A convergent synthesis of the macrolide core of migrastatin

Article abstract of DOI:10.1016/j.tetlet.2006.06.082

We describe an efficient synthesis of the 14-membered macrolide core 2 of migrastatin via key intermediate 3 employing a diastereoselective aldol condensation, Lewis acid mediated diastereoselective addition and an exclusive (Z)-olefination sequence. Yama

Full text of DOI:10.1016/j.tetlet.2006.06.082

Tetrahedron Letters 47 (2006) 6083–6086
A convergent synthesis of the macrolide core of migrastatinI
V. Sai Baba,a,b Parthasarathi Das,a,* K. Mukkantib and Javed Iqbala,*
aDiscovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
bChemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, AP, India
Received 16 May 2006; revised 9 June 2006; accepted 16 June 2006
Available online 10 July 2006
Abstract—We describe an efficient synthesis of the 14-membered macrolide core 2 of migrastatin via key intermediate 3 employing a
diastereoselective aldol condensation, Lewis acid mediated diastereoselective addition and an exclusive (Z)-olefination sequence.
Yamaguchi esterification of the key intermediate 3 followed by ring-closing metathesis (RCM) produced macrolide 2 with high selec-
tivity and good yield.
Ó 2006 Elsevier Ltd. All rights reserved.
Around half of the drugs currently in clinical use are of
natural product origin.1,2 The synthesis of natural prod-
ucts of therapeutic use, in particular, anticancer agents,
is an important area of research in drug discovery. Re-
search has led to the total synthesis of several antitumor
natural products such as epothilones,3 taxol,4 radicicol5
and TMC-95A/B.6 The recent entry of 16-aza-epothi-
lone B (BMS-247550)7 and 12,13-desoxyepothilone B
(KOS-862)8 in clinical trials has further elicited interest
in this area of research. It is generally observed that in
cancer chemotherapy, cytotoxic molecules inhibit tumor
cell proliferation and cause cell death. Thus, the princi-
ple of targeting cell migration as an alternative strategy
for the development of anticancer therapies has recently
attracted considerable interest.9 Migrastatin 1 (Fig. 1) is
a novel macrolide natural product, isolated from a cul-
tured broth of Streptomyces sp.Mk 929-43F1 by Imoto
and co-workers10 and has the potential for metastasis
suppression through its ability to inhibit tumor cell
migration (IC50 = 29 lM in 4T1 cells).11 The specific
inhibition property of migrastatin in tumor cell migra-
tion renders it an interesting target for medicinal chem-
ists.12 Following their successful total synthesis of
migrastatin,13 Danishefsky and co-workers have synthe-
sized various closely related analogues of migrastatin14
and found that the macrolide core 2 of migrastatin
exhibits a maximum biological activity of IC50 = 22 nM.
The combination of novel structure and promising bio-
logical activity prompted us to explore a general strategy
for the synthesis of this macrolide core and its ana-
logues. We herein report our efforts on the synthesis of
the core of migrastatin from a commercially available
starting material.
The retrosynthetic analysis revealed that the macrolide
core can be assembled using a Yamaguchi esterification
between 3 and 2,6-heptadienoic acid, followed by ring-
closing metathesis (RCM) as earlier reported by Dani-
shefsky and co-workers.13 The key intermediate 3 can
be synthesized from 4 by employing a (Z)-olefination
reaction (Scheme 1). Compound 4 can be achieved by
diastereoselective addition of vinylmagnesium bromide
to aldehyde 6, which in turn can be accessed in a diaste-
reoselective manner in a few steps.
O
O
NH
O
O
14
13
1
O
7
1
OH
OMe
Figure 1. Structures of migrastatin.
As depicted in Scheme 2, our synthesis commenced with
dibutylboron triflate mediated Evans aldol condensation
of (S)-benzyl oxazolidinone and acrolein to furnish
the aldol product 8 in good yield and with excellent
diastereoselectivity.15 Reductive removal of the chiral
q DRL Publication No. 366-C.
*
Corresponding authors. Tel.: +91 40 2304 5439; fax: +91 40
2304 5438 (J.I.); e-mail addresses: parthasarathi@drreddys.com;
Javediqbaldrf@hotmail.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.082

6084
V. Sai Baba et al. / Tetrahedron Letters 47 (2006) 6083–6086
O
MPMO
OTBS
MPMO
OTBS
b
a
HO
O
OMe CH3
OH CH3
13
5
OMPM
OH
OMe
OMe
macrolide
MPMO
O
MPMO
OH
d
key intermediate
c
2
3
OMe CH3
OMe CH3
MPMO
OTBS
MPMO
O
14
4
EtOOC
OMe CH3
OMe CH3
HO
5
4
e
MPMO
O
OTBS
OMPM
OMPM
OMe
OMe
CH3
15
3
6
Scheme 3. Reagents and conditions: (a) MeOTf, 2,6-di-tert-butyl-4-
methyl pyridine, CH2Cl2, reflux, 6 h, 62%; (b) TBAF, THF, rt, 12 h,
94%; (c) DMP, CH2Cl2, rt, 40 min, 85%; (d) (PhO)2P(O)CH(CH3)-
CO2C2H5, DBU/NaI, THF, ꢀ78 °C to 0 °C, 3 h, 60%; (e) DIBAL-H,
CH2Cl2, ꢀ78 °C, 1 h, 96%.
Scheme 1. Retrosynthesis of macrolide 2.
auxiliary by lithium borohydride in THF gave 9, which
on 1,3-diol protection with 4-methoxybenzaldehyde di-
methyl acetal16 afforded the corresponding acetal 10 in
high yield. At this stage, we conceived the selective open-
ing of the acetal to furnish the primary alcohol to be cru-
cial, since this functionality can be transformed to the
aldehyde necessary for the crucial (Z)-olefination at a
later stage. Hence, the acetal 10 was selectively opened
using DIBAL-H16 and the resulting primary alcohol
was protected as its TBS ether to enable selective depro-
tection of this functionality in the presence of MPM
protection at a later stage of the synthesis. With this
intermediate in hand, we pursued the oxidative cleavage
of the terminal olefin which was successfully accom-
fination reaction. Exclusive (Z)-olefination was achieved
by reacting Ando’s phosphonate20 with aldehyde 4 in
the presence of DBU as base. Reduction of the resulting
ethyl ester 15 with DIBAL-H yielded the crucial C7–C13
core fragment 321 possessing the required stereocentres.
With the key intermediate 3 in hand, the primary hydr-
oxyl group was reacted with 2,6-heptadienoic acid follow-
ing the Yamaguchi esterification protocol22 (Scheme 4)
to produce the acylated product 16 in 64% yield. The
versatile ring-closing metathesis23 (RCM) strategy using
Grubbs’ II generation catalyst (20 mol %, 0.5 mM) was
employed on 16 to give 17.24 Finally, deprotection of
the MPM group using DDQ25 gave the desired
(E,E,Z)-trienyl 14-membered macrolide 2.14
17
plished using OsO4–NaIO4 in the presence of 2,6-luti-
dine to afford aldehyde 6 in good yield.
Lewis acid mediated diastereoselective addition of vinyl-
magnesium bromide to aldehyde 6 yielded compound 13
with high diastereoselectivity (dr = 7:1) and good yield
(72%) at rt. However, at this stage due to the close Rf
values we failed to isolate the pure required diastereo-
mer. Later the required diastereomer was separated after
protecting the secondary hydroxyl (Scheme 3) as its
methyl ether using MeOTf.18 Deprotection of the TBS
group in 5 using TBAF followed by the oxidation of
the primary alcohol with Dess–Martin periodinane19
afforded the desired aldehyde 4 required for the (Z)-ole-
In summary, we have developed an efficient synthesis of
the macrolactone core of migrastatin utilizing a diaste-
reoselective aldol condensation, an exclusive (Z)-olefin-
ation reaction followed by Yamaguchi esterification
and ring-closing metathesis (RCM) as key steps. This
flexible approach starting from an inexpensive and com-
mercially available starting material has provided us
with a robust route to generate structural analogues of
PMP
OH
O
O
OH OH
O
O
a
d
b
c
N
CHO
O
O
O
H3C
CH3
Bn
CH3
N
e
O
7
9
10
8
Bn
MPMO
OTBS
MPMO
O
OTBS
MPMO
OTBS
f
g
MPMO
OH
OH CH3
CH3
CH3
CH3
12
11
13
6
Scheme 2. Reagents and conditions: (a) n-Bu2BOTf, i-Pr2NEt, CH2Cl2, ꢀ78 °C to 0 °C, 1 h, 84%; (b) LiBH4, MeOH, THF, 0 °C, 2 h, 96%; (c)
(OMe)2CHC6H4OMe, CSA, CH2Cl2, rt, 12 h, 70%; (d) DIBAL-H, CH2Cl2, ꢀ78 °C to 0 °C, 2 h, 95%; (e) TBDMSCl, imidazole, DMF, rt, 12 h, 88%;
(f) OsO4, NaIO4, 2,6-lutidine, dioxane/H2O (3:1), rt, 3 h, 82%; (g) H2C@CHMgBr, MgBr2ÆOEt2, CH2Cl2, rt, 2 h, 72%.

V. Sai Baba et al. / Tetrahedron Letters 47 (2006) 6083–6086
6085
1280–1284; (d) Yang, Z. Q.; Danishefsky, S. J. J. Am.
Chem. Soc. 2003, 125, 9602–9603.
O
HO
O
6. (a) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001,
40, 512–515; (b) Ma, D.; Wu, Q. Tetrahedron Lett. 2001,
42, 5279–5281; (c) Lin, S.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2002, 41, 512–515; (d) Yang, Z. Q.; Kwok,
B. H.; Lin, S.; Koldobskiy, M. A.; Crews, C. M.;
Danishefsky, S. J. Chembiochem 2003, 6, 508–513; (e)
Inoue, M.; Sakazaki, H.; Furuyama, H.; Hirama, M.
Angew. Chem., Int. Ed. 2003, 42, 2654–2657.
a
b
OMPM
OMPM
OMe
3
OMe
16
O
O
O
O
7. (a) Galsky, M. D.; Small, E. J.; Oh, W. K.; Chen, I.;
Smith, D. C.; Dimitrios Colevas, A.; Martone, L.; Curley,
T.; DeLaCruz, A.; Scher, H. I.; Kelly, W. K. J. Clin.
Oncol. 2005, 23, 1439–1446; (b) Zhuang, S. H.; Agrawal,
M.; Edgerly, M.; Bakke, S.; Kotz, H.; Thambi, P.; Rutt,
A.; Balis, F. M.; Bates, S.; Fojo, T. Cancer 2005, 103,
1932–1938; (c) Annual Meeting of the American Society of
Clinical Oncology (ASCO), Orlando, May 13–17, 2005,
Abstract 2050.
8. (a) Spriggs, D.; Dupont, J.; Pezzulli, S.; Larkin, J.; Cropp,
J.; Johnson, R. Phase 1 dose escalating and pharmacoki-
netic (PK) study of KOS-862 (epothilone D): Phase 2 dose
and schedule defined; AACR-NCI-EORTC International
Conference: Molecular Targets and Cancer Therapeutics,
November 17–21, 2003, Boston, MA, USA. Clin. Cancer
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Abstract 2049.
c
OH
OMPM
OMe
OMe
17
2
macrolide
Scheme 4. Reagents and conditions: (a) 2,6-heptadienoic acid, 2,4,6-
trichlorobenzoyl chloride, i-Pr2NEt, pyridine, toluene, rt, 24 h, 64%;
(b) Grubbs’ II catalyst (20 mol %), toluene (0.5 mM), reflux, 15 min,
50%; (c) DDQ, CH2Cl2/H2O (20:1), rt, 30 min, 73%.
the macrolide for further biological investigation, these
studies are currently underway in our laboratory.
Acknowledgements
9. Fenteany, G.; Zhu, S. Curr. Top. Med. Chem. 2003, 3,
593–616.
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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Imoto, M. J. Antibiot. 2000, 53, 1228–1230.
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20
21. Spectral data for compound 3: ½aꢁD +2.6 (c 1.00, CHCl3);
IR (neat, cmꢀ1) 3420, 2934, 1613, 1514, 1455, 1248; 1H
NMR (CDCl3, 400 MHz) d 7.28 (d, J = 8.6 Hz, 2H), 6.86
(d, J = 8.6 Hz, 2H), 5.89–5.80 (m, 1H), 5.31–5.26 (m, 2H),
5.14 (d, J = 10.2 Hz, 1H), 4.62 (d, J = 11.0 Hz, 1H), 4.51
(d, J = 11.0 Hz, 1H), 4.16 (d, J = 11.8 Hz, 1H), 3.96 (d,

6086
V. Sai Baba et al. / Tetrahedron Letters 47 (2006) 6083–6086
J = 11.5 Hz, 1H), 3.79 (s, 3H), 3.67–3.64 (m, 1H), 3.24 (s,
(CDCl3, 400 MHz) d 7.31 (d, J = 8.6 Hz, 2H), 6.90 (d,
J = 8.6 Hz, 2H), 6.88–6.76 (m, 1H), 5.72 (d, J = 15.8 Hz,
1H), 5.60–5.52 (m, 1H), 5.38 (dd, J = 9.7, 1.3 Hz, 1H),
5.18 (dd, J = 15.4, 8.4 Hz, 1H), 4.90 (d, J = 11.3 Hz, 1H),
4.67 (d, J = 15.8 Hz, 1H), 4.59 (d, J = 15.6 Hz, 1H), 4.52
(d, J = 11.3 Hz, 1H), 3.80 (s, 3H), 3.64 (t, J = 8.3 Hz, 1H),
3.29 (s, 3H), 3.25–3.21 (m, 1H), 3.03–2.99 (m, 1H), 2.46–
2.36 (m, 2H), 2.32–2.19 (m, 2H), 1.59 (s, 3H), 0.86 (d,
J = 7.0 Hz, 3H); 13C NMR (CDCl3, 50 MHz) 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; MS (ESI) 423
[M+Na+]; HRMS calcd for C24H32O5Na [M+Na+]
423.2147, found 423.2131.
3H), 3.18–3.15 (m, 1H), 2.90–2.84 (m, 1H), 1.78 (d, J =
1.3 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3,
50 MHz) 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; MS (ESI) 343 [M+Na+]; HRMS calcd
for C19H28O4Na [M+Na+] 343.1885, found 343.1876.
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20
24. Spectral data for compound 17: ½aꢁD +9.6 (c 1.00, CHCl3);
1
IR (neat, cmꢀ1) 2927, 1726, 1612, 1513, 1247; H NMR