol) in CH2Cl2. The mixture was stirred for 15 min,
before 4-methylmorpholine N-oxide (23 mg, 0.20 mmol) was added
followed by TPAP (a few crystals) after 15 min. The resulting mix-
4.35 (d, J = 11.3 Hz, 1 H), 4.42 (d, J = 11.3 Hz, 1 H), 6.79 (d, J = ture was stirred for 30 min, filtered (Celite), and the filtrate was
8.8 Hz, 2 H), 7.16 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = –4.50, –4.43, 11.75, 18.12, 25.89, 38.82, 55.22, 65.03,
71.34, 71.94, 73.02, 73.31, 113.81, 129.50, 129.86, 159.27 ppm. IR
concentrated. Without purification, Cp2TiMe2 (0.5 m, 0.52 mL,
0.26 mmol) was added to a solution of the resulting aldehyde in
toluene (1 mL) and under argon. The resulting mixture was pro-
tected from light and stirred vigorously at 60 °C for 4 h. The mix-
ture was concentrated, and the residue was purified by silica gel
flash column chromatography (20% EtOAc/hexane) to afford 27
(37.9 mg, 75%). Rf = 0.74 (20% EtOAc/hexane). [α]2D0 = –10 (c =
2.0, CH2Cl2).1H NMR (300 MHz, CDCl3): δ = 0.03 (s, 6 H), 0.04
(s, 6 H), 0.93–0.84 (m, 21 H), 1.89–1.81 (m, 1 H), 3.24 (s, 3 H),
3.52–3.31 (m, 3 H), 3.82–3.80 (m, 1 H), 5.30–5.18 (m, 2 H), 5.76
(ddd, J = 17.0, 10.4, 8.0 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = –5.36, –5.32, –4.62, –3.61, 11.69, 18.27, 18.43, 25.84,
26.03, 38.42, 56.09, 65.83, 74.26, 85.42, 118.74, 136.20 ppm. IR
(film): ν = 3423, 2931, 2858, 1612, 1514, 1464, 1250, 1090, 1040,
˜
835 cm–1. HRMS: calcd. for C20H37O5Si [M + H]+ 385.2410; found
385.2464.
(2R,3S,4R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-1-(4-methoxy-
benzyloxy)-4-methylpentan-2-ol (25): Imidazole (71 mg, 1.04 mmol)
and TBSCl (128 mg, 0.84 mmol) were added to a solution of diol
24 (250 mg, 0.65 mmol) in CH2Cl2 (7 mL) at 0 °C. The resulting
mixture was stirred for 1 h. The solution was diluted with brine
(10 mL), and the aqueous phase was extracted with CH2Cl2
(3ϫ5 mL). The combined organic phases were dried with MgSO4,
the solvent was removed under reduced pressure, and the resulting
mixture was purified by silica gel flash column chromatography
(20% EtOAc/hexanes) to give alcohol 25 in 98% yield as a colorless
oil. Rf = 0.61 (40% EtOAc/hexane). [α]2D0 = +1 (c = 1.0, CH2Cl2).
(film): ν = 2959, 2930, 2863, 1471, 1391, 1254, 1090 cm–1.
˜
(2R,3S,4R)-3-[(tert-Butyldimethylsilyl)oxy]-4-methoxy-2-methylhex-
5-en-1-ol (28): A solution of HF/pyridine/THF (1:4:5, 0.8 mL) was
added to a stirred solution of TBS ether 27 (30.0 mg, 0.08 mmol) in
1H NMR (300 MHz, CDCl3): δ = 0.08–0.05 (m, 12 H), 0.91–0.88 THF (1.0 mL) at 0 °C. The reaction mixture was stirred at ambient
(m, 21 H), 1.92–1.82 (m, 1 H), 2.61 (d, J = 2.1 Hz, 1 H), 3.50–3.45 temperature for 12 h, diluted with Et2O (10 mL), and powdered
(m, 3 H), 3.60–3.56 (m, 1 H), 3.86–3.81 (m, 5 H), 4.46 (d, J = NaHCO3 was slowly added until pH = 7. After 10 min, the reaction
11.3 Hz, 1 H), 4.53 (d, J = 11.3 Hz, 1 H), 6.88 (d, J = 8.8 Hz, 2
mixture was filtered and concentrated. The crude product was puri-
H), 7.27 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ fied by silica gel flash column chromatography on silica gel (20%
= –5.35, –4.51, –4.35, 11.33, 18.20, 18.25, 25.89, 25.97, 38.35, 55.24,
65.12, 71.30, 72.20, 72.62, 73.00, 113.78, 129.40, 130.15,
EtOAc/hexane) to give alcohol 28 (15.8 mg, 72% yield). Rf = 0.30
(20% EtOAc/hexane). [α]2D0 = –18 (c = 1.20, CHCl3). 1H NMR
159.23 ppm. IR (film): ν = 3054, 2954, 2930, 2858, 1612, 1514, (250 MHz, C6D6): δ = 0.13 (s, 3 H), 0.15 (s, 3 H), 0.95 (d, J =
˜
1463, 1265, 1092, 1040, 914 cm–1. HRMS: calcd. for C26H51O5Si2
[M + H]+ 499.3275; found 499.3211.
7.0 Hz, 3 H), 1.01 (s, 12 H), 1.01 (s, 9 H), 1.99–1.84 (m, 1 H), 3.07
(s, 3 H), 3.47–3.26 (m, 3 H), 3.97–3.93 (m, 1 H), 5.15–5.05 (m, 2
H), 5.81 (ddd, J = 17.1, 10.0, 8.1 Hz, 1 H) ppm. 13C NMR
(125 MHz, C6D6): δ = –4.08, –3.02, 12.61, 19.02, 26.75, 39.52,
(2R,3S,4R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-2-methoxy-4-
methylpentan-1-ol (26): A proton sponge [1,8-bis(dimethylamino)-
naphthalene, 170 mg, 0.80 mmol] and Me3OBF4 (100 mg,
0.70 mmol) were added to a solution of alcohol 25 (200 mg,
0.40 mmol) in CH2Cl2 (10 mL) at ambient temperature under ar-
gon, and the heterogeneous reaction mixture was stirred with pro-
tection from light for 12 h. The reaction was quenched by the ad-
dition of a cold 1% aqueous solution of HCl (25 mL), and the
mixture was extracted with Et2O (3ϫ25 mL). The combined or-
ganic layers were filtered through silica gel, dried with anhydrous
MgSO4, and concentrated in vacuo. The crude reaction mixture
was diluted with CH2Cl2 (4 mL) and H2O (0.2 mL), and then DDQ
56.19, 65.77, 75.80, 85.81, 119.33, 136.94 ppm. IR (film): ν = 3429,
˜
3019, 2929, 2882, 2858, 2816, 1471, 1248, 1216, 1105, 929, 838,
759, 669 cm–1. HRMS: calcd. for C14H31O3Si [M + H]+ 275.2042;
found 275.2105.
Ethyl (4R,5S,6R,Z)-5-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-2,4-
dimethylocta-2,7-dienoate (29): At ambient temperature, molecular
sieves (4 Å) were added to a stirred solution of alcohol 28
(110.0 mg, 0.40 mmol) in CH2Cl2 (8 mL). The mixture was stirred
for 15 min before 4-methylmorpholine N-oxide (71 mg, 0.60 mmol)
was added followed by TPAP (a few crystals) after 15 min. The
Eur. J. Org. Chem. 2010, 6748–6759
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6757

L. C. Dias et al.
FULL PAPER
resulting mixture was stirred for 30 min, filtered (Celite), and the
filtrate was concentrated to give an intermediate aldehyde. Phos-
phonate 17 (40 mg, 1.00 mmol) in THF (8 mL) was added to a
stirred suspension of 60 % NaH (282 mg, 1.00 mmol, previously
washed with hexane) in THF (2 mL) under argon at 0 °C. After
stirring at 0 °C for 15 min, a solution of the previously prepared
aldehyde in THF (5.0 mL) was added. The resulting mixture was
warmed to ambient temperature and stirred for 12 h. The reaction
mixture was diluted with H2O (15 mL), extracted with EtOAc
(2 ϫ 10 mL), and the combined organic layers were dried with
MgSO4, filtered, and concentrated. The crude product was purified
by silica gel flash column chromatography (5% EtOAc/hexane) to
give the (Z)-unsaturated ester 29 (95.6 mg, 67% yield over two
steps). Rf = 0.72 (20% EtOAc/hexane). [α]2D0 = –33 (c = 1.50,
2.60–2.45 (m, 1 H), 3.19 (s, 3 H), 3.43 (dd, J = 8.5, 3.0 Hz, 1 H),
3.52 (dd, J = 7.5, 2.3 Hz, 1 H), 4.45 (d, J = 12 Hz, 1 H), 4.60 (d,
J = 12 Hz, 1 H), 5.29–4.92 (m, 5 H), 5.87–5.68 (m, 2 H) ppm. 13C
NMR (62.5 MHz, CDCl3): δ = –4.61, –3.68, 17.60, 18.49, 21.49,
24.43, 26.06, 26.15, 28.34, 33.35, 34.12, 35.76, 55.52, 63.35, 78.71,
84.92, 114.68, 119.51, 129.03, 133.89, 134.86, 138.36, 173.63 ppm.
IR (film): ν = 3082, 3025, 2930, 2859, 2401, 1728, 1462, 1423, 1217,
˜
1097, 999, 932, 760 cm–1. HRMS: calcd. for C24H44O4SiNa [M +
Na]+ 447.2901; found 447.2916.
(7E,9R,10S,11R,12Z)-10-[(tert-Butyldimethylsilyl)oxy]-9-methoxy-
11,13-dimethyl-1-oxacyclotetradeca-7,12-dien-2-one (33): Grubbs II
catalyst (17.2 mg, 0.02 mmol) was added to a solution of ester 32
(43 mg, 0.10 mmol) in toluene (200 mL) at reflux. After stirring for
30 min, the reaction mixture was cooled to room temperature and
filtered through a plug of silica gel (hexane/EtOAc, 4:1). Purifica-
tion by silica gel flash column chromatography (5% EtOAc/hexane)
afforded the desired product 32 (32 mg, 80 %). Rf = 0.60 (5 %
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 0.03 (s, 3 H), 0.05 (s, 3
H), 0.89 (s, 9 H), 1.01 (d, J = 6.7 Hz, 3 H), 1.28 (t, J = 7.0 Hz, 3
H), 1.89 (d, J = 1.5 Hz, 3 H), 3.20 (s, 3 H), 3.24–3.20 (m, 1 H),
3.39 (dd, J = 8.0, 3.5 Hz, 1 H), 3.58 (dd, J = 7.0, 3.5 Hz, 1 H), 4.17
(q, J = 7.0 Hz, 2 H), 5.12 (dd, J = 17.5, 2.0 Hz, 1 H), 5.25 (dd, J
= 10.5, 2.0 Hz, 1 H), 5.76–5.69 (m, 2 H) ppm. 13C NMR
(125 MHz, C6D6): δ = –4.39, –3.30, 14.20, 16.71, 18.80, 20.98,
26.45, 37.25, 55.51, 60.05, 79.13, 85.66, 119.50, 127.26, 135.18,
EtOAc/hexane). [α]2D0
= +19 (c =
1.19, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 0.06 (s, 3 H), 0.08 (s, 3 H), 0.89 (s, 9 H),
0.96 (d, J = 7 Hz, 3 H), 1.78 (d, J = 1 Hz, 3 H), 2.41–1.82 (m, 8
H), 2.60–2.59 (s, 1 H), 3.16 (s, 3 H), 3.42 (dd, J = 9.0, 1.3 Hz, 1
H), 3.53 (dd, J = 9.0, 1.5 Hz, 1 H), 4.14 (d, J = 12 Hz, 1 H), 4.59
(d, J = 12 Hz, 1 H), 5.20–5.24 (m, 1 H), 5.44–5.34 (m, 1 H), 5.84–
5.73 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = –4.74, –3.74,
18.65, 19.48, 22.13, 22.55, 26.26, 28.95, 30.49, 35.09, 36.33, 54.96,
63.66, 79.08, 84.72, 124.89, 128.40, 134.09, 136.08, 173.85 ppm. IR
144.27, 167.57 ppm. IR (film): ν = 3019, 2965, 2929, 2858, 1708,
˜
1463, 1373, 1216, 1099, 1027, 837, 739, 669 cm–1. HRMS: calcd.
for C19H37O4Si [M + H]+ 357.2461; found 357.2415.
(4R,5S,6R,Z)-5-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-2,4-di-
methylocta-2,7-dien-1-ol (30): A solution of DIBAL-H in toluene
(2.0 m, 0.35 mL, 0.50 mmol) was added dropwise to a solution of
(film): ν = 3025, 2960, 2930, 2860, 2817, 1732, 1462, 1379, 1250,
˜
1149, 1101, 972, 837, 758, 667 cm–1. HRMS: calcd. for C22H40O4-
unsaturated ester 29 (72 mg, 0.20 mmol) in CH2Cl2 (2 mL) at SiNa [M + Na]+ 419.2588; found 419.2608.
–15 °C. After stirring for 1 h, the reaction mixture was warmed to
(7E,9R,10S,11R,12Z)-10-Hydroxy-9-methoxy-11,13-dimethyl-1-
oxacyclotetradeca-7,12-dien-2-one (34): 48% HF solution
0 °C, and EtOAc (15 mL) was added. After 30 min, the reaction
mixture was warmed to ambient temperature, and a cold solution
of aqueous potassium sodium tartrate (10 mL) was added. The re-
sulting mixture was stirred vigorously at ambient temperature until
phase separation occurred (about 1 h). The aqueous phase was ex-
tracted with CH2Cl2 (3ϫ15 mL), the combined organic layers were
dried with MgSO4, filtered, and concentrated. The residue was
purified by silica gel flash column chromatography (20% EtOAc/
hexane) to provide allylic alcohol 30 (57.9 mg, 92% yield) as an oil.
A
(1 drop) was added to a solution of macrolactone 33 (32 mg,
0.08 mmol) in CH3CN/CH2Cl2 (2:1; 1.6 mL) at room temperature.
After stirring for 24 h, the reaction mixture was diluted with Et2O
and carefully treated with NaHCO3 (pH = 7), filtered, and concen-
trated under reduced pressure. Purification by silica gel flash col-
umn chromatography (EtOAc/hexane 5%) afforded macrolactone
34 (8.6 mg, 40%). Rf = 0.50 (5% EtOAc/hexane). [α]2D0 = +38 (c =
1
0.9, CHCl3). H NMR (250 MHz, CDCl3): δ = 1.04 (d, J = 7 Hz,
1
Rf = 0.33 (20% EtOAc/hexane). [α]2D0 = –35 (c = 1.85, CHCl3). H
3 H), 1.79 (d, J = 1 Hz, 3 H), 2.60–1.87 (m, 10 H), 3.27 (s, 3 H),
3.60–3.50 (m, 2 H), 4.19 (d, J = 11.6 Hz, 1 H), 4.57 (d, J = 11.6 Hz,
1 H), 5.22 (dd, J = 11.6, 1.0 Hz, 1 H), 5.42 (dd, J = 15.7, 8.5 Hz,
1 H), 5.89–5.78 (m, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
18.70, 22.16, 22.49, 28.61, 30.09, 34.98, 35.04, 55.73, 63.51, 77.23,
NMR (250 MHz, CDCl3): δ = 0.05 (s, 3 H), 0.06 (s, 3 H), 0.90 (s,
9 H), 0.96 (d, J = 6.7 Hz, 3 H), 2.59 (br. s, 1 H), 1.79 (d, J = 1.4 Hz,
3 H), 2.71–2.56 (m, 1 H), 3.26 (s, 3 H), 3.55–3.45 (m, 2 H), 3.89
(dd, J = 11.7, 5.0 Hz, 1 H), 4.17 (d, J = 11.7 Hz, 1 H), 5.29–5.04
(m, 3 H), 5.74 (ddd, J = 17.3, 10.5, 7.9 Hz, 1 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = –4.54, –3.84, 18.33, 18.39, 21.78, 26.08,
35.63, 56.32, 61.85, 79.46, 85.92, 118.58, 131.57, 133.85,
83.73, 123.79, 129.37, 132.91, 136.14, 173.74 ppm. IR (film): ν =
˜
3462, 3003, 2932, 2876, 2823, 1724, 1454, 1252, 1095, 974,
756 cm–1. HRMS: calcd. for C16H26O4Na [M + Na]+ 305.1723;
found 305.1723.
135.73 ppm. IR (film): ν = 3396, 3080, 2965, 2931, 2858, 2822,
˜
1462, 1373, 1254, 1100, 1004, 932, 836 cm–1.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectroscopic data for the pre-
pared compounds.
(4R,5S,6R,Z)-5-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-2,4-di-
methylocta-2,7-dienyl Hept-6-enoate (32): DCC (92.4 mg,
0.45 mmol) and DMAP (14 mg, 0.11 mmol) were added to a solu-
tion of hept-6-enoic acid (31; 57.4 mg, 0.45 mmol) in CH2Cl2
(2 mL) under argon at ambient temperature. A solution of allylic
alcohol 30 (70.4 mg, 0.22 mmol) in CH2Cl2 (2 mL) was added to
Acknowledgments
the reaction mixture through cannula. After stirring at ambient We are grateful to the Fundo de Apoio ao Ensino e Pesquisa da
temperature for 12 h, the crude reaction mixture was concentrated.
Purification by silica gel flash column chromatography (6% EtOAc/
hexane) provided the desired ester 32 (87.2 mg, 92% yield). Rf =
UNICAMP (FAEP-UNICAMP), the Fundação de Apoio ao En-
sino e Pesquisa do Estado de São Paulo (FAPESP), the Conselho
Nacional de Desenvolvimento Científico e Tecnológico (CNPq),
and the Instituto Nacional de Ciência e Tecnologia de Fármacos e
Medicamentos (INCT-INOFAR) (Proc. CNPq573.564/2008-6) for
financial support. We also thank Mr. Ricardo N. Santos for his
1
0.85 (5% EtOAc/hexane). [α]2D0 = –21 (c = 1.4, CHCl3). H NMR
(250 MHz, CDCl3): δ = 0.04 (s, 3 H), 0.05 (s, 3 H), 0.89 (s, 9 H),
0.96 (d, J = 6.7 Hz, 3 H), 1.48–1.35 (m, 2 H), 1.68–1.59 (m, 2 H),
1.72 (d, J = 1.3 Hz, 3 H), 2.06 (m, 2 H), 2.32 (t, J = 7.7 Hz, 2 H), valuable assistance in the molecular modeling studies and Prof. Ca-
6758 Eur. J. Org. Chem. 2010, 6748–6759
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of the Macrolactone of Migrastatin and Analogues
J. Massagué, S. J. Danishefsky, J. Am. Chem. Soc. 2010, 132,
3224–3228.
[10] a) T. Schneider-Poetsch, J. Ju, D. E. Eyler, Y. Dang, S. Bhat,
W. C. Merrick, R. Green, B. Shen, J. O. Liu, Nat. Chem. Biol.
2010, 6, 209–217; b) B. B. Metaferia, L. Chen, H. L. Baker, X.-
Y. Huang, C. A. Bewley, J. Am. Chem. Soc. 2007, 129, 2434–
2435.
rol H. Collins for helpful suggestions relating to English grammar
and style. This paper is dedicated to Prof. Glaucius Oliva (Instituto
de Física, Universidade de São Paulo, São Carlos) for his outstand-
ing contributions to the field of Medicinal Chemistry in Brazil.
[1]
a) K. Nakae, Y. Yoshimoto, T. Sawa, Y. Homma, M. Hamada,
T. Takeuchi, M. Imoto, J. Antibiot. 2000, 53, 1130–1136; b) K.
Nakae, Y. Yoshimoto, M. Ueda, T. Sawa, Y. Takahashi, H.
Naganawa, T. Takeuchi, M. Imoto, J. Antibiot. 2000, 53, 1228–
1230; c) H. Nakamura, Y. Takahashi, H. Naganawa, K. Nakae,
M. Imoto, M. Shiro, K. Matsumura, H. Watanabe, T. Kitah-
ara, J. Antibiot. 2002, 55, 442–444.
[11] L. Chen, S. Yang, J. Jakoncic, J. J. Zhang, X. Y. Huang, Nature
2010, 464, 1062–1066.
[12] J. C. Adams, Curr. Opin. Cell Biol. 2004, 16, 590–596.
[13] P. Nagorny, I. Krauss, J. T. Njardarson, L. Perez, C. Gaul,
G. G. Yang, O. Ouerfelli, S. J. Danishefsky, Tetrahedron Lett.
2010, 51, 3873–3875.
[14] The numbering of macrolactone 2 as well as of each intermedi-
ate follows that suggested in ref.[8]
[2]
[3]
[4]
E. J. Woo, C. M. Starks, J. R. Carney, R. Arslanian, L. Cada-
pan, S. Zavala, P. Licari, J. Antibiot. 2002, 55, 141–146.
Y. Takemoto, K. Nakae, M. Kawatani, Y. Takahashi, H. Na-
ganawa, M. Imoto, J. Antibiot. 2001, 54, 1104–1107.
J. T. Njardarson, C. Gaul, D. Shan, X. Huang, S. J. Danishef-
sky, J. Am. Chem. Soc. 2004, 126, 1038–1040.
[15] a) D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981,
103, 2127–2129; b) D. A. Evans, T. R. Taber, Tetrahedron Lett.
1980, 21, 4675–4678; c) M. T. Crimmins, J. She, Synlett 2004,
8, 1371–1374; d) M. T. Crimmins, B. W. King, E. A. Tabet, K.
Chaudhary, J. Org. Chem. 2001, 66, 894–902.
[5] G. Y. Perret, M. Crépin, Fundam. Clin. Pharm. 2008, 22, 465– [16] a) L. C. Dias, L. G. de Oliveira, M. A. de Sousa, Org. Lett.
492.
2003, 5, 265–268; b) L. C. Dias, P. R. R. Meira, Tetrahedron
Lett. 2002, 43, 185–187; c) L. C. Dias, L. G. de Oliveira, J. D.
Vilcachagua, F. Nigsch, J. Org. Chem. 2005, 70, 2225–2234; d)
L. C. Dias, L. G. de Oliveira, Org. Lett. 2001, 3, 3951–3954; e)
L. C. Dias, L. G. de Oliveira, Org. Lett. 2004, 6, 2587–2590.
[17] L. C. Dias, I. B. D. de Castro, L. J. Steil, T. Augusto, Tetrahe-
dron Lett. 2006, 47, 213–216.
[18] The relative stereochemistry of lactones 9 and 10 was sub-
sequently confirmed by correlation with the spectroscopic data
of allylic alcohol 19 from the literature.[8–10]
[6] a) L. B. Salum, L. C. Dias, A. D. Andricopulo, QSAR Comb.
Sci. 2009, 28, 325–337; b) L. B. Salum, L. C. Dias, A. D. And-
ricopulo, J. Braz. Chem. Soc. 2009, 20, 693–703; c) A. D. And-
ricopulo, L. B. Salum, D. J. Abraham, Curr. Top. Med. Chem.
2009, 9, 771–790.
[7] G. Anquetin, S. L. Rawe, K. McMahon, E. P. Murphy, P. V.
Murphy, Chem. Eur. J. 2008, 14, 1592–1600.
[8] a) C. Gaul, S. J. Danishefsky, Tetrahedron Lett. 2002, 43, 9039–
9042; b) C. Gaul, J. T. Njardarson, S. J. Danishefsky, J. Am.
Chem. Soc. 2003, 125, 6042–6043; c) C. Gaul, J. T. Njardarson, [19] D. A. Evans, A. M. Ratz, B. E. Huff, G. S. Sheppard, J. Am.
D. Shan, D. C. Dorn, K. Wu, W. P. Tong, X. Huang, M. A. S.
Moore, S. J. Danishefsky, J. Am. Chem. Soc. 2004, 126, 11326–
11337; d) V. S. Baba, P. Das, K. Mukkantib, J. Iqbal, Tetrahe-
dron Lett. 2006, 47, 6083–6086; e) P. Das, V. Saibaba, C. K.
Kumar, V. Mahendar, Synthesis 2008, 3, 445–451; f) S. Re-
ymond, J. Cossy, Eur. J. Org. Chem. 2006, 21, 4800–4804; g)
S. Reymond, J. Cossy, Tetrahedron 2007, 63, 5918–5929; h) J.
Le Brazidec, C. A. Gilson III, M. F. Boehm, J. Org. Chem.
2005, 70, 8212–8215; i) I. J. Krauss, M. Mandal, S. J. Danishef-
sky, Angew. Chem. Int. Ed. 2007, 46, 5576–5579; j) S. Reymond,
J. Cossy, C. R. Chim. 2008, 11, 1447–1462;k) J. Ju, S. R. Rajski,
S.-K. Lim, J.-W. Seo, N. R. Peters, F. M. Hoffmann, B. Shen,
J. Am. Chem. Soc. 2009, 131, 1370–1371; l) J. S. Yadav, P. N.
Lakshmi, Synlett 2010, 1033–1036; m) J. Ju, S. R. Rajski, S.-
K. Lim, J.-W. Seo, N. R. Peters, F. M. Hoffmann, B. Shen, Bi-
oorg. Med. Chem. Lett. 2008, 18, 5951–5954; n) K. Micoine,
A. Fürstner, J. Am. Chem. Soc. 2010, 132, 14064–14066.
Chem. Soc. 1995, 117, 3448–3467.
[20] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis
1994, 639–666.
[21] N. A. Petasis, E. I. Bzowej, J. Am. Chem. Soc. 1990, 112, 6392–
6394.
[22] a) K. Ando, Tetrahedron Lett. 1995, 36, 4105–4108; b) K.
Ando, J. Org. Chem. 1997, 62, 1934–1939; c) K. Ando, J. Org.
Chem. 2000, 65, 4745–4749.
[23] a) L. C. Dias, E. Ferreira, Tetrahedron Lett. 2001, 42, 7159–
7162; b) L. C. Dias, A. A. Ferreira, G. Diaz, Synlett 2002,
1845–1849; c) L. C. Dias, G. Diaz, A. A. Ferreira, P. R. R.
Meira, E. Ferreira, Synthesis 2003, 4, 603–622; d) L. C. Dias,
P. R. R. Meira, E. Ferreira, Org. Lett. 1999, 1, 1335–1338; e)
L. C. Dias, R. Giacomini, Tetrahedron Lett. 1998, 39, 5343–
5346; f) L. C. Dias, P. R. R. Meira, Synlett 2000, 37–40; g)
L. C. Dias, P. R. R. Meira, J. Org. Chem. 2005, 70, 4762–4773.
[24] a) S. H. Hong, M. W. Day, R. H. Grubbs, J. Am. Chem. Soc.
2004, 126, 7414–7415; b) A. K. Chatterjee, T. Choi, D. P. San-
ders, R. H. Grubbs, J. Am. Chem. Soc. 2003, 125, 11360–11370.
Received: August 4, 2010
[9] a) D. Shan, L. Chen, J. T. Njardarson, C. Gaul, X. Ma, S. J.
Danishefsky, X. Huang, Proc. Natl. Acad. Sci. USA 2005, 102,
3772–3776; b) T. Oskarsson, P. Nagorny, I. J. Krauss, L. Perez,
M. Mandal, G. Yang, O. Ouerfelli, D. Xiao, M. A. S. Moore,
Published Online: October 28, 2010
Eur. J. Org. Chem. 2010, 6748–6759
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