Total synthesis of (+)-migrastatin

Article abstract of DOI:10.1002/ejoc.200600760

(+)-Migrastatin, an antimetastatic agent, was synthesized by using three ruthenium-catalyzed metathesis reactions: a ring-closing metathesis (RCM) to control the (Z)-trisubstituted double bond at C11-C12, another RCM at C6-C7 to establish the macrolactone

Full text of DOI:10.1002/ejoc.200600760

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600760
Total Synthesis of (+)-Migrastatin
Sébastien Reymond[a] and Janine Cossy*[a]
Keywords: Ring-closing metathesis / Crotyltitanation / Crotylstannylation / Cross-metathesis / Total synthesis
(+)-Migrastatin, an antimetastatic agent, was synthesized by
using three ruthenium-catalyzed metathesis reactions: a
ring-closing metathesis (RCM) to control the (Z)-trisubsti-
tuted double bond at C11–C12, another RCM at C6–C7 to
establish the macrolactone core, and a cross-metathesis to
install the glutarimide side chain at C16–C17. The ste-
reogenic centers at C9, C10, C13, and C14 were introduced
by using two stereoselective crotylmetalations.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
tions: one ring-closing metathesis (RCM) to control the
(Z)-double bond at C11–C12, another RCM to establish
the macrolactone core and to control the (E)-double bond
at C6–C7, and a cross-metathesis (CM) to install the glutar-
imide side chain by forming the C16–C17 bond. The ste-
reogenic centers at C9, C10 and C13, C14 were controlled
by using two enantio- and diastereoselective crotylmetala-
tions of aldehydes.
As depicted in Scheme 1, the macrocyclic lactone could
be the result of a chemoselective RCM applied to diene A.
This diene could in turn be formed by the esterification of
2,6-heptadienoic acid (18) with alcohol B. The construction
of fragment B relies on the chemoselective CM reaction be-
tween allylglutarimide (17) and vinyl ketone C (C7–C16)
followed by a chemoselective hydrogenation of the double
bond of the enone.
The C7–C16 fragment (fragment C) contains all the five
stereogenic centers of migrastatin as well as the (Z)-trisub-
stituted C11–C12 double bond. Enone C could be obtained
from olefin D by functional transformation of the C15–C16
double bond. The anti relationship at C13–C14 in fragment
D should be obtained by using an anti-selective enantio-
and diastereoselective crotylmetalation applied to an alde-
hyde of type E. This aldehyde, which possesses the (Z)-con-
figuration at C11–C12 and is required for the structure of
migrastatin, could be obtained by reduction of the unsatu-
rated lactone F. This lactone could be built by a RCM in-
volving diene G, which possesses the methacrylate moiety
that is a precursor of the (Z)-C11–C12 double bond. A
diene of type G should be easily prepared from the corre-
sponding syn,syn-stereotriad H, which could be obtained
by using a stereoselective crotylmetalation applied to alde-
hyde J. Finally, aldehyde J could be synthesized from the
commercially available methyl (S)-(+)-2,2-dimethyl-1,3-di-
oxolane-4-carboxylate (2) (Scheme 2).
Introduction
(+)-Migrastatin is a naturally occurring macrolide, iso-
lated from broth cultures of two strains of Streptomyces.[1,2]
This compound has been shown to inhibit cell migration in
a wide range of tumor cell lines, at micromolar concentra-
tions. Because of the unusual mode of action of migrastatin
and its potential use in anticancer treatment, we decided to
devise a convergent and flexible synthesis, giving access to
both the natural product itself as well as to a number of
analogues. To the best of our knowledge, only one synthesis
of migrastatin has been reported in the literature to date,
and the synthesis of analogues has also been achieved.[3,4]
The structure of migrastatin was established unambigu-
ously by X-ray analysis of a derivative.[1d] This compound
consists of a 14-membered lactone linked to an alkylglutari-
mide side chain. The molecule contains five stereogenic cen-
ters, two (E)-disubstituted double bonds, and one (Z)-tri-
substituted double bond (Figure 1).
Figure 1. Structure of migrastatin (1).
Results and Discussion
The key steps in our synthesis of migrastatin were based
on the use of three ruthenium-catalyzed metathesis reac-
[a] Laboratoire de Chimie Organique, UMR CNRS 7084,
ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax: +33-1-40-79-46-60
Our synthesis of migrastatin started from methyl ester 2,
which was transformed to alcohol 3 in four steps (58%
yield). After oxidation of alcohol 3 under Swern conditions,
E-mail: janine.cossy@espci.fr
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Total Synthesis of (+)-Migrastatin
SHORT COMMUNICATION
cat, CH2Cl2, 0 °C to room temp. 80%), diene 5 was treated
with the second-generation Grubbs catalyst [Ru]-I
(16.5 mol-%) in refluxing CH2Cl2 to afford the unsaturated
lactone 6 in 65% yield.[7,8] At this point of the synthesis,
three of the five stereogenic centers and the trisubstituted
(Z)-C11–C12 double bond were established.
In order to introduce the remaining two stereogenic cen-
ters at C13 and C14, lactone 6 was converted to the (Z)-
homoallylic alcohol 8 in three steps. After the reduction of
lactone 6 with LiBH4 (7 equiv.) in the presence of
CeCl3·7H2O (1 equiv.) in THF/H2O (4:1) at room temp.,
diol 7 was isolated in 74% yield.[9] To differentiate the hy-
droxy groups at C9 and C13, both of them were silylated
(TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to room temp., 75%
yield), and the primary alcohol at C13 was selectively de-
protected (THF/H2O/AcOH, 1:1:3, room temp., 36 h) to
produce the allylic alcohol 8 in 75% yield (Scheme 3).
Scheme 1. Retrosynthetic plan for the synthesis of migrastatin (1).
CM = Cross-Metathesis; RCM = Ring-Closing Metathesis.
Scheme 3. Synthesis of alcohol 8. Reagents and conditions:
a) pTsOH, MeOH/H2O (1:1), room temp., 83%; b) TBDPSCl,
imidazole, CH2Cl2, 0 °C to room temp. 81%; c) Ag2O, MeI, MS
4 Å, Et2O, 40 °C, 96%; d) DIBAL-H, CH2Cl2, –78 °C to room
temp. 90%; e) (COCl)2, DMSO, CH2Cl2, –78 °C, then Et3N –78 °C
to room temp.; f) MgBr2·OEt2, CH2Cl2, –20 °C, then but-2-enyl-
[(tri(n-butyl)]stannane, –60 °C, 87% (over two steps); g) meth-
acryloyl chloride, Et3N, DMAP, CH2Cl2, 0 °C to room temp. 80%;
h) [Ru]-I (16.5 mol-%), CH2Cl2 (c = 10–2 ), 40 °C, 144 h, 65%;
i) LiBH4 (7 equiv.), CeCl3.7H2O (1 equiv.), THF/H2O (4:1), room
temp., 74%; j) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to room temp.
75%; k) THF/H2O/AcOH (1:1:3), 36 h, room temp., 75%. pTsOH
= para-toluenesulfonic acid; TBDPSCl = tert-butyldiphenylsilyl
chloride; MS = molecular sieves; DIBAL-H = di-isobutylaluminum
hydride; DMAP = 4-dimethylaminopyridine; TBSOTf = tert-butyl-
dimethylsilyl trifluoromethanesulfonate.
Scheme 2. Retrosynthetic analysis of fragment C (C7–C16).
the resultant crude aldehyde was directly treated with but-
2-enyl[tri(n-butyl)]stannane (1.5 equiv., CH2Cl2, –60 °C) in
the presence of MgBr2·OEt2 (2.2 equiv.) to give the syn,syn-
stereotriad 4 in 83% yield with good stereocontrol (dr =
90:10).[5,6] The stereochemical outcome of this addition is
likely to be the result of an open chair transition state of
type K, in which both the carbonyl and the methoxy groups
Scheme 5 delineates the synthesis of compound 15 (C7–
of the aldehyde are chelated with MgBr2·OEt2.[5] After es- C21 fragment). To control the stereogenic centers at C13
terification of 4 with methacryloyl chloride (Et3N, DMAP and C14, the allylic alcohol 8 was oxidized to aldehyde 9
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S. Reymond, J. Cossy
SHORT COMMUNICATION
(MnO2, CH2Cl2, room temperature) and then treated di-
rectly with the highly face-selective crotyltitanium complex
Ti-(S,S)-I,[10] which gave the homoallylic alcohol 10 in 80%
yield (from 8) with good diastereoselectivity (dr
=
90:10).[11,12] The following step involved the selective oxi-
dative cleavage of the terminal C15–C16 double bond. The
hydroxy group at C13 in compound 10 was converted to
the corresponding TES ether 11 (TESCl, imidazole,
CH2Cl2, room temp., 90%) in order to sterically protect the
internal double bond at C11–C12 from oxidative cleavage.
Therefore, the C15–C16 double bond was chemoselectively
transformed to an aldehyde by using a dihydroxylation-oxi-
dative cleavage sequence (OsO4, N-methylmorpholine N-ox-
ide, then NaIO4) to produce aldehyde 12 in 80% yield. This
aldehyde was then converted to the α,β-unsaturated ketone
13 in two steps by treatment with vinylmagnesium chloride
(THF, –78 °C) followed by oxidation of the resultant allylic
alcohol (Dess–Martin periodinane, CH2Cl2, 0 °C to room
temp., 73% yield for the last two steps).[13]
With vinyl ketone 13 (C7–C16 fragment) in hand, enone
15 (C7–C21 fragment) was assembled by using a CM reac-
tion between vinyl ketone 13 and allylglutarimide (17),
which was prepared in five steps from the commercially
available diethyl allylmalonate (16) with an overall yield of
20% (Scheme 4).
Scheme 4. Synthesis of allylglutarimide (17). Reagents and condi-
tions: a) LiAlH4, Et2O, 0 °C to room temp. 12 h, 69%; b) pTsCl,
KOH, THF, 0 °C, 2 h, then room temp., 4 h, 93%; c) NaCN,
DMSO, 45 °C, 22 h; d) NaOH, MeOH, reflux, 4 h, 42% yield for
the two steps; e) urea, 145 °C, 2 h, then 180 °C, 20 min; 73%. pTsCl
= para-toluenesulfonyl chloride.
Scheme 5. Synthesis of fragment C7–C21 (15). Reagents and condi-
tions: a) MnO2, CH2Cl2, room temp., 16 h; b) Ti-(S,S)-I,
(1.4 equiv.), Et2O, –78 °C, 24 h, 80% over two steps; c) TESCl,
CH2Cl2, room temp., 16 h, 90%; d) OsO4 (4 mol-%), NMO
(1 equiv.), tBuOH/H2O (1:1), room temp., 24 h; e) NaIO4
(4.5 equiv.), THF/H2O (1:1), room temp., 10 h, 80% over two steps;
f) vinylmagnesium chloride (3 equiv.), –78 °C, THF, 0.5 h; g) Dess–
Martin periodinane (2 equiv.), CH2Cl2, 0 °C to room temp. 1 h,
73% over two steps; h) [Ru]-II (30 mol-%), 17 (3 equiv.), CH2Cl2,
room temp., 72 h, 32%; i) Pd/C 5% (5 mol-% Pd), EtOAc, room
temp., 10 h, 96%. TESCl = triethylsilyl chloride, NMO = N-
methyl-morpholine N-oxide.
When the CM reaction between vinyl ketone 13 and
allylglutarimide (17) was performed in the presence of Hov-
eyda–Grubbs catalyst [Ru]-II, the CM product 14 was iso-
lated with a moderate yield (32%) ([Ru]-II, 30 mol-%; 17,
3 equiv; CH2Cl2, room temp., 72 h).[14–16] In order to com-
plete the synthesis of 15 (C7–C21 fragment), enone 14 was
selectively hydrogenated (Pd/C 5%, H2, AcOEt, room
temp., 10 h) to afford 15 in 96% yield (Scheme 5).
Having synthesized the C7–C21 fragment (compound
15), we could consider the construction of the macrolactone
core leading to the complete synthesis of migrastatin. After
selective deprotection of the hydroxy group at C13 in com-
pound 15 (THF/H2O/AcOH, 1:1:3, room temp., 80%
yield), the obtained alcohol was transformed to ester 20 in
74% yield by using the freshly prepared mixed anhydride
19 (toluene, room temp., 48 h).[17] In order to prepare the
RCM precursor 21, ester 20 was selectively deprotected at
C7 by employing ammonium fluoride in methanol. The re-
sulting primary alcohol was oxidized to the corresponding
aldehyde, which was directly treated under Takai conditions
(20 mol-%) in refluxing toluene to produce macrolactone 22
in 39% yield. Finally, after removal of the last protecting
group at C9 by using HF·pyridine complex in THF,
(+)-migrastatin (1) was isolated in 62% yield (Scheme 6).
All the spectroscopic (1H, 13C NMR), HRMS, and optical
rotation data of our synthetic (+)-migrastatin matched
those reported in the literature.[3]
Conclusions
In conclusion, migrastatin was synthesized in 27 steps
to afford diene 21 in 44% yield (over three steps).[18–20] As from the commercially available (S)-(+)-2,2-dimethyl-1,3-di-
described previously,[3] diene 21 was treated with [Ru]-I oxolane-4-carboxylate (2). Synthetic highlights include the
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Total Synthesis of (+)-Migrastatin
SHORT COMMUNICATION
14: [α]2D0 = –6.6 (c = 0.99, CHCl3). 1H NMR (400 MHz, CDCl3): δ
= 8.13 (br. s, 1 NH), 7.73 (m, 4 H), 7.41 (m, 6 H), 6.69 (dt, J =
15.5 and 6.4 Hz, 1 H), 6.25 (d, J = 15.8 Hz, 1 H), 5.37 (d, J =
10.3 Hz, 1 H), 4.54 (d, J = 9.5 Hz, 1 H), 3.78 (dd, J = 11.0 and
4.6 Hz, 1 H), 3.67 (dd, J = 11.1 and 5.9 Hz, 1 H), 3.48 (d, J =
7.4 Hz, 1 H), 3.27 (s, 3 H), 3.16 (m, 1 H), 3.01 (m, 1 H), 2.65–2.79
(m, 3 H), 2.24–2.38 (m, 5 H), 1.66 (s, 3 H), 1.07 (s, 9 H), 0.90 (s, 9
H), 0.88 (d, J = 7.7 Hz, 3 H), 0.78–0.85 (m, 12 H), 0.45 (q, J =
8 Hz, 6 H), 0.03 (s, 3 H), 0.00 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 202.6, 171.5, 140.1, 135.8, 135.8, 134.3, 134.1, 133.6,
133.5, 132.4, 129.7, 127.8, 127.8, 85.4, 76.9, 72.9, 64.1, 59.1, 47.9,
37.5, 37.5, 37.4, 33.1, 29.9, 27.0, 26.2, 19.2, 18.5, 17.6, 14.3, 14.1,
6.9, 4.7, –3.8, –4.5 ppm. HRMS (ESI): calcd. for C49H79O7NSi3Na
[M + Na]+ 900.5062; found 900.5040.
1
1: [α]2D5 = +11.1 (c = 0.05, MeOH). H NMR (400 MHz, CDCl3):
δ = 7.75 (br. s, 1 NH), 6.50 (m, 1 H), 5.65 (dd, J = 10.4 and 1.7 Hz,
1 H), 5.59 (dd, J = 16.0 and 1.4 Hz, 1 H), 5.47–5.56 (m, 1 H), 5.24
(dd, J = 15.5 and 5.0 Hz, 1 H), 5.09 (d, J = 10.0 Hz, 1 H), 3.47
(dd, J = 9.0 and 5.0 Hz, 1 H), 3.30 (s, 3 H), 3.05 (dd, J = 8.6 and
2 Hz, 1 H), 2.87–3.02 (m, 2 H), 2.66–2.74 (m, 2 H), 2.50 (app t, J
= 7.0 Hz, 2 H), 2.38–2.47 (m, 2 H), 2.07–2.30 (m, 5 H), 1.86 (d, J
= 1.2 Hz, 3 H), 1.50–1.70 (m, 2 H), 1.30–1.39 (m, 2 H), 1.12 (d, J
= 7.3 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 210.9, 171.8, 164.0, 150.0, 133.2, 131.3,
130.7, 128.2, 122.3, 82.6, 78.1, 77.3, 57.0, 51.4, 40.1, 37.8, 37.8,
34.3, 32.1, 31.2, 30.5, 30.2, 26.1, 20.3, 13.5 ppm. HRMS (DCI+,
NH3): calcd. for C27H43O7N2 [M + NH4]+ 507.3070; found
507.3069.
Scheme 6. Completion of the total synthesis of migrastatin (1).
Reagents and conditions: a) THF/H2O/AcOH (1:1:3), 36 h, room
temp., 80%; b) mixed anhydride 19 (3 equiv.), pyridine (4 equiv.),
toluene, 48 h, room temp., 74%; c) NH4F (30 equiv.), MeOH, room
temp., 24 h, 81%; d) Dess–Martin periodinane (1.5 equiv.),
CH2Cl2, 0 °C to room temp. 3 h; e) Zn, PbCl2 (cat), CH2I2,
Ti(OiPr)4, THF, room temp., 54% yield for the last two steps; f)
[Ru]-I (20 mol-%), toluene (c = 0.5·10–3 ), reflux, 0.3 h, 39%; g)
HF·pyr complex, THF, room temp., 24 h, 62% yield.
Acknowledgments
We wish to thank Dr. Fisher and Dr. Trimmer, from Materia (US)
for a generous gift of Grubbs and Hoveyda–Grubbs catalysts.
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[3] C. Gaul, J. T. Njardarson, S. J. Danishefsky, J. Am. Chem. Soc.
2003, 125, 6042–6043.
[4] a) C. Gaul, S. J. Danishefsky, Tetrahedron Lett. 2002, 43, 9039–
9042; b) J. T. Njardarson, C. Gaul, D. Shan, X.-Y. Huang, S. J.
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use of versatile reactions such as a syn,syn-stereoselective
crotylstannylation to control the stereogenic centers at C9
and C10, a crotyltitanation to control the stereogenic cen-
ters at C13 and C14, two ruthenium-catalyzed ring-closing
methatheses, one to control the (Z)-trisubstituted double
bond at C11–C12, one to establish the macrolactone core,
and a ruthenium-catalyzed cross-metathesis to install the
glutarimide side chain. These flexible synthetic methods
should allow access to a variety of migrastatin analogues
for biological evaluation.
Experimental Section
Selected analytical data for compounds 6, 14, and 1.
6: M.p. 110–115 °C. [α]2D0 = –49.8 (c = 0.46, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.68 (m, 4 H), 7.47–7.36 (m, 6 H), 6.60
(dd, J = 6.1 and 1.4 Hz, 1 H), 4.54 (dd, J = 7.6 and 1.4 Hz, 1 H),
3.84 (dd, J = 11.5 and 4.0 Hz, 1 H), 3.68 (dd, J = 11.5 and 4.0 Hz,
1 H), 3.41 (s, 3 H), 3.37 (dt, J = 8.0 and 4.0 Hz, 1 H), 2.42 (m, 1
H), 1.90 (s, 3 H), 1.05 (s, 9 H), 0.97 (d, J = 6.9 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 165.8, 145.1, 135.8, 135.6, 133.2,
132.9, 129.9, 127.9, 127.8, 127.3 ppm. HRMS (ESI): calcd. for
C26H34O4SiNa [M + Na]+ 461.2124; found 461.2107.
[5] G. E. Keck, K. A. Savin, E. N. K. Cressman, D. E. Abbott, J.
Org. Chem. 1994, 59, 7889–7896.
[6] On the basis of the 1H NMR spectra of the crude reaction
mixture.
[7] Conversion was monitored by GC/MS. The catalyst [Ru]-I was
added in six portions over 144 h.
[8] The homodimer of diene 5 was also isolated in 5% yield.
[9] The corresponding saturated diol was also isolated in 10%
yield.
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S. Reymond, J. Cossy
SHORT COMMUNICATION
[10] A. Hafner, R. O. Duthaler, R. Marti, J. Rihs, P. Rhote-Streit,
pont, S. Oualef, L. Elkaïm, L. Grimaud, Synlett 2005, 670–
672.
F. Schwarzenbach, J. Am. Chem. Soc. 1992, 114, 2321–2336.
1
[11] Based on the H NMR spectra of the crude reaction mixture.
[17] 2,6-Heptadienoic acid (18) and mixed anhydride 19 were pre-
[12] Crotyltitanium complex Ti-(S,S)-I allows the delivery of the
pared according to ref.[4c]
.
nucleophile on the Re face of aldehyde 9.
[18] Diene 21 was contaminated by a minor impurity, which was
[13] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277–
7287.
removed in the following step.
[19] T. Okazoe, J.-I. Hibino, K. Takai, H. Nozaki, Tetrahedron Lett.
1985, 26, 5581–5584.
[20] The original procedure was modified by adding a catalytic
amount of PbCl2: K. Takai, T. Kakiuchi, Y. Kataoka, K. Utim-
oto, J. Org. Chem. 1994, 59, 2668–2670.
[14] Enone 13 was recovered with 40% yield. The catalyst [Ru]-II
and compound 17 were added in three portions over 72 h.
Yields for this reaction range from 27% to 50%.
[15] When the reaction was performed under microwave irradiation,
the yield of this CM did not increase. See: F. C. Bargiggia, W. V.
Murray, J. Org. Chem. 2005, 70, 9636–9639.
Received: August 29, 2006
Published Online: September 18, 2006
[16] When chlorodicyclohexylborane was used as an additive, the
yield of this CM did not increase. See: E. Vedrenne, H. Du-
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