A Common Synthetic Protocol for the Cyclic and Acyclic Core of Migrastatin, Isomigrastatin, and Dorrigocin via a Chiral β-Hydroxy-γ-butyrolactone Intermediate

Article abstract of DOI:10.1002/ejoc.201402830

A facile synthetic route has been developed for the synthesis of the cyclic and acyclic cores of migrastatin, isomigrastatin, and dorrigocin. The common synthetic route goes via a β-hydroxy-γ-butyrolactone intermediate that is obtained by a Pd^II-catalysed asymmetric allylic intramolecular cyclization of 3-hydroxy-2-methylhex-5-enoic acid following a protocol developed by White and coworkers. The synthesis of a key intermediate chiral β-hydroxy-γ-butyrolactone (A) by Pd^II-catalysed stereoselective allylic C-H oxidation is reported. A common synthetic route to transform this intermediate into key building blocks for the synthesis of migrastatin family members has been developed.

Full text of DOI:10.1002/ejoc.201402830

FULL PAPER
DOI: 10.1002/ejoc.201402830
A Common Synthetic Protocol for the Cyclic and Acyclic Core of Migrastatin,
Isomigrastatin, and Dorrigocin via a Chiral β-Hydroxy-γ-butyrolactone
Intermediate
Narendar Reddy Gade*[a] and Javed Iqbal*[a]
Keywords: Synthesis design / Metathesis / C–H activation / Oxidation / Natural products / Lactones
A facile synthetic route has been developed for the synthesis
of the cyclic and acyclic cores of migrastatin, isomigrastatin,
and dorrigocin. The common synthetic route goes via a β-
hydroxy-γ-butyrolactone intermediate that is obtained by a
PdII-catalysed asymmetric allylic intramolecular cyclization
of 3-hydroxy-2-methylhex-5-enoic acid following a protocol
developed by White and coworkers.
Introduction
Cancer metastasis is a major cause of death from cancer.
Its inhibition using small-molecule-derived cell-migration
inhibitors has elicited keen interest among researchers. The
migrastatin family of natural products (Figure 1) is an im-
portant class of molecules with cell-migration-inhibitory
properties.[1] Structurally, migrastatin (1) is a 14-membered
macrolide, while its related analogues, dorrigocin A (2) and
13-epi dorrigocin A (3) are acyclic variants with an E-olefin
geometry at C11–C12. Similarly, isomigrastatin (4) is a 12-
membered macrocycle, and dorrigocin B (5) is an acyclic
variant of that molecule (Figure 1). All these compounds
have a common C1–C10 skeleton.
Danishefsky’s pioneering work on the synthesis of mol-
ecules of the migrastatin family and their analogues has
shown the importance of this class of molecules. It has also
demonstrated that analogous skeletons present in these nat-
ural products could be synthesized using a diverted total
synthesis approach.[2] Thus, the structural complexity and
biological activity of the migrastatin family has prompted
many research groups to work on the synthesis of these
molecules.[3] In spite of several reported synthetic studies
towards these natural products and their analogues, there is
still a need to develop commercially viable new strategies to
access these pharmaceutically important molecules. In this
paper, we report our synthetic efforts to access migrastatin
analogues using an asymmetric C–H oxidation reaction as
the key step.
Figure 1. Migrastatin family members.
Results and Discussion
In the light of our previous studies,[3d–3f] and the re-
ported literature[2,3] we envisioned that a β-hydroxy-γ-
butyrolactone 7 could be a common intermediate for ac-
cessing all the family members of migrastatin (Scheme 1).
An extensive literature search also revealed that the β-hy-
droxy-γ-butyrolactones are privileged substructures that are
present in several biologically important natural products,
and that they are also used as intermediates in natural prod-
uct synthesis.[4] The synthesis of five-membered vinyl lact-
ones using C–H oxidation methods has been reported,[5]
but the stereoselective syntheses of β-hydroxy-γ-butyro-
lactones 7 is not yet known. So we envisioned that the all-
ylic C–H oxidation of fragments like 2-methyl-3-hydroxy-
hex-5-enoic acid 6 to lead to 7 could serve as a versatile
route to the fully substituted chiral vinyl lactones.
[a] Dr. Reddy’s Institute of Life Sciences, University of Hyderabad
Campus,
Gachibowli, Hyderabad 500046, India
E-mail: g.narendarreddy@gmail.com
prof.javediqbal@gmail.com
www.drils.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402830.
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Migrastatin, Isomigrastatin, and Dorrigocin
Scheme 1. Proposed synthetic plan.
It is noteworthy that lactone 7 is characterized by three
important features: i) an alk-1-en-3,4-diol[6] system (num-
bering based on the olefin); ii) three contiguous chiral
centres (a very common pattern that is found in tedanol-
ides,[7a] amphidinolides,[7b] bafilomycins,[7c,7d] thuggacins,[7e]
and benzoquinone ansamycin antibiotics,[7f] etc.); and most
importantly iii) terminal olefin and ester orthogonal func-
tionalities, which could be used as handles to install further
functionalities required for the synthesis of natural prod-
ucts. In our approach to β-hydroxy-γ-butyrolactones [Fig-
ure 2, Equation (1)], we used a regio- and stereoselective
PdII/sulfoxide-catalysed allylic C–H oxidation reaction de-
veloped by White and co-workers for the synthesis of anti-
1,4-dioxan-2-ones from homoallylic oxygenates [Figure 2,
Equation (2)].[8] Accordingly, we prepared racemic 3-hy-
droxyhex-5-enoic acid derivative 10 (Scheme 2) from 9,
which was derived from ethyl cyanoacetate (8) using a
Barbier reaction.[9] The β-keto ester was reduced to the cor-
responding alcohol, which, upon PMB (p-methoxybenzyl)
protection [with PMBOC(=NH)CCl3 and CSA (cam-
phorsulfonic acid)] followed by ester hydrolysis, gave the
desired racemic acid (i.e., 10). Acid 10 was subjected to
White’s oxidation conditions to give a diastereomeric mix-
ture (5:1) of lactones 11 in 60% yield. The relative stereo-
chemistry of the major diastereomer of 11 was confirmed
by its conversion into known compound 12.[10]
Scheme 2. Synthesis of β-hydroxy-γ-butyrolactone 12; CAN = ce-
rium(IV) ammonium nitrate; BQ = p-benzoquinone.
To access the chiral trisubstituted β-hydroxy-γ-butyro-
lactones (Scheme 3), we converted aldol adduct 13[3f] into
PMB ether 14 [with PMBOC(=NH)CCl3 and Sc(OTf)3],
which was followed by hydrolysis to give acid 15 in good
yield. White’s oxidation of acid 15 gave the desired lactone
(i.e., 16) in 65% yield with good diastereoselectivity. The
diastereomers were easily separated by flash chromatog-
raphy leading to a ratio of 9:1.
Scheme 3. Synthesis of chiral trisubstituted lactone 16 and its key
NOE correlations. DTBMP = 2,6-di-tert-butyl-4-methylpyridine.
Figure 2. Application of White’s oxidation in the synthesis of vinyl
lactones.
With chiral lactone 16 in hand, we embarked upon the
synthesis of the C1–C13 fragment of dorrigocin
A
A literature search revealed the versatility of lactone 12, (Scheme 3). Reduction of 16 with diisobutylaluminium
which has been used in the synthesis of (+)-cardiobutanol- hydride (DIBAL) gave the corresponding lactol (i.e., 17),
ide[11a] and Hagen’s gland lactones.[11b] Equally, the benzyl- and reaction of the resulting lactol with stabilized phos-
protected analogue of lactone 11 has been used in the syn- phorilidene 18 gave E-olefin 19 in good yield. Subsequently,
theses of the brevicomins, styryl lactones, cardiobutan- the hydroxy group in 19 was transformed into its methyl
olide, cardiobutanolide, and goniofufurone.[11c] Also, the ether (with MeOTf), and the product was reduced to give
saturated lactone has been used in the formal synthesis of the corresponding allylic alcohol (i.e., 21; Scheme 4). Com-
(–) isolaurepinnacin and (+)-rogioloxepane,[11d] and the cor- pound 21 contains the C6–C13 fragment of dorrigocin A,
responding acid has been used in the total synthesis of which is also found in the bafilomycin subclass of natural
decarestrictine D.[11e]
products as the C12–C19 fragment.[7c,12,13]
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N. R. Gade, J. Iqbal
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Scheme 5. Synthesis of acetyl-protected allylic alcohol 26.
resorted to a complete reduction of lactone 16. Accordingly,
lactone 16 was reduced using DIBAL (3 equiv.) at –78 °C
for 3 h to give diol 29 in 98% yield. The primary alcohol in
29 was protected as its silyl ether to give 30, which has al-
ready been converted by our group into the macrolide core
of migrastatin 32 [Scheme 6, Equation (1)].[3d] A similar in-
termediate 33 was also used by Dias and coworkers in their
synthesis of isomigrastain analogues [Scheme 6, Equa-
tion (2)].[18] So the synthesis of 30 constitutes a formal syn-
thesis of macrolide core of migrastatin and isomigrastatin
analogues.
Scheme 4. Synthesis of allylic alcohol 21.
Our initial attempts at the cross metathesis[14] of 21 with
olefin partner 22[15] or the corresponding (E)-2,6-hepta-
dienoate 23[16] using Grubbs’ second-generation catalyst
were not successful (Table 1, entries 1 and 2), however, the
corresponding acetyl-protected compound 26 (synthesized
from 19 in three steps; Scheme 5) underwent a smooth
cross-metathesis reaction with ethyl ester 23 to give the de-
sired product (i.e., 28) (Table 1, entries 2 and 3) in moderate
yields. The reaction proceeded slightly better in toluene
than in dichloromethane. Thus, we have demonstrated that
the C1–C13 fragment of dorrigocin A can be simply synthe-
sized from lactone 16.
Table 1. Attempts at the olefin metathesis.[a]
Scheme 6. Synthesis of the migrastatin macrolide core; TBS = tert-
butyldimethylsilyl, TBAF = tetrabutylammonium fluoride.
Entry
R1, R2
Solvent
Time [h]
Isolated yield [%]
1[b]
2
3
H, H
CH2Cl2
CH2Cl2
CH2Cl2
toluene
4
4
2
2
–
–
15
20
H, Et
Ac, Et
Ac, Et
Conclusions
4
[a] All reactions were carried out on a 0.06 mmol scale at r.t. [b] Re-
action was conducted at 40 °C.
We have demonstrated the synthesis of a versatile chiral
trisubstituted butyrolactone 16 for the first time using a
PdII/sulfoxide-catalysed asymmetric C–H oxidation. A
Our attempts to access migrastatin macrolide core 33 common synthetic protocol was developed to convert
from lactone 16 (Scheme 6) by Wittig olefination of the cor- butyrolactone 16 into key building blocks for the synthesis
responding lactol (i.e., 17) did not lead to the expected Z- of migrastatin, isomigrastatin, and the C1–C13 fragment of
olefin product,[17] which would have given direct access to dorrigocin A. The further exploration of these functionally
the migrastatin key intermediate. Having failed to ac- substituted chiral β-hydroxy-γ-butyrolactones in the synthe-
complish this transformation using other strategies,[18] we sis of other natural products is in progress in our laboratory.
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Migrastatin, Isomigrastatin, and Dorrigocin
it was acidified with HCl (1 m), and extracted with EtOAc (5ϫ
4 mL). The combined organic extracts were dried (Na2SO4) and
concentrated under reduced pressure to give acid 10 (187 mg, 75%
over three steps). Rf = 0.5 (25% EtOAc in hexane). 1H NMR
(400 MHz, CDCl3): δ = 7.30–7.21 (m, 2 H), 6.88 (dd, J = 11.0,
Experimental Section
General Methods: All reactions were carried out in oven-dried
glassware, and were stirred with Teflon-coated magnetic stirring
bars. All solvents were distilled before use. Thin-layer chromatog-
raphy was carried out using Merck Silica gel 60 F-254 precoated
plates (0.25 mm), which were visualized by UV irradiation. Silica
gel from Merck (particle size 230–400 mesh) was used for flash
chromatography. 1H NMR spectra were recorded at 400 MHz in
CDCl3, and 13C NMR spectra were recorded at 100 MHz in CDCl3
with TMS as internal standard. All coupling constants (J values)
are reported in Hertz (Hz). Chemical shifts (δ) are reported in ppm
relative to residual solvent signals (δ = 7.26 ppm for 1H NMR and
δ = 77.0 ppm for 13C NMR). Data for 1H NMR spectra are re-
ported as follows: chemical shift (multiplicity, coupling constants,
and number of hydrogen atoms). The following abbreviations are
used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet).
Infrared spectra were recorded with an FTIR spectrometer, and the
data are reported in wavenumbers (cm–1). Only selected IR ab-
sorbances are reported. Mass spectra were obtained with an Ag-
ilent 6430 series Triple Quard LC-MS/MS spectrometer. High-reso-
lution mass spectra were measured with a Waters LCT premier XE
instrument. Optical rotations were measured with a HORIBA
high-sensitivity polarimeter SEPA-300.
5.2 Hz, 2 H), 5.80 (m, 1 H), 5.21–5.07 (m, 2 H), 4.52 (ABq, JAB
=
11.2 Hz, 2 H), 3.99–3.88 (m, 1 H), 3.80 (s, 3 H), 2.63–2.51 (m, 2
H), 2.26–2.31 (m, 2 H) ppm.
Lactone 11: 1,2-Bis(phenylsulfinyl)ethanepalladium(II) acetate 1
(25 mg, 0.05 mmol), (1R,2R)-(–)-[1,2-cyclohexanediamine-N,NЈ-
bis(3,5-di-tert-butylsalicylidine)]chromium(III) chloride [(R,R)-
Cr(salen)Cl; 32 mg, 0.05 mmol], and p-benzoquinone (108 mg,
1.0 mmol) were dissolved in 1,4-dioxane (1.5 mL) in a round-bot-
tomed flask (5 mL) with a stopper, and acid 10 (125 mg, 0.5 mmol)
was added. The mixture was stirred at 45 °C in an oil bath for 6 h.
Then the mixture was cooled to room temperature and transferred
to a separatory funnel with EtOAc. The organic phase was washed
with saturated aqueous sodium metabisulfite (2ϫ 10 mL) and brine
(2ϫ 10 mL). The organic layer was dried with Na2SO4, filtered,
and concentrated under reduced pressure. Purification by flash
chromatography (10% EtOAc in hexane) gave lactone 11 (75 mg,
60%) as a diastereomeric mixture (major/minor, 5:1).
Data for the major isomer of 11: Rf = 0.25 (20% EtOAc in hexane).
1H NMR (400 MHz, CDCl3): δ = 7.28–7.20 (m, 2 H), 6.89 (d, J =
8.6 Hz, 2 H), 5.86–5.78 (m, 1 H), 5.40 (d, J = 17.2 Hz, 1 H), 5.28
(d, J = 10.7 Hz, 1 H), 4.97–4.90 (m, 1 H), 4.50 (s, 2 H), 4.08–4.02
(m, 1 H), 3.81 (s, 3 H), 2.75–2.67 (dd, J = 17.6, 3.2 Hz, 1 H), 2.55
(dd, J = 17.8, 3.4 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 174.8, 159.5, 133.1, 129.4, 128.8, 117.9, 114.0, 84.6, 71.2, 55.3,
β-Keto Ester 9:[19] Zinc powder (1.31 g, 20 mmol) was suspended in
anhydrous THF (10 mL), and a solution of ethyl cyanoacetate 8
(0.565 g, 5 mmol) in anhydrous THF (30 mL) and allyl bromide
(0.907 g, 7.5 mmol) were added under a nitrogen atmosphere. The
mixture was cooled to 0 °C. Aluminum trichloride (0.266 g,
2 mmol) was dissolved in cold anhydrous THF, and this solution
was then slowly added to the reaction mixture. The reaction mix-
ture was allowed to warm to room temperature, and stirred for
16 h. After the reaction was complete, HCl (2 m aq.; 25 mL) was
added, and the mixture was stirred at room temperature for 5 min.
The mixture was passed through a short silica gel column. The
phases were separated, and the aqueous layer was extracted with
EtOAc (3ϫ 25 mL). The combined organic extracts were dried
with sodium sulfate, and the solvent was removed under reduced
pressure using a rotary evaporator. This gave compound 9 (0.7 g,
90%) as a yellow oil that was used without further purification. Rf
34.3 ppm. IR (neat): ν = 3082, 2955, 2922, 1770, 1611, 1512, 1247,
˜
1019 cm–1. MS (ES): m/z = 249.2 [M + 1].
Data for the minor isomer of 11: Rf = 0.28 (20% EtOAc in hexane).
1H NMR (400 MHz, CDCl3): δ = 7.22 (d, J = 8.6 Hz, 2 H), 6.88
(d, J = 8.6 Hz, 2 H), 6.12–6.02 (m, 1 H), 5.44 (dd, J = 22.1, 13.9 Hz,
2 H), 4.92–4.86 (m, 1 H), 4.47 (ABq, JAB = 11.6 Hz, 2 H), 4.27 (q,
J = 4.7 Hz, 1 H), 3.81 (s, 3 H), 2.66 (d, J = 4.6 Hz, 2 H) ppm. IR
(neat): ν = 3080, 2955, 2924, 1771, 1604, 1510, 1242, 1010 cm–1.
˜
MS (ES): m/z = 249.2 [M + 1].
Lactone 12:[10] CAN (109 mg, 0.02 mmol) was added to a solution
of the above compound 11 (25 mg, 0.01 mmol) in a mixture of
CH3CN and H2O (9:1; 4 mL) at room temperature. The mixture
was stirred for 1 h, then it was filtered and concentrated under
reduced pressure. Water (5 mL) and CH2Cl2 (5 mL) were added,
and the organic phase was dried with Na2SO4, filtered, and concen-
trated under vacuum. The residue was purified by column
chromatography (50% EtOAc in hexane) to give lactone 12 (11 mg,
80%) as a colourless oil. Rf = 0.2 (40% EtOAc in hexane). 1H
NMR (400 MHz, CDCl3): δ = 5.95–5.82 (m, 1 H), 5.50–5.42 (m, 1
H), 5.37–5.32 (m, 1 H), 4.88–4.80 (m, 1 H), 4.44–4.35 (m, 1 H),
2.83 (dd, J = 17.6, 6.6 Hz, 1 H), 2.52 (dd, J = 17.6, 3.6 Hz, 1 H)
1
= 0.5 (20% EtOAc in hexane). H NMR (400 MHz, CDCl3): δ =
5.98–5.85 (m, 1 H), 5.27–5.15 (m, 2 H), 4.21 (q, J = 7.2 Hz, 2 H),
3.48 (s, 2 H), 3.32 (d, J = 6.9 Hz, 2 H), 1.29 (t, J = 7.2 Hz, 3 H)
ppm.
Acid 10:[20] Sodium borohydride (23.5 mg) was added to a solution
of β-keto ester 9 (156 mg, 1 mmol) in methanol (5 mL) at 0 °C, and
the mixture was stirred at the same temperature for 1 h. The mix-
ture was partitioned between hydrochloric acid (1 n) and EtOAc.
The organic layer was separated, washed with water and brine, and
dried with sodium sulfate, and the solvents were evaporated. This
gave the crude product (160 mg, crude) as a yellow oil.
ppm. IR (neat): ν = 3446, 2934, 1770, 1639, 1430, 1413, 1333, 1309,
˜
1203, 1158, 1080, 1015 cm–1. MS (ES): m/z = 129.2 [M + 1].
The crude oil was dissolved in solution of CSA (23 mg, 0.1 mmol)
in CH2Cl2 (10 mL), and then (4-methoxybenzyl)-2,2,2-trichloro-
acetimidate (562 mg, 2 mmol) was added. The mixture was stirred
for 24 h. The reaction mixture was quenched by the addition of
saturated NaHCO3 solution (5 mL), and the aqueous layer was ex-
tracted with CH2Cl2 (3ϫ 5 mL). The combined organic extracts
were dried with sodium sulfate, and the solvent was removed under
reduced pressure using a rotary evaporator.
PMB Ether 14: Sc(OTf)3 (30 mg, 0.06 mmol) was added to a stirred
solution of alcohol 13 (610 mg, 2 mmol) and PMBOC(=NH)CCl3
(1.4 g, 5 mmol) in dry toluene (15 mL) at room temperature. The
reaction mixture was stirred for 0.5 h, and then it was concentrated
in vacuo. To precipitate the trichloroacetamide, the residual oil was
taken up in a mixture of n-pentane and CH2Cl2 (5:1; 50 mL) and
filtered. The filtrate was concentrated, and the residue was purified
by flash chromatography (8% EtOAc in hexane) to give PMB ether
The PMB ether (208 mg) was dissolved in THF/MeOH/H2O (2:1:1;
10 mL), and LiOH·H2O (0.024 mg, 1.08 mmol) was added at 0 °C. 14 (721 mg, 85%) as a colourless gel. Rf = 0.67 (10% EtOAc in
The resulting mixture was stirred for 2 h at room temperature, then
petroleum ether). [α]2D7 = +37.8 (c = 1.15, CHCl3). 1H NMR
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(400 MHz, CDCl3): δ = 7.34–7.24 (m, 5 H), 7.19 (d, J = 7.2 Hz, 2
H), 6.85 (d, J = 8.4 Hz, 2 H), 5.94–5.80 (m, 1 H), 5.08 (t, J =
Data for the minor isomer of 16: Rf = 0.62 (20% EtOAc in petro-
leum ether). 1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 8.5 Hz,
14.0 Hz, 2 H), 4.56–4.39 (m, 3 H), 4.09 (dd, J = 9.0, 0.9 Hz, 1 H), 2 H), 6.90 (d, J = 8.5 Hz, 2 H), 5.94–5.83 (m, 1 H), 5.49 (d, J =
4.04–3.95 (m, 2 H), 3.82–3.71 (m, 4 H), 3.26 (dd, J = 13.4, 2.7 Hz, 17.2 Hz, 1 H), 5.34 (d, J = 10.5 Hz, 1 H), 4.68 (t, J = 6.4 Hz, 1 H),
1 H), 2.73 (dd, J = 13.3, 9.7 Hz, 1 H), 2.44–2.34 (m, 2 H), 1.27 (d, 4.61–4.51 (m, 2 H), 3.82 (s, 3 H), 3.69 (t, J = 6.9 Hz, 1 H), 2.76–
J = 6.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.0,
159.1, 153.0, 135.3, 134.9, 130.5, 129.7, 129.4, 128.9, 127.3, 117.1,
2.67 (m, 1 H), 1.29 (d, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 176.5, 159.5, 134.2, 129.4, 129.1, 119.2, 113.9, 85.0,
113.6, 78.6, 71.6, 65.9, 55.6, 55.2, 41.4, 37.7, 36.7, 12.5 ppm. IR 83.0, 72.3, 55.3, 42.1, 13.9 ppm. IR (neat): ν = 3082, 2922, 2853,
˜
(neat): ν = 3066, 2955, 2925, 2856, 1779, 1695, 1511, 1381, 1350, 1777, 1611, 1512, 1459, 1247, 1175, 1114, 1019 cm–1. MS (ES): m/z
˜
1245, 1210, 1034 cm–1. HRMS: calcd. for C25H30NO5 424.2124; = 263.2 [M + 1].
found 424.2121.
Alcohol 19: Diisobutylaluminum hydride (1.0 m in cyclohexane;
0.4 mL, 0.4 mmol) was added dropwise to a stirred solution of lact-
one 16 (100 mg, 0.38 mmol) in dry dichloromethane (5 mL) at
Acid 15: PMB ether 14 (425 mg, 1.0 mmol) was dissolved in a mix-
ture of THF and distilled water (4:1; 5 mL), and the solution was
cooled to 0 °C in an ice/water bath. Hydrogen peroxide (30%;
–78 °C. The reaction mixture was stirred for 1 h at –78 °C under
4 equiv.) and a solution of lithium hydroxide (42 mg, 1 mmol) in
an atmosphere of nitrogen. The reaction was quenched with meth-
distilled water (2.0 mL) were then added to the cooled, stirring
anol, and then it was warmed up to room temperature. Saturated
solution by syringe. The reaction flask was kept in an ice bath, and
aqueous sodium/potassium tartrate solution (2 mL) was added,
the mixture was stirred for 1 h. Then the septum was removed, and
and the resulting mixture was stirred for 4 h. Then the product was
extracted with EtOAc (2ϫ 5 mL). The combined organic extracts
were dried with Na2SO4, and concentrated in vacuo. Crude lactol
17 (100 mg, 98%) was used directly in the next reaction without
a solution of sodium sulfite (0.5 g) in water (3 mL) was added. The
THF was removed on the rotary evaporator (taking care to avoid
bumping with the aqueous THF). The remaining solution (mostly
aqueous) was extracted with dichloromethane (3ϫ 6 mL) to re-
further purification.
move the free oxazolidinone. The aqueous layer containing the
The lactol was dissolved in toluene (5 mL), and [1-(ethoxycarbonyl)-
ethylidene]triphenylphosphorane (18) (206 mg, 57 mmol) was
added under a nitrogen atmosphere. The reaction mixture was
heated at reflux for 6 h. After the reaction was complete, the tolu-
ene was removed, and the residue was purified by flash column
chromatography to give 19 (106 mg, 80%) as a colourless liquid.
Rf = 0.65 (20% EtOAc in petroleum ether). [α]2D7 = –1.0 (c = 1.05,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.29–7.22 (m, 2 H), 6.88
(d, J = 8.63 Hz, 2 H), 6.64 (dd, J = 10.3, 1.3 Hz, 1 H), 5.97–5.89
(m, 1 H), 5.37 (d, J = 17.2 Hz, 1 H), 5.23 (d, J = 10.5 Hz, 1 H),
4.55 (s, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.07–4.01 (m, 1 H), 3.81
(s, 3 H), 3.27–3.24 (m, 1 H), 2.96–2.85 (m, 1 H), 1.86 (d, J = 1.3 Hz,
3 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.10 (d, J = 6.7 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.2, 159.4, 143.5, 138.8, 130.0,
129.7, 128.2, 116.0, 113.8, 84.8, 75.1, 72.9, 60.6, 55.3, 35.7, 15.8,
carboxylate salt of the desired product was cooled in an ice bath,
and brought to pH 1 with hydrochloric acid (6 n). The aqueous
solution was then extracted with EtOAc (4ϫ 5 mL). The combined
EtOAc layers were dried with anhydrous sodium sulfate, then they
were concentrated in vacuo. The residue was passed through a
short pad of silica gel to give 15 (252 mg, 95%) as a pale yellow
oil. Rf = 0.25 (20% EtOAc in petroleum ether). [α]2D7 = –5.2 (c =
1.04, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.28–7.21 (m, 2
H), 6.86 (d, J = 8.6 Hz, 2 H), 5.87–5.74 (m, 1 H), 5.12 (dd, J =
22.6, 5.5 Hz, 2 H), 4.52 (dd, J = 30.3, 11.0 Hz, 2 H), 3.84–3.76 (m,
4 H), 2.75–2.66 (m, 1 H), 2.45–2.26 (m, 2 H), 1.20 (d, J = 7.5 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 179.6, 159.3, 133.9,
129.9, 129.5, 118.0, 113.8, 78.9, 71.9, 55.2, 42.5, 36.1, 11.2 ppm. IR
(neat): ν = 3404, 2932, 1735, 1639, 1612, 1586, 1513, 1463, 1441,
˜
1352, 1301, 1170 cm–1. MS (ES): m/z = 265.2 [M + 1].
14.3, 12.6 ppm. IR (neat): ν = 3491, 3080, 2979, 2962, 2932, 2875,
˜
Lactone 16: Lactone 16 was prepared starting from acid 15
(200 mg, 0.76 mmol) following the same procedure that was used
for the C–H oxidation reaction leading to 11. Purification by flash
column chromatography gave 16 (130 mg, 65%) as a mixture of
diastereomers (major/minor, 9:1). The relative stereochemistry of
the major isomer of 16 was established based on NOE studies.
NOEs between the methyl group (δ = 1.26 ppm) and Hc (δ =
4.95 ppm) clearly showed the trans orientation of the vinyl group
and the methyl group. Another key NOE between Ha (δ = 2.7 ppm)
and the vinylic C–H (δ = 6.0 ppm) further confirmed the trans rela-
tionship of the vinyl and methyl groups. The relative stereochemis-
try of the minor isomer of 16 was also established based on NOE
studies. A key NOE between Ha (δ = 2.72 ppm) and Hc (δ =
4.68 ppm) confirmed the cis relationship of the vinyl and methyl
groups.
1707, 1613, 1513, 1462, 1249, 1175, 1033 cm–1. HRMS: calcd. for
C20H29O5 349.2015; found 349.2001.
Ethyl Ester 20: 2,6-Di-tert-butyl-4-methylpyridine (310 mg,
1.51 mmol) and methyl triflate (120 mg, 0.73 mmol) were added
sequentially to
a stirred solution of compound 19 (52 mg,
0.15 mmol) in dry CH2Cl2 at room temperature. The reaction mix-
ture was stirred at 40 °C for 6 h. Then the reaction mixture was
diluted with CH2Cl2, and washed with HCl (3 n aq.), saturated
NaHCO3 solution, and then brine. The organic layer was dried
with Na2SO4, and concentrated under reduced pressure. The re-
sulting residue was purified by column chromatography (5%
EtOAc in hexane) to give 20 (32 mg, 60%) as a pale yellow liquid.
Rf = 0.6 (10% EtOAc in petroleum ether). [α]3D0 = –17.0 (c = 1.1,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.31–7.25 (m, 2 H), 6.86
(d, J = 8.6 Hz, 2 H), 6.67 (dd, J = 10.4, 1.3 Hz, 1 H), 5.84–5.75
(m, 1 H), 5.34–5.24 (m, 2 H), 4.66 (d, J = 10.8 Hz, 1 H), 4.49 (d,
Data for the major isomer of 16: Rf = 0.65 (20% EtOAc in petro-
leum ether). [α]2D7 = –72.1 (c = 1.4, CHCl3). H NMR (400 MHz,
1
CDCl3): δ = 7.28–7.20 (m, 2 H), 6.89 (d, J = 8.7 Hz, 2 H), 6.05– J = 10.8 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 3.80 (s, 3 H), 3.52–
5.97 (m, 1 H), 5.42 (dd, J = 21.2, 13.9 Hz, 2 H), 4.95 (t, J = 6.3 Hz, 3.51 (m, 1 H), 3.30–3.22 (m, 4 H), 2.97–2.85 (m, 1 H), 1.85–1.82
1 H), 4.55–4.45 (m, 2 H), 3.98–3.92 (m, 1 H), 3.81 (s, 3 H), 2.75– (m, 3 H), 1.31 (t, J = 7.1 Hz, 3 H), 1.04 (d, J = 7.2 Hz, 3 H) ppm.
2.67 (m, 1 H), 1.26 (d, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 176.5, 159.5, 131.3, 129.4, 129.0, 119.6, 113.9, 81.5,
13C NMR (100 MHz, CDCl3): δ = 168.3, 159.1, 144.4, 135.8, 130.6,
129.8, 127.0, 118.4, 113.6, 84.6, 84.5, 75.0, 60.5, 56.6, 55.2, 35.3,
80.2, 71.9, 55.3, 39.6, 13.1 ppm. IR (neat): ν = 3080, 2922, 2854,
15.3, 14.3, 12.4 ppm. IR (neat): ν = 3074 2978, 2931, 2876, 1708,
˜
˜
1777, 1611, 1512, 1459, 1247, 1175, 1113, 1022 cm–1. HRMS: calcd.
for C15H19O4 263.1283; found 263.1274.
1611, 1512, 1462, 1250, 1123, 1017 cm–1. HRMS: calcd. for
C21H30O5Na [M + Na]+ 385.1990; found 385.1987.
6562
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6558–6564

Migrastatin, Isomigrastatin, and Dorrigocin
Allylic Alcohol 21: DIBAL (1 m in THF; 0.5 mL) was added to a J = 10.9 Hz, 1 H), 4.51–4.38 (m, 3 H), 3.80 (s, 3 H), 3.63–3.54 (m,
stirred solution of ester 20 (91 mg, 0.25 mmol) in CH2Cl2 at –78 °C.
After 1 h, the temperature of the reaction mixture was increased to
0 °C. After a further 1 h, the reaction mixture was quenched with
saturated aqueous potassium sodium tartrate solution. The mixture
was warmed to room temperature, and stirred for 4 h. Then the
layers were separated, and the aqueous layer was extracted with
EtOAc. The combined organic extracts was washed with brine,
dried with Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography (10% EtOAc in
hexane) to give allylic alcohol 21 (78 mg, 98%) as a colourless li-
quid. Rf = 0.25 (25% EtOAc in petroleum ether). [α]3D0 = –28.0 (c
= 0.8, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.27 (d, J =
8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 5.86–5.74 (m, 1 H), 5.27
(dd, J = 11.6, 4.4 Hz, 3 H), 4.65 (d, J = 11.0 Hz, 1 H), 4.49 (d, J
= 11.0 Hz, 1 H), 3.95 (s, 2 H), 3.79 (s, 3 H), 3.61 (dd, J = 7.7,
4.6 Hz, 1 H), 3.23 (s, 3 H), 3.18 (dd, J = 6.4, 4.7 Hz, 1 H), 2.85–
2.73 (m, 1 H), 1.65 (s, 3 H), 0.97 (t, J = 7.7 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.0, 136.1, 134.0, 131.0, 129.7,
129.1, 118.1, 113.5, 85.3, 84.6, 74.7, 68.8, 56.6, 55.2, 34.0, 29.7,
1 H), 3.24 (s, 3 H), 3.18 (dd, J = 6.6, 4.6 Hz, 1 H), 2.85–2.75 (m,
1 H), 2.06 (s, 3 H), 1.66 (s, 3 H), 0.99 (d, J = 6.7 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 171.0, 159.1, 136.1, 132.6, 131.0,
129.6, 129.4, 118.1, 113.6, 85.3, 84.5, 74.9, 70.2, 56.6, 55.3, 34.3,
21.0, 15.9, 14.0 ppm. IR (neat): ν = 3068, 2977, 2932, 1738, 1613,
˜
1513, 1372, 1247, 1121, 1080 cm–1. HRMS: calcd. for C21H30O5 [M
+ Na]+ 385.1985; found 385.1985.
Compound 28: Grubbs’ 2nd generation catalyst (1.5 mg, 3 mol-%)
was added to a mixture of compound 26 (21 mg, 0.06 mmol) and
ethyl (E)-hepta-2,6-dienoate (23; 36 mg, 0.18 mmol) in toluene
(0.5 mL) at room temperature. The reaction mixture was stirred for
1 h, then the solvent was removed in vacuo. The residue was puri-
fied by flash column chromatography (10% EtOAc in hexane) to
give 28 (6 mg, 20%) as a colourless oil. Rf = 0.30 (25% EtOAc in
petroleum ether). [α]2D5 = +6.0 (c = 0.25, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.28–7.26 (m, 2 H), 7.00–6.92 (m, 1 H),
6.87 (d, J = 8.7 Hz, 2 H), 5.85 (dd, J = 14.7, 2.9 Hz, 1 H), 5.66 (dt,
J = 15.6, 6.2 Hz, 1 H), 5.45 (dd, J = 15.6, 8.0 Hz, 1 H), 5.34 (dd,
J = 10.0, 0.97 Hz, 1 H), 4.62 (d, J = 11.0 Hz, 1 H), 4.54–4.40 (m,
3 H), 4.21–4.16 (m, 2 H), 3.81 (s, 3 H), 3.55–3.51 (m, 1 H), 3.20 (s,
3 H), 3.17–3.12 (m, 1 H), 2.85–2.76 (m, 1 H), 2.34–2.23 (m, 4 H),
2.07 (s, 3 H), 1.66 (d, J = 1.1 Hz, 3 H), 1.29–1.26 (m, 3 H), 0.99
(d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.0,
166.5, 159.1, 148.0, 132.9, 132.7, 131.0, 129.7, 129.3, 129.1, 121.9,
113.6, 85.6, 83.8, 74.9, 70.2, 60.2, 56.3, 55.3, 34.4, 31.7, 30.7, 21.0,
16.1, 13.7 ppm. IR (neat): ν = 3383, 2919, 2881, 1609, 1512, 1463,
˜
1247, 1118, 1077, 1037 cm–1. HRMS: calcd. for C20H29O5 [M +
Na]+ 343.1885; found 343.1876.
Acetylated Allylic Alcohol 26: The first step of this three-step pro-
cedure was carried out following the procedure described above for
the reduction of ester 20. Thus, ester 19 (0.5 mmol) and DIBAL
(2 equiv.) gave diallylic alcohol 24 (152 mg, 98%), which was used 15.9, 14.2, 14.0 ppm. IR (neat): ν = 3068, 2978, 2929, 1735, 1721,
˜
directly in the next step without further purification. Rf = 0.5 (50%
EtOAc in petroleum ether). 1H NMR (400 MHz, CDCl3): δ = 7.29–
7.22 (m, 2 H), 6.88 (d, J = 8.5 Hz, 2 H), 6.02–5.89 (m, 1 H), 5.40–
5.18 (m, 3 H), 4.58–4.50 (m, 2 H), 4.13–4.09 (m, 1 H), 3.99 (s, 2
H), 3.81 (s, 3 H), 3.20–3.15 (m, 1 H), 2.85–2.75 (m, 1 H), 1.67 (s,
3 H), 1.05 (d, J = 6.7 Hz, 3 H) ppm. MS (ES): m/z = 323.1 [M +
NH3]+.
1655, 1512, 1370, 1248, 1078, 1033 cm–1. HRMS: calcd. for
C28H40O7 [M + Na]+ 511.2666; found 511.2666.
Diol 29: DIBAL (1 m in THF; 0.75 mL) was added to a stirred
solution of lactone 16 (65.5 mg, 0.25 mmol) in CH2Cl2 at –78 °C.
The mixture was stirred for 3 h, then the reaction temperature was
increased to 0 °C. After a further 1 h, the reaction mixture was
quenched by the addition of saturated aqueous potassium sodium
tartrate solution. The mixture was warmed to room temperature
Compound 24 (152 mg, 0.46 mmol) was dissolved in CH2Cl2
(5 mL), and 2,6-lutidine (64 mg, 0.07 mL, 0.6 mmol) was added. and stirred overnight. Then the layers were separated, and the
Then acetyl chloride (46 mg, 0.6 mmol) was added dropwise under
argon at 0 °C. After the addition, the mixture was stirred for 3 h,
then the reaction was quenched by the addition of saturated aque-
ous ammonium chloride solution. The layers were separated, and
the aqueous layer was extracted with dichloromethane (3ϫ 3 mL).
The combined organic extracts were washed with brine, dried with
anhydrous sodium sulfate, and concentrated. This gave 25 (156 mg,
90%) as a colourless oil that was used in the next step without
aqueous layer was extracted with EtOAc. The combined organic
extracts was washed with brine, dried with Na2SO4, and concen-
trated under reduced pressure. The residue was purified by column
chromatography (40% EtOAc in hexane) to give diol 29 (65 mg,
98%) as a colourless liquid. Rf = 0.30 (40% EtOAc in petroleum
ether). [α]2D5 = –2.5 (c = 0.6, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 7.27 (d, J = 8.6 Hz, 2 H), 6.89 (d, J = 8.6 Hz, 2 H), 5.98–5.87
(m, 1 H), 5.35 (d, J = 17.2 Hz, 1 H), 5.21 (d, J = 10.5 Hz, 1 H),
further purification. 1H NMR (400 MHz, CDCl3): δ = 7.27–7.24 4.57 (ABq, JAB = 11.2 Hz, 2 H), 4.26–4.21 (m, 1 H), 3.81 (s, 3 H),
(m, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 6.0–5.9 (m, 1 H), 5.40–5.19 (m, 3.72 (dd, J = 11.1, 3.9 Hz, 1 H), 3.52 (dd, J = 11.0, 6.6 Hz, 1 H),
3 H), 4.60–4.50 (m, 2 H), 4.49–4.39 (m, 2 H), 4.13–4.09 (m, 1 H),
3.81 (s, 3 H), 3.20–3.16 (m, 1 H), 2.83–2.74 (m, 1 H), 2.36 (d, J =
7.9 Hz, 1 H), 2.07 (s, 3 H), 1.68 (s, 3 H), 1.04 (t, J = 6.4 Hz, 3 H)
ppm. MS (ES): m/z = 365.2 [M + NH3]+.
3.44 (t, J = 4.8 Hz, 1 H), 2.91–2.74 (br. s, 1 H), 2.03–1.95 (m, 1
H), 0.98 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 159.3, 138.5, 130.2, 129.6, 116.2, 113.8, 82.7, 73.6, 72.2, 64.1,
55.3, 36.9, 12.3 ppm. IR (neat): ν = 3423, 2919, 2881, 1612, 1513,
˜
1463, 1247, 1118, 1077 cm–1. HRMS: calcd. for C15H22O4 [M +
Na]+ 289.1410; found 289.1410.
Step iii) Proton sponge (171 mg, 0.8 mmol) and Me3OBF4 (120 mg,
0.8 mmol) were added to a stirred solution of allylic alcohol 25
(70 mg, 0.2 mmol) in CH2Cl2 (5 mL) at room temperature. The
mixture was stirred for 1 h, then it was quenched with saturated
NaHCO3 solution, and the aqueous layer was extracted with
CH2Cl2. The combined organic extracts were washed with brine,
dried with anhydrous sodium sulfate, and concentrated. The resi-
due was purified by column chromatography (7% EtOAc in hex-
ane) to give 26 (65 mg, 90%) as a colourless oil. Rf = 0.25 (20%
EtOAc in petroleum ether). [α]2D5 = –18.0 (c = 0.5, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 8.0 Hz, 2 H), 6.86 (d,
TBS Ether 30: Imidazole (25 mg, 0.38 mmol) and tert-butyldi-
methylsilyl chloride (36 mg, 0.23 mmol) were added to an ice-co-
oled solution of compound 29 (50 mg, 0.19 mmol) in dichlorometh-
ane (4 mL), and the mixture was stirred at room temperature for
12 h. The mixture was diluted with dichloromethane, and washed
with water and brine. The organic layer was dried with anhydrous
Na2SO4, and rotary evaporated under reduced pressure. The resi-
due was purified over silica gel (100–200 mesh; 20% EtOAc in pe-
troleum ether) to give 30 (61 mg, 85%) as a gummy material. Rf =
J = 8.6 Hz, 2 H), 5.87–5.74 (m, 1 H), 5.38–5.24 (m, 3 H), 4.66 (d, 0.30 (20% EtOAc in petroleum ether). [α]2D5 = –2.0 (c = 0.6, CHCl3).
Eur. J. Org. Chem. 2014, 6558–6564
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6563

N. R. Gade, J. Iqbal
FULL PAPER
1H NMR (400 MHz, CDCl3): δ = 7.28 (d, J = 8.1 Hz, 2 H), 6.88
(d, J = 8.5 Hz, 2 H), 5.95–5.85 (m, 1 H), 5.36 (d, J = 17.2 Hz, 1
H), 5.21 (d, J = 10.5 Hz, 1 H), 4.59 (ABq, JAB = 6.8 Hz, 2 H),
4.21–4.14 (m, 1 H), 3.81 (s, 3 H), 3.66–3.60 (m, 1 H), 3.58–3.48 (m,
2 H), 3.01 (d, J = 4.3 Hz, 1 H), 1.96–1.87 (m, 1 H), 0.95–0.89 (m,
12 H), 0.06 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.2,
138.2, 130.7, 129.4, 116.3, 113.8, 82.4, 74.2, 73.1, 65.1, 55.2, 37.5,
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Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of new compounds.
Acknowledgments
N. R. G. thanks the Council of Scientific and Industrial Research
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Received: June 27, 2014
Published Online: August 26, 2014
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