Synthesis of congeners of migrastatin and dorrigocin A from d-xylose

Article abstract of DOI:10.1016/j.tetlet.2010.07.141

Migrastatin and dorrigocin A analogues have potential as anti-metastatic agents that act by targeting the actin-bundling protein, fascin. Syntheses of close structural analogues of these agents have been achieved. Wittig and Ando olefination reactions with an aldehyde obtained from d-xylose, respectively, gave two trisubstituted alkene intermediates that were then elaborated into either macrolactone or macrolactam analogues of migrastatin or to an acyclic dorrigocin A analogue.

Full text of DOI:10.1016/j.tetlet.2010.07.141

Tetrahedron Letters 51 (2010) 5262–5264
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Tetrahedron Letters
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Synthesis of congeners of migrastatin and dorrigocin A from D-xylose
*
Ying Zhou, Paul V. Murphy
School of Chemistry, National University of Ireland, Galway, University Road, Galway, Ireland
Centre for Synthesis and Chemical Biology and School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Migrastatin and dorrigocin A analogues have potential as anti-metastatic agents that act by targeting the
actin-bundling protein, fascin. Syntheses of close structural analogues of these agents have been
achieved. Wittig and Ando olefination reactions with an aldehyde obtained from D-xylose, respectively,
gave two trisubstituted alkene intermediates that were then elaborated into either macrolactone or mac-
rolactam analogues of migrastatin or to an acyclic dorrigocin A analogue.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 22 June 2010
Revised 14 July 2010
Accepted 23 July 2010
Available online 3 August 2010
Tumour metastasis is the primary cause of death of cancer
patients and the development of therapeutic agents that would inhi-
bit this process would be of major benefit. Migrastatin (1), a macro-
pound 4a differs from 3a in having a hydroxy substituent at C-10 in-
stead of the methyl group; the stereochemistry is the same as in 3a.
The retrosynthetic analysis (Scheme 1) revealed that macrolac-
tone 4a and dorrigocin A analogue 7 could be assembled from 8
and 9, respectively. We envisaged that both 8 and 9 would be ob-
tained from the aldehyde 10; the reaction of 10 with an Ando phos-
phonate10 would give 8, whereas the reaction of 10 with the
appropriate Wittig reagent11 would give 9. The aldehyde 10 was
lide natural product first isolated from
a cultured broth of
Streptomyces, is an inhibitor of tumour cell migration.1 Dorrigocin
A (2), a naturally occurring antifungal antibiotic, is structurally re-
latedtomigrastatinbya lactonehydrolysisand alkeneisomerisation
and it also displays interesting biological properties. Dorrigocin A
inhibits the carboxymethyltransferase involved in ras processing2
and reverses the morphology of ras-transformed NIH/3T3 cells.3
Importantly,simpleranaloguesofmigrastatin, suchasthemacrolide
3a (Fig. 1), are ꢀ1000-fold more active than migrastatin itself in cell
migration assays in vitro.4 The macrolactam 3b, macroketone 3c and
a macroether (not shown) inhibit the metastasis of highly metastatic
tumour cells in mouse models.5 An analogue of dorrigocin A 6
showed the ability to inhibit potently, gastric tumour cell migration
invitro.6 Related naturalproductssuchas isomigrastatin andlactim-
idomycin are also active cell migration inhibitors.7 Very recently, the
macroketone 3c was shown totarget the actin-bundling protein, fas-
cin, providing a mechanism by which migrastatin analogues and
possibly dorrigocin A analogues inhibit tumour metastasis.8 There-
fore, the development of synthetic routes to new migrastatin and
dorrigocin A analogues is important.9
envisaged to be prepared from
The synthesis began with the conversion of
key intermediate 10 (Scheme 2). The -xylofuranoside derivative
11 was prepared in three steps. Hence the reaction of -xylose with
D
-xylose.12
D
-xylose into the
D
D
allyl alcohol in the presence of pyridinium p-toluenesulfonate to
O
O
NH
O O
O
1
O
O
13
10
2
O
X
O
X
12
11
3
HO
HO
7
OH
OH
OH
OH
6
OMe
OMe
OMe
OMe
5
4a
3a
X = O
Migrastatin 1
X = O
The migrastatin and dorrigocin A analogues 5 and 6 have been
4b X = NH
3b X = NH
O
prepared previously from D
-glucal.7 Structurally, these analogues
3c
X = CH2
O
NH
differ from migrastatin and dorrigocin A in that they lack the glutari-
mide-containing side chain at C-13 and the methyl substituent at C-
12. They contain a hydroxy group instead of a methyl group at C-10
with the opposite configuration to that found in the natural com-
pounds. Herein, we report the synthesis of 4a, macrolactam 4b and
O
O
O
O
13
12
OH
OH
1
OH
HO
OH
OH
HO
OH
10
OH
acyclic dorrigocin A analogue 7 from the inexpensive D-xylose. Com-
OH
OH
OMe
OMe
OMe
7
6
Dorrigocin A 2
* Corresponding author. Tel.: +353 91 492465; fax: +353 91 525700.
E-mail address: paul.v.murphy@nuigalway.ie (P.V. Murphy).
Figure 1. Structures of natural products 1–2 and synthetic analogues 3–7.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.141

Y. Zhou, P. V. Murphy / Tetrahedron Letters 51 (2010) 5262–5264
5263
O
P
give an allyl xylofuranoside was followed by introduction of an iso-
EtO2C
TBSO
propylidene group at C-3 and C-5,13 and then methylation of the
O
CO2Et
15
PhO
PhO
TBSO
hydroxy group at C-2 to give 11. The hemiacetal 12 was obtained
from 11 (36% from D-xylose) by the removal of the allyl ether using
H
NaH,THF,-78 o
C
OTBS
OTBS
the conditions reported by Gigg and Warren.14 The reaction of 12
with the Wittig reagent obtained from the reaction of methyltri-
phenylphosphonium bromide with a base in anhydrous THF at
À50 °C gave the olefin 13. Removal of the acetonide gave a triol
which when reacted with an excess of TBSOTf in the presence of
a base gave a fully silylated intermediate. Subsequent regioselec-
tive removal of the TBS group at the primary position led to the for-
mation of alcohol 14. This alcohol was then converted into
aldehyde 10 by Dess–Martin oxidation.
OMe
8
OMe
10
83%
CO2Et
17
DIBAL-H
-78 oC
93%
Ph3P
toluene
110 oC, 87%
CO2Et
HO
TBSO
TBSO
OTBS
OMe
16
The conversion of 10 into the key intermediates 8 and 9 was
next investigated (Scheme 3). Firstly, the aldehyde 10 was reacted
with the Ando phosphonate 158 in a variation of the Horner–Wads-
worth–Emmons (HWE) olefination, which gave the trisubstituted
alkene 8 as the major product. This reaction proceeded with
acceptable Z-selectivity (Z:E = 92:8) and hence gave also a small
DIBAL-H
OTBS
-78 oC
OMe
OH
9
TBSO
92%
OTBS
OMe
18
Scheme 3. Synthesis of alkenes 8, 9, 16 and 18.
O
O
O
OH
HO
OH
HO
amount of 9. The mixture of isomers was then converted into a
mixture of the allylic alcohols 16 and 18 using diisobutylaluminum
hydride (DIBAL-H). In this mixture the ratio of 87:13 was 85:15
and it was difficult to separate these two isomers by chromatogra-
phy. This problem was resolved during subsequent manipulations
(Schemes 4 and 5). When the aldehyde 10 was treated with Wittig
reagent 179 the trisubstituted alkene derivative 9 was obtained as
the major product (E:Z = 98:2). In this case, a small amount of the
unreacted aldehyde 10 was difficult to separate from the alkene
product, but purification was achieved after the reductive step.
Hence reduction of 9 using DIBAL-H gave the allylic alcohol 18 in
high yield.
OH
OH
OMe
4a
OMe
7
CO2Et
EtO2C
TBSO
TBSO
OTBS
OTBS
8
OMe
OMe
9
Ando
Wittig
olefination
TBSO
olefination
With 16 in hand the synthesis of 4a15 was then completed.
Esterification with 6-heptenoic acid promoted by triphenylphos-
phine and diisopropyl azodicarboxylate gave 19.16 Stereoselective
ring-closing metathesis17 was then achieved using the Grubbs sec-
ond generation catalyst and removal of the TBS groups gave 4a.18
Next, the synthesis of the macrolactam 4b was carried out. The
reaction of 16 with diphenylphosphoryl azide in the presence of
triphenylphosphine and diisopropyl azodicarboxylate (DIAD) led
to the exchange of the free hydroxy group for an azide group and
gave 20 in 80% yield (Scheme 5). The azide 20 was reduced via
Staudinger reaction, and the resulting amine was coupled to 6-
heptenoic acid using EDC in the presence of a base to give 21
O
H
D
-Xylose
OTBS
OMe
10
Scheme 1. Retrosynthetic analysis of 4a and 7.
1. PPTS, allyl alcohol
O
OAll
OMe
80 o
C
O
D
-Xylose
2. CuSO4, acetone
3. NaH, MeI
O
11
18-crown-6, THF
1. t-BuOK, DMSO
100 oC
O
HO
TBSO
O
TBSO
2. Hg(OAc)2
THF/H2O
Ph3P, DIAD
toluene
6-heptenoic acid
O
OH
O
O
Ph3PCH3Br
nBuLi, THF
OTBS
OTBS
O
85%
OMe
16
OMe
O
OMe
19
OMe OH
60%
12
13
1. Grubbs-II
36% from
D
-xylose
toluene
2. TBAF-THF
O
1. 60% HOAc-H2O, 85%
2. TBSOTf, Et 3N
CH2Cl2, 85%
O
HO
3. PTSA, MeOH, 80%
O
TBSO
OTBS
H
DMP, py, CH2Cl2
89%
OH
OH
OMe OTBS
14
OTBS
OMe
OMe
10
4a (37%)
Scheme 2. Synthesis of 10.
Scheme 4. Synthesis of migrastatin analogue 4a.

5264
Y. Zhou, P. V. Murphy / Tetrahedron Letters 51 (2010) 5262–5264
having a hydroxy group instead of a methyl group. The biological
properties of these new agents are currently being investigated
and will be reported in due course.
HO
TBSO
N3
TBSO
PPh3, DIAD
DPPA, THF
80%
OTBS
OTBS
OMe
20
1. Ph3P, THF-H2O
OMe
16
Acknowledgement
The material described herein was funded by the Science Foun-
dation Ireland (PI/IN1/B966).
2. 6-heptenoic acid,
EDC.HCl, DIPEA
CH2Cl2
65%, two steps
O
O
Supplementary data
1. Grubbs-II
toluene, 80 o
40%
C
N
N
H
H
Supplementary data (selected NMR spectra for key intermedi-
ates and final compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.07.141.
HO
TBSO
2. TBAF-THF
CaCO3
DOWEX, 78%
OTBS
OH
OMe
21
OMe
4b
References and notes
Scheme 5. Synthesis of macrolactam 4b.
1. (a) Nakae, N.; Yoshimoto, Y.; Ueda, M.; Sawa, T.; Takahashi, Y.; Naganawa, H.;
Takeuchi, T.; Imoto, M. J. J. Antibiot. 2000, 53, 1228–1230; (b) Woo, E. J.; Starks,
C. M.; Carney, J. R.; Arslanian, R.; Cadapan, L.; Zavala, S.; Licari, P. J. Antibiot.
2002, 55, 141–146; (c) Ju, J.; Lim, S.-K.; Jiang, H.; Shen, B. J. Am. Chem. Soc. 2005,
127, 1622–1623.
2. Kloog, Y.; Cox, A. D. Mol. Med. Today 2000, 6, 398–402.
3. Kadam, S.; McAlpine, J. B. J. Antibiot. 1994, 47, 875–880.
4. (a) 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,
11326–11337; (b) Njardarson, J. T.; Gaul, C.; Shan, D.; Huang, X.-Y.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 1038–1040.
5. (a) Shan, D.; Chen, L.; Njardarson, J. T.; Gaul, C.; Ma, X.; Danishefsky, S. J.;
Huang, X.-Z. Proc. Nat. Acad. Sci. U.S.A. 2005, 102, 3772–3776; (b) Oskarsson, T.;
Nagorny, P.; Krauss, I. J.; Perez, L.; Mandal, M.; Yang, G.; Ouerfelli, O.; Xiao, D.;
Moore, M. A. S.; Massagu, M.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132,
3224–3228.
O
OH
Grubbs-II, CH2Cl2,
OEt
OH
TBSO
ethyl 6-heptenoate
TBSO
33%
OTBS
OMe
18
OTBS
OMe
22
TBAF, THF, 85%
O
O
6. (a) Anquetin, G.; Rawe, S. L.; McMahon, K.; Murphy, E. P.; Murphy, P. V. Chem.
Eur. J. 2008, 14, 1592–1600; (b) Anquetin, G.; Horgan, G.; Rawe, S. L.; Murray,
D.; Madden, A.; McMathuna, P.; Doran, P.; Murphy, P. V. Eur. J. Org. Chem. 2008,
1953–1958.
7. Ju, J.; Rajski, S. R.; Lim, S.-K.; Seo, J.-W.; Peters, N. R.; Hoffmann, F. M.; Shen, B. J.
Am. Chem. Soc. 2009, 131, 1370–1371.
8. Chen, L.; Yang, S.; Jakoncic, J.; Jillian Zhang, J.; Huang, X.-Z. Nature 2010, 464,
1062–1066.
9. For a recent review, see: Reymond, S.; Cossy, J. C. R. Chim. 2008, 11, 1447–1462.
10. (a) Ando, K. J. Org. Chem. 1998, 63, 8411–8416; (b) Ando, K. J. Org. Chem. 2000,
65, 4745–4749.
OH
HO
OH
OEt
HO
OH
LiOH
THF-H2O-MeOH
81%
OH
OH
OMe
OMe
23
Scheme 6. Synthesis of dorrigocin A analogue 7.
7
11. (a) Dunetz, J. R.; Roush, W. R. Org. Lett. 2008, 10, 2059–2062; (b) Hayashi, Y.;
Yamaguchi, H.; Toyoshima, M.; Okado, K.; Toyo, T.; Shoji, M. Org. Lett. 2008, 10,
1405–1408.
(65% yield over two steps). The ring-closing metathesis of 21 in the
presence of Grubbs second generation catalyst and the subsequent
removal of the TBS groups using TBAF/THF, as recently described
by Kaburagi and Kishi,19 gave the macrolactam 4b.
12. For a recent application of D-xylose as a starting material in natural product
synthesis, see: (a) Chen, Q.; Du, Y. Tetrahedron Lett. 2006, 47, 8489–8492; (b)
Du, Y.; Chen, Q.; Linhardt, R. J. J. Org. Chem. 2006, 71, 8446–8451.
Finally, the preparation of the dorrigocin A analogue 720 was
achieved from 18. The synthesis of the C1–C13 fragment of 2,3-
dihydrodorrigocin A has been reported by Brazidec et al.21 They
sequentially employed the Julia–Kocienski coupling, an aldol addi-
tion and a Wittig reaction to introduce the desired alkenes and to
achieve stereocontrol. Herein, we completed the preparation of a
similar C1–C13 fragment using the primary alcohol 18. Thus the
cross metathesis22 of 18 with both 6-heptenoic acid and ethyl 6-
heptenoate was investigated, respectively. The reaction with the
acid was unproductive but 22 was obtained (33%) from the ester
(Scheme 6) using the Grubbs second generation catalyst in dichlo-
romethane at 40 °C; the yield of 22 was low, but the starting com-
pound 18 was also recovered in ꢀ30% yield. Removal of the TBS-
protecting groups using TBAF/THF (85%) and the subsequent
saponification gave 7 (81%).
13. Ireland, R. E.; Norbeck, D. W. J. Am. Chem. Soc. 1985, 107, 3279–3285.
14. Gigg, R.; Warren, C. D. Journal. Chem. Soc. C 1968, 1903–1911.
15. Analytical data for 4a: 1H NMR (CDCl3, 500 MHz) d 5.83–5.72 (m, 2H), 5.26 (dd,
1H, J = 15.6 Hz, 8.2 Hz), 4.64 (dd, 1H, J = 13.9 Hz, 1.1 Hz), 4.59 (d, 1H, J = 9.7 Hz),
4.38 (d, 1H, J = 13.9 Hz), 3.72 (t, 1H, J = 8.7 Hz), 3.38 (d, 1H, J = 9.2 Hz), 3.32 (s,
3H), 2.40 (ddd, 1H, J = 13.5 Hz, 7.3 Hz, 6.2 Hz), 2.30–2.24 (m, 1H), 2.17 (td, 1H,
J = 13.6 Hz, 7.8 Hz, 7.8 Hz), 2.05–1.95 (m, 1H), 1.78 (d, 3H, J = 1.0 Hz), 1.75–1.66
(m, 1H), 1.65–1.59 (m, 1H), 1.58–1.48 (m, 1H), 1.40–1.35 (m, 1H); 13C NMR
(CDCl3, 125 MHz) d 173.2 (C), 136.5 (CH), 131.6 (C), 129.7 (CH), 128.6 (CH),
82.5 (CH), 75.8 (CH), 65.2 (CH), 64.9 (CH2), 56.4 (CH3), 33.7 (CH2), 30.1 (CH2),
26.5 (CH2), 23.3 (CH2), 23.1 (CH3); ESI/MS- (m/z): 307.39 (M+Na)+; HRMS-ESI:
calcd for C15H23O5 (MÀH)À: 283.1545. Found: 283.1556.
16. The mixture of 19 and unreacted DIAD could not be separated by
chromatography; the yield was determined by 1H NMR spectroscopy.
17. Nguyen, S. T.; Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29.
18. For a similar final approach to migrastatin lactone analogues, see: Refs.4,5 and
Reymond, S.; Cossy, J. Tetrahedron 2007, 63, 5918–5929.
19. Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723–726.
20. Analytical data for 7: [a]
+10.8 (c 0.66, MeOH); 1H NMR (CD3OD, 500 MHz) d
D
5.81–5.70 (m, 2H), 5.51 (dd, 1H, J = 9.2 Hz, 1.3 Hz), 5.49–5.44 (m, 1H), 4.47 (dd,
1H, J = 9.2 Hz, 5.8 Hz), 3.96 (s, 2H), 3.59 (dd, 1H, J = 8.5 Hz, 4.3 Hz), 3.28 (t, 1H,
J = 2.4 Hz), 3.21 (s, 3H), 2.20–2.10 (m, 4H), 3.45 (s, 3H), 1.64 (td, 2H, J = 15.2 Hz,
7.5 Hz), 1.47 (td, 2H, J = 14.7 Hz, 7.3 Hz); 13C NMR (CD3OD, 125 MHz): d 182.4
(C), 139.7 (C), 137.4 (CH), 128.5 (CH), 125.6 (CH), 83.9 (CH), 78.7 (CH), 69.4
(CH), 68.2 (CH2), 56.3 (CH3), 38.8 (CH2), 33.3 (CH2), 30.4 (CH2), 27.1 (CH2), 14.2
(CH3); ESI/MS- (m/z): 325.2 (M+Na)+; HRMS-ESI: calcd for C15H26O6Na
(M+Na)+: 325.1627. Found: 325.1613.
In conclusion, the synthesis of close structural analogues of
migrastatin and dorrigocin A core structures has been achieved.
D-Xylose was employed to generate an aldohexene intermediate
with three stereocentres, with a similar stereochemical arrange-
ment to that found in the natural products. The Ando and Wittig
olefinations of this aldehyde were used to respectively prepare,
in a stereocontrolled manner, the two trisubstituted alkene inter-
mediates that were elaborated to macrolactone, macrolactam and
acyclic target compounds, differing from the core structures by
21. Brazidec, J. L.; Gilson, C. L., III; Boehm, M. F. J. Org. Chem. 2005, 70, 8212–8215.
22. Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370.