Stereoselective synthesis of analogs of the macrolactone of isomigrastatin

Article abstract of DOI:10.1016/j.tetlet.2011.12.020

An approach for the highly stereoselective synthesis of analogs of the macrolactone of isomigrastatin is described. Our optimized strategy is based on a very efficient lactone opening, a Wittig olefination reaction and a ring closing metathesis. The synth

Full text of DOI:10.1016/j.tetlet.2011.12.020

Tetrahedron Letters 53 (2012) 707–709
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of analogs of the macrolactone of isomigrastatin
⇑
Luiz C. Dias , Gustavo C. Monteiro, Giovanni W. Amarante, Leila S. Conegero, Fernanda G. Finelli
University of Campinas, Institute of Chemistry, Organic Chemistry Department, PO Box 6154, 13083-970 Campinas, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
An approach for the highly stereoselective synthesis of analogs of the macrolactone of isomigrastatin is
described. Our optimized strategy is based on a very efficient lactone opening, a Wittig olefination reac-
tion and a ring closing metathesis. The syntheses were accomplished in 10–11 steps and good overall
yields.
Received 11 November 2011
Revised 5 December 2011
Accepted 5 December 2011
Available online 9 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Migrastatin
Macrolactone
Tumor metastasis
Ring closing metathesis
Dihydroxilation reaction
Isomigrastatin (1) was first isolated in 2002 from cultures of
Streptomyces platensis (strain NRRL 18993) by Kosan Biosciences
researchers (Fig. 1).1 This natural product belongs to the glutari-
mide polyketide family and it is a precursor of migrastatin (2) in
its biosynthetic pathway.2 Isomigrastatin can also undergo a con-
certed [3,3]-sigmatropic rearrangement under neat heating to pro-
duce migrastatin regio- and enantiospecifically.3
Due to an attractive inhibitory effect on the migration of human
tumor cells, migrastatin has been considered an interesting lead
compound and a synthetic target for many researchers since 2000,
when it was first isolated.4
co-workers9 identified potent analogs that target the actin-bun-
dling protein fascin, which is over-expressed in many types of met-
astatic tumors and whose elevated expression has been associated
with the aggressiveness of tumors.
Recently, our group developed a straightforward approach for
the synthesis of the macrolactone of migrastatin (3) and a new mac-
rolactone analog 4, which exhibited one of the highest biological
activities among the migrastatin related compounds. The macrolac-
tone 4 is a saturated version of the macrolactone of migrastatin (3)
and epimeric at C8 (Fig. 1).10
In 2003, the Danishefsky’s group reported the first total synthe-
sis of migrastatin, moreover, they also described the synthesis of
the macrolactone of migrastatin (3) and found that this macrolide
has a biological activity 103 times higher than the natural product.5
In 2007, the same group completed the first total synthesis of
isomigrastatin.6 Recently, they described two new ether-derivative
analogs of migrastatin with high inhibition of tumor cell migration
and metastasis in lung cancer.7
In 2009, Shen and co-workers investigated the effect of
isomigrastatin on the migration of 4T1 mouse mammary tumor
and MDA-MB-231 cells and found IC50 values of 23 nm and 32 nm,
respectively.8 They also cloned the isomigrastatin biosynthetic gene
cluster from S. platensis and developed an artificial chromosome to
produce a larger scale of this natural product in five-selected
Streptomyces heterologous hosts.8
O
R
R1
Me
O
O
O
Me
Me
OH
Me
OH
OMe
OMe
R = R1 Migrastatin ( )
R = H Macrolactone of migrastatin (3)
2
1
Isomigrastatin ( )
O
Me
Me
O
Me
O
NH
R1
=
O
OH
In order to understand the molecular basis by which migrasta-
tin related compounds inhibit tumor metastasis, Chen and
O
OMe
Macrolactone analogue
4
Figure 1. Isomigrastatin (1) and related compounds 2–4.
⇑
Corresponding author.
E-mail address: ldias@iqm.unicamp.br (L.C. Dias).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.020

708
L. C. Dias et al. / Tetrahedron Letters 53 (2012) 707–709
O
O
O
O
O
OH Me
Me
a
b
OTBS
OMe
a
OH
O
PMBO
c, d
OH
b
8
Me
Me
7
11
OTBS
6
TBSO
OMe
5
OPMB
12
15
OMe Me
OTBS
OH Me
O
O
O
O
HO
OTBS
OH
PMBO
e, f
OTBS
OMe
OMe
OMe
OMe
8
7
OTBS
Me
Me
c
OMe Me
OMe Me
g
16
17
OTBS
9
Scheme 3. Preparation of macrolactone (17). Reagents and conditions: (a) HF/Py
soln, THF, 0 °C to rt, 24 h, quench with MeOTMS, 67%; (b) proton sponge, Me3OBF4,
CH2Cl2, rt, 12 h, 78%; (c) 20 mol % Grubbs catalyst II, toluene, reflux, 5 min, 51%.
OTBS
10
OTBS
Scheme 1. Preparation of alcohol (10). (a) NaBH4, THF/H2O, rt, 2 h, 89%; (b) TBSCl,
imidazole, CH2Cl2, 0 °C, 1 h, 93%; (c) proton sponge, Me3OBF4, CH2Cl2, rt, 12 h; (d)
DDQ/H2O, CH2Cl2, rt, 2 h, 79% yield for two steps; (e) NMO, TPAP cat., CH2Cl2, rt, 1 h;
(f) PPh3CH3Br, n-BuLi, THF, À78 °C, 1 h, 83% (two steps); (g) HF-Py-THF, THF, 0 °C to
rt, 12 h, 72%.
Treatment of alcohol 10 with 6-heptenoic acid 11, DCC, and
DMAP in CH2Cl2 gave the corresponding ester 12 in an 87% yield
(Scheme 2). The alkene ring closing metathesis was performed by
using 20 mol % of the second generation Grubbs catalyst in reflux-
ing toluene for 5 min.12 Lactone 13 was then isolated in a 90% yield.
To conclude the synthesis, the TBS protecting group was removed in
the presence of HF/Py solution, followed by quenching with MeO-
TMS, leading to the desired macrolactone 14 in a 76% yield (Scheme
2).10 It should be mentioned that the use of MeOTMS is essential as
it led to better yields, in a very clean reaction, amenable to scale-up.
The macrolactone 14 as well as the new intermediates were fully
characterized by conventional spectrometric analysis.
In addition, we have prepared another isomigrastatin macrolac-
tone analog, by the sequence described in Scheme 3. Removal of
the TBS protecting group in 12 with HF/Py solution followed by
quenching with MeOTMS provided ester 15 in a 67% yield (Scheme
3). Methylation of the secondary alcohol functionality in 15 in the
presence of proton sponge and Me3OBF4 in CH2Cl2 afforded ester
16 in a 78% yield. Alkene ring closing metathesis of 16 by using
20 mol % of the second generation Grubbs catalyst in refluxing tol-
uene for 5 min provided lactone 17 in a 51% yield.
Regarding the biological importance of the macrolactone 4 and
taking into consideration that isomigrastatin analogs have not yet
been explored, we decided to extend and optimize our strategy to
the syntheses of analogs of the macrolactone of isomigrastatin.
Our studies began with the opening of the previously described
lactone 5 (Scheme 1).10 The lactone opening was carried out in the
presence of NaBH4 at room temperature, a milder alternative than
our previous condition using LiAlH4, providing diol 6 in an 89%
yield (Scheme 1).10 This condition has a lot of advantages, such
as it provides alcohol 6 in higher yields, uses cheaper NaBH4 in-
stead of the pyroforic LiAlH4, and is easier to scale-up.10
Selective protection of the primary hydroxyl group of 6 with
TBSCl/imidazole gave alcohol 7 in a 93% yield (Scheme 1). Methyl-
ation of the secondary alcohol 7 in the presence of proton sponge
and Me3OBF4, followed by removal of the PMB group using DDQ/
H2O provided alcohol 8 in a 79% overall yield for two steps. We
were able to get better yields for this sequence, as compared to
the previously described results, probably due to the quality of
the Me3OBF4 reagent.10 Oxidation of the primary alcohol 8 with
NMO and catalytic amounts of TPAP gave the corresponding alde-
hyde, which was used in the Wittig olefination. This reaction was
shown to be cleaner, faster and more effective than the Petasis
and Bzowej reaction reported in our first synthetic approach.10
The olefin 9 was then obtained in an 83% overall yield for the
two step sequence. Selective deprotection of the silyl group in
the presence of HF-Py-THF gave the primary alcohol 10 in a 72%
yield (Scheme 1).11
In summary, two new analogs of the macrolactone of isomigr-
astatin were synthesized. The strategy was based on an efficient
lactone opening with NaBH4, a high yielding Wittig olefination
and a ring closing metathesis. Moreover, the strategy allows the
synthesis of a diversity of analogs with different substituents and
stereochemistries and also a scale-up without problems. The anti-
tumoral activity studies of the final products are ongoing and will
be reported in due course.
Acknowledgments
We are grateful to FAEP-UNICAMP, FAPESP, CNPq, and INCT-
INOFAR (Proc. CNPq 573.564/2008-6) for the financial support
and to Professor Carol H. Collins (IQ-UNICAMP) for helpful sugges-
tions about English grammar and style. We also thank Marco Antô-
nio Barbosa Ferreira for optimizing the conditions for the reduction
of lactone 5 to diol 6.
OMe Me
OH
10
O
O
OTBS
+
OTBS
OMe
a
Me
OH
11
O
12
Supplementary data
O
O
O
O
Supplementary data (Product characterization as well as copies
of NMR spectra for the prepared compounds.) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.12.020.
b
c
OH
OMe
OTBS
OMe
Me
Me
14
13
References and notes
Scheme 2. Preparation of macrolactone (14). Reagents and conditions: (a) DCC,
DMAP, CH2Cl2, rt, 12 h, 87%; (b) 20 mol % Grubbs catalyst II, toluene, reflux, 5 min,
90%; (c) HF/Py soln, THF, 0 °C to rt, 24 h, quench with MeOTMS, 76%.
1. Woo, E. J.; Starks, C. M.; Carney, J. R.; Arslanian, R.; Cadapan, L.; Zavala, S.; Licari,
P. J. Antibiot. 2002, 55, 141.

L. C. Dias et al. / Tetrahedron Letters 53 (2012) 707–709
709
2. Ju, J.; Lim, S.-K.; Jiang, H.; Shen, B. J. Am. Chem. Soc. 2005, 127, 1622.
3. Ju, J.; Lim, S.-K.; Jiang, H.; Seo, J.-W.; Her, Y.; Shen, B. Org. Lett. 2006, 8, 5865.
4. Nakae, K.; Yoshimoto, Y.; Sawa, T.; Homma, Y.; Hamada, M.; Takeuchi, T.;
Imoto, M. J. Antibiot. 2000, 53, 1130.
5. (a) Gaul, C.; Danishefsky, S. J. Tetrahedron Lett. 2002, 43, 9039; (b) Gaul, C.;
Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042; (c) Gaul, C.;
Njardarson, J. T.; Shan, D.; Dorn, D. C.; Wu, K.; Tong, W. P.; Huang, X.; Moore, M.
A. S.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 11326.
6. Krauss, I. J.; Mandal, M.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2007, 46, 5576.
7. Lecomte, N.; Njardarson, J. T.; Nagorny, P.; Yang, G.; Downey, R.; Ouerfelli, O.;
Moore, M. A. S.; Danishefsky, S. J. PNAS 2011, 108, 15074.
8. (a) Ju, J.; Rajski, S. R.; Lim, S.-K.; Seo, J.-W.; Peters, N. R.; Hoffmann, M.; Shen, B.
J. Am. Chem. Soc. 2009, 131, 1370; (b) Yang, D.; Zhu, X.; Wu, X.; Feng, Z.; Huang,
L.; Shen, B.; Xu, Z. Appl. Microbiol. Biotechnol. 2011, 89, 1709.
10. Dias, L. C.; Finelli, F. G.; Conegero, L. S.; Krogh, R.; Andricopulo, A. D. Eur. J. Org.
Chem. 2010, 6748.
11. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127; (b)
Evans, D. A.; Taber, T. R. Tetrahedron Lett. 1980, 21, 4675; (c) Crimmins, M. T.;
She, J. Synlett 2004, 1371; (d) Crimmins, M. T.; King, B. W.; Tabet, E. A.;
Chaudhary, K. J. Org. Chem. 2001, 66, 894; (e) Dias, L. C.; de Oliveira, L. G.; de
Sousa, M. A. Org. Lett. 2003, 5, 265; (f) Dias, L. C.; Meira, P. R. R. Tetrahedron Lett.
2002, 43, 185; (g) Dias, L. C.; de Oliveira, L. G.; Vilcachagua, J. D.; Nigsch, F. J.
Org. Chem. 2005, 70, 2225; (h) Dias, L. C.; de Oliveira, L. G. Org. Lett. 2001, 3,
3951; (i) Dias, L. C.; de Oliveira, L. G. Org. Lett. 2004, 6, 2587; (j) Dias, L. C.;
Meira, P. R. R.; Ferreira, E. Org. Lett. 1999, 1, 1335; (k) Dias, L. C.; de Castro, I. B.
D.; Steil, L. J.; Augusto, T. Tetrahedron Lett. 2006, 47, 213.
12. (a) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004, 126, 7414; (b)
Chatterjee, A. K.; Choi, T.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360.
9. Chen, L.; Yang, S.; Jakoncic, J.; Zhang, J. J.; Huang, X.-Y. Nature 2010, 464, 1062.