Studies directed toward the synthesis of rhizopodin: Stereoselective synthesis of the C1-C15 fragment

Article abstract of DOI:10.1016/j.tetlet.2010.09.144

A stereoselective synthesis of the C1-C15 fragment of a G-actin binding natural macrodiolide, rhizopodin was achieved using, as key steps, highly stereoselective acetate aldol reactions to build the C1-C7 fragment, one pot oxazole synthesis and an asymmet

Full text of DOI:10.1016/j.tetlet.2010.09.144

Tetrahedron Letters 51 (2010) 6444–6446
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies directed toward the synthesis of rhizopodin: stereoselective synthesis
of the C1–C15 fragment q
Tushar Kanti Chakraborty a, , Kiran Kumar Pulukuri a, Midde Sreekanth b
⇑
a Central Drug Research Institute, CSIR, Lucknow 226001, India
b Indian Institute of Chemical Technology, CSIR, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective synthesis of the C1–C15 fragment of a G-actin binding natural macrodiolide, rhizopodin
was achieved using, as key steps, highly stereoselective acetate aldol reactions to build the C1–C7 frag-
ment, one pot oxazole synthesis and an asymmetric Keck allylation reaction to build the C8–C15 frag-
ment and finally, a Stille reaction to couple both the fragments.
Received 3 September 2010
Revised 27 September 2010
Accepted 29 September 2010
Available online 7 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Rhizopodin
Acetate aldol reaction
Keck allylation
Stille coupling
Rhizopodin (1) is a novel polyketide isolated from the myxobac-
terium Myxococcus stipitatus.1 Based on the crystal structure of
rhizopodin—G-actin complex, its structure was identified as a C2-
symmetric, 38-membered dilactone having 18 chiral centers, two
disubstituted oxazole rings, and two conjugated diene systems.2
Rhizopodin has been found to dramatically affect the cytoskeleton
of eukaryotic cells even at nanomolar concentrations, an ability
traced to its property of binding there by inhibiting the polymeri-
zation of actin.2,3 Unlike other dimeric macrolides with actin poly-
merization inhibitory activity like swinholides, misakinolide A, and
bisteonelide B, rhizopodin behaves as a bivalent inhibitor forming
a ternary complex with the two actin molecules.2 The challenging
structure of the molecule coupled with its unique biological activ-
ities prompted us to undertake its total synthesis. A stereoselective
synthesis of the C9–C23 fragment has been reported.4 In this Let-
ter, we report the stereoselective synthesis of the C1–C15 fragment
of the molecule.
a Nozaki–Hiyama–Kishi reaction5 to obtain the entire length of
C1–C28 of the monomer.
Schemes 2–4 outlines the synthesis of the first C1–C15 frag-
ment 3. The synthesis of vinyl stannane (Scheme 2) was started
with cinnamaldehyde dimethyl acetal 7 which was prepared
from trans-cinnamaldehyde following standard procedures.6 An
acetal aldol reaction of dimethyl-acetal 7 with (R)-N-acetyl-4-
isopropyl-1,3-thiozolidine-2-thione 8 according to the conditions
described by Urpi7 provided the aldol products in 91% yield in
4:1 diastereomeric ratio. The required, diastereomerically pure
product 9 could be easily separated through silica gel column
chromatography.8 Reductive cleavage of the chiral auxiliary using
DIBAL-H afforded aldehyde 10 in 92% yield, which was subjected
to an acetate aldol reaction with (S)-N-acetyl-4-isopropyl-1,3-thi-
ozolidine-2-thione 11 to afford the desired alcohol 12 in 84%
yield and 14:1 diastereomeric ratio.10 Removal of the chiral aux-
iliary using imidazole in MeOH afforded the methyl ester 13 in
92% yield.11 Protection of the hydroxy group of 13 using TBSOTf
and 2,6-lutidine afforded the TBS protected compound 14 in
96% yield. The cinnamyl moiety was transformed to vinylstann-
ane by oxidation of the olefin using OsO4 and NMO followed
by oxidative cleavage to afford the aldehyde 15 in 90% yield.
The resultant aldehyde was transformed to alkyne 17 using
Bestmann–Ohira reagent 16 in 72% yield.12 Hydrostannyllation
of alkyne with Pd(PPh3)2Cl2 and n-Bu3SnH afforded the E-vinylst-
annane 5 in 76% yield.13
The retrosynthetic analysis of rhizopodin (1) is outlined in
Scheme 1. A sequential esterification/macrolactonization or cyc-
lodimerization was contemplated to construct the macrocyclic
ring from the suitably protected monomeric hydroxyl acid 2.
We envisaged that the two halves of the monomer, the
C1–C15 unit 3 and the C16–C28 unit 4, could be combined by
q
CDRI Communication No. 7964.
For the preparation of the vinyl iodide–oxazole fragment 6
(Scheme 3), coupling of p-methoxybenzyloxyacetic acid 18 with
⇑
Corresponding author. Tel.: +91 522 2623286; fax: +91 522 2623405/3938.
E-mail address: chakraborty@cdri.res.in (T.K. Chakraborty).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.144

T. K. Chakraborty et al. / Tetrahedron Letters 51 (2010) 6444–6446
6445
DL-serine methyl ester hydrochloride 19 using ethyl chloroformate
and N-methylmorpholine afforded the amide 20 in 74% yield.14 The
resultant amide was converted to the oxazole 21 in one pot
following the Wipf and Williams15 methodology with Deoxo-Fluor,
bromochloroform, and DBU to afford 21 in 70% yield. Reduction of
oxazole ester using DIBAL-H at ꢀ80 °C afforded the aldehyde 22 in
90% yield.16 Asymmetric allylation of aldehyde with (S)-BINOL,
Ti(OiPr)4, and allyl tributylstannane afforded the allylic alcohol
23 in 87% yield with 94% ee.17 Methylation of hydroxyl with NaH
and iodomethane in DMF afforded the methyl ether 24 in 83%
yield. Dihydroxylation of the double bond followed by oxidative
cleavage using sodium periodate furnished the aldehyde 25 in
84% yield. The aldehyde 25 was converted to dibromoalkene 26,
using TPP, CBr4, and triethylamine, which was next transformed
into alkynyl bromide 27 using NaHMDS.18 One pot hydrostannyla-
tion–iodination of 27 produced E-vinyl iodide 28 in 84% yield.19
Oxidative removal of PMB group with DDQ afforded the desired
C8–C15 fragment 6 in 94% yield.20
OMe O
28
O
N
OMe
OMe OH
O
OMe
O
O
16
15
N
HO
HO
N
O
1
O
OMe
OMe
MeO
O
HO
N
O
O
OMe
1
OMe OTIPS
28
BnO
OMe
With the requisite C1–C7 and C8–C15 fragments in hand, their
coupling was undertaken next as shown in Scheme 4. This was
done using Stille coupling21 conditions in the presence of bis-
acetonitrile palladium(II) chloride complex in DMF to give the
desired E,E-diene 3 in 54% yield.22
HO
16
15
TBSO
N
O
1
HO
In summary, we have achieved a highly stereoselective con-
vergent synthesis of the C1–C15 fragment of rhizopodin. Further
work toward the total synthesis of the molecule is currently in
progress.
O
O
OMe
TBS
OMe
2
OMe OTIPS
HO
N
28
15
BnO
Acknowledgments
O
OMe
1
MeO
The authors wish to thank the CSIR, New Delhi for a research
fellowship (P.K.K. and M.S.) and the SAIF, CDRI for providing the
spectroscopic and analytical data.
TESO
OMe
O
O
OMe
TBS
16
3
4
HO
HO
N
MeO
SnBu3
O
Supplementary data
I
O
O
OMe
OMe
TBS
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.144.
6
5
Scheme 1. Retrosynthetic analysis of rhizopodin (1).
S
O
OMe
OMe O
OMe
i
N
S
ii
H
OMe
S
O
10
9
7
N
S
8
S
OMe OH
OMe OH
O
COOMe
iii
S
iv
N
S
O
13
12
N
S
11
OMe OTBS
OMe OTBS
COOMe
vi, vii
v
H
COOMe
O
14
15
OMe OTBS
ix
viii
5
COOMe
O
P
O
17
MeO
MeO
N2
16
Scheme 2. Synthesis of 5. Reagents and conditions: (i) TiCl4, i-Pr2NEt, CH2Cl2, ꢀ50 °C, 2 h, BF3Et2O, ꢀ78 °C, 10 min, 71%; (ii) DIBAL-H, ꢀ78 °C, CH2Cl2, 30 min, 92%; (iii)
Sn(OTf)2, N-ethylpiperidine, CH2Cl2, ꢀ50 °C, 8 h, 84%; (iv) Imidazole , methanol, rt, 12 h, 92%; (v) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 10 min, 96%; (vi) OsO4, acetone/H2O
(8:1), rt, 4 h; (vii) NaIO4, THF: pH 7 buffer (1:1), 0 °C to rt, 0.5 h, 90% after two steps; (viii) K2CO3, methanol, 0 °C to rt, 4 h, 72%; (ix) PdCl2 (PPh3)2, n-Bu3SnH, CH2Cl2,
0 °C, 0.5 h, 76%.

6446
T. K. Chakraborty et al. / Tetrahedron Letters 51 (2010) 6444–6446
H
i
OH
ClH3N
19
COOMe
OH
ii
N
COOMe
OH
PMBO
PMBO
O
O
18
20
O
O
O
iii
H
v
iv
MeO
N
N
OPMB
N
OPMB
OPMB
21
O
O
OH
22
23
O
N
O
N
O
N
Br
Br
vi, vii
viii
H
OPMB
OPMB
OPMB
OMe
OMe
ix
OMe
O
26
24
25
O
N
O
N
xi
x
OPMB
OPMB
I
6
OMe
OMe
Br
27
28
Scheme 3. Synthesis of 6. Reagents and conditions: (i) Ethyl chloroformate, NMM, CH2Cl2, ꢀ20–0 °C, 12 h, 74%; (ii) Deoxo-Fluor, ꢀ20 °C, 0.5 h, BrCCl3, DBU, 0 °C, CH2Cl2, 8 h,
70%; (iii) DIBAL-H, ꢀ80 °C, CH2Cl2, 20 min, 90%; (iv) (S)-BINOL, Ti(OiPr)4, allyl tributylstannane, CH2Cl2, ꢀ20 °C, 72 h, 87%, 94% ee; (v) NaH, MeI, DMF, 0 °C, 4 h, 83%; (vi) OsO4,
acetone/H2O (8:1), rt, 2 h; (vii) NaIO4, THF/H2O (1:1), 0 °C , 1 h, 84% after two steps; (viii) PPh3, CBr4, NEt3, CH2Cl2, 0 °C, 0.5 h, 92%; (ix) NaHMDS, ꢀ78 °C, THF, 2 h, 78%; (x)
PdCl2(PPh3)2, n-Bu3SnH, THF, 0 °C, 2 h, then I2, 0 °C, 0.5 h, 84%; (xi) DDQ, CHCl3/H2O 20:1, 0 °C, 3 h, 94%.
10. Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.;
Fujita, E. J. Org. Chem. 1986, 51, 2391–2393.
11. Patel, J.; Clave, G.; Renard, P. Y.; Frank, X. Angew. Chem. Int. Ed. 2008, 47, 4224–
4227.
12. (a) Ohira, S. Synth. Commun. 1989, 19, 561–564; (b) Muller, S.; Liepold, B.; Roth,
G. J.; Bestmann, H. J. Synlett 1996, 521–522.
HO
N
O
i
MeO
5
6
+
O
O
OMe
OMe
TBS
3
13. Analytical and spectral data/Selected physical data of compound 5: Rf = 0.6
(SiO2, 10% EtOAc in petroleum ether); ½a D28
ꢁ
= +36.8 (c 0.156, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 0.03 (s, 3H), 0.06 (s, 3H), 0.81–0.92 (m, 21H), 1.25–1.37 (m,
9H), 1.42–1.55 (m, 6H), 1.63 (ddd, J = 14.1, 6.4, 5.2 Hz, 1H), 1.84 (ddd, J = 14.1,
7.9, 5.2 Hz, 1H), 2.48 (dd, J = 14.8, 7.5 Hz, 1H), 2.55 (dd, J = 14.8, 5.4 Hz, 1H),
3.23 (s, 3H), 3.56–3.70 (m, 4H), 4.3 (m, 1H), 5.75 (dd, J = 19.1, 7.1 Hz, 1H), 6.12
(d, J = 19.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d 172.1, 148.2, 131.7, 82.3, 66.9,
55.9, 51.3, 43.2, 42.5, 29.1, 27.2, 25.7, 17.9, 13.6, 9.5, ꢀ4.5, ꢀ4.8; IR (KBr): mmax
2927, 2856, 1735, 1590, 1461, 1373, 1217, 1093, 766 cmꢀ1; MS (ESI): m/z (%)
592.2 (70) [M+H]+.
Scheme 4. Synthesis of 3. Reagents and conditions: (i) PdCl2(CH3CN)2, DMF, rt, 54%.
References and notes
1. Sasse, F.; Steinmetz, H.; Hofle, G.; Reichenbach, H. J. Antibiot. 1993, 46, 741–748.
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Kalesse, M.; Schubert, W. D. Angew. Chem. Int. Ed. 2009, 48, 595–598;
(b) Horstmann, N.; Menche, D. Chem. Commun. 2008, 5173–5175; (c) Jansen,
R.; Steinmetz, H.; Sasse, F.; Schubert, W. D.; Hagelueken, G.; Muller, R.
Tetrahedron Lett. 2008, 49, 5796–5799.
14. Ramana Rao, M. H. V.; Kiran Kumar, S.; Kunwar, A. C. Tetrahedron Lett. 2003, 44,
7369–7372.
15. Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2,
1165–1168.
16. Williams, D. R.; Lowder, P. D.; Gu, Y. G.; Brooks, D. A. Tetrahedron Lett. 1997, 38,
331–334.
3. Gronewold, T. M. A.; Sasse, F.; Lunsdorf, H.; Reichenbach, H. Cell Tissue Res.
1999, 295, 121–129.
17. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467–8468.
18. Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett. 1994, 35, 3529–3530.
19. Zhang, H. X.; Guibé, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857–1867.
20. Analytical and spectral data/Selected physical data of compound 6: Rf = 0.5
4. Chen, Z.; Song, L.; Xu, Z.; Ye, T. Org. Lett. 2010, 12, 2036–2039.
5. (a) Breuilles, P.; Uguen, D. Tetrahedron Lett. 1998, 39, 3149–3152; (b) Takai, K.;
Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281–
5284; (c) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99,
3179–3181.
(SiO2, 50% EtOAc in petroleum ether); ½a D28
ꢁ
= ꢀ16.0 (c 0.368, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 2.56 (t, J = 6.7 Hz, 2H), 3.47 (br s, 1H), 3.30 (s, 3H), 4.21 (t,
J = 6.2 Hz, 1H), 4.73 (s, 2H), 6.11 (d, J = 14.4 Hz, 1H), 6.49 (dt, J = 14.4, 7.3 Hz,
1H), 7.54 (s, 1H); 13C NMR (CDCl3, 100 MHz): d 164.1, 141.3, 139.7, 136.0, 77.6,
6. Mikami, K.; Ohmura, H. Org. Lett. 2002, 4, 3355–3357.
7. (a) Cosp, A.; Llacer, E.; Romea, P.; Urpí, F. Tetrahedron Lett. 2006, 47, 5819–
5823; (b) Cosp, A.; Romea, P.; Urpí, F.; Vilarrasa, J. Tetrahedron Lett. 2001, 42,
4629–4631.
74.8, 57.1, 56.8, 40.6; IR (KBr): mmax 3358, 3157, 2922, 2855, 1655, 1584, 1460,
1218, 768 cmꢀ1; MS (ESI): m/z (%) 310.1 (100) [M+H]+.
8. To prove the stereochemistry of adduct, compound
9 was converted to
21. Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813–817.
22. Analytical and spectral data/Selected physical data of compound 3: Rf = 0.4
compound 29. The spectral data of 29 matched with the reported data.9
(SiO2, 50% EtOAc in petroleum ether); ½a D28
ꢁ
= +24.6 (c 0.16, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 0.02 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H), 1.62 (ddd, J = 14.1,
6.4, 5.2 Hz, 1H), 1.83 (ddd, J = 14.1, 7.7, 5.2 Hz, 1H), 2.45–2.55 (m, 3H), 2.63 (t,
J = 6.5 Hz, 2H), 3.21 (s, 3H), 3.34 (s, 3H), 3.56–3.70 (m, 4H), 4.20–4.28 (m, 2H),
4.73 (s, 2H), 5.39 (dd, J = 14.2, 7.9 Hz, 1H), 5.65 (dt, J = 14.32, 7.23 Hz, 1H),
6.05–6.16 (m, 2H), 7.54 (s, 1H); 13C NMR (CDCl3, 50 MHz): d 172.2, 163.5,
140.4, 136.2, 132.5, 132.1, 131.9, 129.7, 78.6, 76.0, 75.3, 66.7, 57.6, 56.9, 51.4,
43.3, 42.3, 37.8, 25.7, 17.9, ꢀ4.4, ꢀ4.8; IR (KBr): mmax 3420, 3143, 2922, 2854,
1732, 1658, 1581, 1461, 1461, 1372, 1218, 768 cmꢀ1; HRMS (ESI): calcd for
Reagents and conditions: (i) NaBH4, EtOH, rt, 45 min, 92%; (ii) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 °C, 10 min, 96%; (iii) OsO4, acetone–H2O (8:1), rt, 4 h; then
NaIO4, THF: pH 7 buffer (1:1), 0 °C to rt, 10 min, 90%; (iv) NaBH4, MeOH, rt,
15 min, 92%.
C
24H41NO7NaSi [M+Na]+: 506.2544, found 506.2557 [M+Na]+.
9. Makoto, K.; Mitsuru, S.; Masahiro, Y.; Kozo, S. Synthesis 2009, 2893–2904.