Synthesis of migrastatin and its macrolide core

Article abstract of DOI:10.1016/j.tet.2007.02.107

Migrastatin and its macrolactone subunit are potent antimetastatic agents. Both were synthesized by using a ring-closing metathesis (RCM) to establish the macrolactone core, and the control of the (Z)-trisubstituted double bond at C11-C12 was achieved by?

Full text of DOI:10.1016/j.tet.2007.02.107

Tetrahedron 63 (2007) 5918–5929
Synthesis of migrastatin and its macrolide core
*
ꢀ
Sebastien Reymond and Janine Cossy
´
Laboratoire de Chimie Organique associe au CNRS, ESPCI, 10, Rue Vauquelin, 75231 Paris Cedex 05, France
Received 21 January 2007; revised 22 February 2007; accepted 23 February 2007
Available online 28 February 2007
Abstract—Migrastatin and its macrolactone subunit are potent antimetastatic agents. Both were synthesized by using a ring-closing meta-
thesis (RCM) to establish the macrolactone core, and the control of the (Z)-trisubstituted double bond at C11–C12 was achieved by using
a Still–Gennari olefination.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Before our preliminary contribution on the total synthesis of
migrastatin,5 only one total synthesis of migrastatin (1) had
been achieved.4 In addition, a library of migrastatin ana-
logues,6 one of which is the macrolide core of migrastatin
2, has been found to be 1000 times more active than migras-
tatin itself, as macrolactone 2 possesses an IC50¼22 nM in
mouse breast tumor 4T1 cells.6a Due to their interesting bio-
logical properties, we embarked on the synthesis of migras-
tatin (1) and its macrolactone subunit 2. In the present work
we would like to report the whole study on the total synthesis
of migrastatin (1), including a new synthesis of the macro-
lactone subunit 2. Furthermore, a new approach for the
C7–C13 fragment 8, a common key intermediate for the syn-
thesis of 1 and 2, will be discussed.
Since tumor spreading is responsible for the majority of
death cases among cancer patients, the development of
therapeutic agents that inhibit tumor metastasis is highly
desirable. Such agents could be effective in restraining
the formation of new tumor when earlier therapy or surgery
has failed, or in increasing the chances of success in contain-
ing solid tumors in combination therapy with other agents.
Migrastatin (1) is a macrolide natural product isolated from
broth cultures of two strains of Streptomyces (Fig. 1).1,2 This
product has the potential for metastasis suppression through
its ability to inhibit tumor cell migration (IC50¼29 mM in
mouse breast tumor 4T1 cells) but has no effect on the
biosyntheses of DNA, RNA or protein in these cells.1a The
specific inhibition property of migrastatin in tumor cell mi-
gration renders it an interesting target. More recently, it has
been shown that migrastatin also inhibits P-glycoprotein and
consequently sensitizes drug resistant P-glycoprotein-over-
expressing cells to anticancer drugs like taxol, vinblastine
or vincristine.3
2. Synthesis of the macrolactone 2
The key steps in the synthesis of macrolactone 2 were based
on a Still–Gennari olefination to control the (Z)-double bond
at C11–C12, a ring-closing metathesis (RCM) to establish
the macrolactone core and to control the (E)-double bond at
C6–C7,7 and a diastereoselective crotylmetalation of a chiral
aldehyde to control the stereogenic centers at C9 and C10.
As depicted in Scheme 1, the macrocyclic lactone 2 would
be the result of a chemoselective RCM applied to diene A.
This diene would be formed by esterification of 2,6-hepta-
dienoic acid (I) with alcohol B. The (Z)-configuration of
the C11–C12 double bond in fragment B would be installed
by using a Still–Gennari olefination of aldehyde C. The con-
struction of C relies on the syn-selective crotylmetalation of
an aldehyde of type D, which would be synthesized from the
commercially available methyl (S)-2,2-dimethyl-1,3-dioxo-
lane-4-carboxylate (3) (Scheme 1).
O
O
NH
O
Me
Me
O
O
O
Me
Me
O
Me
OH
OMe
OH
OMe
Migrastatin (1)
2
Figure 1. Structure of migrastatin (1) and migrastatin analogue 2.
The synthesis of compound 2 started from methyl ester 3,
which was transformed to alcohol 4 in four steps with an
overall yield of 58%. After oxidation of alcohol 4 under
* Corresponding author. Tel.: +33 1 40794429; fax: +33 1 40794660;
e-mail: janine.cossy@espci.fr
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.107

S. Reymond, J. Cossy / Tetrahedron 63 (2007) 5918–5929
5919
(4.8 equiv), THF, ꢀ78 ꢁC, 12 h] to produce the unsaturated
ester 7 in 80% yield (from olefin 6) with a good 97/3 Z/E ra-
tio.9 After reduction of 7 with DIBAL-H (2.2 equiv, CH2Cl2,
ꢀ78 ꢁC), allylic alcohol 8 was isolated in 94% yield. Com-
pound 8 corresponds to the C7–C13 fragment of the macro-
lide core of migrastatin 2, which was obtained from 3 in 11
steps with an overall yield of 35% (Scheme 2).
O
O
13
1
1
Me
Me
O
O
12
Still-Gennari
olefination
11
Me
7
Me
7
10
9
6
OH
OR
6
Crotylmetalation
OMe
2
OMe
A
RCM
O
In our previous approach to migrastatin,5 we explored an-
other access to allylic alcohol 8 using an RCM to establish
the (Z)-configuration of the C11–C12 double bond (Scheme
3). After esterification of 5 with methacryloyl chloride
(Et3N, DMAP cat, CH2Cl2, 0 ꢁC to rt, 80%), diene 9 was
13
1
Me
OH
HO
Me
12
OR
O
11
7
11
7
R'O
H
6
OR
OMe Me
OMe
B
C
I
Me
O
O
7
7
Methacryloyl chloride
OH
O
O
OMe
R'O
H
Et3N, DMAP cat
O
O
OMe
TBDPSO
TBDPSO
CH2Cl2, 0 °C to rt
80%
MeO Me
5
MeO Me
9
D
3
Scheme 1. Retrosynthetic analysis of the macrolide core of migrastatin 2.
[Ru]-II (16.5 mol %)
CH2Cl2, 40 °C
65%
Swern conditions, the obtained crude aldehyde was
directly treated with but-2-enyl-[(tri-n-butyl)]-stannane II
(1.5 equiv, CH2Cl2, ꢀ60 ꢁC) in the presence of MgBr2$OEt2
(2.2 equiv) to give the syn,syn-stereotriad 5 in 87% yield
with a good stereocontrol (dr¼90/10).8,9 As described previ-
ously,8 the stereochemical outcome of this addition is likely
to be the result of an open-chair transition state of type E, in
which both the carbonyl and the methoxy groups of the alde-
hyde are chelated with MgBr2$OEt2. After the protection of
5 (TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ20 ꢁC to 0 ꢁC, 93%
yield), olefin 6 was subjected to an oxidative cleavage in a
two-step sequence (OsO4, N-methylmorpholine N-oxide in
t-BuOH/water, then NaIO4 in THF/water). The obtained al-
dehyde was directly treated with Still–Gennari phosphonate
III10,11 [III (1.2 equiv), KHMDS (1.2 equiv), 18-crown-6
13
HO
Me
O
O
Me
Me
12
11
3 steps
7
7
TBDPSO
TBDPSO
OTBS
MeO Me
OMe
10
8
MesN NMes
Cl
Cl
Ru
Ph
PCy3
[Ru]-II
2
nd generation
Grubbs catalyst
Scheme 3. Other synthetic route to allylic alcohol 8.
LA
O
Me
H
H
OMe
R'
H
1) p-TsOH, MeOH/H2O (1/1)
SnBu3
E
rt (83%)
OH
O
2) TBDPSCl, imidazole
CH2Cl2, 0 °C to rt (81%)
1) Swern oxidation
2)
TBDPSO
OH
TBDPSO
OMe
O
3) Ag2O, MeI, MS 4Å
Et2O, 40 °C (96%)
4) DIBAL-H, CH2Cl2
-78 °C to rt (90%)
OMe
Me
MeO Me
O
SnBu3
II
3
4
5
MgBr2 OEt2
CH2Cl2, -60 °C
87% (2 steps)
TBSOTf
2,6-lutidine
CH2Cl2, -20 °C
93%
1) OsO4, NMO
t-BuOH/H2O (1/1), rt
13
EtO2C
Me
Me
HO
Me
2) NaIO4,
TBSO
DIBAL-H, CH2Cl2
-78 °C to rt
THF/H2O (1/1), rt
TBDPSO
7
3)
O
TBDPSO
OTBS
TBDPSO
OTBS
MeO Me
94%
CF3CH2O
CF3CH2O
CO2Et
P
OMe
7
OMe
8
6
III
KHMDS, 18-crown-6
THF, -78 °C
80% (3 steps)
Scheme 2. Synthesis of allylic alcohol 8.

5920
S. Reymond, J. Cossy / Tetrahedron 63 (2007) 5918–5929
Cl
O
O
O
O
O
Me
HO
Me
Me
Me
O
O
Cl
IV
Cl
Me
Me
NH4F
7
7
Pyridine
Toluene, rt
67%
MeOH, reflux
77%
TBDPSO
OTBS
HO
OTBS
TBDPSO
OTBS
OMe
OMe
12
OMe
11
8
1) Dess-Martin Periodinane
CH2Cl2, 0 °C to rt
2) Zn, PbCl2 cat, CH2I2
Ti(Oi-Pr)4, THF, rt
63%
O
O
O
Me
Me
Me
O
Me
O
Me
O
Me
[Ru]-II (20 mol %)
HF Pyr
7
7
Toluene, reflux
47%
THF, rt
67%
6
OTBS
OH
OTBS
6
OMe
13
OMe
2
OMe
14
Scheme 4. Completion of the synthesis of macrolactone 2.
treated with the second generation Grubbs catalyst [Ru]-II
(16.5 mol %)12 in refluxing CH2Cl2 to afford the unsaturated
lactone 10 in 65% isolated yield accompanied by the homo-
dimer of diene 9 in 5% isolated yield. This unsaturated lac-
tone was converted to the (Z)-homoallylic alcohol 8 in three
steps following Danishefsky’s strategy.6c This approach led
to alcohol 8 in 11 steps and 11% yield from 3. Thus, our new
strategy is more efficient than the previous one for the syn-
thesis of 8 (10 steps, 35% yield).
In this approach, the glutarimide side chain would be intro-
duced before the C1–C6 fragment I. The vinyl ketone H
would be obtained after functional transformation of an alde-
hyde of type J, which is in turn derived from allylic alcohol
8. The anti-relationship at C13, C14 in fragment H would be
the result of an anti-selective enantio- and diastereoselective
crotylmetalation applied to aldehyde J (Scheme 5).
O
O
O
NH
O
NH
To complete the synthesis of macrolide 2, allylic alcohol 8
was then transformed to ester 11 in 67% yield by using the
freshly prepared mixed anhydride IV (Scheme 4).13 In order
to obtain the RCM precursor 13, ester 11 was selectively de-
protected at C7 (NH4F, MeOH reflux, 7.5 h) thus producing
the primary alcohol 12 in 77% yield.14 This alcohol was then
oxidized with Dess–Martin periodinane and the obtained
aldehyde was directly treated under Takai conditions (Zn,
PbCl2 cat, CH2I2, Ti(Oi-Pr)4, THF, rt) to afford the expected
diene 13 in 63% yield (over two steps).15,16 As described pre-
viously,6a,c diene 13 was treated with [Ru]-II (20 mol %) in
refluxing toluene to produce the macrocyclic lactone 14 in
47% yield, and after deprotection (HF$Py, THF, rt) the macro-
lide core of migrastatin 2 was obtained in 67% yield. Com-
pound 2 was thus obtained in 17 steps from the commercially
available methyl ester 3 with an overall yield of 4%.
17
17
Me
Me
O
O
O
O
16
16
1
1
Me
Me
O
Me
O
Me
12
12
11
11
7
7
F
6
OH
OR
6
OMe
OMe
1
O
O
O
NH
NH
17
17
Me
O
O
O
16
15
1
Me
HO
Me
12
OH
Me
+
+
11
O
7
Me
6
OR
16
Me
OMe
HO
Me
G
I
12
11
3. Total synthesis of migrastatin (1)
7
H
13
R'O
OR
Me
In view of our improved synthesis of the key intermediate 8,
we envisioned a more efficient synthesis of migrastatin (1),
compared to the one previously reported.5 The synthesis of
migrastatin was envisaged by using a chemoselective RCM
applied to diene F. This diene would be formed by the ester-
ification of 2,6-heptadienoic acid (I) with alcohol G, which
would be assembled by using a chemoselective cross-me-
tathesis (CM) between allylglutarimide 15 and vinyl ketone
H (C7–C16 fragment).17 In this strategy, it would be neces-
sary to perform either a conjugate reduction of the enone or
a chemoselective hydrogenation of the enone double bond.
HO
Me
O
Me
12
OMe
11
H
7
7
TBDPSO
OTBS
R'O
OR
OMe
8
OMe
J
Scheme 5. Retrosynthetic analysis of migrastatin (1).
As depicted in Scheme 6, the synthesis of migrastatin starts
with the oxidation of the previously prepared allylic alcohol
8 to aldehyde 16 (MnO2, CH2Cl2, rt). To control the

S. Reymond, J. Cossy / Tetrahedron 63 (2007) 5918–5929
5921
Ph
Ti
O
O
O
Ph
16
15
Ph
Ph
O
H
Me
Me
14
13
Ti(S,S)-I
Me
13
O
Me
Me
Me
MnO2
TESCl
HO
Me
TESO
Me
12
11
12
11
Ti(S,S)-I (1.4 equiv)
CH2Cl2, rt
imidazole
8
CH2Cl2, rt
90%
Et2O, -78 °C
80% (from 8)
TBDPSO
OTBS
TBDPSO
OTBS
TBDPSO
OTBS
OMe
16
OMe
17
OMe
18
1) OsO4, NMO
t-BuOH/H2O (1/1), rt
2) NaIO4
80%
O
THF/H2O (1/1), rt
O
NH
O
O
17
15
Me
Me
Me
O
H
Me
21
16
16
Me
1) VinylMgCl
Me
TESO
Me
7
TESO
Me
7
TESO
Me
[Ru]-III (30 mol %)
THF, -78 °C
15 (3 equiv)
CH2Cl2, rt
32%
2) Dess-Martin Periodinane
CH2Cl2, 0 °C to rt
TBDPSO
OTBS
TBDPSO
OTBS
TBDPSO
OTBS
73%
OMe
OMe
20
OMe
19
24
Scheme 6. Synthesis of fragment 24 (C7–C21).
stereogenic centers at C13 and C14, aldehyde 16 was treated
with the highly face-selective crotyltitanium complex
Ti(S,S)-I,18 which gave the homoallylic alcohol 17 in 80%
yield (from 8) with good diastereoselectivity (dr¼90/
10).9,19 The following step involved the selective oxidative
cleavage of the terminal C15–C16 double bond. To protect
sterically the internal double bond at C11–C12 from oxida-
tive cleavage, the hydroxy group at C13 in compound 17,
was converted to the bulky triethylsilyl ether 18 (TESCl,
imidazole, CH2Cl2, rt, 90%). Due to this protection, the
C15–C16 double bond was chemoselectively transformed
to an aldehyde by using a two-step dihydroxylation/oxida-
tive cleavage sequence (OsO4, N-methylmorpholine N-
oxide, then NaIO4) to produce aldehyde 19 in 80% yield.
This aldehyde was then converted to the a,b-unsaturated
ketone 20 in two steps by treatment with vinylmagnesium
chloride (THF, ꢀ78 ꢁC) followed by oxidation of the result-
ing allylic alcohol with Dess–Martin periodinane in 73%
yield for the two steps.
catalyst [Ru]-III, yielding the CM product 24 in a moderate
yield of 32% with 60% conversion based on the recovery of
the starting material 20 [[Ru]-III (30 mol %), 15 (3 equiv),
CH2Cl2, rt, 72 h] (Scheme 7).21 We have to point out that dur-
ing the CM reaction, olefin 15 homodimerized leading to the
formation of a white precipitate in the reaction mixture. In
our effort to improve theyield of this reaction, we tried to per-
form the CM under microwave irradiation22 or in the pres-
ence of chlorodicyclohexylborane, previously reported to
improve the CM reaction of nitrogen containing substrates,23
however in both cases, the obtained yields were around 30%.
At this stage of the synthesis, the second crucial step to be
performed was the selective reduction of the C16–C17 enone
O
Urea
CO2Et
CO2Et
CH2CO2H
CH2CO2H
Ref 20
180 °C
NH
87%
O
At this stage, the first CM partner was obtained and the sec-
ond partner, allylglutarimide 15, was prepared from the
commercially available allyldiethyl malonate 21. 3-(2-Pro-
penyl)-glutaric acid (22) was synthesized from diester 21
in four steps following a previously reported procedure.20
Diacid 22 was then cyclized to glutarimide 15 by reaction
with urea at high temperature (180 ꢁC). In order to test our
crucial CM with this glutarimide, 15 was reacted with ethyl
vinyl ketone as a test substrate in the presence of Hoveyda–
Grubbs catalyst [Ru]-III and interestingly, the CM product
23 was isolated in 60% yield (Scheme 7). With the two
CM partners in hand, enone 24 (C7–C21 fragment) was syn-
thesized by using a CM reaction.
21
22
15
MesN
NMes
Cl
Cl
Ru
O
[Ru]-III
Hoveyda-Grubbs catalyst
O
O
Ethyl vinyl ketone
[Ru]-III (5 mol %)
NH
NH
CH2Cl2, rt
60%
O
O
O
15
23
The CM reaction between vinyl ketone 20 and allylglutar-
imide 15 was performed in the presence of Hoveyda–Grubbs
Scheme 7. Synthesis of allylglutarimide 15 and CM with ethyl vinyl ketone.

5922
S. Reymond, J. Cossy / Tetrahedron 63 (2007) 5918–5929
double bond. A conjugate reduction of this enone was envis-
aged by using Buchwald copper carbene complex [Cu]-I in
the presence of a silane as the hydride donor.24 Therefore,
enone 24 was subjected to the conjugate reduction with di-
phenylsilane in the presence of a catalytic amount of Cu-H
species generated in situ from [Cu]-I (5 mol %),25 yielding
the corresponding ketone 25 in 63% yield. This copper-car-
benic species appears to be a good alternative to the Stryker
reagent.26
Having synthesized the C7–C21 fragment 25, the construc-
tion of the macrolactone core leading to the complete syn-
thesis of migrastatin could be considered. After a selective
deprotection of the hydroxyl group at C13 in compound 25
(THF/H2O/AcOH, 1/1/3, rt, 80% yield), the obtained alco-
hol was transformed to ester 26 in 74% yield by using the
freshly prepared mixed anhydride IV (toluene, rt, 48 h). In
order to prepare the RCM precursor 28, ester 26 was selec-
tively deprotected at C7 by employing ammonium fluoride
in methanol providing alcohol 27 in 81% yield. This primary
alcohol was then oxidized to the corresponding aldehyde,
which was directly treated under the Takai conditions to af-
ford diene 28 in 54% yield (for the two steps). As described
previously,4,6c diene 28 was treated with [Ru]-II (20 mol %)
in refluxing toluene to produce macrolactone 29 in 39%
yield. Finally, after removal of the last protecting group
at C9 by HF$Py in THF, migrastatin (1) was isolated in
As the bulky TES protecting group at C13 provided a good
protection for the C11–C12 trisubstituted double bond dur-
ing the dihydroxylation step applied to olefin 18, the chemo-
selective hydrogenation of the C16–C17 enone double bond
was also investigated. Thus, when 24 was treated with
hydrogen in the presence of Pd/C, the enone double bond
was selectively hydrogenated to afford 25 in 96% yield
(Scheme 8).
62% yield (Scheme 9). All the spectral data (1H NMR, 13
C
NMR, HRMS) and the optical rotation of our synthetic
migrastatin matched those reported in the literature.4,6c
i-Pr
24
i-Pr
4. Conclusion
N
H2
CuCl
i-Pr
96%
Pd/C 5% (12 wt %)
AcOEt, rt
N
We have developed an efficient access to the C7–C13 frag-
ment of both migrastatin (1) and its macrolactone core 2,
involving the use of a syn,syn-stereoselective crotylstannyl-
ation to control the stereogenic centers present at C9 and
C10, and a Still–Gennari olefination to establish the (Z)-tri-
substituted C11–C12 double bond. The macrolactone core of
migrastatin 2 was synthesized in 17 steps from commercially
available (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (3)
with an overall yield of 4%. Based on a similar strategy,
the total synthesis of migrastatin (1) was realized in 27 steps.
Synthetic highlights include an enantio- and diastereoselec-
tive crotyltitanation to control the stereogenic centers at C13
and C14 as well as a versatile ruthenium-catalyzed CM
i-Pr
O
[Cu]-I
O
NH
Buchwald catalyst
17
Me
O
21
[Cu]-I (5 mol %)
NaOt-Bu (5 mol %)
16
Me
TESO
Me
7
12
24
Ph2SiH2, t-BuOH
Toluene, rt
63%
11
TBDPSO
OTBS
OMe
25
Scheme 8. Synthesis of fragment 25 (C7–C21).
O
O
O
O
NH
O
NH
O
NH
Me
Me
Me
21
21
21
O
O
O
O
O
Me
Me
Me
1
NH4F
1) THF/H2O/AcOH (1/1/3)
TESO
Me
7
O
1
O
Me
Me
7
rt (80%)
2) IV, Pyridine
Toluene, rt (74%)
MeOH, rt
81%
6
6
7
TBDPSO
OTBS
TBDPSO
OTBS
HO
OTBS
OMe
OMe
OMe
25
26
27
1) Dess-Martin Periodinane
CH2Cl2, 0 °C to rt
2) Zn, PbCl2 cat, CH2I2
Ti(Oi-Pr)4, THF, rt
54%
O
O
O
O
NH
O
NH
O
NH
Me
Me
Me
O
21
21
O
O
O
O
O
21
Me
Me
Me
1
1
1
O
Me
O
O
HF Pyr
[Ru]-II (20 mol %)
Me
7
Me
7
Toluene, reflux
39%
THF, rt
62%
7
6
OTBS
OH
OTBS
6
6
OMe
OMe
Migrastatin (1)
OMe
29
28
Scheme 9. Completion of the synthesis of migrastatin (1).

S. Reymond, J. Cossy / Tetrahedron 63 (2007) 5918–5929
5923
reaction to install the glutarimide side chain, and a RCM to
establish the macrolactone core. As the methods employed
for the synthesis of 1 and 2 are flexible, they should allow
us to access a wide range of migrastatin analogues for bio-
logical evaluation.
To a solution of freshly prepared Ag2O (13.96 g,
˚
60.16 mmol) and activated MS 4 A (3.49 g) in Et2O (40 mL)
was added the above alcohol (14.36 g, 40.06 mmol) fol-
lowed by iodomethane (22.48 mL, 361 mmol). After 1 h at
40 ꢁC, the mixture was filtered on a pad of Celite and washed
with Et2O. The solvent was removed under reduced pressure
to give (2S)-methyl 3-(tert-butyldiphenylsilyloxy)-2-meth-
oxy-propionate (14.53 g, 39 mmol, 96%).
5. Experimental
5.1. General
To a solution of the above ester (14.53 g, 39 mmol) in
CH2Cl2 (290 mL) at ꢀ78 ꢁC, was added dropwise DIBAL-
H (86 mL, 1 M in hexanes, 86 mmol). The cooling bath
was removed and after 2.5 h at rt, an aqueous 10% HCl
solution (115 mL) was slowly added at 0 ꢁC. The aqueous
phase was extracted with CH2Cl2 and the combined extracts
were washed with brine, dried over MgSO4, and filtered. The
solvent was removed under reduced pressure and the residue
was purified by flash chromatography on silica gel (petro-
leum ether/EtOAc; 9/1) to yield (2R)-3-(tert-butyldiphenyl-
silyloxy)-2-methoxy-propan-1-ol (4) (12.06 g, 35.01 mmol,
90%). [a]2D0 +23.1 (c 0.54, CHCl3); IR (neat) 3420, 2929,
All reactions were carried out under argon. Unless specified
otherwise, materials were purchased from commercial sup-
pliers and used without purification. THF and diethyl ether
were distilled from sodium/benzophenone. CH2Cl2, Et3N,
benzene, and toluene were distilled from CaH2. Flash col-
umn chromatography was carried out on Merck Geduran
Si60 silica gel (40–63 mm) and analytical thin-layer chroma-
tography was performed on Merck precoated silica gel (60
F254). Elemental analyses were performed by the Service
de Microanalyse (ICSN-CNRS, Gif sur Yvette). Mass spec-
tra with electronic impact (MS-EI) were recorded from a
Hewlett–Packard tandem 5890 GC (12 m capillary col-
umn)–5971 MS (70 eV): only selected ions are reported.
HRMS were performed at the Laboratoire de Spectrochimie
2957, 1471, 1427, 1108, 1079, 1029 cmꢀ1 1H NMR
;
(CDCl3, 300 MHz) d 7.66 (m, 4H), 7.36–7.43 (m, 6H),
3.68 (m, 4H), 3.37 (s, 3H), 3.37 (m, 1H), 2.05 (m, 1H),
1.05 (s, 9H); 13C NMR (CDCl3, 75 MHz) d 135.7 (4C),
133.3, 133.2, 129.9 (2C), 127.8 (4C), 81.6, 63.1, 62.7,
58.0, 26.9 (3C), 19.3; EIMS m/z 287 (Mꢀt-Bu+), 239, 225,
214, 213, 211, 209, 200, 199, 197, 184, 183, 181, 180,
179, 177, 165, 161, 153, 135, 131, 117, 105, 93, 91, 77.
Anal. Calcd for C20H28O3Si: C, 69.72; H, 8.19. Found: C,
69.54; H, 8.21.
ꢀ
de l’Ecole Normale Superieure in Paris and at the Labora-
3
ꢀ
ꢀ
toire de Spectrometrie de Masse SM E de l’Universite Pierre
et Marie Curie in Paris. Infrared (IR) spectra were recorded
on a Bruker TENSORÔ 27 (IRFT), wavenumbers are indi-
cated in cmꢀ1. 1H NMR spectra were recorded on a Bruker
AC 300 at 300 MHz or on a Bruker AVANCE 400 at
400 MHz in CDCl3 and data are reported as follows: chem-
ical shift in parts per million from tetramethylsilane as
an internal standard, multiplicity (s¼singlet, d¼doublet,
t¼triplet, q¼quartet, sext¼sextet, m¼multiplet or overlap
of non-equivalent resonances, br¼broad), integration. 13C
NMR spectra were recorded on a Bruker AC 300 at
75 MHz or on a Bruker AVANCE 400 at 100 MHz in
CDCl3 and data are reported as follows: chemical shift in
parts per million from tetramethylsilane.
5.2.2. Stereotriad 5. To a stirred solution of oxalyl chloride
(6.53 mL, 76.12 mmol) in CH2Cl2 (520 mL) at ꢀ78 ꢁC, was
slowly added DMSO (6.87 mL, 96.88 mmol). After 30 min
at ꢀ78 ꢁC, a solution of alcohol 4 (11.90 g, 34.60 mmol)
in CH2Cl2 (130 mL) was added and after 20 min at
ꢀ78 ꢁC, Et3N (22.62 mL) was introduced. After 30 min at
ꢀ78 ꢁC, the reaction was slowly warmed to rt and diluted
with pentane (100 mL) and brine (100 mL). The aqueous
layer was extracted with pentane and the combined organic
extracts were dried over MgSO4 and filtered. The solvent
was removed in vacuo to afford the corresponding aldehyde,
which was used in the next step without further purification.
5.2. Synthesis of the C7–C13 fragment (8)
5.2.1. Alcohol 4. To a solution of (S)-(+)-2,2-dimethyl-1,3-
dioxolane-4-carboxylate (3) (5.33 g, 33.28 mmol) in a
mixture of MeOH (25 mL) and water (25 mL) was added
p-TsOH (3.47 g, 18.24 mmol). The mixture was stirred at
rt for 3 h and then Et3N (5 mL) was added. After evaporation
under reduced pressure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc; 7/
3) to afford (2S)-methyl 2,3-dihydroxypropionate (3.32 g,
27.64 mmol, 83%).27
To a solution of the above crude aldehyde in CH2Cl2
(346 mL) at ꢀ21 ꢁC, was added MgBr2$OEt2 (19.7 g,
76.12 mmol). After 40 min at ꢀ21 ꢁC, the reaction was
cooled to ꢀ60 ꢁC and but-2-enyl-[(tri-n-butyl)]-stannane II
(17.9 g, 51.9 mmol) was added. After 7 h, the reaction mix-
ture was quenched by the addition of a saturated aqueous
NaHCO3 solution (200 mL). The aqueous layer was ex-
tracted with CH2Cl2 and the combined organic extracts
were dried over MgSO4 and filtered. Purification by flash
chromatography on silica gel with 10 wt % finely ground
KF28 (CH2Cl2) allowed to isolate (2S,3S,4R)-1-(tert-butyl-
diphenylsilyloxy)-2-methoxy-4-methyl-hex-5-en-3-ol (5)
(12.01 g, 30.13 mmol, 87%). [a]2D0 +15.3 (c 1.02, CHCl3);
IR (neat) 2929, 2857, 1640, 1590, 1471, 1427, 1390, 1361,
To a solution of the above diol (5.95 g, 49.54 mmol) in
CH2Cl2 (73 mL) at 0 ꢁC, were added imidazole (3.54 g,
52 mmol) followed by tert-butyldiphenylsilyl chloride
(13.52 mL, 52 mmol). After 6 h at rt, NH4Cl was added.
The aqueous layer was extracted with CH2Cl2 and the com-
bined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification by flash
chromatography on silica gel (petroleum ether/EtOAc; 9/1)
allowed us to isolate (2S)-methyl 3-(tert-butyldiphenyl-silyl-
oxy)-2-hydroxypropionate (14.36 g, 40.06 mmol, 81%).
1
1108, 1079 cmꢀ1; H NMR (CDCl3, 300 MHz) d 7.67 (m,
4H), 7.36–7.43 (m, 6H), 5.71 (ddd, J¼17.6, 10.5, 8.5 Hz,
1H), 5.01–5.10 (m, 2H), 3.80 (dd, J¼10.5, 5.5 Hz, 1H),
3.73 (dd, J¼10.5, 4.5 Hz, 1H), 3.50 (td, J¼7.0, 2.5 Hz,

5924
S. Reymond, J. Cossy / Tetrahedron 63 (2007) 5918–5929
1H), 3.33 (s, 3H), 3.27 (m, 1H), 2.38–2.49 (m, 2H), 1.09 (d,
J¼7.0 Hz, 3H), 1.06 (s, 9H); 13C NMR (CDCl3, 75 MHz)
d 141.6, 135.7 (2C), 135.6 (2C), 133.3, 133.2, 129.8 (2C),
127.8 (4C), 115.0, 80.5, 74.8, 63.2, 58.4, 41.5, 26.8 (3C),
19.2, 16.2; HRMS (ESI) calcd for C24H34O3NaSi [M+Na+]
421.2175. Found 421.2141.
was then poured on a mixture of water (200 mL), pentane
(150 mL) and Et2O (150 mL). The aqueous layer was ex-
tracted with a mixture of pentane/Et2O (1/1) and the com-
bined organic extracts were washed with a 5% aqueous
NaHCO3 solution and next with brine. The organic layer
was dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by flash chromatography on
silica gel (petroleum ether/Et2O; 100/0 to 100/3) allowed
us to isolate (Z)-(4R,5S,6S)-5-(tert-butyldimethylsilyloxy)-
7-(tert-butyldiphenylsilyloxy)-6-methoxy-2,4-dimethyl-hept-
2-enoic acid ethyl ester (7) (4.77 g, 7.97 mmol, 80% for the
last three steps). [a]D20 ꢀ11.2 (c 0.91, CHCl3); IR (neat)
2929, 2856, 1713, 1472, 1428, 1370, 1250, 1221, 1195,
1107, 1082, 1055, 1028 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d 7.68–7.71 (m, 4H), 7.35–7.41 (m, 6H), 5.92 (dd, J¼9.5,
1.6 Hz, 1H), 4.05 (m, 2H), 3.78 (dd, J¼11.0, 4.3 Hz, 1H),
3.63–3.68 (m, 2H), 3.29 (s, 3H), 3.24–3.34 (m, 1H), 3.16
(m, 1H), 1.86 (d, J¼1.3 Hz, 3H), 1.15 (t, J¼7.2 Hz, 3H),
1.04 (s, 9H), 0.94 (d, J¼6.6 Hz, 3H), 0.89 (s, 9H), 0.05 (s,
3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 167.8,
146.3, 135.7 (4C), 133.6 (2C), 129.6 (2C), 127.6 (4C),
125.5, 84.6, 75.8, 63.4, 60.0, 58.8, 35.9, 26.8 (3C), 26.2
(3C), 20.8, 19.2, 18.5, 15.0, 14.2, ꢀ3.9, ꢀ4.6; HRMS
(ESI) calcd for C34H54O5KSi2 [M+K+] 637.3147. Found
637.3150.
5.2.3. Olefin 6. To a solution of alcohol 5 (4.82 g,
12.09 mmol) in CH2Cl2 (120 mL) at ꢀ20 ꢁC, was added
dropwise 2,6-lutidine (3.52 mL, 30.28 mmol) followed by
tert-butyldimethylsilyl trifluoromethanesulfonate (5.57 mL,
24.22 mmol). After stirring for 3 h at 0 ꢁC, the reaction mix-
ture was quenched by addition of a saturated aqueous
NaHCO3 solution and warmed at rt. The aqueous layer
was extracted with Et2O and the combined organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by flash chromatography on
silica gel (petroleum ether/Et2O; from 100/0 to 100/5)
furnished (2S,3S,4R)-3-(tert-butyldimethylsilyloxy)-1-(tert-
butyldiphenyl-silyloxy)-2-methoxy-4-methyl-hex-5-ene (6)
(5.77 g, 11.25 mmol, 93%). [a]2D0 +4.4 (c 0.5, CHCl3); IR
(neat) 2929, 2856, 1472, 1428, 1389, 1361, 1251, 1112,
1075, 1050, 999 cmꢀ1
;
1H NMR (CDCl3, 400 MHz)
d 7.68–7.71 (m, 4H), 7.36–7.45 (m, 6H), 5.88 (m, 1H),
4.93–4.99 (m, 2H), 3.72–3.78 (m, 2H), 3.68 (dd, J¼11.1,
5.0 Hz, 1H), 3.27 (s, 3H), 3.14 (m, 1H), 2.42 (m, 1H), 1.06
(s, 9H), 0.96 (d, J¼6.8 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 3H),
0.04 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 142.9, 135.7
(4C), 133.6, 133.5, 129.7, 129.6, 127.7 (2C), 127.6 (2C),
113.3, 84.1, 75.9, 62.8, 58.4, 40.33, 26.8 (3C), 26.2 (3C),
19.2, 18.5, 14.5, ꢀ4.0, ꢀ4.4; EIMS m/z 455 (Mꢀt-Bu+),
323, 287, 267, 247, 227, 226, 225, 214, 213, 200, 199,
195, 193, 183, 181, 179, 174, 173, 165, 163, 135, 115, 91,
89, 75, 73, 59.
5.2.5. Alcohol 8. To a solution of ester 7 (4.21 g, 7.04 mmol)
in CH2Cl2 (125 mL) at ꢀ78 ꢁC, was added dropwise DI-
BAL-H (15.5 mL, 1 M in hexanes, 15.5 mmol). The cooling
bath was removed and after 2 h at rt, the reaction mixture
was cooled to ꢀ60 ꢁC and then transferred via cannula to
a saturated aqueous solution of potassium sodium tartrate.
After 2 h stirring at rt, the aqueous layer was extracted
with ethyl acetate. The combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash chromatography on
silica gel (petroleum ether/Et2O; 8/2) furnished allylic alco-
hol 8 (3.66 g, 6.59 mmol, 94%). [a]2D0 +2.5 (c 1.075, CHCl3);
IR (neat) 3417, 3071, 2929, 2885, 2856, 1472, 1428, 1389,
1361, 1252, 1189, 1111, 1081, 1026, 1005 cmꢀ1; 1H NMR
(CDCl3, 400 MHz) d 7.67–7.70 (m, 4H), 7.37–7.45 (m,
6H), 5.15 (d, J¼10.0 Hz, 1H), 4.10 (dd, J¼12.1, 3.3 Hz,
1H), 3.92 (dd, J¼11.5, 6.7 Hz, 1H), 3.78 (dd, J¼10.9,
4.8 Hz, 1H), 3.73 (dd, J¼11.2, 5.4 Hz, 1H), 3.59 (t,
J¼5.4 Hz, 1H), 3.26 (s, 3H), 3.21 (q, J¼5.1 Hz, 1H), 2.72
(m, 1H), 1.83 (m, 1H, OH), 1.78 (d, J¼1.1 Hz, 3H), 1.06
(s, 9H), 0.91 (d, J¼6.8 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H);
13C NMR (CDCl3, 100 MHz) d 135.7 (4C), 133.6, 133.5
(2C), 132.5, 129.7 (2C), 127.7 (4C), 83.6, 76.2, 62.7, 61.8,
57.8, 34.7, 26.9 (3C), 26.2 (3C), 21.7, 19.2, 18.4, 17.2,
ꢀ4.0, ꢀ4.4; HRMS (ESI) calcd for C32H52O4KSi2
[M+K+] 595.3041. Found 595.3041.
5.2.4. Ethyl ester 7. To a stirred solution of olefin 6 (5.12 g,
10 mmol) in a mixture of t-BuOH (25 mL) and deionized
water (25 mL) at rt was added OsO4 (5.06 mL, 2.5 wt % in
t-BuOH, 0.4 mmol) followed by N-methylmorpholine N-ox-
ide (1.2 g, 11 mmol). After 6.5 h the reaction was quenched
by the addition of Na2S2O3 (11 g) followed by Celite (22 g)
and ethyl acetate (25 mL) and the mixture was stirred for
20 min. The reaction mixture was filtered on Celite, the
residue was washed with EtOAc, and the solvents were
removed in vacuo.
To a solution of the above diol in a mixture of THF (100 mL)
and deionized water (100 mL) at rt was added NaIO4
(5.35 g, 25 mmol). After 3 h the mixture was filtered on Cel-
ite and the residue was washed with ethyl acetate. The aque-
ous layer was extracted with EtOAc and the combined
organic layers were dried over MgSO4, filtered, and concen-
trated under reduced pressure. The resulting aldehyde was
used in the next step without further purification.
5.3. Synthesis of macrolide 2
To a solution of phosphonate III (4.15 g, 12 mmol) and
18-crown-6 (12.69 g, 48 mmol) in THF (180 mL) at 0 ꢁC,
was added dropwise KHMDS (24 mL, 0.5 M in toluene,
12 mmol). After 30 min at 0 ꢁC, the reaction was cooled to
ꢀ78 ꢁC and the above crude aldehyde in THF (50 mL)
was added dropwise via cannula. After 18 h at ꢀ78 ꢁC, the
reaction was quenched by addition of a saturated aqueous
NH4Cl solution (100 mL) and warmed to rt. The mixture
5.3.1. Ester 11. To a solution of alcohol 8 (556 mg, 1 mmol)
in toluene (25 mL) at rt was added pyridine (326 mL,
4 mmol) followed by the mixed anhydride IV (3 mmol).13
After stirring for 24 h, the reaction was directly loaded
onto a silica gel column and purification by flash chromato-
graphy (petroleum ether/Et2O; 100/0 to 100/3) furnished
ester 11 (444 mg, 0.67 mmol, 67%). [a]2D0 +1.7 (c 0.06,
CHCl3); IR (neat) 2956, 2929, 2856, 1721, 1656, 1472,

S. Reymond, J. Cossy / Tetrahedron 63 (2007) 5918–5929
5925
1428, 1361, 1252, 1194, 1166, 1112, 1083, 1026,
(52 mg, 0.12 mmol, 63%, two steps). [a]2D0 +3.0 (c 1.15,
CHCl3); IR (neat) 2928, 2883, 2855, 2820, 1721, 1656,
1471, 1461, 1379, 1360, 1314, 1251, 1201, 1166, 1125,
1
1005 cmꢀ1; H NMR (CDCl3, 400 MHz) d 7.69 (m, 4H),
7.36–7.44 (m, 6H), 6.94 (dt, J¼15.4, 7.0 Hz, 1H), 5.74–
5.85 (m, 2H), 5.38 (d, J¼9.9 Hz, 1H), 4.98–5.08 (m, 2H),
4.70 (d, J¼11.8 Hz, 1H), 4.52 (d, J¼12.2 Hz, 1H), 3.74
(dd, J¼11.0, 5.4 Hz, 1H), 3.68 (dd, J¼11.0, 5.1 Hz, 1H),
3.63 (t, J¼5.0 Hz, 1H), 3.21 (s, 3H), 3.10 (q, J¼5.1 Hz,
1H), 2.76 (m, 1H), 2.26–2.33 (m, 2H), 2.17–2.24 (m, 2H),
1.73 (d, J¼1.7 Hz, 3H), 1.05 (s, 9H), 0.93 (d, J¼6.8 Hz,
3H), 0.90 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 166.5, 148.3, 137.1, 135.7 (4C),
135.2, 133.6, 133.5, 129.7 (2C), 128.5, 127.7 (4C), 121.6,
115.5, 84.0, 76.2, 63.0, 62.8, 58.4, 34.6, 32.1, 31.5, 26.8
(3C), 26.2 (3C), 21.5, 19.2, 18.5, 16.2, ꢀ3.9, ꢀ4.4; HRMS
(ESI) calcd for C39H60O5KSi2 [M+K+] 703.3616. Found
703.3624.
1097, 1080, 1025, 1004 cmꢀ1 1H NMR (CDCl3, 400
;
MHz) d 6.96 (dt, J¼15.2, 7.0 Hz, 1H), 5.74–5.87 (m, 2H),
5.62 (m, 1H), 5.43 (d, J¼10.0 Hz, 1H), 5.21–5.29 (m, 2H),
4.98–5.08 (m, 2H), 4.61 (d, J¼12.0 Hz, 1H), 4.56 (d,
J¼12.0 Hz, 1H), 3.46 (dd, J¼7.3, 3.0 Hz, 1H), 3.36 (app t,
J¼7.7 Hz, 1H), 3.19 (s, 3H), 2.61 (m, 1H), 2.27–2.33 (m,
2H), 2.18–2.24 (m, 2H), 1.73 (d, J¼1.3 Hz, 3H), 0.89–0.91
(m, 12H), 0.05 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3,
100 MHz) d 166.6, 148.5, 137.1, 135.6, 135.1, 128.2,
121.5, 118.8, 115.5, 86.3, 78.4, 63.1, 56.1, 34.3, 32.0, 31.5,
26.2 (3C), 21.5, 18.6, 14.0, ꢀ3.8, ꢀ4.8; HRMS (ESI) calcd
for C24H42O4KSi [M+K+] 461.2489. Found 461.2490.
5.3.4. Macrolactone 14.6c To a solution of diene 13 (45 mg,
107 mmol) in refluxing toluene (200 mL) was added the sec-
ond generation Grubbs catalyst [Ru]-II (18 mg, 21.2 mmol).
After stirring for 20 min, the reaction was cooled to rt and
filtered through a pad of silica gel (hexane/EtOAc; 4/1).
The residue was purified by flash chromatography on silica
gel (petroleum ether/EtOAc; from 20/1 to 20/2) to afford
macrolactone 14 (20 mg, 51 mmol, 47%). 1H NMR
(CDCl3, 400 MHz) d 6.81 (dt, J¼16.0, 7.5 Hz, 1H), 5.72
(d, J¼16 Hz, 1H), 5.48–5.55 (m, 2H), 5.10 (dd, J¼15.6,
8.7 Hz, 1H), 4.67 (d, J¼15.6 Hz, 1H), 4.61 (d, J¼16.0 Hz,
1H), 3.44 (dd, J¼8.5, 1.6 Hz, 1H), 3.30 (app t, J¼8.4 Hz,
1H), 3.16 (s, 3H), 2.98 (m, 1H), 2.32–2.46 (m, 2H), 2.12–
2.30 (m, 2H), 1.63 (s, 3H), 0.91 (s, 9H), 0.82 (d, J¼
6.9 Hz, 3H), 0.06 (s, 6H); 13C NMR (CDCl3, 100 MHz)
d 165.4, 149.9, 132.0, 130.5 (2C), 126.6, 121.9, 85.8, 77.5,
65.6, 55.9, 33.1, 32.5, 30.0, 26.3 (3C), 22.2, 18.7, 12.9,
ꢀ3.6, ꢀ5.0.
5.3.2. Alcohol 12. To a solution of ester 11 (350 mg,
0.53 mmol) in refluxing MeOH (20 mL) was added NH4F
by portions (466 mg, 3.69 mmol) over 7 h. The reaction
mixture was quenched by the addition of a saturated aqueous
NaHCO3 solution (15 mL). The aqueous layer was extracted
with Et2O and the combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (petro-
leum ether/Et2O; from 100/0 to 50/50) yielded alcohol 12
(175 mg, 0.41 mmol, 77%). [a]2D0 +2.4 (c 0.35, CHCl3); IR
(neat) 3450, 2922, 2853, 1722, 1657, 1461, 1377, 1362,
1255, 1167, 1157, 1113, 1080, 1024 cmꢀ1 1H NMR
;
(CDCl3, 400 MHz) d 6.91 (dt, J¼15.7, 6.6 Hz, 1H), 5.71–
5.82 (m, 2H), 5.35 (d, J¼9.6 Hz, 1H), 4.94–5.02 (m, 2H),
4.61 (s, 2H), 3.76 (dd, J¼11.9, 3.3 Hz, 1H), 3.62 (dd,
J¼6.5, 3.6 Hz, 1H), 3.56 (dd, J¼11.9, 5.0 Hz, 1H), 3.35 (s,
3H), 3.11 (m, 1H), 2.68 (m, 1H), 2.35 (br s, 1H, OH), 2.23–
2.28 (m, 2H), 2.15–2.19 (m, 2H), 1.70 (d, J¼1.3 Hz, 3H),
0.90 (d, J¼6.7 Hz, 3H), 0.86 (s, 9H), 0.03 (s, 3H), 0.02 (s,
3H); 13C NMR (CDCl3, 100 MHz) d 166.5, 148.6, 137.0,
135.2, 128.5, 121.5, 115.5, 84.4, 75.6, 63.0, 60.6, 58.1,
34.2, 32.0, 31.5, 26.1 (3C), 21.5, 18.3, 15.3, ꢀ4.1, ꢀ4.6.
5.3.5. Macrolide 2.6c To a solution of macrolactone 14
(20 mg, 50.8 mmol) in THF (1.5 mL) was added HF$Py
(350 mL). After 16 h at rt, the reaction was quenched by ad-
dition of NaHCO3. Water was added to the reaction mixture
and the aqueous phase was extracted with Et2O. The com-
bined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification by flash
chromatography on silica gel (petroleum ether/Et2O; from
9/1 to 8/2) furnished macrolide 2 (9.5 mg, 33.9 mmol,
67%). [a]2D0 +80.9 (c 0.47, CHCl3); IR (neat) 3491, 2928,
2877, 1720, 1660, 1440, 1379, 1325, 1248, 1188, 1157,
5.3.3. Diene 13. To a solution of alcohol 12 (83 mg,
0.19 mmol) in CH2Cl2 (8 mL) at 0 ꢁC was added Dess–Mar-
tin periodinane (608 mL, 15 wt % in CH2Cl2, 0.29 mmol).
After 2 h at rt, the reaction was quenched by the addition
of a saturated aqueous Na2S2O3 solution followed by the ad-
dition of a saturated aqueous NaHCO3 solution. The aqueous
layer was extracted with Et2O and the combined organic
layers were dried over MgSO4, filtered, and concentrated un-
der reduced pressure to yield the corresponding aldehyde,
which was used in the next step without further purification.
1
1100, 1052 cmꢀ1; H NMR (CDCl3, 400 MHz) d 6.78 (m,
1H), 5.75 (d, J¼15.7 Hz, 1H), 5.55–5.63 (m, 2H), 5.10–
5.16 (m, 1H), 4.74 (d, J¼15.6 Hz, 1H), 4.63 (d, J¼
15.6 Hz, 1H), 3.39–3.42 (m, 2H), 3.29 (s, 3H), 3.01 (m,
1H), 2.70 (s, 1H), 2.38–2.49 (m, 2H), 2.17–2.33 (m, 2H),
1.68 (s, 3H), 0.88 (d, J¼7.0 Hz, 3H); 13C NMR (CDCl3,
100 MHz) d 165.4, 149.5, 133.8, 129.8, 129.5, 127.5,
122.1, 84.6, 76.1, 65.4, 56.2, 32.2, 31.3, 30.0, 22.3, 12.7.
To an oven-dried tube was added under argon freshly acti-
vated Zn (115 mg, 1.76 mmol) and PbCl2 (2.4 mg, 2 wt %/
Zn) followed by THF (2 mL). CH2I2 (80 mL, 0.98 mmol)
was added slowly and after 0.5 h, Ti(Oi-Pr)4 (57 mL,
0.19 mmol) in THF (200 mL) was added dropwise. After
0.5 h, a solution of the above aldehyde in THF (1.6 mL)
was added dropwise at rt. After 0.5 h, the reaction was
quenched by the addition of a 5% aqueous Na2CO3 solution
and the mixture was filtered on a pad of Celite and rinsed
with Et2O. After evaporation of the solvent, the residue
was purified by flash chromatography on silica gel (petro-
leum ether/Et2O; from 100/0 to 90/10) to afford diene 13
5.4. Synthesis of allylglutarimide 15
3-(2-Propenyl)-glutaric acid 2220 (1.81 g, 10.54 mmol) and
urea (0.7 g, 11.59 mmol) were heated at 140 ꢁC. After 2 h,
the temperature was raised to 180 ꢁC for 20 min. Purification
by flash chromatography on silica gel (CHCl3/acetone; 9/1)
furnished allylglutarimide 15 (1.40 g, 9.16 mmol, 87%). IR
(neat) 3188, 3079, 2903, 1717, 1671, 1641, 1428, 1377,

5926
S. Reymond, J. Cossy / Tetrahedron 63 (2007) 5918–5929
1
1288, 1261, 1142, 993 cmꢀ1; H NMR (CDCl3, 400 MHz)
d 8.45 (br s, 1H, NH), 5.70 (ddt, J¼17.1, 10.1, 7.0 Hz,
1H), 5.06–5.14 (m, 2H), 2.65–2.72 (m, 2H), 2.12–2.31 (m,
5H); 13C NMR (CDCl3, 100 MHz) d 172.4 (2C), 133.7,
118.5, 38.8, 37.3 (2C), 30.0. Anal. Calcd for C8H11NO2:
C, 62.73; H, 7.24; N, 9.14. Found: C, 62.84; H, 7.05; N, 9.18.
9H), 0.86–0.91 (m, 12H), 0.79 (d, J¼7.1 Hz, 3H), 0.49 (q,
J¼8.0 Hz, 6H), 0.04 (s, 3H), 0.01 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 142.2, 135.7 (2C), 135.6 (2C), 134.6,
133.4 (2C), 132.1, 129.7 (2C), 127.7 (4C), 113.8, 85.1,
76.8, 74.3, 64.2, 59.2, 42.7, 33.1, 26.9 (3C), 26.2 (3C),
19.2, 18.5, 18.2, 16.7, 14.1, 6.9 (3C), 4.9 (3C), ꢀ3.9,
ꢀ4.6; HRMS (ESI) calcd for C42H72O4KSi [M+K+]
763.4375. Found 763.4383.
5.5. Synthesis of migrastatin (1)
5.5.1. Alcohol 17. To a stirred solution of alcohol 8 (1.18 g,
2.12 mmol) in CH2Cl2 (15 mL) at rt was added MnO2
(5.1 g). After 24 h, the reaction mixture was filtered on
Celite. The solvent was removed in vacuo and aldehyde 16
was used in the next step without further purification.
5.5.3. Vinyl ketone 20. To a stirred solution of olefin 18
(548 mg, 0.76 mmol) in a mixture of t-BuOH (2 mL) and
deionized water (2 mL) at rt was added OsO4 (383 mL,
2.5 wt % in t-BuOH, 0.03 mmol) followed by N-methylmor-
pholine N-oxide (89 mg, 0.76 mmol). After 12 h the reaction
was quenched by addition of Na2S2O3 (800 mg) followed by
addition of Celite (2 g) and EtOAc (5 mL) and the mixture
was stirred for 20 min. The reaction mixture was filtered
on a pad of Celite, the residue was washed with EtOAc,
and the solvents were removed in vacuo.
To a stirred solution of Ti(S,S)-I18 (2.97 mmol) in Et2O
(48 mL) at ꢀ78 ꢁC was added dropwise a solution of the
freshly prepared crude aldehyde 16 in Et2O (15 mL). After
16 h at ꢀ78 ꢁC, water (20 mL) was added to the reaction
mixture. After stirring for 24 h at rt, the reaction mixture
was filtered on Celite and the organic phase was washed
with brine and then dried over MgSO4. After evaporation
of the solvent, the residue was diluted with pentane
(100 mL) and stirred for 2 h. The white precipitate (Taddol)
was filtered and pentane was removed in vacuo. Purification
of the residue by flash chromatography on silica gel (petro-
leum ether/EtOAc; 100/5) furnished alcohol 17 (1.03 g,
1.69 mmol, 80% from 8). [a]2D0 +2.2 (c 0.76, CHCl3); IR
(neat) 2957, 2929, 2857, 1472, 1428, 1361, 1251, 1190,
To a solution of the above crude diol in a mixture of THF
(7 mL) and deionized water (7 mL) at rt was added NaIO4
(729 mg, 3.4 mmol). After 2 h the reaction mixture was fil-
tered on Celite and the residue was washed with EtOAc.
The aqueous layer was extracted with EtOAc and the com-
bined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. After a rapid purifica-
tion by flash chromatography on silica gel (petroleum ether/
Et2O; 9/1) aldehyde 19 (441 g, 0.61 mmol, 80%) was iso-
1110, 1085, 1054, 1026, 1005 cmꢀ1
;
1H NMR (CDCl3,
lated and directly engaged in the following reaction. H
1
400 MHz) d 7.67–7.71 (m, 4H), 7.36–7.45 (m, 6H), 5.59
(ddd, J¼17.1, 10.2, 8.7 Hz, 1H), 5.42 (dd, J¼10.2, 1.2 Hz,
1H), 5.09–5.16 (m, 2H), 4.05 (d, J¼9.4 Hz, 1H), 3.70 (dd,
J¼11.1, 4.6 Hz, 1H), 3.67 (dd, J¼11.0, 5.0 Hz, 1H), 3.52
(dd, J¼6.5, 3.0 Hz, 1H), 3.28 (s, 3H), 3.15 (dt, J¼6.6,
5.0 Hz, 1H), 2.75 (m, 1H), 2.27 (m, 1H), 1.70 (m, 1H,
OH), 1.67 (d, J¼1.0 Hz, 3H), 1.06 (s, 9H), 0.91 (d,
J¼6.6 Hz, 3H), 0.90 (s, 9H), 0.79 (d, J¼6.8 Hz, 3H), 0.05
(s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 141.5, 135.7 (4C), 135.0, 133.5, 133.5, 132.5, 129.8,
129.7, 127.7 (4C), 116.6, 84.7, 76.7, 72.7, 63.5, 58.7, 42.7,
33.3, 26.9 (3C), 26.2 (3C), 19.2, 18.5, 17.8, 16.7, 15.7,
ꢀ3.8, ꢀ4.5; HRMS (ESI) calcd for C36H58O4KSi2
[M+K+] 649.3511. Found 649.3514.
NMR (CDCl3, 400 MHz) d 9.66 (m, 1H), 7.69 (m, 4H),
7.37–7.45 (m, 6H), 5.36 (d, J¼10.4 Hz, 1H), 4.60 (d,
J¼9.2 Hz, 1H), 3.73 (dd, J¼11.0, 4.0 Hz, 1H), 3.65 (dd,
J¼11.0, 5.7 Hz, 1H), 3.47 (d, J¼7.4 Hz, 1H), 3.28 (s, 3H),
3.15 (m, 1H), 2.65 (m, 1H), 2.52 (m, 1H), 1.65 (s, 3H),
1.07 (s, 9H), 0.90 (s, 9H), 0.85–0.90 (m, 12H), 0.79 (d,
J¼7.1 Hz, 3H), 0.51 (q, J¼7.9 Hz, 6H), 0.04 (s, 3H), 0.00
(s, 3H); 13C NMR (CDCl3, 100 MHz) d 205.0, 135.7 (2C),
135.6 (2C), 134.1, 133.3, 132.2, 129.8 (2C), 127.7 (4C),
85.1, 76.7, 71.3, 64.0, 59.0, 50.8, 33.1, 26.9 (3C), 26.2
(3C), 22.6, 19.2, 18.5, 17.6, 14.2, 11.1, 6.8 (3C), 4.8 (3C),
ꢀ3.9, ꢀ4.6.
To a solution of the freshly prepared aldehyde 19 in THF
(8 mL) at ꢀ78 ꢁC was added dropwise vinylmagnesium
chloride (1.14 mL, 1.6 M in THF, 1.82 mmol). After 30 min,
the reaction was quenched by the addition of a saturated
aqueous NH4Cl solution (4.5 mL). The aqueous layer was
extracted with Et2O and the combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced
pressure to yield the corresponding allylic alcohol, which
was used in the next step without further purification.
5.5.2. Olefin 18. To a solution of alcohol 17 (220 mg,
0.36 mmol) in CH2Cl2 (5 mL) at 0 ꢁC, were added imidazole
(98 mg, 1.44 mmol) followed by Et3SiCl (181 mL,
1.08 mmol). After 6 h at rt, water (2 mL) was added to the
reaction mixture. The aqueous layer was extracted with
CH2Cl2 and the combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (petro-
leum ether/Et2O; 100/1) allowed us to isolate olefin 18
(235 mg, 0.33 mmol, 90%). [a]2D0 ꢀ4.9 (c 0.68, CHCl3);
IR (neat) 2955, 2931, 2877, 2857, 1641, 1590, 1461, 1428,
1376, 1248, 1191, 1110, 1056, 1029, 1005 cmꢀ1; 1H NMR
(CDCl3, 400 MHz) d 7.68–7.71 (m, 4H), 7.36–7.45 (m,
6H), 5.77–5.86 (m, 1H), 5.25 (d, J¼10.3 Hz, 1H), 4.91–
4.97 (m, 2H), 4.11 (d, J¼8.0 Hz, 1H), 3.73 (dd, J¼11.2,
4.7 Hz, 1H), 3.61–3.68 (m, 1H), 3.47 (dd, J¼7.4, 2.0 Hz,
1H), 3.29 (s, 3H), 3.15 (m, 1H), 2.58 (m, 1H), 2.23 (app
sext, J¼7.4 Hz, 1H), 1.63 (s, 3H), 1.07 (s, 9H), 0.91 (s,
To a solution of the above alcohol in CH2Cl2 (10 mL) at 0 ꢁC
was added Dess–Martin periodinane (2.5 mL, 15 wt % in
CH2Cl2, 1.21 mmol). After 30 min at rt, the reaction was
quenched by addition of a saturated aqueous Na2S2O3 solu-
tion (8 mL) followed by the addition of a saturated aqueous
NaHCO3 solution (15 mL). The aqueous layer was extracted
with Et2O and the combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (petro-
leum ether/Et2O; from 100/0 to 100/4) yielded vinyl ketone

S. Reymond, J. Cossy / Tetrahedron 63 (2007) 5918–5929
5927
20 (331 mg, 0.44 mmol, 73%). [a]2D0 ꢀ14.1 (c 0.46, CHCl3);
IR (neat) 2930, 2855, 1699, 1678, 1615, 1589, 1456, 1428,
1377, 1365, 1245, 1188, 1131, 1109, 1051, 1017 cmꢀ1; 1H
NMR (CDCl3, 400 MHz) d 7.72–7.74 (m, 4H), 7.40–7.43
(m, 6H), 6.40 (dd, J¼17.2, 10.5 Hz, 1H), 6.23 (dd,
J¼17.4, 1.3 Hz, 1H), 5.73 (dd, J¼10.6, 1.4 Hz, 1H), 5.37
(d, J¼10.6 Hz, 1H), 4.67 (d, J¼9.6 Hz, 1H), 3.78 (dd,
J¼11.0, 4.5 Hz, 1H), 3.67 (dd, J¼11.1, 6.0 Hz, 1H), 3.48
(dd, J¼7.4, 1.5 Hz, 1H), 3.28 (s, 3H), 3.07–3.20 (m, 2H),
2.74 (m, 1H), 1.67 (s, 3H), 1.08 (s, 9H), 0.91 (s, 9H), 0.88
(d, J¼6.6 Hz, 3H), 0.82 (d, J¼6.9 Hz, 3H), 0.82 (t,
J¼7.9 Hz, 9H), 0.45 (q, J¼8.1 Hz, 6H), 0.03 (s, 3H), 0.00
(s, 3H); 13C NMR (CDCl3, 100 MHz) d 203.5, 137.2,
135.8 (2C), 135.7 (2C), 134.1, 133.5, 133.4, 132.5, 129.7
(2C), 127.7 (4C), 127.5, 85.3, 76.9, 72.7, 64.1, 59.1, 46.8,
33.0, 26.9 (3C), 26.2 (3C), 19.2, 18.5, 17.6, 14.2, 14.1, 6.8
(3C), 4.7 (3C), ꢀ3.9, ꢀ4.6; HRMS (ESI): calcd for
C43H72O5Si3Na [M+Na]+: 775.4586. Found: 775.4622.
0.01 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 212.7, 172.3
(2C), 135.8 (2C), 135.7 (2C), 134.4, 133.5, 133.4, 132.1,
129.7 (2C), 127.7 (4C), 85.4, 76.9, 72.9, 64.0, 59.1, 49.5,
44.2, 37.8 (2C), 34.4, 33.0, 30.5, 26.9 (3C), 26.2 (3C),
20.1, 19.2, 18.5, 17.5, 14.1, 13.8, 6.8 (3C), 4.7 (3C), ꢀ3.9,
ꢀ4.6; HRMS (ESI) calcd for C49H81O7NKSi3 [M+K+]
918.4958. Found 918.4968.
5.5.6. Ester 26. Ketone 25 (115 mg, 0.130 mmol) was
stirred in a mixture of acetic acid (3 mL), THF (1 mL),
and water (1 mL) at rt. After 6 h, the reaction was quenched
by addition of Na2CO3. Water was added and the aqueous
phase was extracted with EtOAc and the combined organic
layers were dried over MgSO4, filtered, and concentrated un-
der reduced pressure. Purification by flash chromatography
(hexanes/EtOAc; 7/3) furnished the corresponding alcohol
(80 mg, 0.105 mmol, 80%). [a]2D0 ꢀ5.9 (c 1.42, CHCl3);
IR (neat) 3468, 2956, 2931, 2857, 1700, 1461, 1428, 1377,
1362, 1257, 1112, 1086, 1056, 1026, 1006 cmꢀ1; 1H NMR
(CDCl3, 400 MHz) d 8.19 (br s, 1H, NH), 7.68–7.70 (m,
4H), 7.36–7.44 (m, 6H), 5.43 (d, J¼9.9 Hz, 1H), 4.60 (d,
J¼9.5 Hz, 1H), 3.74 (dd, J¼11.1, 4.8 Hz, 1H), 3.68 (dd,
J¼11.1, 5.6 Hz, 1H), 3.54 (dd, J¼6.4, 3.6 Hz, 1H), 3.26 (s,
3H), 3.16 (app q, J¼5.6 Hz, 1H), 2.67–2.82 (m, 4H), 2.50
(t, J¼7.1 Hz, 2H), 2.21–2.28 (m, 2H), 2.07–2.17 (m, 2H),
1.66 (s, 3H), 1.57–1.64 (m, 2H), 1.32–1.39 (m, 2H), 1.05
(s, 9H), 0.89–0.91 (m, 3H), 0.89 (s, 9H), 0.83 (d,
J¼6.7 Hz, 3H), 0.05 (s, 3H), 0.02 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 213.7, 172.2 (2C), 135.7 (4C), 135.4,
133.5, 133.4, 131.9, 129.7 (2C), 127.7 (4C), 84.6, 76.3,
71.8, 63.3, 58.6, 49.3, 42.2, 37.7 (2C), 34.1, 33.5, 30.4,
26.9 (3C), 26.2 (3C), 20.1, 19.2, 18.5, 17.9, 16.2, 13.7,
ꢀ3.9, ꢀ4.5; HRMS (ESI) calcd for C43H67O7NKSi2
[M+K+] 804.4093. Found 804.4101.
5.5.4. Enone 24. To a stirred solution of vinyl ketone 20
(98 mg, 0.13 mmol) in CH2Cl2 (3 mL) at rt was added allyl-
glutarimide 15 (40 mg, 0.26 mmol) followed by [Ru]-III
(12 mg, 20 mmol). After 36 h, allylglutarimide 15 (20 mg,
0.13 mmol) and [Ru]-III (12 mg, 20 mmol) were added. Af-
ter 36 h, purification by flash chromatography on silica gel
(petroleum ether/EtOAc; from 100/0 to 80/20) yielded the
unreacted vinyl ketone 20 (39 mg, 51.9 mmol, 40%) and
enone 24 (36.5 mg, 41.6 mmol, 32%). [a]2D0 ꢀ6.6 (c 0.35,
CHCl3); IR (neat) 3210, 2931, 2857, 1697, 1627, 1461,
1428, 1370, 1361, 1255, 1191, 1111, 1054 cmꢀ1; 1H NMR
(CDCl3, 400 MHz) d 8.13 (br s, 1H, NH), 7.73 (m, 4H),
7.41 (m, 6H), 6.69 (dt, J¼15.5, 6.4 Hz, 1H), 6.25 (d,
J¼15.8 Hz, 1H), 5.37 (d, J¼10.3 Hz, 1H), 4.54 (d,
J¼9.5 Hz, 1H), 3.78 (dd, J¼11.0, 4.6 Hz, 1H), 3.67 (dd,
J¼11.1, 5.9 Hz, 1H), 3.48 (d, J¼7.4 Hz, 1H), 3.27 (s, 3H),
3.16 (m, 1H), 3.01 (m, 1H), 2.65–2.79 (m, 3H), 2.24–2.38
(m, 5H), 1.66 (s, 3H), 1.07 (s, 9H), 0.90 (s, 9H), 0.88 (d,
J¼7.7 Hz, 3H), 0.78–0.85 (m, 12H), 0.45 (q, J¼8 Hz, 6H),
0.03 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 202.6, 171.5 (2C), 140.1, 135.8 (4C), 134.3, 134.1,
133.6, 133.5, 132.4, 129.7 (2C), 127.8 (4C), 85.4, 76.9,
72.9, 64.1, 59.1, 47.9, 37.5 (2C), 37.4, 33.1, 29.9, 27.0
(3C), 26.2 (3C), 19.2, 18.5, 17.6, 14.3, 14.1, 6.9 (3C), 4.7
(3C), ꢀ3.8, ꢀ4.5; HRMS (ESI): calcd for C49H79O7NSi3Na
[M+Na]+: 900.5062. Found: 900.5040.
To a solution of the above alcohol (70 mg, 91.5 mmol) in tol-
uene (840 mL) at rt was added pyridine (30 mL, 0.37 mmol)
followed by the mixed anhydride (0.275 mmol).13 After stir-
ring for 48 h, the reaction was directly loaded onto a silica
gel column and purification by flash chromatography (petro-
leum ether/EtOAc; 9/1 to 7/3) furnished ester 26 (58.8 mg,
67.4 mmol, 74%). [a]2D0 ꢀ31.7 (c 1.08, CHCl3); IR (neat)
2930, 2857, 1723, 1461, 1428, 1378, 1361, 1258, 1150,
1113, 1086, 1057, 1026 cmꢀ1
;
1H NMR (CDCl3,
400 MHz) d 7.92 (br s, 1H, NH), 7.69–7.72 (m, 4H), 7.35–
7.43 (m, 6H), 6.89 (dt, J¼15.5, 6.4 Hz, 1H), 5.69–5.83 (m,
3H), 5.52 (d, J¼10.5 Hz, 1H), 4.98–5.06 (m, 2H), 3.80
(dd, J¼11.1, 4.2 Hz, 1H), 3.73 (dd, J¼11.1, 5.5 Hz, 1H),
3.56 (dd, J¼6.8, 2.4 Hz, 1H), 3.27 (s, 3H), 3.18 (m, 1H),
2.85–3.00 (m, 2H), 2.64–2.68 (m, 2H), 2.30–2.45 (m, 2H),
2.15–2.30 (m, 6H), 2.01–2.11 (m, 1H), 1.61 (d, J¼0.9 Hz,
3H), 1.52 (m, 2H), 1.20–1.27 (m, 2H), 1.07 (s, 9H), 0.93
(d, J¼6.4 Hz, 3H), 0.89 (s, 9H), 0.87–0.89 (m, 3H), 0.05
(s, 3H), 0.01 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d 210.8, 172.0 (2C), 164.6, 148.9, 137.4, 137.0, 135.7
(4C), 133.7, 133.6, 129.6 (2C), 127.7 (4C), 127.0, 121.3,
115.6, 84.9, 76.0, 73.6, 63.5, 58.7, 47.9, 40.4, 37.7 (2C),
34.1, 33.9, 32.0, 31.5, 30.4, 27.0 (3C), 26.2 (3C), 20.1,
19.3, 18.5, 18.0, 14.6, 13.5, ꢀ3.8, ꢀ4.6; HRMS (ESI): calcd
for C50H75O8NSi2Na [M+Na]+: 896.4929. Found: 896.4888.
5.5.5. Ketone 25. To a stirred solution of enone 24 (78 mg,
88.9 mmol) in EtOAc (2 mL) at rt was added Pd/C 5%
(9.5 mg). H2 was bubbled in the reaction mixture and after
9 h Celite was added. The mixture was filtered on Celite
and the solvent was removed in vacuo to yield ketone 25
(75 mg, 85.3 mmol, 96%). [a]2D0 ꢀ6.6 (c 0.99, CHCl3); IR
(neat) 3213, 2955, 2932, 2878, 2857, 1709, 1461, 1428,
1377, 1256, 1112, 1056, 1026, 1007 cmꢀ1 1H NMR
;
(CDCl3, 400 MHz) d 8.03 (br s, 1H, NH), 7.70–7.73 (m,
4H), 7.38–7.44 (m, 6H), 5.36 (d, J¼10.6 Hz, 1H), 4.60 (d,
J¼9.4 Hz, 1H), 3.77 (dd, J¼11.3, 4.7 Hz, 1H), 3.66 (dd,
J¼11.0, 6.0 Hz, 1H), 3.47 (dd, J¼7.4, 1.5 Hz, 1H), 3.27 (s,
3H), 3.16 (m, 1H), 2.68–2.80 (m, 4H), 2.43–2.58 (m, 2H),
2.21–2.30 (m, 2H), 2.10–2.19 (m, 1H), 1.63 (s, 3H), 1.53–
1.67 (m, 2H), 1.33–1.43 (m, 2H), 1.07 (s, 9H), 0.90 (s,
9H), 0.87 (d, J¼6.5 Hz, 3H), 0.84 (t, J¼8.0 Hz, 9H), 0.76
(d, J¼7.0 Hz, 3H), 0.46 (q, J¼8.0 Hz, 6H), 0.02 (s, 3H),
5.5.7. Alcohol 27. To a solution of ester 26 (50 mg,
57.3 mmol) at rt in MeOH (2.5 mL) was added NH4F

5928
S. Reymond, J. Cossy / Tetrahedron 63 (2007) 5918–5929
(51 mg, 1.37 mmol). After 18 h, more NH4F (13 mg,
0.34 mmol) was added. The reaction mixture was quenched
by addition of a saturated aqueous NaHCO3 solution
(1.5 mL), brine (1.5 mL) followed by EtOAc (6 mL). The
aqueous layer was extracted with EtOAc and the combined
organic layers were dried over MgSO4, filtered, and concen-
trated under reduced pressure. Purification by flash chroma-
tography on silica gel (petroleum ether/EtOAc; 5/5) allowed
us to isolate alcohol 27 (29.3 mg, 46.1 mmol, 81%). IR (neat)
2926, 2854, 1702, 1655, 1460, 1428, 1376, 1363, 1245,
1H), 3.39 (m, 1H), 3.19 (s, 3H), 3.06 (d, J¼8.3 Hz, 1H),
2.84–3.00 (m, 2H), 2.66–2.74 (m, 2H), 2.50 (app t,
J¼7.0 Hz, 2H), 2.38–2.47 (m, 2H), 2.08–2.31 (m, 5H),
1.81 (s, 3H), 1.54–1.66 (m, 2H), 1.31–1.38 (m, 2H), 1.11
(d, J¼7.0 Hz, 3H), 0.90 (s, 9H), 0.90–0.92 (m, 3H), 0.05
(s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 210.8, 171.8 (2C), 163.8, 150.4, 134.0, 130.2, 129.5,
128.8, 121.9, 83.4, 79.3, 76.9, 56.7, 51.2, 40.3, 37.7 (2C),
34.2, 33.5, 31.2, 30.4, 30.3, 26.3 (3C), 25.7, 20.2, 18.7,
13.6, 13.3, ꢀ3.6, ꢀ4.9.
1113, 1054, 1023 cmꢀ1 1H NMR (CDCl3, 400 MHz) d
;
8.12 (br s, 1H, NH), 6.89 (dt, J¼15.6, 6.4 Hz, 1H), 5.86
(d, J¼10.8 Hz, 1H), 5.69–5.81 (m, 3H), 5.52 (d, J¼9.8 Hz,
1H), 4.97–5.04 (m, 2H), 3.90 (dd, J¼12.2, 3.1 Hz, 1H),
3.62–3.78 (m, 2H), 3.37 (s, 3H), 3.11 (m, 1H), 3.04 (m,
1H), 2.93 (m, 1H), 2.65–2.70 (m, 2H), 2.48 (t, J¼6.9 Hz,
2H), 2.04–2.31 (m, 7H), 1.62 (s, 3H), 1.52–1.62 (m, 2H),
1.25–1.34 (m, 2H), 0.97 (d, J¼6.8 Hz, 3H), 0.95 (d,
J¼6.0 Hz, 3H), 0.90 (s, 9H), 0.05 (s, 3H), ꢀ0.01 (s, 3H);
13C NMR (CDCl3, 100 MHz) d 211.6, 172.2 (2C), 165.0,
149.1, 138.2, 137.0, 127.4, 121.3, 115.7, 84.5, 76.0, 73.3,
60.0, 58.0, 48.0, 40.2, 37.8 (2C), 34.1, 33.6, 32.0, 31.5,
30.3, 26.1 (3C), 20.2, 18.5, 17.6, 13.5, 13.4, ꢀ3.8, ꢀ4.6;
HRMS (ESI) calcd for C34H57O8NKSi [M+K+] 674.3491.
Found 674.3496.
5.5.9. Migrastatin (1).4,6c To a solution of macrolactone 29
(3 mg, 5.0 mmol) in THF (250 mL) was added HF$Py
(50 mL). After 24 h at rt, the reaction was quenched by the
addition of Na2CO3. Water was added to the reaction mix-
ture and the aqueous phase was extracted with EtOAc. The
combined organic layers were dried over MgSO4, filtered,
and concentrated under reduced pressure. Purification by
preparative TLC (ethyl acetate/hexane; 2/8) furnished
migrastatin (1.5 mg, 3.1 mmol, 62%).4,6c [a]D25 +11.1
(c 0.05, MeOH); IR (neat) 3472, 3220, 2924, 2854, 1715,
1561, 1455, 1378, 1265, 1193, 1150, 1107, 1031, 1014,
1
982 cmꢀ1; H NMR (CDCl3, 400 MHz) d 7.75 (br s, 1H,
NH), 6.50 (m, 1H), 5.65 (dd, J¼10.4, 1.7 Hz, 1H), 5.59
(dd, J¼16.0, 1.4 Hz, 1H), 5.47–5.56 (m, 1H), 5.24 (dd,
J¼15.5, 5.0 Hz, 1H), 5.09 (d, J¼10.0 Hz, 1H), 3.47 (dd,
J¼9.0, 5.0 Hz, 1H), 3.30 (s, 3H), 3.05 (dd, J¼8.6, 2.0 Hz,
1H), 2.87–3.02 (m, 2H), 2.66–2.74 (m, 2H), 2.50 (app t,
J¼7.0 Hz, 2H), 2.38–2.47 (m, 2H), 2.07–2.30 (m, 5H),
1.86 (d, J¼1.2 Hz, 3H), 1.50–1.70 (m, 2H), 1.30–1.39 (m,
2H), 1.12 (d, J¼7.3 Hz, 3H), 0.96 (d, J¼6.6 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) d 210.9, 171.8 (2C), 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 (2C), 34.3, 32.1, 31.2, 30.5, 30.2,
26.1, 20.3, 13.5 (2C); HRMS (DCI+, NH3): calcd for
C27H43O7N2 [M+NH4]+: 507.3070. Found: 507.3069.
5.5.8. Macrolactone 29.4,6c To a solution of alcohol 27
(15 mg, 23.6 mmol) in CH2Cl2 (4 mL) at 0 ꢁC was added
Dess–Martin periodinane (70 mL, 15 wt % in CH2Cl2,
35.4 mmol). After 1 h at rt, the reaction mixture was
quenched by the addition of a saturated aqueous Na2S2O3 so-
lution followed by addition of a saturated aqueous NaHCO3
solution. The aqueous layer was extracted with CH2Cl2 and
the combined organic layers were dried over MgSO4, fil-
tered, and concentrated under reduced pressure to yield the
corresponding aldehyde, which was used in the next step
without further purification.
References and notes
To an oven-dried tube was added under argon freshly acti-
vated Zn (14 mg, 0.21 mmol) and PbCl2 (0.3 mg, 2 wt %/
Zn) followed by THF (300 mL). CH2I2 (10 mL, 0.12 mmol)
was added slowly and after 30 min, Ti(Oi-Pr)4 (7 mL) was
added dropwise. After 30 min, a solution of the above alde-
hyde in THF (150 mL) was added dropwise at rt. After 1 h,
the reaction was quenched by addition of a 5% aqueous
Na2CO3 solution and the mixture was filtered on Celite and
rinsed with EtOAc. After evaporation of the solvent, the resi-
due was purified by flash chromatography on silica gel (hex-
ane/EtOAc; 2/1) to afford diene 28 (8 mg, 12.7 mmol, 54%
for the two steps) accompanied by a minor impurity. Diene
28 was used in the next step without further purification.
1. (a) Nakae, K.; Yoshimoto, Y.; Sawa, T.; Homma, Y.; Hamada,
M.; Takeuchi, T.; Imoto, M. J. Antibiot. 2000, 53, 1130–1136;
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To a solution of diene 28 (8 mg, 12.7 mmol) in refluxing tol-
uene (30 mL) was added second generation Grubbs catalyst
[Ru]-II (2.5 mg, 2.9 mmol). After stirring for 20 min, the re-
action was cooled to rt and filtered through a pad of silica gel
(hexane/EtOAc; 1/3). The residue was purified by prepara-
tive TLC (hexane/EtOAc; 3/7) to afford macrolactone 29
(3 mg, 5.0 mmol, 39%).4,6c [a]D20 +10.0 (c 0.12, CHCl3); IR
(neat) 2955, 2929, 2856, 1721, 1461, 1377, 1264, 1131,
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11337; (d) Shan, D.; Chen, L.; Njardarson, J. T.; Gaul, C.;
1
1115, 1029 cmꢀ1; H NMR (CDCl3, 400 MHz) d 7.79 (br
s, 1H, NH), 6.52 (m, 1H), 5.52–5.61 (m, 2H), 5.44–5.52
(m, 1H), 5.22 (dd, J¼15.4, 5.3 Hz, 1H), 5.09 (d, J¼9.4 Hz,

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5929
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nucleophile on the Re face of aldehyde 16.
ꢀ
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ꢀ
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11. Phosphonoacetate III can be easily prepared from inexpensive
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according to Ref. 6c.
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€
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