Stereoselective formal synthesis of macrolidecore of migrastatin using late stage C-H oxidation

Article abstract of DOI:10.1016/j.tetlet.2013.05.137

An efficient synthesis of macrolide core of migrastatin is described here by following a novel approach of Pd(II)-catalyzed late stage intramolecular C-H oxidation.

Full text of DOI:10.1016/j.tetlet.2013.05.137

Tetrahedron Letters 54 (2013) 4225–4227
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Stereoselective formal synthesis of macrolidecore of migrastatin
using late stage C–H oxidation
⇑
Narendar Reddy Gade, Javed Iqbal
Department of Organic and Medicinal Chemistry, Dr. Reddy’s Institute of Life Sciences, Hyderabad Central University Campus, Gachibowli, Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of macrolide core of migrastatin is described here by following a novel approach of
Pd(II)-catalyzed late stage intramolecular C–H oxidation.
Received 25 February 2013
Revised 27 May 2013
Accepted 29 May 2013
Available online 7 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Macrolide
Migrastatin
Palladium
C–H oxidation
Over the last decade, our group has been engaged in the synthe-
sis of macrocylic natural products as potential anti-cancer agents1
and currently we are working on the synthesis of the macrolide
core of migrastatin. Migrastatin 1 (Fig. 1) is a novel macrolide nat-
ural product, isolated from a cultured broth of Streptomyces sp.
Mk929-43F1 by Imoto and co-workers2 and it has been demon-
strated to have the potential for metastasis suppression.3 Follow-
ing their successful initial total synthesis of migrastatin,4
Danishefsky and co-workers have synthesized various closely re-
lated analogues of migrastatin5–7 and found that they inhibit can-
cer cell migration even at low concentrations. The presence of
novel cyclic structure and promising biological activity associated
with migrastatin prompted us to explore a novel strategy for the
synthesis of its macrolide core1b,8 2 (Fig. 1).
O
O
NH
O
O
O
13
13
1
6
1
6
O
8
O
8
11
11
OH
OH
OMe
OMe
Migrastatin Macrolide Core 2
Migrastatin 1
Figure 1.
We have earlier reported1b a convenient synthesis of macrolide
core 2 of migrastatin where the C-8 chiral center was created at an
early stage of the synthesis. We now report a different approach for
the macrolide core 2 of migrastatin by introducing the C-8 chiral
center at a later stage via a Pd(II) catalyzed intramolecular C–H oxi-
dation on carboxylic acid 5 (Scheme 1).
Lately, the concept of late stage C–H oxidation has been demon-
strated to be a useful strategy during the synthesis of macrocylic
compounds.9 As a practical application to this approach, we report
a formal synthesis of migrastatin macrolide core 2 using a late
stage C–H oxidation as a key step promoted by Pd(II) catalyst.
The synthesis of macrolide core 2 was initiated via Crimmins mod-
ified Evans aldol reaction10 between the Evan’s chiral auxiliary 8
and 3-butenal 7 (Scheme 2) to afford the aldol 9. The protection
of aldol 9 with TBSOTf, followed by reductive removal of chiral
auxiliary using sodium borohydride gave the corresponding alco-
hol 10. Subsequent oxidation of alcohol 10 under Dess–Martin
periodinane conditions afforded the aldehyde 611 which upon
treatment with ethyl 2-(diphenylphosphono)acetate 11,12 gave
the product 12 in good overall yield. Our initial efforts to promote
intermolecular allylic C–H oxidation on ester 12 with Pd(II) cata-
lyst, as developed by White and co-workers13 gave two regioisom-
ers 13 and 14 in equal ratio (Scheme 2) which is in conformity with
the one reported.14
In order to achieve high regio and diastereoselectivity, we re-
sorted to an intramolecular cyclization via a Pd(II) promoted C–H
oxidation on the corresponding acid 5 derived from the corre-
⇑
Corresponding author. Tel.: +91 40 66571571; fax: +91 40 66571581.
E-mail address: jiqbal@drils.org (J. Iqbal).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.137

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N. R. Gade, J. Iqbal / Tetrahedron Letters 54 (2013) 4225–4227
Table 1
O
Optimization of intramolecular C–H oxidation
HO
8
O
8
O
S
O
S Ph
TBSO
9
Ph
8
OTBS
Pd(OAc)2
BQ
OH
OTBS
OTBS
O
10
OMe
3
OMe
HO2C
additive
5
O
2
solvent, temp,
72 h
4
O
O
HO
O
8
Solvent/additive
Temperature
Conversion
(%)
Isolated yield
(%)
10
9
DCM
DCE
DCM
45 °C
5
5
5
4
––
––
OTBS
5
65–70 °C
50 °C In sealed
tube
4
DCM/DIPEA
DCM/Cr(III)salenCl
Dioxane/
45 °C
45 °C
45 °C
40
50
50
20
35
40
O
O
7
6
Cr(III)salenCl
OTBS
Scheme 1. Retrosynthesis of migrastatin macrolide core.
O
O
OH
PMP
O
O
TiCl4, 7, (-) spartein,
i) NaBH4,
DCM, 0 °C, 1h, 83 %
THF:H2O, 2 h
N
O
N
O
O
DIBAL-H,
O
9
20:1 d.r
9
ii) p-anisaldehyde
dimethyl acetal, CSA,
24 h, 90% for 2 steps
-78 - 0 °C,
Bn
Bn
8
DCM, 2 h, 96%
15
1) TBSOTf, DIPEA,
DCM, 0 °C, 90%
2) NaBH4, THF:H2O,
90 h, 80%
OPMB
OH OPMB
i) DMP, DCM, 2 h
ii) 11, NaI, DBU,
O
OTBS
OH OTBS
EtO2C
16
-78 - 0 °C, THF, 3 h,
Z:E, 95:5,
17
DMP, DCM
2h, 90%
6
70% for two steps,
O
O
Ph
S
S Ph
10
OPMB
11
, NaI, DBU,
Pd(OAc)2
LiOH.H2O
-78 - 0 °C, THF, 3 h,
Z:E, 95:5, 60%
BQ, Dioxane
MeOH:THF:H2O
50 °C, 4 h, 99%.
18
HO2C
Cr(III)(salen)Cl,
45 °C, 72 h, 40%,
(80% brsm),
OTBS
PMBO
19a : 19b (5:1)
O
S
O
S Ph
PMBO
9
8
9
8
Ph
OTBS
Pd(OAc)2
BQ
EtO2C
OR1
10
O
10
O
13
19a
19b
OTBS
O
p-NO2BzOH, Dioxane,
45 °C, 72 h, 13:14 (1.2:1)
68%
EtO2C
O
12
Scheme 3. Synthesis of seven-membered lactone with PMB protecting group.
EtO2C
OR1
14
R1=p-NO2Bz
Scheme 2. Synthesis of precursor of macrolide core.
TBSO
OTBS
8
8
DIBAL-H,
O
-78 - 0 °C,
OH
sponding ester 12. Accordingly, we hydrolyzed the compound 12
to give the acid 5 which was subjected to cyclization under condi-
tions reported by White and co-workers9 to give lactone 4 as a sin-
gle diastereomer in less than 5% yield. We attempted
intramolecular C–H oxidation in the presence of chiral Lewis acid
((R,R)-Cr(III)salenCl) (Table 1).14 Gratifyingly, White’s oxidation
on acid 5 under chiral Lewis acid promoter afforded the seven-
membered lactone 4 in 40% yield along with 50% recovered start-
ing material after 72 h. However, we did not observe the formation
of the nine-membered lactone in any of the attempted conditions
(Table 1). We then changed the protecting group on 5 from TBS to
PMB (Scheme 3), in this case we did not observe any improvement
in yields but observed a decrease in diastereoselectivity (5:1). Ste-
reochemistry of the C-8 in lactone 5 and 19a was established using
NOESY experiments which showed a correlation between C-8 pro-
HO
DCM, 2 h, 90%
20
O
4
OTBS
8
TBSCl,
DTBMP, DCM
OH
Imidazole,
MeOTf, 6 h,
reflux, 70%
BSO
21
DTMF, 2 h, 90%
HO
8
OTBS
8
CSA, MeOH
2 h, 90%
ref. 5
2
OMe
OTBS
OTBS
22
OMe
3
Scheme 4. Synthesis of macrolide core 2 of migrastatin.

N. R. Gade, J. Iqbal / Tetrahedron Letters 54 (2013) 4225–4227
4227
ton and C-10 methyl group and was further confirmed by elabora-
References and notes
tion of lactone 4 to known compound 3 (Scheme 4).5
1. (a) Padakanti, S.; Pal, M.; Mukkanti, K.; Iqbal, J. Tetrahedron Lett. 2006, 47, 5969;
(b) Sai Baba, V.; Das, P.; Mukkanti, K.; Iqbal, J. Tetrahedron Lett. 2006, 47, 6083;
(c) Sai Baba, V.; Das, P.; Mukkanti, K.; Iqbal, J. Tetrahedron Lett. 2006, 47, 7927;
(d) Nyavanandi, V. K.; Nadipalli, P.; Nanduri, S.; Naidu, A.; Iqbal, J. Tetrahedron
Lett. 2007, 48, 6905; (e) Prasad Narasimhulu, C.; Iqbal, J.; Mukkanti, K.; Das, P.
Tetrahedron Lett. 2008, 49, 3185; (f) Vamsee Krishna, C.; Bhonde, V. R.;
Devendar, A.; Maitra, S.; Mukkanti, K.; Iqbal, J. Tetrahedron Lett. 2008, 49, 2013;
(g) Sasmal, P. K.; Abbineni, C.; Iqbal, J.; Mukkanti, K. Tetrahedron 2010, 66, 5000.
2. (a) Nakae, K.; Yoshimoto, Y.; Sawa, T.; Homma, Y.; Hamada, M.; Takeuchi, T.;
Imoto, M. J. Antibiot. 2000, 53, 1130; (b) Nakae, K.; Yoshimoto, Y.; Ueda, M.;
Sawa, T.; Takahashi, Y.; Naganava, H.; Takeuchi, T.; Imoto, M. J. Antibiot. 2000,
53, 1228.
The lactone 4 was reduced with DIBAL-H to give the corre-
sponding diallylic alcohol 20, which upon selective protection of
primary alcohol as a silyl ether and methylation of secondary alco-
hol with MeOTf furnished the intermediate 22. The deprotection of
the silyl group on 22 using CSA/MeOH provided the key fragment 3
required for the synthesis of macrolide core of migrastatin. The key
fragment 3 has already been converted to the macrocycle 2 by us1b
and others5 and this approach thus constitutes a formal synthesis
of macrolide core 2 of migrastatin (Scheme 4).
3. Takemoto, Y.; Nakae, K.; Kawatani, M.; Takahashi, Y.; Naganawa, H.; Imoto, M.
J. Antibiot. 2001, 54, 1104.
4. Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042.
5. Njardarson, J. T.; Gaul, C.; Shan, D.; Huang, X. Y.; Danishefsky, S. J. J. Am. Chem.
Soc. 2004, 126, 1038.
In conclusion, we have successfully installed the C-8 chiral cen-
ter of migrastatin using Pd(II) catalyzed intramolecular C–H oxida-
tion. We have demonstrated a stereoselective formal synthesis of
macrolide core of migrastatin (C6–C13 fragment).
6. Gaul, C.; Njardarson, J. T.; Shan, D.; Dorn, D. C.; Kai-Da, W.; Tong, W. P.; Huang,
X. Y.; Moore, M. A. S.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 11326.
7. Oskarsson, T.; Nagorny, P.; Krauss, I. J.; Perez, L.; Mandal, M.; Yang, G.; Ouerfelli,
O.; Xiao, D.; Moore, M. A. S.; Massagué, J.; Danishefsky, S. J. J. Am. Chem. Soc.
2010, 132, 3224.
Acknowledgment
N.R.G. thanks CSIR, New Delhi, India for a fellowship and Prof.
M. Pal and Dr. Pallavi Rao for their support. We thank DRILS for
the analytical support.
8. Reymond, S.; Cossy, J. Tetrahedron 2007, 63, 5918.
9. (a) Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am. Chem. Soc.
2006, 128, 9032; (b) Stang, E. M.; White, M. C. Nat. Chem. 2009, 1, 547; (c) Stang,
E. M.; White, M. C. Angew. Chem., Int. Ed. 2011, 50, 2094.
10. (a) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001,
66, 894; (b) Crimmins, M. T.; Katz, J. D.; McAtee, L. C.; Tabet, E. A.; Kirincich, S. J.
Org. Lett. 2001, 3, 949.
Supplementary data
11. Synthesis of enatiomer of 6 has been reported by us (see ref 1e) and other
group (see ref10b).
12. Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem. 1998, 63, 8411.
13. Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005,
127, 6970.
Supplementary data (all experimental procedures, NMR spectra
(1H, 13C NMR, 1H–1H COSY, 1H–1H NOESY) and characterization
data for all new compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.05.137.
14. Gormisky, P. E.; White, M. C. J. Am. Chem. Soc. 2011, 133, 12584.