A stereoselective synthesis of the macrolide core of migrastatin

Article abstract of DOI:10.1055/s-2008-1032028

A concise and efficient synthesis of the macrolide core of migrastatin, an antimetastatic agent, is reported. In this synthetic protocol, the key intermediate (4R,5S,6S)-6-methoxy-5-(4-methoxybenzyloxy)-2,4-dimethylocta-2,7- dien-1-ol is obtained after di

Full text of DOI:10.1055/s-2008-1032028

PAPER
445
A Stereoselective Synthesis of the Macrolide Core of Migrastatin1
S
tereoselectiv
a
e
S
ynthesis
r
of the
M
t
acrolid
h
e
Core of
M
a
igrastatin sarathi Das,* Vobbalareddy Saibaba, Chetlur Kiran Kumar, Velisoju Mahendar
Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, India
Fax +91(40)23045438; E-mail: parthasarathi@drreddys.com
Received 11 October 2007
O
Abstract: A concise and efficient synthesis of the macrolide core of
migrastatin, an antimetastatic agent, is reported. In this synthetic
protocol, the key intermediate (4R,5S,6S)-6-methoxy-5-(4-meth-
oxybenzyloxy)-2,4-dimethylocta-2,7-dien-1-ol is obtained after
diastereoselective aldol condensation, Lewis acid mediated diaste-
reoselective addition, and an exclusive Z-olefination sequence have
been employed. Yamaguchi esterification of the key intermediate,
followed by ring-closing metathesis produced the desired macrolide
in high selectivity and good yield.
O
NH
O
O
O
14
O
O
1
13
7
OH
OH
Key words: metastasis, macrolide, Evans aldol condensation, Wit-
tig olefination, ring-closing metathesis
OMe
OMe
migrastatin (1)
macrolide 2
Figure 1 Structure of migrastatin (1) and its macrolide core 2
Metastasis is the multistep process wherein a primary tu-
mor spreads from its initial site to secondary tissues or or-
gans.2,3 Because tumor spreading is responsible for the
majority of deaths of cancer patients, the development of
therapeutic agents that inhibit tumor metastasis is very de-
sirable. Such agents could be effective in restraining new
tumor formation when earlier therapy or surgery has
failed or in increasing the successful containment of solid
tumor in combination therapy with other agents. Thus, the
principle of targeting cell migration as an alternative strat-
egy for the development of anticancer therapies has re-
cently attracted considerable interest.4
The retrosynthetic analysis (Scheme 1) revealed that the
macrolide core could be assembled by use of a Yamagu-
chi esterification between 3 and hepta-2,6-dienoic acid,
followed by ring-closing metathesis (RCM) as earlier re-
ported by Danishefsky and co-workers.9 The key interme-
diate 3 could be synthesized from 4 by a Z-olefination
reaction (Scheme 1). Compound 4 could be obtained by
diastereoselective addition of vinylmagnesium bromide to
aldehyde 6, which, in turn, could be accessed diastereo-
selectively in a few steps.
Migrastatin (1; Figure 1) is a novel macrolide natural
product, which has been isolated from a cultured broth of
Streptomyces sp. Mk 929-43F1 by Imoto and co-workers,5
and has the potential for metastasis suppression through
its ability to inhibit tumor cell migration (IC50 = 29 mM in
4T1 cells).6 The specific inhibition properties of migrasta-
tin in tumor cell migration and its interesting structural
features have resulted in synthesis in the groups of
Danishefsky7 and Cossy.8 Following their successful total
synthesis of migrastatin, Danishefsky and co-workers
have synthesized various closely related analogues of
migrastatin9 and found that the macrolide core 2 of mi-
grastatin (Figure 1) exhibits a maximum biological activ-
ity IC50 of 22 nM.10 The combination of novel structure
and promising biological activity prompted us to explore
a general strategy for the synthesis of this macrolide
core.11 We herein report in detail our efforts in the synthe-
sis of the core of migrastatin from a commercially avail-
able starting material.
O
HO
O
OPMB
OH
O
OMe
OMe
macrolide
2
key intermediate
3
PMBO
OTBS
PMBO
OMe
OMe
5
4
PMBO
OTBS
O
6
Scheme 1 Retrosynthesis of macrolide 2
As depicted in Scheme 2, our synthesis commenced with
an Evans aldol condensation between an (S)-benzylox-
azolidinone and acrolein mediated by dibutylboron tri-
flate to furnish the aldol product 8 in good yield and
SYNTHESIS 2008, No. 3, pp 0445–0451
Advanced online publication: 10.01.2008
DOI: 10.1055/s-2008-1032028; Art ID: P11807SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
8

446
P. Das et al.
PAPER
excellent diastereoselectivity (≥96%), as determined by Therefore, diisobutylaluminum hydride13 was used to se-
1H and 13C NMR spectroscopy.12 Reductive removal of lectively open acetal 10 (Scheme 3), and the resulting pri-
the chiral auxiliary by lithium borohydride in tetrahydro- mary alcohol 13 was protected as its tert-
furan gave 9, which on 1,3-diol protection with 4-meth- butyldimethylsilyl ether to enable selective deprotection
oxybenzaldehyde dimethyl acetal13 afforded the of this functionality in the presence of 4-methoxybenzyl
corresponding acetal 10 in 70% yield (Scheme 2). At this protection at a later stage of the synthesis. With interme-
stage, we converted 10 into the corresponding aldehyde diate 13 in hand, we pursued the oxidative cleavage of the
11 and attempted diastereoselective addition of vinylmag- terminal olefin, which was successfully accomplished
nesium bromide in the presence of a Lewis acid, but this with osmium tetroxide–sodium periodate14 in the pres-
addition resulted in deprotection of the acetal moiety. Ad- ence of 2,6-lutidine, to afford aldehyde 6 in good yield
dition of vinylmagnesium bromide without a Lewis acid (Scheme 3).
to 11 in tetrahydrofuran at 0 °C gave a 1:1 mixture of al-
Aldehyde 6 was stereoselectively converted into second-
lylic alcohol 12 in 45% yield (Scheme 2). Thus, this route
ary alcohol 15 in the presence of vinylmagnesium bro-
failed to give the desired selectivity and good yield.
mide and a Lewis acid (Table 1). The experiments were
carried out with different Lewis acids at various tempera-
OH
O
O
a
b
tures and with different solvents, as depicted in Table 1.
Diastereoselective addition of vinylmagnesium bromide
to aldehyde 6 in tetrahydrofuran in the presence of Lewis
acids at lower temperatures failed to produce any selectiv-
ity (Table 1, entries 1–3). However, addition of vinylmag-
nesium bromide at room temperature in tetrahydrofuran
gave 15 in low diastereoselectivity (70:30) and in 62%
CHO
N
O
O
O
Bn
N
O
7
8
Bn
PMP
O
OH OH
O
c
d
PMP
PMBO
OH
O
O
a
b
9
10
PMP
PMP
O
13
10
O
O
O
e
O
PMBO
OTBS
PMBO
OTBS
c
OH
O
11
12
6
Scheme 2 Reagents and conditions: (a) Bu2BOTf, DIPEA, CH2Cl2,
–78 °C to 0 °C, 1 h, 84%; (b) LiBH4, MeOH, THF, 0 °C, 2 h, 96%;
(c) PMPCH(OMe)2, CSA, CH2Cl2, r.t., 12 h, 70%; (d) OsO4, NaIO4,
2,6-lutidine, dioxane–H2O (3:1), r.t., 2.5 h, 80%; (e) H2C=CHMgBr,
THF, 0 °C to r.t., 1 h, 45%.
14
Scheme 3 Reagents and conditions: (a) DIBAL-H, CH2Cl2, –78 °C
to 0 °C, 2 h, 95%; (b) TBSCl, imidazole, DMF, r.t., 12 h, 88%; (c)
OsO4, NaIO4, 2,6-lutidine, dioxane–H2O (3:1), r.t., 3 h, 82%.
Table 1 Lewis Acid Mediated Addition of Vinylmagnesium Bromide to Aldehyde 6
PMBO
OTBS
PMBO
OTBS
PMBO
OTBS
MgBr
H
+
OH
OH
O
6
epi-15
15
Entry
Lewis acid
Solvent
THF
Temp
Time (h)
Ratioa 15/epi-15
50:50
Yieldb (%)
1
2
3
4
5
6
MgBr2·OEt2
Ti(Oi-Pr)4
BF3·OEt2
–78 °C to r.t.
3
3
3
2
2
2
65
64
56
62
65
72
THF
–78 °C to r.t.
50:50
THF
–78 °C to r.t.
50:50
MgBr2·OEt2
Ti(Oi-Pr)4
MgBr2·OEt2
THF
r.t.
r.t.
r.t.
70:30
CH2Cl2
CH2Cl2
80:20
87:13
a Ratio determined by 1H NMR spectral analysis.
b Isolated yield.
Synthesis 2008, No. 3, 445–451 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of the Macrolide Core of Migrastatin
447
PMBO
OTBS
yield (Table 1, entry 4). For more chelation-controlled
diastereoselective addition of vinylmagnesium bromide to
aldehyde 6, the reaction was performed at room tempera-
ture in dichloromethane in the presence of titanium(IV)
isopropoxide or magnesium bromide–diethyl ether
(Table 1, entries 5 and 6); this resulted in good selectivi-
ty.15 These results suggest that magnesium bromide–
diethyl ether formed a bidentate chelation complex with
the carbonyl group and the alkoxy group (OPMB) of the
a-alkoxy aldehyde, to result in the observed Felkin selec-
tivity via a five-membered ring (Figure 2).
PMBO
OTBS
b
d
a
OMe
OH
15
5
PMBO
O
PMBO
OH
c
OMe
OMe
16
4
EtOOC
HO
e
MgBr2⋅OEt2
HO
O
C
OPMB
TBSO
OPMB
OPMB
OPMB
TBSO
OMe
OMe
17
3
H
H
BrMg
Scheme 4 Reagents and conditions: (a) MeOTf, 2,6-di-tert-butyl-
4-methylpyridine, CH2Cl2, reflux, 6 h, 62%; (b) TBAF, THF, r.t.,
12 h, 94%; (c) DMP, CH2Cl2, r.t., 40 min, 85%; (d)
(PhO)2P(O)CH(Me)CO2Et, DBU, NaI, THF, –78 to 0 °C, 3 h, 60%;
(e) DIBAL-H, CH2Cl2, –78 °C, 1 h, 96%
H
H
6
15
Figure 2 Felkin model for the conversion of aldehyde 6 into alkenol
15
However, at this stage we failed to isolate the pure re-
quired diastereomer 15, due to the close Rf values. Meth-
ylation of the 3-hydroxy group of 15 under classical
conditions (NaH, MeI) resulted in partial intramolecular
rearrangement of the 6-siloxy group to the 3-position. To
overcome this difficulty, methylation was carried out with
methyl triflate16 in the presence of 2,6-di-tert-butyl-4-
methylpyridine; this gave 5 (Scheme 4) which was ob-
tained as a pure diastereomer in 62% yield after purifica-
tion. For the deprotection of the tert-butyldimethylsilyl
group in 5, tetrabutylammonium fluoride was used; sub-
sequent oxidation of primary alcohol 16 with Dess–
Martin periodinane17 afforded the desired aldehyde 4 re-
quired for the Z-olefination reaction (Scheme 4). Exclu-
sive Z-olefination was achieved by reacting Ando’s
phosphonate18 with aldehyde 4 in the presence of 1,8-di-
azabicyclo[5.4.0]undec-7-ene (DBU) as base. Reduction
of the resulting ethyl ester 17 with diisobutylaluminum
hydride yielded the crucial C7–C13 core fragment 3 pos-
sessing the required stereocenters (Scheme 4).
O
HO
O
a
b
OPMB
OPMB
OMe
OMe
18
3
O
O
O
O
c
OH
OPMB
OMe
macrolide 2
OMe
19
Scheme 5 Reagents and conditions: (a) hepta-2,6-dienoic acid,
2,4,6-trichlorobenzoyl chloride, DIPEA, py, toluene, r.t., 24 h, 64%;
(b) Grubbs II cat. (20 mol%), toluene (0.5 mM), reflux, 15 min, 50%;
(c) DDQ, CH2Cl2–H2O (20:1), r.t., 30 min, 73%.
In summary, we have developed an efficient synthesis of
the macrolactone core of migrastatin by utilizing a diaste-
reoselective aldol condensation, an exclusive Z-olefina-
tion reaction followed by Yamaguchi esterification, and
ring-closing metathesis as key steps. This flexible ap-
proach starting from an inexpensive and commercially
available starting material has provided us with a robust
route to generate structural analogues of the macrolide for
further biological investigation. These studies are current-
ly underway in our laboratory and the findings will be
published in due course.
The primary hydroxy group of key intermediate 3 was es-
terified with hepta-2,6-dienoic acid by the Yamaguchi es-
terification protocol19 to produce the acylated product 18
in 64% yield (Scheme 5). The Danishefsky group em-
ployed a ring-closing-metathesis20 strategy on a moiety
similar to 18 in the presence of the Grubbs first-generation
catalyst in refluxing dichloromethane, which exclusively
gave a dimeric product. To avoid obtaining the dimeric
product, we employed the Grubbs second-generation cat-
alyst (20 mol%, 0.5 mM) with 18, and thus obtained 19 in
50% yield as a single olefinic isomer (the desired E-con-
gener) (Scheme 5). Finally, deprotection of the 4-meth-
oxybenzyl group by use of 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone21 gave the desired 14-membered-ring
(E,E,Z)-trienyl macrolactone 2 (Scheme 5).10
Optical rotations were measured on a JASCO DIP-370 digital pola-
rimeter at 20 °C, and concentrations (c) are quoted in g/100 mL. In-
frared spectra were recorded on a Shimadzu IR Prestige 21 FT-IR
Synthesis 2008, No. 3, 445–451 © Thieme Stuttgart · New York

448
P. Das et al.
PAPER
(4S,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxane-4-carb-
spectrometer. H (400 MHz) and 13C (50 MHz) NMR spectra of
samples dissolved in CDCl3 were determined on Varian Mercury
Plus (400 MHz) and Varian Gemini 2000 (200 MHz) spectrome-
1
aldehyde (11)
2,6-Lutidine (1.83 g, 17.09 mmol), 1.0% OsO4 in t-BuOH (56.4 mg,
0.22 mmol), and NaIO4 (7.31 g, 34.19 mmol) were added to a soln
of acetal 10 (2.0 g, 8.55 mmol) in dioxane–H2O (3:1, 60 mL). The
mixture was stirred at r.t. for 2.5 h before the addition of H2O (50
mL) and CH2Cl2 (100 mL). The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were washed with brine (2 × 50 mL), dried
(Na2SO4), and evaporated under vacuum. The residue was purified
by column chromatography (silica gel, EtOAc–hexane, 8:92); this
gave aldehyde 11.
1
ters, respectively. The H NMR chemical shifts (d) are relative to
TMS (d = 0.00 ppm) as internal standard. Melting points were de-
termined on a Büchi B-540 melting point apparatus and are uncor-
rected. ESI-MS spectra were obtained on a Perkin-Elmer API 3000
spectrometer. Column chromatography was carried out on silica
gel, grade 60–120, 100–200 mesh. Reactions were monitored by
TLC on silica gel plates (60 F254); visualization was aided by UV
light or I2 spray. Unless stated otherwise, the reactions were per-
formed under argon atmosphere. THF, Et2O, DMF, CH2Cl2, and tol-
uene were obtained from a dry-solvent system. Et3N, DIPEA, py,
and 2,6-lutidine were distilled from CaH2 immediately prior to use.
All other reagents were purchased from Aldrich at the highest com-
mercial quality and used without further purification.
Yield: 1.6 g (80%); pale yellow oil.
1H NMR (400 MHz, CDCl3): d = 9.68 (s, 1 H), 7.47 (d, J = 8.60 Hz,
2 H), 6.92 (d, J = 8.60 Hz, 2 H), 5.55 (s, 1 H), 4.37 (d, J = 2.69 Hz,
1 H), 4.11–4.05 (m, 2 H), 3.82 (s, 3 H), 2.16–2.09 (m, 1 H), 1.22 (d,
J = 6.98 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 202.21, 160.23, 130.20, 127.45,
113.72, 101.65, 83.50, 73.02, 55.27, 30.41, 11.80.
(2R,3R)-2-Methylpent-4-ene-1,3-diol (9)
A 2 M soln of LiBH4 in THF (24.17 mL, 48.34 mmol) was added
dropwise to a soln of aldol adduct 8 (6.35 g, 21.97 mmol) and anhyd
MeOH (1.95 mL, 48.34 mmol) in anhyd THF (350 mL) at 0 °C. The
mixture was stirred for 2 h at 0 °C and then quenched with 2 M aq
NaOH (70.6 mL). After the mixture had stirred for 18 h at r.t., the
volatiles were removed under vacuum and the resulting slurry was
extracted with Et2O (5 × 150 mL). The combined organic extracts
were dried (Na2SO4) and concentrated under vacuum. The residue
was purified by column chromatography (silica gel, MeOH–CHCl3,
0.5:99.5); this gave 1,3-diol 9.
Yield: 2.45 g (96%); pale green oil; [a]D20 +17.6 (c 3.00, CH2Cl2).
IR (neat): 3375, 2966, 2882, 1743, 1643, 1456, 1425 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.93 (ddd, J = 17.2, 10.5, 5.6 Hz,
1 H), 5.30 (td, J = 17.2, 1.6 Hz, 1 H), 5.21 (td, J = 10.6, 1.5 Hz, 1
H), 4.33–4.31 (m, 1 H), 3.74–3.65 (m, 2 H), 2.38 (br s, 1 H, OH),
2.25 (br s, 1 H, OH), 2.00–1.94 (m, 1 H), 0.89 (d, J = 7.0 Hz, 3 H).
ESI-MS: m/z = 237 [M + H+].
1-[(4S,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-4-
yl]prop-2-en-1-ol (12)
A 1 M soln of H2C=CHMgBr in THF (13.5 mL, 13.56 mmol) was
added slowly by syringe over 15 min to a soln of aldehyde 11 (1.6
g, 6.78 mmol) in THF (30 mL) at 0 °C. The mixture was stirred at
r.t. for 1 h, and then cooled to 0 °C and quenched with aq NH4Cl (20
mL). The mixture was extracted with Et2O (3 × 50 mL), and the
combined organic layers were washed with sat. aq NaHCO3 (2 × 30
mL) and brine (2 × 30 mL), dried (Na2SO4), and concentrated under
vacuum. The residue was purified by column chromatography (sil-
ica gel, EtOAc–hexane, 8:92); this gave alcohol 12.
Yield: 0.8 g (45%); colorless oil.
1H NMR (400 MHz, CDCl3): d (mixture of diastereomers) = 7.44–
7.39 (m, 2 H), 6.92–6.87 (m, 2 H), 6.22–5.75 (m, 1 H), 5.55–5.21
(m, 3 H), 4.22–4.09 (br s, 1 H, OH), 4.07–4.01 (m, 2 H), 3.82–3.71
(m, 5 H), 1.91–1.87 (m, 1 H), 1.29–1.24 (m, 3 H).
13C NMR (50 MHz, CDCl3): d = 138.32, 115.37, 75.15, 65.62,
39.54, 10.99.
ESI-MS: m/z = 116 [M+].
ESI-MS: m/z = 265 [M + H+].
(4R,5R)-2-(4-Methoxyphenyl)-5-methyl-4-vinyl-1,3-dioxane
(10)
(2R,3R)-3-(4-Methoxybenzyloxy)-2-methylpent-4-en-1-ol (13)
DIBAL-H (76 mL, 106.84 mmol) was added to a soln of acetal 10
(5.0 g, 21.37 mmol) in CH2Cl2 (100 mL) at –78 °C. The mixture
was then warmed to 0 °C over 15 min, and was stirred at this tem-
perature for 2 h. The clear colorless soln was then re-cooled to
–78 °C and the excess DIBAL-H was quenched by the dropwise ad-
dition of MeOH (11.0 mL). On warming to 0 °C, the mixture was
diluted with CH2Cl2 (100 mL); the addition of sat. aq sodium potas-
sium tartrate (150 mL) followed, and the mixture was stirred vigor-
ously for 6 h. The layers were separated and the aqueous layer was
extracted with CH2Cl2 (4 × 100 mL). The combined organic layers
were washed with brine (2 × 150 mL), dried (Na2SO4), and concen-
trated under vacuum; this gave a yellow oil. The residue was puri-
fied by column chromatography (silica gel, EtOAc–hexane, 20:80);
this gave alcohol 13.
Yield: 4.75 g (95%); colorless oil; [a]D20 –45.0 (c 1.00, CHCl3).
IR (neat): 3423, 2934, 1612, 1513, 1463, 1247 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.25 (d, J = 8.7 Hz, 2 H), 6.88 (d,
J = 8.7 Hz, 2 H), 5.83 (ddd, J = 17.2, 10.2, 7.5 Hz, 1 H), 5.34 (ddd,
J = 10.2, 1.6, 0.8 Hz, 1 H), 5.28 (ddd, J = 17.2, 1.6, 1.1 Hz, 1 H),
4.56 (d, J = 11.5 Hz, 1 H), 4.27 (d, J = 11.5 Hz, 1 H), 3.89–3.86 (m,
1 H), 3.80 (s, 3 H), 3.68–3.62 (m, 1 H), 3.54–3.49 (m, 1 H), 2.43–
2.41 (m, 1 H, OH), 2.01–1.98 (m, 1 H), 0.88 (d, J = 7.0 Hz, 3 H).
PMPCH(OMe)2 (10.8 mL, 63.53 mmol) and CSA (1.0 g, 4.33
mmol) were added to a soln of diol 9 (6.7 g, 57.76 mmol) in CH2Cl2
(100 mL) at r.t., and the mixture was stirred for another 12 h. Then
the mixture was quenched with sat. aq NaHCO3 (100 mL) and ex-
tracted with CH2Cl2 (3 × 150 mL). The combined organic extracts
were dried (Na2SO4) and concentrated under vacuum. The residue
was purified by column chromatography (silica gel, Et2O–hexane,
3:97); this gave dioxane 10.
20
Yield: 9.5 g (70%); colorless solid; mp 63–65 °C; [a]D +20.3 (c
1.00, CHCl3).
IR (neat): 2966, 2853, 1616, 1518, 1463, 1391, 1303, 1249, 1169
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.45 (d, J = 8.5 Hz, 2 H), 6.89 (d,
J = 8.5 Hz, 2 H), 5.84 (ddd, J = 17.5, 11.0, 5.1 Hz, 1 H), 5.52 (s, 1
H), 5.31 (td, J = 17.5, 1.6 Hz, 1 H), 5.18 (td, J = 10.7, 1.6 Hz, 1 H),
4.51–4.48 (m, 1 H), 4.11 (dd, J = 11.3, 2.4 Hz, 1 H), 4.00 (dd,
J = 11.0, 1.3 Hz, 1 H), 3.79 (s, 3 H), 1.67–1.63 (m, 1 H), 1.17 (d,
J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 159.91, 136.70, 131.35, 127.44,
115.26, 113.55, 101.51, 80.01, 73.23, 55.23, 32.68, 11.37.
ESI-MS: m/z = 235 [M + H+].
ESI-HRMS: m/z calcd for C14H19O3: 235.1334; found: 235.1338.
Synthesis 2008, No. 3, 445–451 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of the Macrolide Core of Migrastatin
449
13C NMR (50 MHz, CDCl3): d = 159.07, 135.88, 130. 28, 129.22,
was purified by column chromatography (silica gel, EtOAc–hex-
ane, 8:92); this gave a diastereomeric mixture of alcohols 15 and
epi-15.
118.42, 113.72, 82.87, 69.93, 65.54, 55.14, 39.49, 11.99.
ESI-MS: m/z = 259 [M + Na+].
Yield: 0.78 g (72%); colorless oil.
IR (neat): 3455, 2955, 2930, 2857, 1613, 1514, 1463 cm–1.
ESI-HRMS: m/z calcd for C14H20O3Na: 259.1310; found: 259.1298.
tert-Butyl[(2R,3R)-3-(4-methoxybenzyloxy)-2-methylpent-4-
enyloxy]dimethylsilane (14)
1H NMR (400 MHz, CDCl3): d = 7.27 (d, J = 8.7 Hz, 2 H), 6.88 (d,
J = 8.7 Hz, 2 H), 5.92–5.85 (m, 1 H, major diastereomer), 5.37–5.32
(m, 1 H), 5.22–5.17 (m, 1 H), 4.61–4.49 (m, 2 H), 4.18–4.14 (m, 1
H, major diastereomer), 3.80 (s, 3 H), 3.63–3.48 (m, 3 H), 2.91 (d,
J = 4.6 Hz, 1 H, OH), 1.95–1.88 (m, 1 H), 0.98–0.85 (m, 12 H), 0.06
(s, 6 H).
TBSCl (2.3 g, 15.2 mmol) and imidazole (1.55 g, 22.88 mmol) were
added to a soln of alcohol 13 (1.8 g, 7.63 mmol) in anhyd DMF (12
mL) at r.t. The mixture was stirred at r.t. for 12 h, after which it was
treated with sat. aq NH4Cl (15 mL) and partitioned between Et2O
(50 mL) and H2O (50 mL). The organic layer was separated, and the
aqueous layer was extracted with Et2O (3 × 50 mL). The combined
organic layers were washed with H2O (2 × 30 mL) and brine (2 × 30
mL), dried (Na2SO4), and concentrated. The residue was purified by
column chromatography (silica gel, EtOAc–hexane, 5:95); this
gave the TBS ether 14.
ESI-MS: m/z = 381 [M + H+].
tert-Butyl[(2R,3S,4S)-4-methoxy-3-(4-methoxybenzyloxy)-2-
methylhex-5-enyloxy]dimethylsilane (5)
2,6-Di-tert-butyl-4-methylpyridine (11.33 g, 55.26 mmol) and
MeOTf (4.53 g, 27.63 mmol) were added sequentially to a soln of
15 (2.1 g, 5.53 mmol) in anhyd CH2Cl2 (45 mL) at r.t. The mixture
was stirred at 40 °C for 6 h. The solvent was evaporated under re-
duced pressure and the resulting residue was purified by column
chromatography (silica gel, Et2O–hexane, 4:96); this gave methoxy
compound 5 as a single diastereomer.
Yield: 2.35 g (88%); colorless oil; [a]D20 –24.5 (c 1.00, CHCl3).
IR (neat): 2955, 2857, 1613, 1514, 1464, 1210 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.25 (d, J = 7.3 Hz, 2 H), 6.87 (d,
J = 7.3 Hz, 2 H), 5.77 (ddd, J = 17.1, 10.5, 7.5 Hz, 1 H), 5.25–5.18
(m, 2 H), 4.52 (d, J = 11.5 Hz, 1 H), 4.25 (d, J = 11.3 Hz, 1 H),
3.81–3.80 (m, 1 H), 3.79 (s, 3 H), 3.60 (dd, J = 9.7, 5.9 Hz, 1 H),
3.44 (dd, J = 9.7, 6.2 Hz, 1 H), 1.76–1.73 (m, 1 H), 0.93 (d, J = 7.0
Hz, 3 H), 0.88 (s, 9 H), 0.02 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 158.94, 137.83, 131.17, 129.13,
117.09, 113.64, 80.85, 70.13, 64.87, 55.23, 40.86, 25.90, 18.25,
12.04, –5.43.
Yield: 1.35 g (62%); colorless oil; [a]D20 –21.7 (c 1.00, CHCl3).
IR (neat): 2928, 2857, 1613, 1514, 1463, 1248, 1085 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.27 (d, J = 8.8 Hz, 2 H), 6.86 (d,
J = 8.8 Hz, 2 H), 5.67 (ddd, J = 11.8, 9.7, 8.06 Hz, 1 H), 5.29–5.24
(m, 2 H), 4.78 (d, J = 11.0 Hz, 1 H), 4.51 (d, J = 11.0 Hz, 1 H), 3.80
(s, 3 H), 3.68 (t, J = 7.5 Hz, 1 H), 3.60 (dd, J = 7.4, 3.0 Hz, 1 H),
3.58–3.50 (m, 1 H), 3.42–3.35 (m, 1 H), 3.31 (s, 3 H), 1.82–1.79 (m,
1 H), 0.88 (s, 9 H), 0.83 (d, J = 7.0 Hz, 3 H), 0.02 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 158.93, 135.55, 131.84, 129.26,
118.25, 113.57, 86.45, 80.82, 74.72, 65.42, 56.46, 55.22, 37.49,
25.91, 18.20, 10.48, –5.38, –5.41.
ESI-MS: m/z = 351 [M + H+].
ESI-HRMS: m/z calcd for C20H35O3Si: 351.2355; found: 351.2362.
(2S,3R)-4-(tert-Butyldimethylsiloxy)-2-(4-methoxybenzyloxy)-
3-methylbutyraldehyde (6)
2,6-Lutidine (1.35 g, 12.57 mmol), 1.0% OsO4 in t-BuOH (41.5 mg,
0.163 mmol), and NaIO4 (5.38 g, 25.14 mmol) were added to a soln
of 14 (2.2 g, 6.28 mmol) in dioxane–H2O (3:1, 60 mL). After the
mixture had stirred at r.t. for 3 h, H2O (50 mL) and CH2Cl2 (100 mL)
were added. The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 100 mL). The combined organic
layers were washed with brine (2 × 50 mL), dried (Na2SO4), and
evaporated under vacuum. The residue was purified by column
chromatography (silica gel, EtOAc–hexane, 6:94); this gave alde-
hyde 6.
ESI-MS: m/z = 395 [M + H+].
ESI-HRMS: m/z calcd for C22H39O4Si: 395.2617; found: 395.2624.
(2R,3S,4S)-4-Methoxy-3-(4-methoxybenzyloxy)-2-methylhex-5-
en-1-ol (16)
A 1.0 M soln of TBAF in THF (4.3 mL, 4.31mmol) was added to a
stirred soln of 5 (0.85 g, 2.16 mmol) in anhyd THF (20 mL) at r.t.
and stirring continued at r.t. for 12 h. H2O (50 mL) was added to the
reaction mixture, the layers were separated, the aqueous layer was
extracted with EtOAc (3 × 50 mL), and the combined organic ex-
tracts were dried (Na2SO4). The solvent was evaporated under re-
duced pressure and the residue was purified by column
chromatography (silica gel, EtOAc–hexane, 20:80); this gave pri-
mary alcohol 16.
Yield: 1.82 g (82%); pale yellow oil.
IR (neat): 2955, 2931, 2858, 1731, 1612, 1514, 1466 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.65 (d, J = 1.9 Hz, 1 H), 7.26 (d,
J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 4.61 (d, J = 11.3 Hz, 1
H), 4.45 (d, J = 11.3 Hz, 1 H), 3.89–3.87 (m, 1 H), 3.80 (s, 3 H),
3.62–3.59 (m, 1 H), 3.54–3.49 (m, 1 H), 2.17–2.13 (m, 1 H), 0.95–
0.85 (m, 12 H), 0.04 (s, 3 H), 0.03 (s, 3 H).
Yield: 0.57 g (94%); colorless oil.
IR (neat): 3442, 2934, 2880, 1613, 1514, 1465 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.27 (d, J = 8.7 Hz, 2 H), 6.88 (d,
J = 8.7 Hz, 2 H), 5.75 (ddd, J = 17.7, 9.9, 7.8 Hz, 1 H), 5.30–5.26
(m, 2 H), 4.72 (d, J = 11.3 Hz, 1 H), 4.56 (d, J = 11.3 Hz, 1 H), 3.80
(s, 3 H), 3.79–3.72 (m, 1 H), 3.60–3.56 (m, 1 H), 3.52–3.45 (m, 2
H), 3.32 (s, 3 H), 1.89–1.83 (m, 1 H), 0.91 (d, J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 159.08, 136.19, 130.84, 129.58,
118.94, 113.64, 85.19, 81.70, 73.76, 65.65, 56.39, 55.12, 37.39,
11.51.
+
ESI-MS: m/z = 370 [M + NH4 ].
(3S,4S,5R)- and (3R,4S,5R)-6-(tert-Butyldimethylsiloxy)-4-(4-
methoxybenzyloxy)-5-methylhex-1-en-3-ol (15 and epi-15)
MgBr2·OEt2 (1.1 g, 4.26 mmol) was added to a stirred soln of 6 (1.0
g, 2.84 mmol) in CH2Cl2 (90 mL) at r.t. and the soln was stirred for
1 h. Then a 1 M soln of H2C=CHMgBr in THF (5.7 mL, 5.68 mmol)
was added slowly by syringe over 15 min to this soln at r.t. After the
mixture had stirred at r.t. for 1 h, it was quenched with sat. aq NH4Cl
(10 mL) and H2O (20 mL). The aqueous layer was separated and ex-
tracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were dried (Na2SO4) and concentrated under vacuum. The residue
ESI-MS: m/z = 303 [M + Na+].
ESI-HRMS: m/z calcd for C16H24O4Na: 303.1572; found: 303.1571.
Synthesis 2008, No. 3, 445–451 © Thieme Stuttgart · New York

450
P. Das et al.
PAPER
(2S,3S,4S)-4-Methoxy-3-(4-methoxybenzyloxy)-2-methylhex-5-
enal (4)
ESI-HRMS: m/z calcd for C19H28O4Na: 343.1885; found: 343.1876.
DMP (1.02 g, 2.4 mmol) was added to a soln of alcohol 16 (0.56 g,
2.0 mmol) in CH2Cl2 (15 mL) at r.t. After stirring for 40 min, the
mixture was treated with sat. aq Na2S2O3 (10 mL) and sat. aq
NaHCO3 (20 mL). The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3 × 100 mL). The combined or-
ganic layers were dried (Na2SO4) and concentrated under reduced
pressure; this gave aldehyde 4 which was used in the next step with-
out any further purification.
(4R,5S,6S)-6-Methoxy-5-(4-methoxybenzyloxy)-2,4-dimethyl-
octa-2,7-dienyl Hepta-2,6-dienoate (18)
To generate the mixed anhydride required for the subsequent acyla-
tion reaction, 2,4,6-trichlorobenzoyl chloride (0.17 mL, 1.09 mmol)
and DIPEA (0.18 mL, 1.03 mmol) were added to a soln of hepta-
2,6-dienoic acid (137 mg, 1.09 mmol) in toluene (2 mL) at r.t., and
the mixture was stirred for 3 h. Pyridine (0.17 mL, 2.11 mmol) and
the thus-generated mixed anhydride were then added to a soln of al-
cohol 3 (225 mg, 0.703 mmol) in toluene (0.6 mL) at r.t. After stir-
ring for 24 h, the mixture was directly loaded onto a silica column
and purified by column chromatography (silica gel, EtOAc–hexane,
4:96); this gave unsaturated ester 18.
Yield: 0.47 g (85%); pale yellow oil.
Ethyl (4R,5S,6S)-6-Methoxy-5-(4-methoxybenzyloxy)-2,4-di-
methylocta-2,7-dienoate (17)
NaI (372 mg, 2.48 mmol) and DBU (309 mg, 2.03 mmol) were add-
ed to a soln of (PhO)2P(O)CH(Me)CO2Et (691 mg, 2.07 mmol) in
THF (5 mL) at 0 °C, and the mixture was stirred for 10 min. It was
then cooled to –78 °C, and a soln of aldehyde 4 (460 mg, 1.65
mmol) in THF (3 mL) was added by syringe. The resulting mixture
was stirred at –78 °C for 30 min and then at 0 °C for 2 h. The mix-
ture was quenched by the addition of sat. aq NH4Cl and extracted
with Et2O (3 × 100 mL). The combined organic extracts were
washed with brine (2 × 30 mL), dried (Na2SO4), and concentrated.
The residue was purified by column chromatography (silica gel,
Et2O–hexane, 3:97); this gave ester 17.
Yield: 0.192 g (64%); colorless oil; [a]D20 –27.9 (c 1.00, CHCl3).
IR (neat): 2976, 2933, 1720, 1655, 1613, 1514 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.27 (d, J = 8.7 Hz, 2 H), 6.99–
6.92 (m, 1 H), 6.86 (d, J = 8.7 Hz, 2 H), 5.86–5.74 (m, 3 H), 5.32–
5.25 (m, 3 H), 5.07–4.98 (m, 2 H), 4.69 (t, J = 11.9 Hz, 2 H), 4.59
(d, J = 12.1 Hz, 1 H), 4.48 (d, J = 11.0 Hz, 1 H), 3.79 (s, 3 H), 3.62–
3.58 (m, 1 H), 3.24 (s, 3 H), 3.18 (dd, J = 6.1, 4.9 Hz, 1 H), 2.87–
2.81 (m, 1 H), 2.33–2.27 (m, 2 H), 2.24–2.20 (m, 2 H), 1.72 (d,
J = 1.3 Hz, 3 H), 0.98 (d, J = 6.7 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 166.48, 159.05, 148.41, 136.99,
136.07, 133.78, 131.02, 129.55, 129.30, 121.49, 118.17, 115.49,
113.55, 85.33, 84.70, 74.67, 63.05, 56.52, 55.20, 34.22, 31.98,
31.43, 21.50, 16.28.
Yield: 0.36 g (60%); colorless oil; [a]D20 –66.2 (c 1.00, CHCl3).
IR (neat): 2979, 2935, 1712, 1613, 1514, 1218 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.27 (d, J = 7.3 Hz, 2 H), 6.86 (d,
J = 7.3 Hz, 2 H), 5.84 (dd, J = 2.6, 1.1 Hz, 1 H), 5.82–5.70 (m, 1 H),
5.28 (s, 1 H), 5.26–5.24 (m, 1 H), 4.72 (d, J = 11.3 Hz, 1 H), 4.47
(d, J = 11.3 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 3.79 (s, 3 H), 3.64–
3.61 (m, 1 H), 3.38–3.28 (m, 2 H), 3.27 (s, 3 H), 1.83 (d, J = 1.5 Hz,
3 H), 1.29–1.25 (m, 3 H), 0.98 (d, J = 6.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 167.97, 159.03, 145.08, 135.49,
131.21, 129.56, 125.99, 118.29, 113.57, 85.87, 84.24, 74.58, 60.04,
56.48, 55.20, 34.97, 20.77, 14.44, 14.23.
ESI-MS: m/z = 451 [M + Na+].
ESI-HRMS: m/z calcd for C26H36O5Na: 451.2460; found: 451.2450.
(9S,10S,11R)-9-Methoxy-10-(4-methoxybenzyloxy)-11,13-di-
methyloxacyclotetradeca-3,7,12-trien-2-one (19)
The Grubbs II catalyst (14.3 mg, 0.0168 mmol) was added to a soln
of unsaturated ester 18 (36 mg, 0.084 mmol) in refluxing toluene
(125 mL). After stirring for 15 min, the mixture was cooled to r.t.
and filtered through a silica plug (EtOAc–hexane, 25:75). The resi-
due was purified by column chromatography (silica gel, EtOAc–
hexane, 5:95); this gave PMB-protected macrolide 19.
Yield: 0.017 g (50%); colorless oil; [a]D20 +9.6 (c 1.00, CHCl3).
IR (neat): 2927, 1726, 1612, 1513, 1247 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.31 (d, J = 8.6 Hz, 2 H), 6.90 (d,
J = 8.6 Hz, 2 H), 6.88–6.76 (m, 1 H), 5.72 (d, J = 15.8 Hz, 1 H),
5.60–5.52 (m, 1 H), 5.38 (dd, J = 9.7, 1.3 Hz, 1 H), 5.18 (dd,
J = 15.4, 8.4 Hz, 1 H), 4.90 (d, J = 11.3 Hz, 1 H), 4.67 (d, J = 15.8
Hz, 1 H), 4.59 (d, J = 15.6 Hz, 1 H), 4.52 (d, J = 11.3 Hz, 1 H), 3.80
(s, 3 H), 3.64 (t, J = 8.3 Hz, 1 H), 3.29 (s, 3 H), 3.25–3.21 (m, 1 H),
3.03–2.99 (m, 1 H), 2.46–2.36 (m, 2 H), 2.32–2.19 (m, 2 H), 1.59
(s, 3 H), 0.86 (d, J = 7.0 Hz, 3 H).
ESI-MS: m/z = 385 [M + Na+].
ESI-HRMS: m/z calcd for C21H30O5Na: 385.1990; found: 385.1987.
(4R,5S,6S)-6-Methoxy-5-(4-methoxybenzyloxy)-2,4-dimethyl-
octa-2,7-dien-1-ol (3)
A 1 M soln of DIBAL-H in toluene (2.27 mL, 3.19 mmol) was add-
ed to a stirred soln of ester 17 (330 mg, 0.91 mmol) in CH2Cl2 (20
mL) at –78 °C. After stirring at –78 °C for 1 h, the mixture was
quenched with EtOAc (3.0 mL), and the addition of sat. aq potassi-
um sodium tartrate (3.0 mL) followed. The mixture was then
warmed to r.t. and stirred vigorously for 2 h. It was then extracted
with EtOAc (3 × 50 mL), and the combined organic extracts were
washed with brine (20 mL), dried (Na2SO4), and concentrated. The
residue was purified by column chromatography (silica gel,
EtOAc–hexane, 20:80); this gave alcohol 3.
13C NMR (50 MHz, CDCl3): d = 165.34, 158.95, 149.77, 131.86,
130.50, 130.06, 129.33, 126.97, 121.92, 113.61, 86.59, 84.25,
75.36, 65.48, 56.42, 55.26, 32.61, 32.34, 30.00, 29.67, 22.34, 13.51.
Yield: 0.28 g (96%); colorless oil; [a]D20 +2.6 (c 1.00, CHCl3).
IR (neat): 3420, 2934, 1613, 1514, 1455, 1248 cm–1.
ESI-MS: m/z = 423 [M + Na+].
1H NMR (400 MHz, CDCl3): d = 7.28 (d, J = 8.6 Hz, 2 H), 6.86 (d,
J = 8.6 Hz, 2 H), 5.89–5.80 (m, 1 H), 5.31–5.26 (m, 2 H), 5.14 (d,
J = 10.2 Hz, 1 H), 4.62 (d, J = 11.0 Hz, 1 H), 4.51 (d, J = 11.0 Hz,
1 H), 4.16 (d, J = 11.8 Hz, 1 H), 3.96 (d, J = 11.5 Hz, 1 H), 3.79 (s,
3 H), 3.67–3.64 (m, 1 H), 3.24 (s, 3 H), 3.18–3.15 (m, 1 H), 2.90–
2.84 (m, 1 H), 1.78 (d, J = 1.3 Hz, 3 H), 0.99 (d, J = 6.7 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 159.10, 136.02, 134.43, 131.05,
130.71, 129.60, 118.30, 113.58, 85.64, 84.12, 74.68, 61.70, 56.24,
55.17, 34.32, 21.76, 17.30.
ESI-HRMS: m/z calcd for C24H32O5Na: 423.2147; found: 423.2131.
(9S,10S,11R)-10-Hydroxy-9-methoxy-11,13-dimethyloxacyclo-
tetradeca-3,7,12-trien-2-one (2)
DDQ (25 mg, 0.11 mmol) was added to a stirred soln of PMB-pro-
tected macrolide 19 (40 mg, 0.1 mmol) in CH2Cl2–H2O (20:1, 5.25
mL), and the mixture was stirred at r.t. for 30 min. It was then dilut-
ed with CH2Cl2 (20 mL), and the layers were separated. The organic
layer was washed with sat. aq NaHCO3 (2 × 10 mL) and brine (10
mL), dried (Na2SO4), filtered, and concentrated. The residue was
ESI-MS: m/z = 343 [M + Na+].
Synthesis 2008, No. 3, 445–451 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of the Macrolide Core of Migrastatin
451
purified by column chromatography (silica gel, EtOAc–hexane,
(8) (a) Reymond, S.; Cossy, J. Eur. J. Org. Chem. 2006, 4800.
10:90); this gave macrolide 2.
Yield: 20.5 mg (73%); colorless oil; [a]D20 +115.2 (c 0.5, CHCl3).
IR (neat): 3502, 2928, 2855, 1725, 1646, 1447, 1380 cm–1.
(b) Reymond, S.; Cossy, J. Tetrahedron 2007, 63, 5918.
(9) (a) Njardarson, J. T.; Gaul, C.; Shan, D.; Huang, X.-Y.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 1038.
(b) Gaul, C.; Njardarson, J. T.; Shan, D.; Dorn, D. C.; Wu,
K.-D.; Tong, W. P.; Huang, X.-Y.; Moore, M. A. S.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 11326.
(10) Shan, D.; Chen, L.; Njardarson, J. T.; Gaul, C.; Ma, X.;
Danishefsky, S. J.; Huang, X.-Y. Proc. Natl. Acad. Sci.
U.S.A. 2005, 102, 3772.
1H NMR (400 MHz, CDCl3): d = 6.82–6.74 (m, 1 H), 5.72 (d,
J = 15.8 Hz, 1 H), 5.63–5.54 (m, 2 H), 5.15 (dd, J = 14.8, 6.4 Hz, 1
H), 4.72 (d, J = 15.6 Hz, 1 H), 4.63 (d, J = 15.6 Hz, 1 H), 3.46–3.40
(m, 2 H), 3.28 (s, 3 H), 3.04–2.97 (m, 1 H), 2.69 (br s, 1 H, OH),
2.46–2.40 (m, 2 H), 2.36–2.19 (m, 2 H), 1.68 (s, 3 H), 0.88 (d,
J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 165.34, 149.50, 133.80, 129.80,
129.50, 127.44, 122.13, 84.62, 76.07, 65.38, 56.21, 32.18, 31.33,
29.95, 22.25, 12.63.
(11) Baba, V. S.; Das, P.; Mukkanti, K.; Iqbal, J. Tetrahedron
Lett. 2006, 47, 6083.
(12) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc.
1992, 114, 9434.
(13) Anderson, J. C.; McDermott, B. P.; Griffin, E. J.
Tetrahedron 2000, 56, 8747.
ESI-MS: m/z = 303 [M + Na+].
(14) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004,
6, 3217.
ESI-HRMS: m/z calcd for C16H24O4Na: 303.1572; found: 303.1574.
(15) Keck, G. E.; Andrus, M. B.; Romer, D. R. J. Org. Chem.
1991, 56, 417.
Acknowledgment
(16) Smith, N. D.; Kocienski, P. J.; Street, S. D. A. Synthesis
1996, 652.
(17) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(18) (a) Ando, K. J. Synth. Org. Chem. Jpn. 2000, 58, 869.
(b) Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J.
Org. Chem. 2000, 65, 4745.
(19) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989. Fora
recent example, see: (b) Song, F.; Fidanze, S.; Benowitz, A.
B.; Kishi, Y. Org. Lett. 2002, 4, 647.
(20) (a) Yamamoto, K.; Biswas, K.; Gaul, C.; Danishefsky, S. J.
Tetrahedron Lett. 2003, 44, 3297. (b) Grubbs, R. H.
Handbook of Metathesis; Wiley-VCH: Weinheim, 2003.
(c) Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J.
L. J. Am. Chem. Soc. 2006, 128, 2796.
We thank Dr. Reddy’s Laboratories Ltd. for financial support and
encouragement. Help from the analytical department in recording
spectral data is appreciated.
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Synthesis 2008, No. 3, 445–451 © Thieme Stuttgart · New York